BOXED WARNING WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS, AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B Hematologic Toxicity Zidovudine, a component of lamivudine and zidovudine tablets, has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV-1) disease [see Warnings and Precautions ( 5.1 )]. Myopathy Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions ( 5.2 )]. 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 and other antiretrovirals. Discontinue lamivudine and zidovudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions ( 5.3 )]. Exacerbations of Hepatitis B: Severe, acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, which is one component of lamivudine and zidovudine tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and zidovudine tablet and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions ( 5.4 )]. WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS, AND SEVERE HEPATOMEGALY and EXACERBATONS OF HEPATITIS B See full prescribing information for complete boxed warning. Hematologic Toxicity •Hematologic toxicity, including neutropenia and anemia has been associated with the use of zidovudine, a component of lamivudine and zidovudine tablets. ( 5.1 ) Myopathy •Symptomatic myopathy associated with prolonged use of zidovudine. ( 5.2 ) 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. ( 5.3 ) Exacerbations of Hepatitis B •Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-l) and have discontinued lamivudine, a component of lamivudine and zidovudine tablet. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.4)
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warnings and cautions
5 WARNINGS AND PRECAUTIONS •Lamivudine and Zidovudine tablet should not be administered with other lamivudine- or zidovudine-containing products or emtricitabine-containing products. ( 5.5 ) •Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue lamivudine and zidovudine tablet as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. ( 5.6 ) •Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. ( 5.6 ) •Pancreatitis: Use with caution in patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. ( 5.7 ) •Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy ( 5.8 , 5.9 ) 5.1 Hemotologic Toxicity/Bone Marrow Suppression Zidovudine, a component of lamivudine and zidovudine tablet, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Lamivudine and Zidovudine tablet should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells/mm 3 or hemoglobin less than 9.5 g/dL [ see Adverse Reactions ( 6.1 )]. Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with lamivudine and zidovudine tablet. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed . 5.2 Myopathy Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with lamivudine and zidovudine tablet. 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 analogues and other antiretrovirals. See full prescribing information for lamivudine tablets and zidovudine tablets. Treatment with lamivudine and zidovudine tablet 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). 5.4 Patients with Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis : Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for lamivudine tablets. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Emergence of Lamivudine-resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for lamivudine. 5.5 Related Products that are Not Recommended Lamivudine and zidovudine tablet is a fixed-dose combination of 2 nucleoside analogue reverse transcriptase inhibitors (lamivudine and zidovudine). Concomitant administration of lamivudine and zidovudine tablets with other products containing lamivudine or zidovudine is not recommended. In addition, do not administer lamivudine and zidovudine tablets in combination with products containing emtricitabine. 5.6 Uses With Interferon- and Ribavirin-Based Regimens Patients receiving interferon alfa with or without ribavirin and lamivudine and zidovudine tablet should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for lamivudine and zidovudine. Discontinuation of lamivudine and zidovudine tablet should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin). Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and lamivudine and zidovudine tablets are not advised. 5.7 Pancreatitis Lamivudine and Zidovudine Tablet should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with lamivudine and zidovudine tablet should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions ( 6.1 )]. 5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine and zidovudine tablet. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.9 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: •Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions ( 5.1 )] . •Symptomatic myopathy [see Boxed Warning, Warnings and Precautions ( 5.2 )] . •Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions ( 5.3 )] . •Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions ( 5.4 )] . •Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions ( 5.6 )]. •Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions ( 5.6 )]. •Pancreatitis [see Warnings and Precautions ( 5.7 )]. •Immune reconstitution syndrome [see Warnings and Precautions ( 5.8 )]. •Fat redistribution [see Warnings and Precautions ( 5.9 )]. Most commonly reported adverse reactions (incidence greater than or equal to 15%) clinical trials of combination lamivudine and zidovudine were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. ( 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Lamivudine Plus Zidovudine Administered As Separate Formulations : In 4 randomized, controlled trials of lamivudine 300 mg per day plus zidovudine 600 mg per day, the following selected adverse reactions and laboratory abnormalities were observed (see Tables 1 and 2). Table 1. Selected Clinical Adverse Reactions (Greater than or equal to 5% Frequency) in 4 Controlled Clinical Trials With lamivudine 300 mg per day and zidovudine 600 mg per day Adverse Reaction Lamivudine plus Zidovudine (n = 251) Body as a whole Headache 35% Malaise & fatigue 27% Fever or chills 10% Digestive Nausea 33% Diarrhea 18% Nausea & vomiting 13% Anorexia and/or decreased appetite 10% Abdominal pain 9% Abdominal cramps 6% Dyspepsia 5% Nervous system Neuropathy 12% Insomnia & other sleep disorders 11% Dizziness 10% Depressive disorders 9% Respiratory Nasal signs & symptoms 20% Cough 18% Skin Skin rashes 9% Musculoskeletal Musculoskeletal pain 12% Myalgia 8% Arthralgia 5% Pancreatitis was observed in 9 of the 2,613 adult patients (0.3%) who received lamivudine in controlled clinical trials [see Warnings and Precautions ( 5.7 )]. Selected laboratory abnormalities observed during therapy are listed in Table 2. Table 2. Frequencies of Selected Laboratory Abnormalities among Adults in 4 Controlled Clinical Trials of Lamivudine 300 mg per day plus Zidovudine 600 mg per day a Test (Abnormal Level) Lamivudine plus Zidovudine % (n) Neutropenia (ANC<750/mm 3 ) 7.2% (237) Anemia (Hgb<8 g/dL) 2.9% (241) Thrombocytopenia (platelets-<50,000/mm 3 ) 0.4% (240) ALT (>5 x ULN) 3.7% (241) AST (>5 x ULN) 1.7% (241) Bilirubin (>2.5x ULN) 0.8% (241) Amylase (>2 x ULN) 4.2% (72) ULN = Upper limit of normal. ANC = Absolute neutrophil count. n = Number of patients assessed. a Frequencies of these laboratory abnormalities were higher in subjects with mild laboratory abnormalities at baseline. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use. 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. Body as a Whole : Redistribution/accumulation of body fat [ see Warnings and Precautions ( 5.9 )]. Cardiovascular : Cardiomyopathy. Endocrine and Metabolic : Gynecomastia, hyperglycemia. Gastrointestinal: Oral mucosal pigmentation, stomatitis. General : Vasculitis, weakness. Hemic and Lymphatic: Anemia, (including pure red cell aplasia and anemias progressing on therapy), lymphadenopathy, splenomegaly. Hepatic and Pancreatic : Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B [see Boxed Warning, Warnings and Precautions ( 5.3 ), 5.4 ), ( 5.7 )]. Hypersensitivity : Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal : Muscle weakness, CPK elevation, rhabdomyolysis. Nervous : Paresthesia, peripheral neuropathy, seizures. Respirator: : Abnormal breath sounds/wheezing. Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.