U.S. Food and Drug Administration approves labeling update for BARACLUDE®

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 BARACLUDE® (entecavir) to include data on African Americans and liver transplant recipients with chronic hepatitis B infection. BARACLUDE, a nucleoside analogue discovered at Bristol-Myers Squibb, was first approved by the U.S. Food and Drug Administration in March 2005 for use in adult chronic hepatitis B patients with compensated liver disease. BARACLUDE is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. The following points should be considered when initiating BARACLUDE: This indication is based on histologic, virologic, biochemical, and serologic responses in nucleoside-treatment-naïve and lamivudine-resistant adult patients with HBeAg-positive or HBeAg-negative chronic HBV infection and compensated liver disease; virologic, biochemical, serologic, and safety data are available from a controlled study in adult patients with chronic HBV infection and decompensated liver disease; virologic, biochemical, serologic, and safety data are available for a limited number of adult subjects with HIV/HBV co-infection who have received prior lamivudine therapy. The current labeling update was accepted based on one study in African-American patients and one study in post-liver transplant recipients, each investigating BARACLUDE in these populations.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted. Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if BARACLUDE (entecavir) is used to treat chronic HBV infection in patients with HIV infection that is not being treated. Therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART). Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, alone or in combination with antiretrovirals. Please see the Important Safety Information section of this press release for additional risk information, including Boxed WARNINGS.

BARACLUDE in Racial/Ethnic Groups (Study ETV-085 Results)

There are no significant racial differences in entecavir pharmacokinetics. The safety and efficacy of BARACLUDE 0.5 mg once daily were assessed in a single-arm, open-label trial in hepatitis B e antigen (HBeAg) positive or negative, nucleoside-naïve, African American (n=40) and Hispanic (n=6) patients with chronic HBV infection. In this trial, 76% of patients were male, the mean age was 42 years, 57% were HBeAg-positive. The mean baseline HBV DNA was 7.0 log10 IU/mL, and the mean baseline ALT was 162 U/L. At 48 weeks of treatment, 32 of 46 (70%) patients had HBV DNA <50 IU/mL (approximately 300 copies/mL), 31 of 46 (67%) patients had aminotransferase (ALT) normalization (≤1 times ULN), and 12 of 26 (46%) HBeAg-positive patients had HBe seroconversion. Safety data were similar to those observed in the larger, controlled BARACLUDE clinical trials. Due to low enrollment, safety and efficacy were not established in Hispanic patients.

BARACLUDE in Liver Transplant Recipients (Study ETV-109 Results)

The safety and efficacy of BARACLUDE were assessed in a single-arm, open-label trial in 65 patients who received a liver transplant for complications from chronic HBV infection. Eligible patients who had HBV DNA less than 172 IU/mL (approximately 1000 copies per mL) at the time of transplant were treated with BARACLUDE 1 mg once daily in addition to post-transplantation management consistent with the standard practice at a site, including hepatitis B immune globulin. The trial population was 82% male, 39% Caucasian, and 37% Asian, with a mean age of 49 years; 89% of patients had HBeAg-negative disease at the time of transplant.

Four of the 65 patients received 4 weeks or less of BARACLUDE (entecavir) (2 deaths, 1 retransplantation, and 1 protocol violation) and were not considered evaluable. Of the 61 patients who received more than 4 weeks of BARACLUDE, 60 received hepatitis B immune globulin post-transplant. Fifty-three patients (82% of all 65 patients treated) completed the trial and had HBV DNA measurements at or after 72 weeks treatment post transplant. All 53 patients had HBV DNA <50 IU/mL (approximately 300 copies/mL). Eight evaluable patients did not have HBV DNA data available at 72 weeks, including 3 patients who died prior to study completion. No patients had HBV DNA values ≥50 IU/mL while receiving BARACLUDE (plus hepatitis B immune globulin). All 61 evaluable patients lost HBsAg post-transplant; 2 of these subjects experienced recurrence of measurable HBsAg without recurrence of HBV viremia. This trial was not designed to determine whether addition of BARACLUDE to hepatitis B immune globulin decreased proportion of patients with measurable HBV DNA post-transplant compared to hepatitis B immune globulin alone. If BARACLUDE treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function must be carefully monitored both before and during treatment with BARACLUDE.

Chronic hepatitis B infection remains an area of concern among African Americans. In the United States, approximately 1.4 to 2.0 million individuals are chronically infected with chronic hepatitis B.

Patients with chronic hepatitis B and end-stage liver disease may undergo a liver transplantation as a treatment option. However, recurrence of a disease that caused the need for a liver transplant, such as chronic hepatitis B, can damage the new liver.

“Treating patients with chronic hepatitis B who have undergone a liver transplant can be complicated,” said Dr. Michael Charlton, MBBS, FACP, Hepatology Director and Liver Transplant Director, Mayo Clinic. “These data included in the BARACLUDE label will help healthcare providers prescribe treatment among chronic hepatitis B patients, including liver transplant recipients.”

INDICATION and IMPORTANT SAFETY INFORMATION about BARACLUDE (entecavir):

INDICATION

BARACLUDE (entecavir) is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

The following points should be considered when initiating BARACLUDE:

1. This indication is based on histologic, virologic, biochemical, and serologic responses in nucleoside-treatment-naïve and lamivudine-resistant adult subjects with HBeAg-positive or HBeAg-negative chronic HBV infection and compensated liver disease.
2. Virologic, biochemical, serologic, and safety data are available from a controlled study in adult subjects with chronic HBV infection and decompensated liver disease.
3. Virologic, biochemical, serologic, and safety data are available for a limited number of adult subjects with HIV/HBV co-infection who have received prior lamivudine therapy.

IMPORTANT SAFETY INFORMATION

WARNINGS: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY

• Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
• Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if BARACLUDE (entecavir)is used to treat chronic HBV infection in patients with HIV infection that is not being treated. Therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, alone or in combination with antiretrovirals.

Warnings and Precautions

• Before initiating BARACLUDE therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.
• Lactic acidosis with BARACLUDE use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. BARACLUDE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Adverse Reactions

• In clinical trials in patients with compensated liver disease, the most common (≥3%) adverse reactions of any severity with at least a possible relation to study drug for BARACLUDE-treated subjects were headache, fatigue, dizziness, and nausea. In these trials, the most common adverse reactions of moderate to severe intensity (grades 2-4) were diarrhea, dyspepsia, nausea, vomiting, fatigue, headache, dizziness, somnolence, and insomnia.
• In the decompensated liver disease trial, the most common adverse reactions of any severity among patients treated with BARACLUDE (entecavir), regardless of causality, included: peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection (10%). In this trial, 18% (18/102) of BARACLUDE patients and 20% (18/89) of adefovir patients died during the first 48 weeks of therapy. The majority of those deaths were due to liver related causes.

Drug Interactions

BARACLUDE is primarily eliminated by the kidneys, therefore coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. Patients should be monitored closely when receiving BARACLUDE with other renally-eliminated drugs.

Pregnancy and Nursing Mothers

• There are no adequate and well-controlled studies of BARACLUDE in pregnant women. BARACLUDE should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits.
• There are no studies on the effect of BARACLUDE on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
• It is not known whether BARACLUDE is excreted into human milk; however, many drugs are excreted into breast milk. Due to the potential for serious adverse reactions in nursing infants from BARACLUDE, risks and benefits should be considered when deciding whether to discontinue breast-feeding or discontinue BARACLUDE in nursing women.

Pediatric Use

• Safety and effectiveness of BARACLUDE in pediatric patients below the age of 16 years have not been established.

Renal Impairment

• Dosage adjustment of BARACLUDE (entecavir) is recommended for patients with a creatinine clearance <50 mL/min, including those on hemodialysis or continuous ambulatory peritoneal dialysis.

Liver Transplant Recipients

• Renal function must be carefully monitored both before and during treatment with BARACLUDE in a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus.

Dosage and Administration

BARACLUDE should be administered on an empty stomach (at least 2 hours after a meal and at least 2 hours before the next meal).

The recommended dose of BARACLUDE:

• in nucleoside-naïve adults and adolescents (16+ yrs) with compensated liver disease is 0.5 mg once daily
• in adults and adolescents (16+ yrs) with compensated liver disease, and refractory to lamivudine or with known lamivudine or telbivudine resistance mutations (rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L) is 1 mg once daily
• in adults with decompensated liver disease is 1 mg once daily

The optimal duration of treatment with BARACLUDE for patients with chronic HBV infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.

Additional Information

BARACLUDE (entecavir) is not a cure for HBV. Patients should be advised that treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others thugh sexual contact or blood contamination.

Please see accompanying Full Prescribing Information, including Boxed WARNINGS, or visit www.BARACLUDE.com or click here.