Important new pharmacokinetic data demonstrating that atazanavir sulfate (Reyataz) combined with ritonavir (Norvir) and proton pump inhibitors should not be coadministered

29 March 2005. Related: Treatment alerts.

Dear Doctor,

Bristol-Myers Squibb Company in agreement with the European Medicines Agency (EMEA) and its scientific Committee (CHMP), would like to make clinicians who are caring for HIV-infected patients aware of important new pharmacokinetic (PK) data concerning the coadministration of ATAZANAVIR (atazanavir sulfate) and proton pump inhibitors.

The following observations were made from a randomized, open-label, multiple-dose drug interaction study performed in healthy volunteers:

A 76% reduction in atazanavir area under the concentration-time curve (AUC) and a 78% reduction in atazanavir trough plasma concentration (Cmin) was observed when ATAZANAVIR/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 ATAZANAVIR absorption, but other mechanisms cannot be ruled out.

Based on the study results:

DO NOT COADMINISTER ATAZANAVIR/RTV 300/100 mg with omeprazole due to the reduction in ATAZANAVIR 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 ATAZANAVIR/RTV dose to 400/100 mg in combination with omeprazole DID NOT result in ATAZANAVIR exposures comparable to those observed with a regimen of ATAZANAVIR/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 ATAZANAVIR and H2-Receptor antagonists when co-administered are ongoing. Until data are available, and as currently recommended in the ATAZANAVIR SmPC, caution should be exercised when these drugs are co-administered.

Description of the study results:

This study was a randomized, open-label, multiple-dose drug interaction study performed in healthy subjects and aimed at assessing comparability of the steady-state pharmacokinetics of :

• Omeprazole 40mg orally OAD + ATV 300mg orally OAD and RTV 100mg orally OAD for 10 days (n=15)
• Omeprazole 40mg orally OAD + ATV 300mg orally OAD with 8 ounces (227 ml) of cola and RTV 100mg orally OAD for 10 days (n=15)

The co-administration with cola was made to explore whether its acidity could compensate for the antacid effect of omeprazole on atazanavir pharmacokinetics.

• Omeprazole 40mg orally OAD + ATV 400mg orally OAD and RTV 100mg orally OAD for 10 days (n=14)

In all cases, ATAZANAVIR/RTV was administered with a light meal, and omeprazole was administered on an empty stomach 2 hours prior to ATAZANAVIR/RTV. Subjects in each treatment arm received ATAZANAVIR/RTV 300/100 mg for 10 days prior to the addition of omeprazole on Day 10.

Pharmacokinetic Parameters for ATAZANAVIR (Geometric Mean Ratios [90% confidence interval] and % Reduction as compared to ATAZANAVIR/RTV 300/100 mg alone)¹ are detailed in the table below:

ATV = atazanavir, RTV = ritonavir, Cmax = peak plasma concentration, AUC(TAU) = area under the plasma concentration-time curve in one dosing interval, Cmin = trough plasma concentration

Omeprazole exposures were generally comparable to literature values, and individual subject exposures overlapped across treatments.

Please refer to the Summary of Product Characteristic for ATAZANAVIR.

Reference:

1. Data on file, Bristol-Myers Squibb Company, Princeton, New Jersey.

Comment

Data on this interaction is not news and is referred to in the current Summary of Product Characteristics but the details of the interaction data and levels of reduction in atazanavir levels is new. Atazanavir needs acid in the stomach to be absorbed properly so none of the PPI (omeprazole, lansoprazole, meprazole, pantoprazole, rabeprazole) or H2-blockers (ranitidine, famotidine, cimetidine, nizatidine) should be taken with atazanavir.

Several posters on interactions between protease inhibitors and was also presented at the Glasgow conference.

Charles Farthing and colleagues from AHF in Los Angeles, reported trough levels of atazanavir in 34 patients using atazanavir with either a proton pump inhibitor (n=15) or an H2 receptor blocker (n=19). 6/15 patients using a PPI (including 5/6 using ritonavir boosting) and 4/20 patients using an H2RB (2/4 using ritonavir boosting) had suboptimal ATZ trough levels (<0.27 mcg/mL). [1] This study identified 50 cases of inappropriately prescibed drugs from medical reords in 10 clinics in Los Angeles . It is clearly important that this interaction has been highlighted with an official safety letter.

This mechanism of poor absorption when acid-reducing agents such as PPIs and H2-blockers reduce absorption of atazanavir causes similar problems with amprenavir and indinavir. Bertz and colleagues from Abbott, in a study also presented at Glasgow, showed no significant impact on levels of PPIs and H2Rbs on absorption of lopinavir/r. [2]

FDA summary of this data
www.thebody.com/fda/atazanavir_warning.html

The pdf file of the US letter
www.thebody.com/fda/pdfs/atazanavir_warning.pdf

References:

1. Farthing C, Khanlou H. Co-adminstration of atazanavir with proton-pump inhibitors and h2-blockers. 7th ICDTHI,14-18 Nov, 2004, Glasgow. Abstract P289.
2. Bertz R et al. Lack of effect of gastric acid reducing agents on lopinavir/r plasma concentrations in HIV infected patients. 7th ICDTHI,14-18 Nov, 2004, Glasgow. Abstract P279.