European Commission Approves Labelling Update for REYATAZ® (atazanavir sulfate) in Pregnant Women Living With HIV

Paris, November 25 (ots/PRNewswire) -

- REYATAZ(R) is the only boosted PI to include dosing and
medical guidance in pregnancy and postpartum in the label -

Bristol-Myers Squibb Company today announced that the European
Commission approved a labelling update for REYATAZ(R) (atazanavir
sulfate) based on new data generated in pregnant women living with
HIV. The updated label provides dosing and medical guidance for
REYATAZ/ritonavir during pregnancy and immediately following birth.
The data came from study AI424-182, which evaluated the
pharmacokinetic parameters, efficacy and safety of REYATAZ/ritonavir
in pregnant women living with HIV. (1,2)

Worldwide, more than 3 million women living with HIV give birth
every year.(3) According to European AIDS Clinical Society (EACS)
treatment guidelines, some antiretroviral (ARV) drugs may be
prescribed during pregnancy to reduce the mother's viral load,(4)
although their optimal dosage is mostly unknown.(5) As pregnancy can
reduce the serum levels of many ARVs, it is important to know the
optimal dosage.(6)

"This labelling update is important news for both physicians and
women with HIV of child-bearing age in that it provides dosing and
medical guidance for the use of REYATAZ/ritonavir during pregnancy
and postpartum," said Margaret Johnson, Clinical Director of HIV
Services, Royal Free NHS Trust, London.

This label update is based on a multicentre, open-label,
prospective, single-arm pharmacokinetic study (Study AI424-182). The
study evaluated 41 pregnant women living with HIV, between 12 to 32
weeks gestation (second and third trimester of gestation) with CD4 >
200 cells/mm(3). Study participants were treated with REYATAZ with
ritonavir 300/100 mg (n=20) or 400/100 mg (n=21) once daily in
combination with zidovudine/lamivudine 300/150 mg twice daily; those
in their second trimester received REYATAZ/ritonavir 300/100 mg.(2)

The primary objective of the study was to determine the dosing of
REYATAZ/ritonavir to produce adequate drug exposure in pregnant women
with HIV compared to historical data in adults living with HIV. The
results showed that both doses of REYATAZ achieved minimum plasma
concentrations (24 hours post-dose) during the third trimester of
pregnancy, comparable to that observed historically in adults living
with HIV.(2)

Secondary outcomes of the study evaluated antiviral efficacy and
safety in pregnant women and their infants. Among the 39 women who
completed the trial, 38 achieved an HIV RNA <50 copies/mL at time of
delivery. Among the 40 infants tested (one patient withdrew), all
were negative for HIV-1 DNA at the time of delivery and/or during the
first six months postpartum. At the end of the study, 30% (6/20) of
the women on REYATAZ/ritonavir 300/100 mg and 62% (13/21) of the
women on REYATAZ/ritonavir 400/100 mg experienced grades 3 to 4
hyperbilirubinemia. Three of 20 infants (15%) born to women treated
with REYATAZ/ritonavir 300/100 mg and four of 20 infants (20%) born
to women treated with REYATAZ/ritonavir 400/100 mg experienced grade
3-4 bilirubin. No evidence of severe hyperbilirubinemia (total
bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin
encephalopathy was observed among newborns in this study. No cases of
lactic acidosis were observed.(2)

A moderate amount of data in pregnant women (between 300-1,000
pregnant outcomes) indicates no malformative toxicity of atazanavir.
Animal studies do not indicate reproductive toxicity. However,
because the studies in humans cannot fully rule out the possibility
of harm, REYATAZ may be considered during pregnancy only if the
potential benefit justifies the risk.(1)

Important Information about REYATAZ(R)(atazanavir sulfate) for
pregnant HIV positive women(1)

During the second and third trimesters of pregnancy:

REYATAZ 300-mg with ritonavir 100-mg may not provide sufficient
exposure to REYATAZ, especially when the activity of REYATAZ or the
whole regimen may be compromised due to drug resistance. Since there
are limited data available and due to inter-patient variability
during pregnancy, Therapeutic Drug Monitoring (TDM) may be considered
to ensure adequate exposure.

The risk of a further decrease in REYATAZ exposure is expected
when REYATAZ is given with medicinal products known to reduce its
exposure (e.g., tenofovir or H2-receptor antagonists).

- If tenofovir or an H2-receptor antagonist is needed, a dose
increase to REYATAZ 400-mg with ritonavir 100-mg with TDM may be
considered.
- It is not recommended to use REYATAZ with ritonavir for pregnant
patients who are receiving both tenofovir and an H2-receptor antagonist.

During postpartum:

Following a possible decrease in REYATAZ exposure during the
second and third trimester, REYATAZ exposures might increase during
the first two months after delivery. Therefore, postpartum patients
should be closely monitored for adverse reactions.

- During this time, postpartum patients should follow the same
dose recommendation as for non-pregnant patients, including those for
co-administration of medicinal products known to affect REYATAZ
exposure.

It is not known whether REYATAZ administered to the mother during
pregnancy will exacerbate physiological hyperbilirubinaemia and lead
to kernicterus in neonates and infants. In the prepartum period,
additional monitoring should be considered.

Breast-feeding

It is unknown whether atazanavir or atazanavir metabolites are
excreted in human milk. Studies in rats have demonstrated that
atazanavir is excreted in the milk. As a general rule, it is
recommended that HIV infected women not breast-feed their infants in
order to avoid transmission of HIV.

About REYATAZ(R)

Developed by Bristol-Myers Squibb, REYATAZ (atazanavir sulfate)
is an antiviral drug used in combination with other medicines to
treat individuals infected with the human immunodeficiency virus-1
(HIV-1).(1) REYATAZ was the first once-daily protease inhibitor
launched in Europe.(6,7) REYATAZ has proven efficacy, safety and
tolerability in HIV treatment-naive and experienced patients.(2,8)

REYATAZ is the only boosted PI with labelling that allows for
co-administration with an oral contraceptive.

About Pregnancy and HIV

Globally, the number of women living with HIV is on the
rise.(9,10) The prevalence of pregnant women living with HIV in
Europe has increased significantly in recent years, with a high
proportion of women diagnosed during antenatal testing. This rate is
increasing due to the growing influx of people living with HIV
immigrating to Europe.(11) In developing countries, many more
pregnant women are also living with HIV. For example, in parts of
Africa, the prevalence is about 30%.(8)

About Bristol-Myers Squibb Company

Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines that
help patients prevail over serious diseases.

References

(1) Reyataz SmPC.

(2) Conradie, F et al. Safety and exposure of once-daily
ritonavir-boosted atazanavir in HIV-infected pregnant women. HIV
Medicine. 2011(12), 570-579.

(3) Gray, G. and McIntyre, J. HIV and Pregnancy. British Medical
Journal. 3 May 2007; 334(7600).

(4) European AIDS Clinical Society (EACS). Guidelines. Version
6.1. November 2011.

(5) Coffey, S et al. Atazanavir/Ritonavir in Pregnancy. HIV Meds
Quarterly. Summer 2009. Available at
http://aidsetc.org/aidsetc?page=hmq-0908-00. Accessed 22 November
2011.

(6) European Medicines Agency. REYATAZ: EPAR Summary for the
public. Updated March 2009. Available at http://www.ema.europa.eu/ema
/index.jsp?curl=pages/medicines/human/medicines/
000494/human_med_001035.jsp&mid=WC0b01ac058001d124 Accessed November
2011 [http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/hum
an/medicines/000494/human_med_001035.jsp&mid=WC0b01ac058001d124%20Acc
essed%20November%202011 ]

(7) The Body, Switching Antiretroviral Therapy. Available at
http://www.thebody.com/content/art38572.html. Accessed 25 May 2010 [h
ttp://www.thebody.com/content/art38572.html.%20Accessed%2025%20May%20
2010 ]

(8) Johnson, M et al. Gender-based differences in
antiretroviral-naive patients treated with ritonavir-boosted protease
inhibitors: CASTLE study 96-Week Results. Presented at EACS 2009.

(9) UNAIDS. AIDS Epidemic Updated, 2009. Available at http://www.
unaids.org/en/media/unaids/contentassets/dataimport/pub/report/2009/j
c1700_epi_update_2009_en.pdf . Accessed November 2011.

(10) UNAIDS. AIDS Epidemic Updated, 2007. Available at
http://data.unaids.org/pub/epislides/2007/2007_epiupdate_en.pdf.
Accessed December 2010.

(11) Haile-Selassie, H. et al. HIV infection in Central and
Eastern European pregnant women living in the UK/Ireland: data from
national surveillance 1992-2007. University College London, Institute
of Child Health Institute of Child Health. BHIVA 2009

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Contact:
Annie Simond, office: +33-01-58-83-65-66, or Joanna Ritter,
office: +33-01-58-83-65-09, both for Bristol-Myers Squibb Company