Labeling Changes for Kaletra Reflecting New QT/QTC Interval and PR Interval Prolongation Information

FDA approved, on April 6, 2009, changes to the product label for Kaletra (lopinavir/ritonavir) Tablets and Oral Solution, reflecting new WARNINGS and PRECAUTIONS regarding QT/QTC interval and PR interval prolongation information.

QT/QTC interval and PR interval prolongation refer to changes in electrical activity and rhythm of the heart.

The following information was added to the product label.

5 WARNINGS AND PRECAUTIONS
5.5 PR Interval Prolongation
Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. KALETRA should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.
The impact on the PR interval of co-administration of KALETRA with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of KALETRA with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended. [See CLINICAL PHARMACOLOGY ( 12.3)].

5.6 QT Interval Prolongation
Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of KALETRA could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval [See CLINICAL PHARMACOLOGY ( 12.3)].

12 CLINICAL PHARMACOLOGY
12.3 Pharmacokinetics
Effects on Electrocardiogram
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice-daily and supratherapeutic 800/200 mg twice-daily KALETRA, respectively. KALETRA 800/200 mg twice daily resulted in a Day 3 mean Cmax approximately 2-fold higher than the mean Cmax observed with the approved once daily and twice daily KALETRA doses at steady state.
PR interval prolongation was also noted in subjects receiving KALETRA in the same study on Day 3. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice-daily and supratherapeutic 800/200 mg twice-daily KALETRA, respectively. [See WARNINGS AND PRECAUTIONS (5.5, 5.6)].

In addition to these label changes, a new Medication Guide is now available for Kaletra.

Medication Guides are paper handouts that are dispensed with some prescription medicines. These handouts are required by FDA for certain drugs, but are created by the drug manufacturer. They are different from the routine information handouts provided by some pharmacies. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. FDA requires that Medication Guides be issued with certain prescribed drugs and biological products when the Agency determines that:

• certain information is necessary to prevent serious adverse effects
• certain information is important for patients to decide whether to take or continue to take the prescribed product, or
• patient adherence to directions for the use of a product are essential to its effectiveness.