Food and Drug Administration - September 2, 2008
Richard Klein & Kimberly Struble

FDA approved, on August 29, 2008, changes to the product label for Norvir (ritonavir) Soft Gelatin Capsules, and Norvir Oral Solution reflecting new, post marketing information regarding QT/QTc interval and PR interval prolongation information from Study M06-80.

The patient package insert has been updated, as well, with language related to electrocardiogram changes and cardiac arrhythmias.

The following information was added to the product label:
Under Clinical Pharmacology -
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state.

PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir. See PRECAUTIONS -PR Interval Prolongation.

Under Precautions -
PR Interval Prolongation
Ritonavir prolongs the PR interval in some patients. Postmarketing cases of second or third degree atrioventricular block have been reported in patients.

NORVIR should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of ritonavir 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 ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended. See CLINICAL PHARMACOLOGY - Effects on Electrocardiogram.

Under Information for Patients -
Cardiovascular System
First -degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported (See PRECAUTIONS - PR Interval Prolongation).

Under Adverse Reactions -
Cardiovascular System
First -degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported (See PRECAUTIONS - PR Interval Prolongation).

In addition, the following information has been added to the Patient Product Insert, under the section What are the Possible Side Effects of Norvir? -

Changes in the electrocardiogram (EKG). Consult your physician if you experience dizziness, lightheadedness, fainting spells or abnormal heart beat, Patients with heart defects or conduction defects should avoid NORVIR.

The complete, revised label is available on the FDA website at Drugs@FDA Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/)

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

080902
FD080901

SOURCE: Food and Drug Administration (FDA).

AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Elton John AIDS Foundation UK, the National Library of Medicine, AIDS Walk of Orange County, and donations from users like you.

Always watch for outdated information. This article first appeared in 2008. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2008. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .