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Important New Pharmacokinetic Data for REYATAZ(tm) (atazanavir sulfate) in combination with Viread® (tenofovir disoproxil fumarate)

Date: August 8, 2003
Source: Food and Drug Administration (FDA)

Dear Health Care Provider,
Bristol-Myers Squibb Company would like to make clinicians caring for HIV-infected patients aware of important new pharmacokinetic (PK) data concerning the coadministration of REYATAZ¿ (atazanavir sulfate) and Viread® (tenofovir disoproxil fumarate, Gilead Sciences, Inc.). Two studies have been conducted to evaluate the potential PK interaction between REYATAZ and tenofovir disoproxil fumarate (tenofovir DF), and an additional ongoing clinical study has provided preliminary data on the safety profile of this combination. Data from these trials are currently under review by the Food and Drug Administration. For more details on these studies please refer to the STUDY INFORMATION section below.
The following observations were made from these three trials:
Study AI454-181: In healthy volunteers atazanavir AUC and Cmin were decreased by approximately 25% and 40%, respectively, when unboosted REYATAZ 400 mg was coadministered with tenofovir DF 300 mg once daily (QD) as compared to REYATAZ alone. In addition, an increase of approximately 24% in tenofovir AUC was observed.
Study PUZZLE 2 (ANRS 107): Atazanavir AUC and Cmin were decreased by approximately 25% and 23%, respectively, when REYATAZ 300 mg and ritonavir 100 mg (boosted REYATAZ) were coadministered with tenofovir DF 300 mg QD, as compared to REYATAZ 300 mg and ritonavir 100 mg administered without tenofovir DF to HIV-infected patients.
For the combination of boosted REYATAZ with tenofovir DF, the atazanavir AUC and Cmin observed in the Puzzle 2 study were approximately 1.2 and 4 fold higher than the respective values observed for unboosted REYATAZ, 400 mg given alone, to healthy volunteers in Study AI424-181.
Study AI424-045: Interim safety data from an ongoing clinical trial suggest that the treatment emergent adverse events of moderate or severe intensity are comparable for boosted REYATAZ in treatment experienced patients and for unboosted REYATAZ treated patients in other clinical trials .
Based on these results:
Clinicians should use caution when administering unboosted REYATAZ with tenofovir DF. Unboosted REYATAZ may be less effective due to decreased atazanavir concentrations in patients taking REYATAZ and tenofovir DF. As a result the coadministration of unboosted REYATAZ with tenofovir DF may lead to loss or lack of virologic response and possible resistance to REYATAZ.
If REYATAZ is coadministered with tenofovir DF, consideration should be given to administering REYATAZ 300 mg with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food), until additional data are obtained. Coadministration of REYATAZ 300 mg and ritonavir 100 mg QD is currently under clinical investigation.
The increase in tenofovir AUC does not appear to be associated with increased toxicity over 24 weeks.
Study AI454-181 conducted by Bristol-Myers Squibb (BMS) Pharmaceutical Research Institute
Design: Phase I, open-label study in healthy subjects to evaluate whether the PK parameters of either unboosted REYATAZ 400 mg QD or tenofovir DF 300 mg QD were affected by their coadministration. The PK parameters of REYATAZ 400 mg QD administered with food were compared to those of REYATAZ 400 mg QD when coadministered with tenofovir 300 mg QD and food.
Puzzle 2 (ANRS 107) Trial - PK Sub-study conducted by Taburet et al.
Design: An ongoing efficacy study and PK sub-study in highly treatment-experienced HIV-infected subjects. HIV-infected subjects experiencing failure on a protease inhibitor (PI)-containing regimen were treated for the initial two weeks of the study with REYATAZ 300 mg QD plus ritonavir 100 mg QD substituted for the failing PI. Current nucleoside reverse transcriptase inhibitors (NRTIs) were continued for the initial two-week period after which time they were replaced with tenofovir DF 300 mg QD and a second NRTI chosen by genotypic testing. Atazanavir pharmacokinetics were determined at Week 2 before the introduction of tenofovir DF and again at Week 6.
Study AI424-045 conducted by Bristol-Myers Squibb (BMS) Pharmaceutical Research Institute
Design: An ongoing 48-week, Phase III, randomized, multinational, open-label three-arm trial of 358 highly treatment-experienced HIV-infected subjects. One arm of this study is evaluating the efficacy, safety and tolerability of the combination of REYATAZ 300 mg and ritonavir 100 mg QD coadministered with tenofovir DF 300 mg QD and one NRTI.
BMS is committed to providing you with current product information for the management of your patients with HIV infection. You can assist us in monitoring the safety of our products by reporting adverse reactions to BMS at 1-800-426-7644 (select option 2) or to FDA's MedWatch program by telephone at 1-800-332-1088, by fax at 1-800-332-0178, via, or by mail to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857.
If you have questions about the new information or want additional medical information, please contact the Virology Medical Services Department at Bristol-Myers Squibb Company at 1-800-426-7644 (select option 3).
Sally Hodder, MD
Vice President, Virology Medical Affairs
Bristol-Myers Squibb Company
REYATAZ¿ is a trademark of Bristol-Myers Squibb Company.
Viread® is a registered trademark of Gilead Sciences, Inc.

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