WARNING: EXACERBATIONS OF HEPATITIS B and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). 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 )] . EPIVIR-HBV is not approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR - HBV and periodically during treatment [see Warnings and Precautions ( 5.2 )]. WARNING: EXACERBATIONS OF HEPATITIS B and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION 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 EPIVIR-HBV). Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.1 ) • EPIVIR ‑ HBV tablets and oral solution contain a lower dose of the same active ingredient (lamivudine) as EPIVIR tablets and oral solution used to treat human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 resistance may emerge in chronic hepatitis B patients with unrecognized or untreated HIV-1 infection because the lamivudine dosage in EPIVIR ‑ HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR ‑ HBV and periodically during treatment. ( 5.2 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Emergence of Resistance-Associated HBV Substitutions: Consider a switch to an alternative regimen if serum HBV DNA remains detectable after 24 weeks of treatment. ( 2.6 , 5.3 ) • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. ( 5.4 ) 5.1 Exacerbations of Hepatitis after Discontinuation of Treatment Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA commonly observed after stopping treatment; see Table 4 for more information regarding frequency of posttreatment ALT elevations [see Adverse Reactions ( 6.1 )] . Although most events appear to have been self-limited, fatalities have been reported in some cases. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with EPIVIR-HBV. There is insufficient evidence to determine whether re-initiation of EPIVIR-HBV alters the course of posttreatment exacerbations of hepatitis. 5.2 Risk of HIV-1 Resistance if EPIVIR-HBV is Used in Patients with Unrecognized or Untreated HIV-1 Infection EPIVIR-HBV tablets and oral solution contain a lower lamivudine dose than the lamivudine dose used to treat HIV-1 infection with EPIVIR tablets and oral solution or with lamivudine-containing antiretroviral fixed-dose combination products. EPIVIR-HBV is not appropriate for patients co-infected with HBV and HIV-1. If a patient with unrecognized or untreated HIV-1 infection is prescribed EPIVIR-HBV for the treatment of HBV, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriate use of monotherapy for HIV-1 treatment. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment because of the risk of rapid emergence of resistant HIV-1 and limitation of treatment options if EPIVIR-HBV is prescribed to treat chronic hepatitis B in a patient who has unrecognized or untreated HIV-1 infection or who acquires HIV-1 infection during treatment. 5.3 Emergence of Resistance-Associated HBV Substitutions In controlled clinical trials, YMDD‑mutant HBV was detected in subjects with on–EPIVIR-HBV re‑appearance of HBV DNA after an initial decline below the assay limit [see Microbiology ( 12.4 )] . Subjects treated with EPIVIR-HBV (adults and children) with YMDD‑mutant HBV at 52 weeks showed diminished treatment responses in comparison with subjects treated with EPIVIR-HBV without evidence of YMDD substitutions, including the following: lower rates of HBeAg seroconversion and HBeAg loss (no greater than placebo recipients), more frequent return of positive HBV DNA, and more frequent ALT elevations. In the controlled trials, when subjects developed YMDD‑mutant HBV, they had a rise in HBV DNA and ALT from their previous on‑treatment levels. Progression of hepatitis B, including death, has been reported in some subjects with YMDD‑mutant HBV, including subjects from the liver transplant setting and from other clinical trials. In order to reduce the risk of resistance in patients receiving monotherapy with EPIVIR-HBV, a switch to an alternative regimen should be considered if serum HBV DNA remains detectable after 24 weeks of treatment. Optimal therapy should be guided by resistance testing. 5.4 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 analogues, including EPIVIR-HBV. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Most of these reports have described patients receiving nucleoside analogues for treatment of HIV infection, but there have been reports of lactic acidosis in patients receiving lamivudine for hepatitis B. Treatment with EPIVIR‑HBV 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.
6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Exacerbations of hepatitis B after discontinuation of treatment [see Warnings and Precautions ( 5.1 )]. • Risk of emergence of resistant HIV-1 infection [see Warnings and Precautions ( 5.2 )]. • Risk of emergence of resistant HBV infection [see Warnings and Precautions ( 5.3 )] . • Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions ( 5.4 )]. The most common reported adverse reactions in those receiving EPIVIR-HBV (incidence greater than or equal to 10% and reported at a rate greater than placebo) were ear, nose, and throat infections; sore throat; and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials Experience in Adult Subjects with Chronic HBV Infection Clinical adverse reactions (regardless of investigator’s causality assessment) reported in greater than or equal to 10% of subjects who received EPIVIR-HBV and reported at a rate greater than in subjects who received placebo are listed in Table 2 . Table 2. Clinical Adverse Reactions a Reported in Greater than or Equal to 10% of Subjects Who Received EPIVIR-HBV for 52 to 68 Weeks and at an Incidence Greater than Placebo (Trials 1-3) a Includes adverse events regardless of severity and causality assessment. Adverse Event EPIVIR-HBV (n = 332) Placebo (n = 200) Ear, Nose, and Throat Ear, nose, and throat infections 25% 21% Sore throat 13% 8% Gastrointestinal Diarrhea 14% 12% Specified laboratory abnormalities reported in subjects who received EPIVIR-HBV and reported at a rate greater than in subjects who received placebo are listed in Table 3 . Table 3. Frequencies of Specified Laboratory Abnormalities Reported during Treatment at a Greater Frequency in Subjects Treated with EPIVIR-HBV than with Placebo (Trials 1-3) a a Includes subjects treated for 52 to 68 weeks. b Includes observations during and after treatment in the 2 placebo-controlled trials that collected this information. ULN = Upper limit of normal. Test (Abnormal Level) Subjects with Abnormality/Subjects with Observations EPIVIR-HBV Placebo Serum Lipase ≥2.5 x ULN b 10% 7% Creatine Phosphokinase (CPK) ≥7 x baseline 9% 5% Platelets <50,000/mm 3 4% 3% In subjects followed for up to 16 weeks after discontinuation of treatment, posttreatment ALT elevations were observed more frequently in subjects who had received EPIVIR-HBV than in subjects who had received placebo. A comparison of ALT elevations between Weeks 52 and 68 in subjects who discontinued EPIVIR-HBV at Week 52 and subjects in the same trials who received placebo throughout the treatment course is shown in Table 4 . Table 4. Posttreatment ALT Elevations with No-Active-Treatment Follow-up (Trials 1 and 3) a Each subject may be represented in one or more category. b During treatment phase. c Comparable to a Grade 3 toxicity in accordance with modified WHO criteria. ULN = Upper limit of normal. Abnormal Value Subjects with ALT Elevation/ Subjects with Observations a EPIVIR-HBV b Placebo b ALT ≥2 x baseline value 27% 19% ALT ≥3 x baseline value c 21% 8% ALT ≥2 x baseline value and absolute ALT >500 IU/L 15% 7% ALT ≥2 x baseline value; and bilirubin >2 x ULN and ≥2 x baseline value 0.7% 0.9% Clinical Trials Experience in Pediatric Subjects with Chronic HBV Infection Most commonly observed adverse reactions in the pediatric trials were similar to those in adult trials. Posttreatment transaminase elevations were observed in some subjects followed after cessation of EPIVIR-HBV. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of EPIVIR-HBV. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine. Blood and Lymphatic Anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia. Digestive Stomatitis. Endocrine and Metabolic Hyperglycemia. General Weakness. Hepatic and Pancreatic Lactic acidosis and steatosis [see Warnings and Precautions ( 5.4 )] , posttreatment exacerbations of hepatitis [see Warnings and Precautions ( 5.1 )] , pancreatitis. Hypersensitivity Anaphylaxis, urticaria. Musculoskeletal Cramps, rhabdomyolysis. Nervous Paresthesia, peripheral neuropathy. Respiratory Abnormal breath sounds/wheezing. Skin Alopecia, pruritus, rash.
adverse reactions table
<table ID="_Reftable2" width="100%"><caption>Table 2. Clinical Adverse Reactions<sup>a</sup> Reported in Greater than or Equal to 10% of Subjects Who Received EPIVIR-HBV for 52 to 68 Weeks and at an Incidence Greater than Placebo (Trials 1-3)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tfoot><tr><td align="left" colspan="3" styleCode="Botrule" valign="top"><sup>a </sup>Includes adverse events regardless of severity and causality assessment.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR-HBV</content> <content styleCode="bold">(n = 332)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 200)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Ear, Nose, and Throat</content></paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Ear, nose, and throat infections</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>21%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Sore throat</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>12%</paragraph></td></tr></tbody></table>
adverse reactions table
<table ID="_Reftable3" width="100%"><caption>Table 3. Frequencies of Specified Laboratory Abnormalities Reported during Treatment at a Greater Frequency in Subjects Treated with EPIVIR-HBV than with Placebo (Trials 1-3)<sup>a</sup></caption><col width="33%"/><col width="33%"/><col width="33%"/><tfoot><tr><td align="left" colspan="6" styleCode="Botrule" valign="top"><sup>a</sup> Includes subjects treated for 52 to 68 weeks. <sup>b</sup> Includes observations during and after treatment in the 2 placebo-controlled trials that collected this information. ULN = Upper limit of normal.</td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Test</content> <content styleCode="bold">(Abnormal Level)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Subjects with Abnormality/Subjects with </content></paragraph><paragraph><content styleCode="bold">Observations</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR-HBV</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Serum Lipase ≥2.5 x ULN<sup>b</sup></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Creatine Phosphokinase (CPK) ≥7 x baseline</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Platelets <50,000/mm<sup>3</sup></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3%</paragraph></td></tr></tbody></table>
adverse reactions table
<table ID="_Reftable4" width="100%"><caption>Table 4. Posttreatment ALT Elevations with No-Active-Treatment Follow-up (Trials 1 and 3)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tfoot><tr><td align="left" colspan="9" styleCode="Botrule" valign="top"><sup>a </sup>Each subject may be represented in one or more category. <sup>b</sup> During treatment phase. <sup>c </sup>Comparable to a Grade 3 toxicity in accordance with modified WHO criteria. ULN = Upper limit of normal.</td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Abnormal Value</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Subjects with ALT Elevation/</content> <content styleCode="bold">Subjects with Observations<sup>a</sup></content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR-HBV<sup>b</sup></content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Placebo<sup>b</sup></content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>ALT ≥2 x baseline value</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>ALT ≥3 x baseline value<sup>c</sup></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>ALT ≥2 x baseline value and absolute ALT >500 IU/L</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>ALT ≥2 x baseline value; and bilirubin >2 x ULN and ≥2 x baseline value</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.7%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.9%</paragraph></td></tr></tbody></table>