LAMIVUDINE ARROW 150 mg

1 INDICATIONS AND USAGE Lamivudine tablets (HBV) are indicated for the treatment of chronic hepatitis B virus (HBV) infection associated with evidence of hepatitis B viral replication and active liver inflammation [see Clinical Studies ( 14.1 , 14.2 )]. The following points should be considered when initiating therapy with lamivudine tablets (HBV): • Due to high rates of resistance development in treated patients, initiation of treatment with lamivudine tablets (HBV) should only be considered when the use of an alternative antiviral agent with a higher genetic barrier to resistance is not available or appropriate. • Lamivudine tablets (HBV) have not been evaluated in patients co-infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis delta virus. • Lamivudine tablets (HBV) have not been evaluated in liver transplant recipients or in patients with chronic hepatitis B virus infection with decompensated liver disease. Lamivudine tablets (HBV) are a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of chronic hepatitis B virus (HBV) infection associated with evidence of hepatitis B viral replication and active liver inflammation. ( 1 )

2 DOSAGE AND ADMINISTRATION • Adults: 100 mg, once daily. ( 2.2 ) • Pediatric Patients aged 2 to 17 years: 3 mg per kg once daily up to 100 mg once daily. Prescribe oral solution for pediatric patients requiring less than 100 mg daily. ( 2.3) • Patients with Renal Impairment: Doses of lamivudine tablets (HBV) must be adjusted in accordance with renal function. ( 2.4 ) • Lamivudine tablets (HBV) should not be used with other medications that contain lamivudine or emtricitabine. ( 2.5) 2.1 HIV Counseling and Testing HIV counseling and testing should be offered to all patients before beginning treatment with lamivudine tablets (HBV) and periodically during treatment because of the risk of emergence of resistant human immunodeficiency virus type 1 (HIV-1) and limitation of treatment options if lamivudine tablets (HBV) is prescribed to treat chronic hepatitis B infection in a patient who has unrecognized HIV-1 infection or acquires HIV-1 infection during treatment [see Warnings and Precautions ( 5.2 )] . 2.2 Recommended Dosage for Adult Patients The recommended oral dosage of lamivudine tablets (HBV) is 100 mg once daily. 2.3 Recommended Dosage for Pediatric Patients The recommended oral dosage of lamivudine tablets (HBV) for pediatric patients aged 2 to 17 years is 3 mg per kg once daily up to a maximum daily dosage of 100 mg. The oral solution formulation should be prescribed for patients requiring a dosage less than 100 mg or if unable to swallow tablets. 2.4 Patients with Renal Impairment Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Clinical Pharmacology ( 12.3 )] . Table 1. Dosage of Lamivudine Tablets (HBV) in Adult Patients with Renal Impairment Cre atinine Clearance ( m L/min) Rec o mme nded Dosage of Lamivudine Tablets (HBV) ≥50 100 mg once daily 30 to 49 100 mg first dose, then 50 mg once daily 15 to 29 100 mg first dose, then 25 mg once daily 5 to 14 35 mg first dose, then 15 mg once daily <5 35 mg first dose, then 10 mg once daily Following correction of the dosage for renal impairment, no additional dosage modification of lamivudine tablets (HBV) is required after routine (4-hour) hemodialysis or peritoneal dialysis [see Clinical Pharmacology ( 12.3) ] . There are insufficient data to recommend a specific dosage of lamivudine tablets (HBV) in pediatric patients with renal impairment. 2.5 Important Administration Instructions • Lamivudine tablets (HBV) may be administered with or without food. • The tablets and oral solution may be used interchangeably [see Clinical Pharmacology ( 12.3)]. • The oral solution should be used for doses less than 100 mg. • Lamivudine tablets (HBV) should not be used with other medications that contain lamivudine or medications that contain emtricitabine. 2.6 Assessing Patients during Treatment Patients should be monitored regularly during treatment by a physician experienced in the management of chronic hepatitis B. During treatment, combinations of events such as return of persistently elevated ALT, increasing levels of HBV DNA over time after an initial decline below assay limit, progression of clinical signs or symptoms of hepatic disease, and/or worsening of hepatic necroinflammatory findings may be considered as potentially reflecting loss of therapeutic response. Such observations should be taken into consideration when determining the advisability of continuing therapy with lamivudine tablets (HBV). The optimal duration of treatment, the durability of HBeAg seroconversions occurring during treatment, and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.

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 lamivudine tablets (HBV). There is insufficient evidence to determine whether re-initiation of lamivudine tablets (HBV) alters the course of posttreatment exacerbations of hepatitis. 5.2 Risk of HIV-1 Resistance if lamivudine tablets (HBV) is Used in Patients with Unrecognized or Untreated HIV-1 Infection Lamivudine tablets (HBV) contain a lower lamivudine dose than the lamivudine dose used to treat HIV-1 infection with lamivudine tablets and oral solution or with lamivudine- containing antiretroviral fixed-dose combination products. Lamivudine tablets (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 lamivudine tablets (HBV) for the treatment of HBV, rapid emergence of HIV-1 resistance is likely to result because of the sub therapeutic 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 lamivudine tablets (HBV) and periodically during treatment because of the risk of rapid emergence of resistant HIV-1 and limitation of treatment options if lamivudine tablets (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– lamivudine tablets (HBV) re-appearance of HBV DNA after an initial decline below the assay limit [see Microbiology (12.4) ]. Subjects treated with lamivudine tablets (HBV) (adults and children) with YMDD-mutant HBV at 52 weeks showed diminished treatment responses in comparison with subjects treated with lamivudine tablets (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 lamivudine tablets (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 lamivudine tablets (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 lamivudine tablets (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 lamivudine tablets (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 Hetero Labs Limited at 1-866-495-1995 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 lamivudine tablets (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 Lamivudine Tablets (HBV) for 52 to 68 Weeks and at an Incidence Greater than Placebo (Trials 1 to 3) Adverse Event Lamivudine Tablets (HBV) (n = 332) P lacebo ( n = 200) Ear, Nose, and Throat Ear, nose, and throat infections 25% 21% Sore throat 13% 8% G astrointestinal Diarrhea 14% 12% a Includes adverse events regardless of severity and causality assessment. Specified laboratory abnormalities reported in subjects who received lamivudine tablets (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 Lamivudine Tablets (HBV) than with Placebo (Trials 1 to 3) a Test (A bnormal Level) Subjects with Abnormality/ Subjects with Observations Lamivudine Tablets (HBV) P lacebo Serum Lipase ≥2.5 x ULN b 10% 7% Creatine Phosphokinase (CPK) ≥7 x baseline 9% 5% Platelets <50,000/mm 3 4% 3% 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. In subjects followed for up to 16 weeks after discontinuation of treatment, posttreatment ALT elevations were observed more frequently in subjects who had received lamivudine tablets (HBV) than in subjects who had received placebo. A comparison of ALT elevations between Weeks 52 and 68 in subjects who discontinued lamivudine tablets (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 bnormal Value Subjects with ALT Elevation/ Subjects with Observations a Lamivudine Tablets (HBV) b P lacebo 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% 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. 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 lamivudine tablets (HBV). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of lamivudine tablets (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 Lymph atic 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.