Ritonavir label updated in the US relating to cardiac arrhythmia reported in high-dose studies
On August 29, 2008, the FDA approved changes to the product label for ritonavir (Norvir) Soft Gelatin Capsules, and 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’ the new label states ‘QTcF interval was evaluated in a randomised, 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.
Under ‘Precautions’ the new label states ritonavir prolongs the PR interval in some patients. Postmarketing cases of second or third degree atrioventricular block have been reported in patients, and that ritonavir 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 metabolised by CYP3A. Clinical monitoring is recommended.
The complete, revised label is available on the FDA website at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda
The clinical significance of these changes is unclear as ritonavir is rarely prescribed at the riginal dose referred to in these studies,while the impact from lower boosting doses currently used, especially in patients with high underlying cardiovascular risk remains unknown.