Lamivudine and Zidovudine

1 INDICATIONS AND USAGE Lamivudine and zidovudine tablets a combination of 2 nucleoside analogues, are indicated in combination with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Lamivudine and zidovudine tablets, a combination of 2 nucleoside analogue reverse transcriptase inibitors, are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. ( 1 )

2 DOSAGE AND ADMINISTRATION • Adults and Adolescents weighing greater than or equal to 30 kg: 1 tablet orally twice daily. ( 2.1 ) • Pediatrics weighing greater than or equal to 30 kg: 1 tablet orally twice daily. ( 2.2 ) • Because lamivudine and zidovudine tablet is a fixed-dose tablet and cannot be dose adjusted, lamivudine and zidovudine tablet is not recommended in patients requiring dosage adjustment or with hepatic impairment or experiencing dose-limiting adverse reactions. ( 2.3 , 4 ) 2.1 Recommended Dosage for Adults and Adolescents The recommended dosage of lamivudine and zidovudine tablet in HIV-1-infected adults and adolescents weighing greater than or equal to 30 kg is 1 tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) taken orally twice daily. 2.2 Recommended Dosage for Pediatric Patients The recommended dosage of scored lamivudine and zidovudine tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet administered orally twice daily. Before prescribing lamivudine and zidovudine tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a lamivudine and zidovudine tablet, the liquid oral formulations should be prescribed: EPIVIR (lamivudine) oral solution and RETROVIR (zidovudine) syrup. 2.3 Not Recommended Due to Lack of Dosage Adjustment Because lamivudine and zidovudine is a fixed-dose tablet and cannot be dose adjusted, lamivudine and zidovudine tablets are not recommended for: • pediatric patients weighing less than 30 kg [see Use in Specific Populations ( 8.4 )]. • patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations ( 8.6 )]. • patients with hepatic impairment [see Use in Specific Populations ( 8.7 )]. • patients experiencing dose-limiting adverse reactions. Liquid and solid oral formulations of the individual components of lamivudine and zidovudine tablets are available for these populations.

5 WARNINGS AND PRECAUTIONS • 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. ( 5.5 ) • 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. ( 5.5 ) • Pancreatitis: Use with caution in patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. ( 5.6 ) • Immune reconstitution syndrome and lipoatrophy have been reported in patients treated with combination antiretroviral therapy. ( 5.7 , 5.8 ) 5.1 Hematologic 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 per mm 3 or hemoglobin less than 9.5 grams per 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, including lamivudine and zidovudine (components of lamivudine and zidovudine tablet). 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. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). 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 EPIVIR (lamivudine). 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 EPIVIR (lamivudine). 5.5 Use 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 RETROVIR (zidovudine). Discont…

4 CONTRAINDICATIONS Lamivudine and zidovudine tablets are contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine. Lamivudine and zidovudine tablets are contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine. ( 4 )

7 DRUG INTERACTIONS • Agents antagonistic with zidovudine: Concomitant use should be avoided. ( 7.1 ) • Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. ( 7.1 ) • Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration. ( 7.2 ) 7.1 Zidovudine Agents Antagonistic with Zidovudine Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro: • Stavudine • Doxorubicine • Nucleoside analogues, e.g., ribavirin Hematologic/Bone Marrow Suppressive/Cytotoxic Agents Coadministration with the following drugs may increase the hematologic toxicity of zidovudine: • Ganciclovir • Interferon alfa • Ribavirin • Other bone marrow suppressive or cytotoxic agents 7.2 Lamivudine Sorbitol Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology ( 12.3 )].

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine and zidovudine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for lamivudine or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks' gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see Data). In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see Data). Data Human Data: Lamivudine : Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens. Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trial assessed pharmacokinetics in 16 women at 36 weeks' gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks' gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks' gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or po…

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 ( 5.5 )]. • Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions ( 5.5 )]. • Pancreatitis [see Warnings and Precautions ( 5.6 )]. • Immune reconstitution syndrome [see Warnings and Precautions ( 5.7 )]. • Lipoatrophy [see Warnings and Precautions ( 5.8 )]. • Most commonly reported adverse reactions (incidence greater than or equal to 15%) in 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Lamivudine plus Zidovudine Administered as Separate Formulations In 4 randomized, controlled trials of EPIVIR 300 mg per day plus RETROVIR 600 mg per day, the following selected adverse reactions and laboratory abnormalities were observed (Tables 1 and 2). Table 1. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in 4 Controlled Clinical Trials with EPIVIR 300 mg per day and RETROVIR 600 mg per day Adverse Reaction EPIVIR plus RETROVIR (n = 251) Body as a whole Headache 35% Malaise & fatigue 27% Fever or chills 10% Digestive Nausea Diarrhea 33% 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 subjects (0.3%) who received EPIVIR in controlled clinical trials [see Warnings and Precautions ( 5.6 )]. 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 EPIVIR 300 mg per day plus RETROVIR 600 mg per day a Test (Abnormal Level) EPIVIR plus RETROVIR % (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 subjects 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 ( 5.8 )]. Cardiovascular Cardiomyopathy. Endocrine and Metabolic Gynecomastia, hyperglycemia. Gastrointestinal Oral mucosal pigmentation, stomatitis. General Vasculitis…