Important new pharmacokinetic data demonstrating that REYATAZ (atazanavirsulfate) combined with NORVIR (ritonavir) and omeprazole should not be co-administered

22 December 2004

The European Medicines Agency (EMEA) and its scientific Committee (CHMP) have been made aware of important new pharmacokinetic (PK) data concerning the coadministration of REYATAZ (atazanavir sulfate) combined with ritonavir (RTV) and 40 mg omeprazole, a proton pump inhibitor.

The following observations were made from a randomized, open-label, multiple-dose drug interaction study performed in healthy volunteers (see annex 1 for details of the study):

A 76% reduction in atazanavir area under the concentration-time curve (AUC) and a 78% reduction in atazanavir trough plasma concentration (Cmin) were observed when REYATAZ/RTV (300/100 mg) was co-administered with omeprazole 40 mg. The exact mechanism is currently unknown. It could be
the result of an alteration of the gastric pH induced by omeprazole which is known to influence REYATAZ absorption, but other mechanisms such as cytochrome-mediated mechanism cannot be ruled out.

The EMEA wishes to point out the following important safety information to physicians:

Based on the study results:

• DO NOT coadminister REYATAZ/RTV 300/100 mg with omeprazole due to the reduction in REYATAZ exposure levels.
• In this study, an omeprazole dose of 40 mg was used. It is not known whether other daily doses would produce similar results and, therefore, coadministration of any doses of omeprazole IS NOT recommended.
• Increasing the REYATAZ/RTV dose to 400/100 mg in combination with omeprazole DID NOT result in REYATAZ exposure levels comparable to those observed with a regimen of REYATAZ/RTV 300/100 mg without omeprazole.
• In the absence of any data with other proton pump inhibitors, the recommendations should be extended to the whole class of proton pump inhibitors.

Moreover, investigations regarding the potential drug interaction between REYATAZ and H2- Receptor antagonists when co-administered are ongoing. Until data are available, and as currently recommended in the REYATAZ SPC, caution should be exercised when these drugs are coadministered.

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Important new pharmacokinetic data demonstrating that REYATAZ (atazanavir sulfate) combined with NORVIR (ritonavir) and omeprazole should not be co-administered

Reference Number: EMEA/202649/2004