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FDA Approves Labeling Update for Bristol-Myers Squibb Company (BMY)'s (JOBS) REYATAZ(R) Capsules to Include 96-Week Data for Previously Untreated HIV-1 Infected Adult Patients



11/6/2009 6:55:39 AM

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY - News) today announced that the U.S. Food and Drug Administration (FDA) has approved a labeling update for REYATAZ® to include long-term data from the CASTLE Study. The CASTLE Study assessed a once-daily REYATAZ/ritonavir (REYATAZ/r)-based regimen versus a twice-daily lopinavir/ritonavir (LPV/r)-based regimen in previously untreated adult patients infected with HIV-1. Data from the study demonstrate enduring virologic response through 96 weeks of treatment with REYATAZ/r as part of combination therapy.

According to the most recent report from the Centers for Disease Control and Prevention, more than one million people are living with HIV and the annual incidence of new infections was 56,300 in the U.S.1 It is critical that effective and tolerable medicines are available to patients initiating antiretroviral therapy. Long-term data from the CASTLE Study demonstrate that treatment with REYATAZ/r can effectively suppress HIV viral load over 96 weeks in treatment-naïve patients.

In the CASTLE Study, a majority of patients on the REYATAZ/r regimen achieved undetectable viral load defined as HIV-1 RNA <50 copies/mL (REYATAZ/r 75% vs. LPV/r 68%) – confirming efficacy through 96 weeks. Low rates of drug resistance were observed at 96 weeks in patients who failed the REYATAZ/r regimen, with one patient developing genotypic/phenotypic resistance to REYATAZ and five patients developing genotypic/phenotypic resistance to emtricitabine. In a pre-specified analysis, efficacy in patients with high baseline viral load (=100,000 copies/mL) was demonstrated: 74% of 223 patients in the once-daily REYATAZ/r arm achieved undetectable viral load at 96 weeks vs. 67% of 222 patients in the twice-daily LPV/r arm.

In addition, the 96-week data confirmed the effect of REYATAZ on lipids. There were lower mean increases from baseline in total cholesterol, LDL cholesterol and triglycerides with REYATAZ/r compared to LPV/r; the REYATAZ/r arm was associated with the following mean increases from baseline: total cholesterol (13%), LDL cholesterol (14%), HDL cholesterol (21%), and triglycerides (13%). The LPV/r regimen was associated with the following mean increases in lipids: total cholesterol (25%), LDL cholesterol (17%), HDL cholesterol (29%), and triglycerides (50%).

Safety events at 96 weeks were consistent with the 48-week results in this study. Grade 2-4 treatment-related adverse events that occurred in 2% or greater of patients on the REYATAZ® (atazanavir sulfate)/r regimen, regardless of causality, included jaundice/scleral icterus (5% and 0%), nausea (4% and 8%), diarrhea (2% and 12%), and rash (3% and 2%) in the REYATAZ/r and LPV/r arms, respectively. Grade 3–4 increases in total bilirubin occured in 44% of patients in the REYATAZ/r arm and in less than 1% of patients on the LPV/r regimen.

About the CASTLE Study

The international, multi-center, open-label, non-inferiority, 96-week CASTLE Study randomized 883 treatment-naive adults infected with HIV-1. Four hundred and forty patients were randomized to receive REYATAZ 300 mg and ritonavir 100 mg once daily and 443 patients were randomized to receive fixed-dose lopinavir 400 mg and ritonavir 100 mg twice daily. Each was given in combination with a once-daily, fixed-dose combination of tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg. All patients had a baseline viral load of greater than or equal to 5,000 copies/mL; there was no CD4+ cell count restriction for study entry. The primary endpoint for the study was the proportion of patients with viral load less than 50 copies/mL at 48 weeks with an intent-to-treat (ITT) analysis according to confirmed virologic response. Of the 440 patients in the REYATAZ/r arm, 78% met the primary endpoint of achieving undetectable viral load at 48 weeks, compared with 76% of the 443 patients in the LPV/r arm.

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 in 2003 by the FDA, REYATAZ has become the most prescribed protease inhibitor, a central drug class in HIV therapy. For more information, please visit www.REYATAZ.com.

Important Information About REYATAZ® (atazanavir sulfate) 200 mg and 300 mg 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 AI424-045, 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: rifampin, irinotecan, orally administered midazolam, triazolam, dihydroergotamine, ergotamine, ergonovine, methylergonovine, cisapride, St. John’s wort (Hypericum perforatum)-containing products, lovastatin, simvastatin, pimozide, or indinavir. Coadministration with the following is not recommended: nevirapine; other protease inhibitors, fluticasone propionate or voriconazole when REYATAZ is given with ritonavir; and proton-pump inhibitors or efavirenz in treatment-experienced patients. 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® (atazanavir sulfate) 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 bilrubin >5 times upper limit of normal. Alternative antiretroviral therapy may be considered if jaundice or scleral icterus presents cosmetic concerns. * Hepatotoxicity: Use REYATAZ 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® (atazanavir sulfate) 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 has 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 subjects with hepatic impairment and is not recommended. * The most common moderate or severe adverse reactions were as follows, regardless of causality: o In treatment-naïve 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%). o In treatment-experienced adult patients (=2%): jaundice/scleral icterus (9%), myalgia (4%), diarrhea (3%), nausea (3%), depression (2%), and fever (2%). o In pediatric patients (=5%): cough (21%), fever (19%), rash (14%), jaundice/scleral icterus (13%), diarrhea (8%), vomiting (8%), headache (7%), and rhinorrhea (6%).

Dose Recommendations:

* In treatment-naive and treatment-experienced adult patients: REYATAZ® (atazanavir sulfate) 300 mg with ritonavir 100 mg once daily, all as a single dose, with food. In treatment-naive adult patients unable to tolerate ritonavir: REYATAZ 400 mg (without ritonavir) once daily with food. Please consult the Full Prescribing Information for efficacy and safety of REYATAZ at this dose. * If used with tenofovir, REYATAZ 300 mg should be coadministered with ritonavir 100 mg. * In pediatric patients 6 to 18 years of age, REYATAZ dosage is based on body weight and should not exceed the recommended adult dosage. See Section 2.2 of the Full Prescribing Information for dosing recommendations in pediatric patients. * See Section 2 of the Full Prescribing Information for complete information regarding REYATAZ dose recommendations, including recommendations related to concomitant therapies and renal and hepatic impairment. Efficacy and safety of REYATAZ with ritonavir in doses greater than 100 mg once daily have not been established. Please consult the complete prescribing information for Norvir (ritonavir).

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 committed to discovering, developing and delivering innovative medicines that help patients prevail over serious diseases. For more information, please visit www.bms.com.

REYATAZ is a registered trademark of Bristol-Myers Squibb. Norvir is a registered trademark of Abbott Laboratories.

References

1. HIV/AIDS in the United States: CDC HIV/AIDS Facts; August 2009. Centers for Disease Control and Prevention website. Available at http://www.cdc.gov/hiv/resources/factsheets/PDF/us.pdf. Accessed September 2009.

Contact:

Bristol-Myers Squibb Media: Cristi Barnett, 609-252-6028 cristi.barnett@bms.com or Investors: John Elicker, 609-252-4611 john.elicker@bms.com


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