Approves Labeling Update for Reyataz (atazanavir sulfate)
Capsules to Include Data Supporting the Recommended Adult
Dose of Reyataz/ritonavir 300/100 mg for HIV-1 Infected Pregnant
confirms appropriate dosing in pregnancy and postpartum
Princeton, N.J. -- February 7, 2011 -- Bristol-Myers Squibb
Company (NYSE: BMY) today announced that the U.S. Food and
Drug Administration (FDA) has approved an update to the labeling
for Reyataz (atazanavir sulfate) to include dose recommendations
in HIV-infected pregnant women.
In HIV combination therapy, treatment with the recommended
adult dose of Reyataz 300 mg, boosted with 100 mg of ritonavir,
achieved minimum plasma concentrations (24 hours post-dose)
during the third trimester of pregnancy comparable to that
observed historically in HIV-infected adults. During the postpartum
period, atazanavir concentrations may be increased; therefore,
while no dose adjustment is necessary, patients should be
monitored for adverse events for two months after delivery.
Reyataz is indicated in combination with other antiretroviral
agents for treatment of HIV-1 infection in patients at least
six years of age. Reyataz should be used during pregnancy
only if the benefit outweighs the risk and HIV-1 strains are
susceptible to atazanavir. Reyataz should not be used without
ritonavir in pregnant or postpartum women. Reyataz does not
have an indication for prevention of maternal-fetal transmission
of HIV-1 infection.
Pregnant women do not require a dose adjustment for Reyataz/ritonavir
except in the case of treatment-experienced pregnant women
during the second or third trimester when Reyataz is co-administered
with either tenofovir or an H2-receptor antagonist (H2RA).
In that case, Reyataz 400 mg plus ritonavir 100 mg once daily
is recommended. There are insufficient data to recommend a
Reyataz dose for use with both tenofovir and an H2RA in treatment-experienced
pregnant women. In addition to dosing instructions during
pregnancy, the full prescribing information for Reyataz includes
general dosing recommendations (see About Reyataz section
below) as well as dosing instructions based on renal function,
hepatic function, and concomitant drug interactions.
"This labeling update is important news for both healthcare
providers and HIV-positive women of child-bearing age in that
it provides guidance for the use of REYATAZ, as part of combination
therapy, during pregnancy and postpartum," said Dr. Awny
Farajallah, MD, FACP, executive director, atazanavir development
lead, Bristol-Myers Squibb. "Bristol-Myers Squibb is
committed to research that furthers the understanding of how
to manage HIV in special populations and to meeting the evolving
needs of individuals with this disease."
The labeling update is based on data from a multicenter, open-label,
prospective, single arm, pharmacokinetic study (Study 182)
of 41 HIV-infected pregnant women between 12 and 32 weeks
gestation (second and third trimester) with CD4 >200
cells/mm3. Patients were treated with Reyataz (atazanavir
sulfate)/ritonavir 300/100 mg (n=20) or 400/100 mg (n=21)
once daily; patients in their second trimester received Reyataz/ritonavir
300/100 mg. All patients received zidovudine/lamivudine 300/150
mg twice daily. 1 The primary objective of Study 182 was to
determine the dosing of Reyataz/ritonavir as part of a regimen
that produces adequate drug exposure in pregnant women compared
to historical data in HIV-infected adults.
Atazanavir has been evaluated in a limited number of women
during pregnancy and postpartum. Available human and animal
data suggest that atazanavir does not increase the risk of
major birth defects overall compared to the background rate.
Because the studies in humans cannot rule out the possibility
of harm, Reyataz should be used during pregnancy only if the
benefit outweighs the risk. Cases of lactic acidosis syndrome,
sometimes fatal, and symptomatic hyperlactatemia have occurred
in pregnant women using Reyataz in combination with nucleoside
analogues. Nucleoside anologues are associated with an increased
risk of lactic acidosis syndrome. Hyperbilirubinemia occurs
frequently in patients who take Reyataz, including pregnant
Secondary outcomes in Study 182 evaluated antiviral efficacy
and safety in pregnant women and their infants. Of the 39
women who completed the study, 38 (97 percent) achieved an
HIV RNA < 50 copies/mL at the time of delivery. Six of
20 (30 percent) women on Reyataz/ritonavir 300/100 mg and
13 of 21 (62 percent) women on Reyataz/ritonavir 400/100 mg
experienced hyperbilirubinemia with a total bilirubin greater
than or equal to 2.6 times the upper limit of normal. No cases
of lactic acidosis were observed.
Among the 40 infants born to 40 HIV-infected pregnant women,
all tested negative for HIV-1 DNA at the time of delivery
and/or during the first 6 months postpartum. All 40 infants
received antiretroviral prophylactic treatment containing
zidovudine. Atazanavir drug concentrations in fetal umbilical
cord blood were approximately 12-19 percent of maternal concentrations.
No evidence of severe hyperbilirubinemia (total bilirubin
levels greater than 20 mg/dL) or acute or chronic bilirubin
encephalopathy was observed among neonates in this study.
A total bilirubin level greater than 20 mg/dL is considered
severe hyperbilirubinemia in newborns born to non-HIV-infected
women. However, 10/36 (28 percent) infants (6 greater than
or equal to 38 weeks gestation and 4 less than 38 weeks gestation)
had bilirubin levels of 4 mg/dL or greater within the first
day of life. All infants, including neonates exposed to Reyataz
(atazanavir sulfate) in-utero, should be monitored for the
development of severe hyperbilirubinemia during the first
few days of life. During the study, it was also noted that
3/38 (8 percent) infants had glucose levels (from adequately
collected serum samples) of less than 40 mg/dL on the first
day of life. These glucose levels could not be attributed
to maternal glucose intolerance, difficult delivery, or sepsis.
Study limitations included lack of ethnic diversity (83 percent
of infants were Black/African American, who have a lower incidence
of neonatal hyperbilirubinemia than Caucasians and Asians),
exclusion of women with Rh incompatibility, and exclusion
of women who had a previous infant with hemolytic disease
and/or neonatal jaundice requiring phototherapy.
As of January 2010, the Antiretroviral Pregnancy Registry
(APR) has received prospective reports of 635 exposures to
atazanavir-containing regimens (425 exposed in the first trimester
and 160 and 50 exposed in second and third trimester, respectively).
Birth defects occurred in 9 of 393 (2.3 percent) live births
(first trimester exposure) and 5 of 212 (2.4 percent) live
births (second/third trimester exposure). Among pregnant women
in the U.S. reference population, the background rate of birth
defects is 2.7 percent. There was no association between atazanavir
and overall birth defects observed in the APR. The APR was
established to monitor maternal-fetal outcomes of pregnant
women exposed to antiretrovirals, including Reyataz (atazanavir
sulfate). Physicians are encouraged to register patients by
Reyataz is a protease inhibitor that has been studied in both
treatment-naive and treatment-experienced HIV-1-infected patients
and is administered once daily as part of combination HIV
therapy. Since its approval by the FDA in 2003, Reyataz is
classified as pregnancy category B. There are general dosing
recommendations that also apply to pregnant women: 1) Reyataz
must be taken with food. 2) When coadministered with H2RAs
or proton-pump inhibitors, dose separation may be required.
3) When coadministered with didanosine buffered or enteric-coated
formulations, Reyataz should be given (with food) 2 hours
before or 1 hour after didanosine. 4) Efficacy and safety
of Reyataz with ritonavir in doses greater than 100 mg once
daily have not been established. The use of higher ritonavir
doses might alter the safety profile of Reyataz (cardiac effects,
hyperbilirubinemia) and, therefore, is not recommended. Prescribers
should consult the complete prescribing information for Norvir
(ritonavir) when using this agent. For additional information
about Reyataz, please visit www.Reyataz.com.
Full Prescribing Information is available at www.Reyataz.com
About Bristol-Myers Squibb
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whose mission is to discover, develop and deliver innovative
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