FDA Approves New Atazanavir Dose Recommendation for Pregnant Women

	SUMMARY: The U.S. Food and Drug Administration (FDA) this week approved revised product label information for the HIV protease inhibitor atazanavir (Reyataz), providing a new dosing recommendation for HIV positive pregnant women. All pregnant women should boost atazanavir with ritonavir (Norvir), and women in their third trimester or those taking certain other medications including tenofovir (Viread, also in the Truvada and Atripla combination pills) should increase their dose.

Below is an edited excerpt from a press release issued by atazanavir manufacturer Bristol-Myers Squibb describing the label changes. The full announcement, including important safety information, is available online at http://www.bms.com/news/press_releases/pages/default.aspx.

FDA 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 Women

Study 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 women.

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 calling 1-800-258-4263.

About Reyataz

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 or www.bms.com.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines. For more information, please visit www.bms.com or follow us on Twitter at www.twitter.com/bmsnews.