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

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/mm³.¹ 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.¹

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.¹ 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.² 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-naïve 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.

About HIV in the U.S.

Despite HIV/AIDS education efforts, there are still more than one million people with HIV in the U.S.³ The most recent data from the Centers for Disease Control and Prevention (CDC) from 2006 indicates that approximately 56,300 new infections occur each year in the U.S. alone, and approximately 25 percent of new HIV-1 infections each year occur in women.^3,4 In addition, the CDC estimates approximately 6,400 pregnant women are infected with HIV each year.⁵

IMPORTANT INFORMATION About REYATAZ^® (atazanavir sulfate) Capsules

INDICATION:

REYATAZ is indicated in combination with other antiretroviral agents for treatment of HIV-1 infection. This is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from controlled studies of 96 weeks (treatment-naive) and 48 weeks (treatment-experienced) duration in adult and pediatric patients at least 6 years of age. The following should be considered when initiating REYATAZ:

• In Study 045, REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy measure of time-averaged difference in change from baseline in HIV RNA. This study was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy measure of proportions below the HIV RNA lower limit of detection.
• The number of baseline primary protease inhibitor mutations affects virologic response to REYATAZ/ritonavir.

IMPORTANT SAFETY INFORMATION:

• Hypersensitivity: REYATAZ is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the product components.
• Drug Interactions: Coadministration with drugs highly dependent on CYP3A or UGT1A1 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. These and other contraindicated drugs are alfuzosin, rifampin, irinotecan, orally administered midazolam, triazolam, dihydroergotamine, ergotamine, ergonovine, methylergonovine, cisapride, St. John’s wort (Hypericum perforatum)-containing products, lovastatin, simvastatin, pimozide, sildenafil dosed as Revatio^®, or indinavir. Coadministration with the following is not recommended: nevirapine or salmeterol; other protease inhibitors, fluticasone propionate, or voriconazole when REYATAZ^® (atazanavir sulfate) is given with ritonavir; buprenorphine or bosentan when REYATAZ is given without ritonavir; proton-pump inhibitors or efavirenz in treatment-experienced patients; and colchicine in patients with renal or hepatic impairment. See Sections 7.1 and 7.3 of the Full Prescribing Information for additional established and other potentially significant drug interactions.
• Cardiac Conduction Abnormalities: PR interval prolongation may occur in some patients. Atrioventricular (AV) conduction abnormalities were asymptomatic and generally limited to first-degree AV block. There have been rare reports of second-degree AV block and other conduction abnormalities. Use REYATAZ with caution in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval (including beta-blockers other than atenolol, diltiazem, verapamil, and digoxin), especially drugs metabolized by CYP3A. When used with REYATAZ, a 50% dose reduction of diltiazem should be considered, and ECG monitoring is recommended.
• Rash (all grades, generally mild-to-moderate maculopapular skin eruptions, regardless of causality) occurred in approximately 20% of patients treated with REYATAZ in controlled clinical trials. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions have been reported. Discontinue REYATAZ if severe rash develops.
• Hyperbilirubinemia: Reversible, asymptomatic elevations in indirect (unconjugated) bilirubin occurred in most patients treated with REYATAZ. There are no long-term safety data for patients with persistent elevations in total bilirubin >5 times upper limit of normal. Alternative antiretroviral therapy may be considered if jaundice or scleral icterus present cosmetic concerns.
• Hepatotoxicity: Use REYATAZ^® (atazanavir sulfate) with caution in patients with hepatic impairment because atazanavir concentrations may be increased. Patients with hepatitis B or C or marked elevations in transaminases are at risk of further transaminase elevations or hepatic decompensation. In these patients, liver function tests should be performed before and during REYATAZ therapy.
• Nephrolithiasis was reported with REYATAZ during post-marketing surveillance. If signs or symptoms of nephrolithiasis occur, consider temporary interruption or discontinuation.
• New onset or exacerbation of diabetes mellitus and hyperglycemia have been reported in patients treated with protease inhibitor therapy. Redistribution and/or accumulation of body fat have been seen in patients receiving antiretroviral therapy. A causal relationship has not been established.
• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. Increased bleeding has been reported in hemophiliacs treated with protease inhibitor therapy. Various degrees of cross-resistance among protease inhibitors have been observed.
• REYATAZ should not be used in patients with severe hepatic impairment (Child-Pugh Class C) or in treatment-experienced patients with end-stage renal disease managed with hemodialysis. REYATAZ/ritonavir has not been studied in patients with hepatic impairment and is not recommended.

The most common moderate or severe adverse reactions were as follows, regardless of causality:

• In treatment-naive adult patients (=2%): nausea (4-14%), jaundice/scleral icterus (5-7%), rash (3-7%), headache (1-6%), abdominal pain (4%), vomiting (3-4%), peripheral neurologic symptoms (<1-4%), diarrhea (1-3%), insomnia (<1-3%), and dizziness (<1-2%)
• In treatment-experienced adult patients (=2%): jaundice/scleral icterus (9%), myalgia (4%), diarrhea (3%), nausea (3%), depression (2%), and fever (2%).
• In pediatric patients (=5%): cough (21%), fever (19%), rash (14%), jaundice/scleral icterus (13%), diarrhea (8%), vomiting (8%), headache (7%), and rhinorrhea (6%).

Please see accompanying Full Prescribing Information, or visit http://www.REYATAZ.com or http://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 http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

REYATAZ^® (atazanavir sulfate) is a registered trademark of Bristol-Myers Squibb. All other trademarks are the property of their respective owners and not of Bristol-Myers Squibb.