FDA label f3d94d16-e8a3-3261-e053-2a95a90ad64e

WARNING: 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 [see Warnings and Precautions (5.1) ] . Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if entecavir is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection that is not being treated. Therapy with entecavir is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART) [see Warnings and Precautions (5.2) ] . Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors alone or in combination with antiretrovirals [see Warnings and Precautions (5.3) ] . WARNING: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY See full prescribing information for complete boxed warning. 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 for at least several months after discontinuation. Initiation of anti-hepatitis B therapy may be warranted. (5.1) Entecavir is not recommended for patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) who are not also receiving highly active antiretroviral therapy (HAART), because of the potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors. (5.2) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors. (5.3)

5 WARNINGS AND PRECAUTIONS Severe acute exacerbations of hepatitis B virus infection after discontinuation: Monitor hepatic function closely for at least several months. (5.1, 6.1 ) Co-infection with HIV: Entecavir is not recommended unless the patient is also receiving HAART. (5.2) Lactic acidosis and severe hepatomegaly with steatosis: If suspected, treatment should be suspended. (5.3) 5.1 Severe Acute Exacerbations of Hepatitis B Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir [see Adverse Reactions (6.1) ] . 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. 5.2 Patients Co-infected with HIV and HBV Entecavir has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if entecavir is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated [see Microbiology (12.4) ] . Therefore, therapy with entecavir is not recommended for HIV/HBV co-infected patients who are not also receiving HAART. Before initiating entecavir therapy, HIV antibody testing should be offered to all patients. Entecavir has not been studied as a treatment for HIV infection and is not recommended for this use. 5.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors, including entecavir, alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside inhibitor exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogue inhibitors to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Lactic acidosis with entecavir 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. Treatment with entecavir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

<table border="0" width="100%"><tbody><tr><td colspan="5"><content styleCode="bold">Table 6: Principal Analyses of Time to Adjudicated Events - Randomized Treated Subjects </content></td></tr><tr><td colspan="1" rowspan="2"><content styleCode="bold">Endpoint ^c</content></td><td colspan="4" rowspan="1"><content styleCode="bold">Number of Subjects with Events</content></td></tr><tr><td><paragraph><content styleCode="bold">BARACLUDE </content></paragraph><paragraph><content styleCode="bold">N=6,216</content></paragraph></td><td><paragraph><content styleCode="bold">Non-ETV </content></paragraph><paragraph><content styleCode="bold">N=6,162</content></paragraph></td><td colspan="2" rowspan="1"><paragraph><content styleCode="bold">Hazard Ratio</content></paragraph><paragraph><content styleCode="bold">[BARACLUDE: Non-ETV]</content></paragraph><paragraph><content styleCode="bold">(CI ^a) </content></paragraph></td></tr><tr><td><content styleCode="bold">Primary Endpoints</content></td><td rowspan="1"/><td colspan="2" rowspan="1"/><td/></tr><tr><td>Overall malignant neoplasm</td><td rowspan="1">331</td><td colspan="2" rowspan="1">337</td><td>0.93 (0.800, 1.084)</td></tr><tr><td>Liver-related HBV disease progression</td><td>350</td><td colspan="2" rowspan="1">375</td><td>0.89 (0.769, 1.030)</td></tr><tr><td>Death</td><td>238</td><td colspan="2" rowspan="1">264</td><td>0.85 (0.713, 1.012)</td></tr><tr><td><content styleCode="bold">Secondary Endpoints</content></td><td colspan="3"/><td/></tr><tr><td>Non-HCC malignant neoplasm</td><td>95</td><td colspan="2" rowspan="1">81</td><td>1.10 (0.817, 1.478)</td></tr><tr><td>HCC</td><td>240 ^b</td><td colspan="2" rowspan="1">263</td><td>0.87 (0.727, 1.032)</td></tr><tr><td colspan="5"><paragraph>Analyses were stratified by geographic region and prior HBV nucleos(t)ide experience.</paragraph><paragraph>^a95.03% CI for overall malignant neoplasm, death, and liver-related HBV disease progression; </paragraph><paragraph>95% CI for non-HCC malignant neoplasm and HCC.</paragraph><paragraph>^b One subject had a pre-treatment HCC event and was excluded from the analysis. </paragraph><paragraph>^c Overall malignant neoplasm is a composite event of liver-related death, HCC, or non-HCC HBV disease progression. </paragraph><paragraph>CI = confidence interval; N = total number of subjects.</paragraph></td></tr></tbody></table>