ADVERSE REACTIONS SECTION.

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 [see Boxed Warning, Warnings and Precautions (5.4)]. Hepatic decompensation in patients co-infected with HIV-1 and hepatitis [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 Macleods Pharma USA, Inc., at 1-888-943-3210 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 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 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 and 2). Table 1. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Controlled Clinical Trials with EPIVIR 300 mg per day and RETROVIR 600 mg per day Adverse ReactionEPIVIR plus RETROVIR(n 251)Body as whole Headache 35% Malaise fatigue 27% Fever or chills Digestive 10% Nausea 33% Diarrhea 18% Nausea vomiting 13% Anorexia and/or decreased appetite 10% Abdominal pain 9% Abdominal cramps 6% Dyspepsia Nervous system 5% Neuropathy 12% Insomnia other sleep disorders 11% Dizziness 10% Depressive disorders Respiratory 9% Nasal signs symptoms 20% Cough Skin 18% Skin rashes Musculoskeletal 9% Musculoskeletal pain 12% Myalgia 8% Arthralgia 5% Pancreatitis was observed in 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 Controlled Clinical Trials of EPIVIR 300 mg per day plus RETROVIR 600 mg per daya Test (Abnormal Level)EPIVIR plus RETROVIR (n)Neutropenia (ANC<750/mm3) 7.2% (237) Anemia (Hgb<8.0 g/dL) 2.9% (241) Thrombocytopenia (platelets<50,000/mm3) 0.4% (240) ALT (>5.0 ULN) 3.7% (241) AST (>5.0 ULN) 1.7% (241) Bilirubin (>2.5 ULN) 0.8% (241) Amylase (>2.0 ULN) 4.2% (72) ULN Upper limit of normal. ANC Absolute neutrophil count. = Number of subjects assessed. 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 population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Body as 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, 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 [see Boxed Warning, Warnings and Precautions (5.3), (5.4), (5.6)]. Hypersensitivity Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal Muscle weakness, CPK elevation, rhabdomyolysis. Nervous Paresthesia, peripheral neuropathy, seizures. Respiratory Abnormal breath sounds/wheezing. Skin Alopecia, erythema multiforme, Stevens-Johnson syndrome.

BOXED WARNING SECTION.

WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS . Zidovudine, 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)]. Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.2)]. 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 tablets). Discontinue lamivudine and zidovudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.3)]. Severe acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis 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 tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis therapy may be warranted [see Warnings and Precautions (5.4)].. WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS See full prescribing information for complete boxed warning. Hematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, component of lamivudine and zidovudine tablets (5.1) Symptomatic myopathy associated with prolonged use of zidovudine. (5.2) 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 tablets). Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.3) Severe acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, component of lamivudine and zidovudine tablets. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis treatment. (5.4).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis Mutagenesis Impairment Of Fertility. CarcinogenicityLamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg. Zidovudine: Zidovudine was administered orally at dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279. In mice, late-appearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, squamous cell papilloma, and squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of middle-dose animal. No vaginal tumors were found at the lowest dose. In rats, late-appearing (after 20 months), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species. At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every hours. It is not known how predictive the results of rodent carcinogenicity studies may be for humans. Mutagenicity Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Zidovudine: Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in cytogenetic study in rats given single dose. Impairment of Fertility Lamivudine: Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg. Zidovudine: Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Lamivudine and zidovudine is an antiretroviral agent [see Microbiology 12.4 )]. 12.3 Pharmacokinetics. 12.3 Pharmacokinetics Pharmacokinetics in Adults One lamivudine and zidovudine tablet was bioequivalent to EPIVIR tablet (150 mg) plus RETROVIR tablet (300 mg) following single-dose administration to fasting healthy subjects (n 24). Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is minor route of elimination (approximately 5% of an oral dose after 12 hours). In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). Zidovudine: Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. second metabolite, 3-amino-3-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC. In humans, lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes. The pharmacokinetic properties of lamivudine and zidovudine in fasting subjects are summarized in Table 3. Table 3. Pharmacokinetic Parametersa for Lamivudine and Zidovudine in Adults ParameterLamivudineZidovudineOral bioavailability (%) 86 +- 16 = 12 64 +- 10 = Apparent volume of distribution (L/kg) 1.3 +- 0.4 n=20 1.6 +- 0.6 = Plasma protein binding (%) <36 <38 CSF:plasma ratiob 0.12[0.04 to 0.47] = 38c 0.60[0.04 to 2.62] = 39d Systemic clearance (L/h/kg) 0.33 +- 0.06 = 20 1.6 +- 0.6 = Renal clearance (L/h/kg) 0.22 +- 0.06 = 20 0.34 +- 0.05 = Elimination half-life (h)e to 0.5 to a Data presented as mean +- standard deviation except where noted. Median [range]. Children. Adults. Approximate range. Effect of Food on Absorption of Lamivudine and Zidovudine Tablets: Lamivudine and zidovudine tablets may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine and zidovudine with food was similar when compared with fasting healthy subjects (n 24). Specific Populations Patients with Renal Impairment: Lamivudine and zidovudine: The effect of renal impairment on the combination of lamivudine and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components). Patients with Hepatic Impairment: Lamivudine and zidovudine: The effect of hepatic impairment on the combination of lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components). Pregnant Women: Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. Zidovudine: Zidovudine pharmacokinetics have been studied in Phase trial of women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in pregnant women did not appear to alter zidovudine pharmacokinetics. Geriatric Patients: The pharmacokinetics of lamivudine and zidovudine have not been studied in subjects over 65 years of age. Male and Female Patients: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (lamivudine or zidovudine) based on the available information that was analyzed for each of the individual components. Racial Groups: Lamivudine: There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics based on the available information that was analyzed for the individual lamivudine component. Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined. Drug Interaction Studies No drug interaction trials have been conducted using lamivudine and zidovudine tablets. Lamivudine and Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours). Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in trial of 19 healthy male subjects. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n 18), stavudine (n 10), or zidovudine (n 6) were coadministered as part of multi-drug regimen to HIV-1/HCV co-infected subjects. Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received single 300-mg dose of lamivudine oral solution alone or coadministered with single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC (0-24); 14%, 32%, and 36% in the AUC(); and 28%, 52%, and 55% in the Cmax: of lamivudine, respectively. Table presents drug interaction information for the individual components of lamivudine and zidovudine tablets. Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUCa Coadministered Drug and Dose Drug and Dose Concentrations of Lamivudine or Zidovudine Concentration of Coadministered Drug AUC Variability Nelfinavir 750 mg every h 7 to 10 days Lamivudine single 150 mg 11 10% 95% CI: 1% to 20% <-> Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily 5 days Lamivudine single 300 mg 14 43% 90% CI: 32% to 55% <-> Atovaquone 750 mg every 12 with food Zidovudine 200 mg every h 14 31% Range:23% to 78%b <-> Clarithromycin 500 mg twice daily Zidovudine 100 mg every h 7 days 12% Range:34% to 14% Not Reported Fluconazole 400 mg daily Zidovudine 200 mg every h 12 74% 95% CI:54% to 98% Not Reported Methadone 30 to 90 mg daily Zidovudine 200 mg every h 43% Range:16% to 64%b <-> Nelfinavir 750 mg every h 7 to 10 days Zidovudine single 200 mg 11 35% Range:28% to 41% <-> Probenecid 500 mg every h 2 days Zidovudine mg/kg every h 3 days 106% Range:100% to 170%b Not Assessed Rifampin 600 mg daily 14 days Zidovudine 200 mg every h 14 days 47% 90% CI:41% to 53% Not Assessed Ritonavir 300 mg every h 4 days Zidovudine 200 mg every h 4 days 25% 95% CI:15% to 34% <-> Valproic acid 250 mg or 500 mg every h 4 days Zidovudine 100 mg every h 4 days 80% Range:64% to 130%b Not Assessed Increase; Decrease; <-> No significant change; AUC Area under the concentration versus time curve; CI Confidence interval. This table is not all inclusive. Estimated range of percent difference.. 12.4 Microbiology. Mechanism of ActionLamivudine: Lamivudine is synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. Zidovudine: Zidovudine is synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Antiviral Activity Lamivudine plus Zidovudine: In HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios was not antagonistic. Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: to 40 nM), 30 nM (range: to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B) respectively. The EC50 values against HIV-2 isolates (n 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells. Zidovudine: The antiviral activity of zidovudine against HIV-1 was assessed in number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM 0.27 mcg per mL) and 0.1 to microM, respectively. HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n 135 baseline samples). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV-2 isolates from 0.00049 to 0.004 microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture. Neither lamivudine nor zidovudine was antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Resistance In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks. HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple amino acid substitutions, the most essential of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown. Lamivudine: Lamivudine-resistant isolates of HIV-1 have been selected in cell culture and have also been recovered from subjects treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of isolates selected in cell culture and recovered from lamivudine-treated subjects showed that the resistance was due to specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either valine or isoleucine (M184V/I). Zidovudine: HIV-1 isolates with reduced susceptibility to zidovudine have been selected in cell culture and were also recovered from subjects treated with zidovudine. Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed thymidine analog mutation (TAM) substitutions in HIV-1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of substitutions. In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Cross-resistance Cross-resistance has been observed among NRTIs. Cross-resistance between lamivudine and zidovudine has not been reported. In some subjects treated with lamivudine alone or in combination with zidovudine, isolates have emerged with substitution at codon 184, which confers resistance to lamivudine. TAM substitutions are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, and tenofovir.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. One lamivudine and zidovudine tablet given twice daily is an alternative regimen to EPIVIR tablets 150 mg twice daily plus RETROVIR 600 mg per day in divided doses.. 14.1 Adults. The NUCB3007 (CAESAR) trial was conducted using EPIVIR 150-mg tablets (150 mg twice daily) and RETROVIR 100-mg capsules (2 100 mg times daily). CAESAR was multi-center, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor, randomized 1:2:1. total of 1,816 HIV-1-infected adults with 25 to 250 (median 122) CD4 cells per mm3 at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on trial was 12 months. Results are summarized in Table 5. Table 5. Number of Subjects (%) with at Least HIV-1 Disease-Progression Event or Death EndpointCurrent Therapy(n 460)EPIVIR plus Current Therapy(n 896)EPIVIR plus NNRTIa plus Current Therapy (n 460)HIV-1 progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%) Death 27 (5.9%) 23 (2.6%) 14 (3.0%) aAn investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.. 14.2 Prevention of Maternal-Fetal HIV-1 Transmission. The utility of zidovudine alone for the prevention of maternal-fetal HIV-1 transmission was demonstrated in randomized, double-blind, placebo-controlled trial conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells per mm3 (median in the treated group: 560 cells per mm3) who had little or no previous exposure to zidovudine. Oral zidovudine was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of zidovudine during labor and delivery. Following birth, neonates received oral zidovudine syrup for weeks. The trial showed statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363 neonates evaluated in the trial, the estimated risk of HIV-1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, relative reduction in transmission risk of 68.7%. Zidovudine was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Neutropenia and Anemia Inform patients that the important toxicities associated with zidovudine are neutropenia and/or anemia. Inform them of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced HIV-1 disease [see Boxed Warning, Warnings and Precautions (5.1 )]. Myopathy Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine [see Warnings and Precautions (5.2)]. Lactic Acidosis/Hepatomegaly with Steatosis Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking lamivudine and zidovudine if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.3 )]. Patients with Hepatitis or Co-infection Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see Warnings and Precautions (5.4)]. Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.5)]. Drug Interactions Advise patients that other medications may interact with lamivudine and zidovudine tablets and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, component of lamivudine and zidovudine tablets [see Drug Interactions (7.1)]. Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when lamivudine and zidovudine tablet is started [see Warnings and Precautions (5.7)]. Lipoatrophy Advise patients that loss of subcutaneous fat may occur in patients receiving lamivudine and zidovudine tablets and that they will be regularly assessed during therapy [see Warnings and Precautions (5.8)]. Pregnancy Registry Advise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine and zidovudine tablets during pregnancy [see Use in Specific Populations (8.1)]. Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)]. Missed Dose Instruct patients that if they miss dose of lamivudine and zidovudine, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].The brands mentioned herewith are the properties of their respective owners. Manufactured for Macleods Pharma USA, Inc. Plainsboro, NJ 08536 Manufactured by: Macleods Pharmaceuticals Ltd. Daman (U.T.) INDIARevised: June 2019.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis Mutagenesis Impairment Of Fertility. CarcinogenicityLamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg. Zidovudine: Zidovudine was administered orally at dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279. In mice, late-appearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, squamous cell papilloma, and squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of middle-dose animal. No vaginal tumors were found at the lowest dose. In rats, late-appearing (after 20 months), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species. At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every hours. It is not known how predictive the results of rodent carcinogenicity studies may be for humans. Mutagenicity Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Zidovudine: Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in cytogenetic study in rats given single dose. Impairment of Fertility Lamivudine: Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg. Zidovudine: Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. 12.3 Pharmacokinetics Pharmacokinetics in Adults One lamivudine and zidovudine tablet was bioequivalent to EPIVIR tablet (150 mg) plus RETROVIR tablet (300 mg) following single-dose administration to fasting healthy subjects (n 24). Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is minor route of elimination (approximately 5% of an oral dose after 12 hours). In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). Zidovudine: Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. second metabolite, 3-amino-3-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC. In humans, lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes. The pharmacokinetic properties of lamivudine and zidovudine in fasting subjects are summarized in Table 3. Table 3. Pharmacokinetic Parametersa for Lamivudine and Zidovudine in Adults ParameterLamivudineZidovudineOral bioavailability (%) 86 +- 16 = 12 64 +- 10 = Apparent volume of distribution (L/kg) 1.3 +- 0.4 n=20 1.6 +- 0.6 = Plasma protein binding (%) <36 <38 CSF:plasma ratiob 0.12[0.04 to 0.47] = 38c 0.60[0.04 to 2.62] = 39d Systemic clearance (L/h/kg) 0.33 +- 0.06 = 20 1.6 +- 0.6 = Renal clearance (L/h/kg) 0.22 +- 0.06 = 20 0.34 +- 0.05 = Elimination half-life (h)e to 0.5 to a Data presented as mean +- standard deviation except where noted. Median [range]. Children. Adults. Approximate range. Effect of Food on Absorption of Lamivudine and Zidovudine Tablets: Lamivudine and zidovudine tablets may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine and zidovudine with food was similar when compared with fasting healthy subjects (n 24). Specific Populations Patients with Renal Impairment: Lamivudine and zidovudine: The effect of renal impairment on the combination of lamivudine and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components). Patients with Hepatic Impairment: Lamivudine and zidovudine: The effect of hepatic impairment on the combination of lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components). Pregnant Women: Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. Zidovudine: Zidovudine pharmacokinetics have been studied in Phase trial of women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in pregnant women did not appear to alter zidovudine pharmacokinetics. Geriatric Patients: The pharmacokinetics of lamivudine and zidovudine have not been studied in subjects over 65 years of age. Male and Female Patients: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (lamivudine or zidovudine) based on the available information that was analyzed for each of the individual components. Racial Groups: Lamivudine: There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics based on the available information that was analyzed for the individual lamivudine component. Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined. Drug Interaction Studies No drug interaction trials have been conducted using lamivudine and zidovudine tablets. Lamivudine and Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours). Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in trial of 19 healthy male subjects. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n 18), stavudine (n 10), or zidovudine (n 6) were coadministered as part of multi-drug regimen to HIV-1/HCV co-infected subjects. Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received single 300-mg dose of lamivudine oral solution alone or coadministered with single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC (0-24); 14%, 32%, and 36% in the AUC(); and 28%, 52%, and 55% in the Cmax: of lamivudine, respectively. Table presents drug interaction information for the individual components of lamivudine and zidovudine tablets. Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUCa Coadministered Drug and Dose Drug and Dose Concentrations of Lamivudine or Zidovudine Concentration of Coadministered Drug AUC Variability Nelfinavir 750 mg every h 7 to 10 days Lamivudine single 150 mg 11 10% 95% CI: 1% to 20% <-> Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily 5 days Lamivudine single 300 mg 14 43% 90% CI: 32% to 55% <-> Atovaquone 750 mg every 12 with food Zidovudine 200 mg every h 14 31% Range:23% to 78%b <-> Clarithromycin 500 mg twice daily Zidovudine 100 mg every h 7 days 12% Range:34% to 14% Not Reported Fluconazole 400 mg daily Zidovudine 200 mg every h 12 74% 95% CI:54% to 98% Not Reported Methadone 30 to 90 mg daily Zidovudine 200 mg every h 43% Range:16% to 64%b <-> Nelfinavir 750 mg every h 7 to 10 days Zidovudine single 200 mg 11 35% Range:28% to 41% <-> Probenecid 500 mg every h 2 days Zidovudine mg/kg every h 3 days 106% Range:100% to 170%b Not Assessed Rifampin 600 mg daily 14 days Zidovudine 200 mg every h 14 days 47% 90% CI:41% to 53% Not Assessed Ritonavir 300 mg every h 4 days Zidovudine 200 mg every h 4 days 25% 95% CI:15% to 34% <-> Valproic acid 250 mg or 500 mg every h 4 days Zidovudine 100 mg every h 4 days 80% Range:64% to 130%b Not Assessed Increase; Decrease; <-> No significant change; AUC Area under the concentration versus time curve; CI Confidence interval. This table is not all inclusive. Estimated range of percent difference.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine and zidovudine tablets 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 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, 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 (Cmax) 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 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 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 powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)-fold greater compared with paired maternal serum concentration (n 8). Zidovudine: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens. randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug [see Clinical Studies (14.2)]. Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)]. There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown. Animal Data: Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days through 16 [rat] and through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine. Zidovudine: study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on gestation Days through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on gestation Days through 18) showed increased fetal resorptions at the 500 mg-per-kg-per-day dose, which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.2). 8.1 Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine and zidovudine tablets 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 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, 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 (Cmax) 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 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 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 powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)-fold greater compared with paired maternal serum concentration (n 8). Zidovudine: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens. randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug [see Clinical Studies (14.2)]. Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)]. There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown. Animal Data: Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days through 16 [rat] and through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine. Zidovudine: study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on gestation Days through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on gestation Days through 18) showed increased fetal resorptions at the 500 mg-per-kg-per-day dose, which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.. 8.2 Lactation. Risk Summary The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Lamivudine and zidovudine are present in human milk. There is no information on the effects of lamivudine or zidovudine on the breastfed infant or the effects of the drugs on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving lamivudine and zidovudine tablets.. 8.4 Pediatric Use. Lamivudine and zidovudine tablets are not recommended for use in pediatric patients who weigh less than 30 kg because it is fixed-dose combination tablet that cannot be adjusted for this patient population [see Dosage and Administration 2.2 )]. 8.5 Geriatric Use. Clinical trials of lamivudine and zidovudine tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of lamivudine and zidovudine tablets in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology 12.3 )]. 8.6 Patients with Impaired Renal Function. Lamivudine and zidovudine tablets are not recommended for patients with creatinine clearance less than 50 mL per min because lamivudine and zidovudine tablets are fixed-dose combination and the dosage of the individual components cannot be adjusted. If dose reduction of the lamivudine or zidovudine components of lamivudine and zidovudine tablets are required for patients with renal impairment then the individual components should be used [see Dosage and Administration 2.3 ), Clinical Pharmacology 12.3 )]. 8.7 Patients with Impaired Hepatic Function. Lamivudine and zidovudine tablets are fixed-dose combination and the dosage of the individual components cannot be adjusted. Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

WARNINGS AND PRECAUTIONS SECTION.

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 tablets 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 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, component of lamivudine and zidovudine tablets, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Lamivudine and zidovudine tablets should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells/mm3 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 tablets. 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 tablets.. 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 tablets). 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 tablets 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 Virus Co-infection. Posttreatment Exacerbations of HepatitisClinical 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 HBVSafety and efficacy of lamivudine have not been established for treatment of chronic hepatitis in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis 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 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 tablets should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for RETROVIR (zidovudine). Discontinuation of lamivudine and zidovudine tablets 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 is not advised.. 5.6 Pancreatitis. Lamivudine and zidovudine tablets should be used with caution in patients with history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with lamivudine and zidovudine tablets should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)]. 5.7 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine and zidovudine tablets. 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-Barre 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.. 5.8 Lipoatrophy. Treatment with zidovudine, component of lamivudine and zidovudine tablets, has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to non-zidovudine-containing regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.