MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of Action: Intracellularly, lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is weak inhibitor of mammalian DNA polymerases , and Antiviral Activity: The antiviral activity of lamivudine against HIV-1 was assessed in number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC50 values (50% effective concentrations) were in the range of 0.003 to 15 uM (1 uM 0.23 mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.429 uM (range: 0.200 to 2.007 uM) from Virco (n 92 baseline samples from COLA40263) and 2.35 uM (1.37 to 3.68 uM) from Monogram Biosciences (n 135 baseline samples from ESS30009). The EC50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 uM, and against HIV-2 isolates from 0.003 to 0.120 uM in peripheral blood mononuclear cells. Ribavirin (50 uM) decreased the anti-HIV-1 activity of lamivudine by 3.5 fold in MT-4 cells. In HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity. Please see the full prescribing information for Epivir-HBV for information regarding the inhibitory activity of lamivudine against HBV.Resistance: Lamivudine-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis 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 isoleucine or valine (M184V/I).HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients.Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.Lamivudine-resistant HBV isolates develop substitutions (rtM204V/I) in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory mutations improving replication efficiency. Other substitutions detected in lamivudine-resistant HBV isolates include: rtL80I and rtA181T. Similar HBV mutants have been reported in HIV-1- infected patients who received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis virus [see Warnings and Precautions (5.2)].Cross-Resistance: Lamivudine-resistant HIV-1 mutants were cross-resistant to didanosine (ddI) and zalcitabine (ddC). In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged.Genotypic and Phenotypic Analysis of On-Therapy HIV-1 Isolates From Patients With Virologic Failure: Study EPV20001: Fifty-three of 554 (10%) patients enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level >=400 copies/mL) by Week 48. Twenty-eight patients were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-1 RNA levels of patients in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log10 copies/mL and 4.6 log10 copies/mL, respectively.Genotypic analysis of on-therapy isolates from 22 patients identified as virologic failures in the lamivudine once-daily group showed that isolates from 0/22 patients contained treatment-emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), isolates from 10/22 patients contained treatment-emergent amino acid substitutions associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C), and isolates from 8/22 patients contained treatment-emergent lamivudine resistance-associated substitution (M184I or M184V).Genotypic analysis of on-therapy isolates from patients (n 22) in the lamivudine twice-daily treatment group showed that isolates from 1/22 patients contained treatment-emergent zidovudine resistance substitutions, isolates from 7/22 contained treatment-emergent efavirenz resistance substitutions, and isolates from 5/22 contained treatment-emergent lamivudine resistance substitutions.Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n 13) receiving lamivudine once daily showed that isolates from 12/13 patients were susceptible to zidovudine; isolates from 8/13 patients exhibited 25- to 295-fold decrease in susceptibility to efavirenz, and isolates from 7/13 patients showed an 85- to 299-fold decrease in susceptibility to lamivudine.Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n 13) receiving lamivudine twice daily showed that isolates from all 13 patients were susceptible to zidovudine; isolates from 3/13 patients exhibited 21- to 342-fold decrease in susceptibility to efavirenz, and isolates from 4/13 patients exhibited 29- to 159-fold decrease in susceptibility to lamivudine.Study EPV40001: Fifty patients received zidovudine 300 mg twice daily plus abacavir 300 mg twice daily plus lamivudine 300 mg once daily and 50 patients received zidovudine 300 mg plus abacavir 300 mg plus lamivudine 150 mg all twice daily. The median baseline plasma HIV-1 RNA levels for patients in the groups were 4.79 log10 copies/mL and 4.83 log10 copies/mL, respectively. Fourteen of 50 patients in the lamivudine once-daily treatment group and of 50 patients in the lamivudine twice-daily group were identified as virologic failures.Genotypic analysis of on-therapy HIV-1 isolates from patients (n 9) in the lamivudine once-daily treatment group showed that isolates from patients had an abacavir and/or lamivudine resistance-associated substitution M184V alone. On-therapy isolates from patients (n 6) receiving lamivudine twice daily showed that isolates from patients had M184V alone, and isolates from patients harbored the M184V substitution in combination with zidovudine resistance-associated amino acid substitutions.Phenotypic analysis of on-therapy isolates from patients (n 6) receiving lamivudine once daily showed that HIV-1 isolates from patients exhibited 32- to 53-fold decrease in susceptibility to lamivudine.HIV-1 isolates from these patients were susceptible to zidovudine.Phenotypic analysis of on-therapy isolates from patients (n 4) receiving lamivudine twice daily showed that HIV-1 isolates from patient exhibited 45-fold decrease in susceptibility to lamivudine and 4.5-fold decrease in susceptibility to zidovudine.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the labeling:Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.1)]. Severe acute exacerbations of hepatitis [see Boxed Warning, Warnings and Precautions (5.2)]. Hepatic decompensation in patients co-infected with HIV-1 and hepatitis [see Warnings and Precautions (5.4)]. Pancreatitis [see Warnings and Precautions (5.5)].. Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.1)]. Severe acute exacerbations of hepatitis [see Boxed Warning, Warnings and Precautions (5.2)]. Hepatic decompensation in patients co-infected with HIV-1 and hepatitis [see Warnings and Precautions (5.4)]. Pancreatitis [see Warnings and Precautions (5.5)].. The most common reported adverse reactions (incidence >=15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. (6.1) The most common reported adverse reactions (incidence >=15%) in pediatric patients were fever and cough. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common reported adverse reactions (incidence >=15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. (6.1) The most common reported adverse reactions (incidence >=15%) in pediatric patients were fever and cough. (6.1) 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Adults Clinical Trials in HIV-1: The safety profile of lamivudine in adults is primarily based on 3,568 HIV-1-infected patients in clinical trials.The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea and cough.Selected clinical adverse reactions in >=5% of patients during therapy with Lamivudine 150 mg twice daily plus Zidovudine 200 mg times daily for up to 24 weeks are listed in Table 2.Table 2. Selected Clinical Adverse Reactions (>=5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)Adverse ReactionLamivudine 150 mg Twice Daily plus Zidovudine (n=251)Zidovudine (n=230)Body as Whole Headache35%27% Malaise and fatigue27%23% Fever or chills10%12%Digestive Nausea33%29% Diarrhea18%22% Nausea and vomiting13%12% Anorexia and/or decreased appetite10%7% Abdominal Pail9%11% Abdominal cramps6%3% Dyspepsia5%5%Nervous System Neuropathy12%10% Insomnia and other sleep disorders11%7% Dizziness10%4% Depressive disorders9%4%Respiratory Nasal signs and symptoms20%11% Cough18%13%Skin Skin rashes9%6%Musculoskeletal Musculoskeletal pain12%10% Myalgia8%6% Arthralgia5%5%a Either zidovudine monotherapy or zidovudine in combination with zalcitabine.Pancreatitis: Pancreatitis was observed in out of 2,613 adult patients (0.3%) who received lamivudine in controlled clinical trials EPV20001, NUCA3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions (5.5)].Lamivudine 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in patients receiving Lamivudine 300 mg once daily or Lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar. Selected laboratory abnormalities observed during therapy are summarized in Table 3. Table 3. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Studies (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and Clinical Endpoint Study (NUCB3007)24-Week Surrogate Endpoint Studies Clinical Endpoint Study Test(Threshold Level)Lamivudine plus ZidovudineZidovudineb Lamivudine plus Current Therapy Placebo plus Current TherapyC Absolute neutrophil count (less than 750/mm3) 7.2%5.4%15%13%Hemoglobin (less than 8.0 g/dL)2.9%1.8%2.2%3.4%Platelets (less than 50,000/mm3) 0.4%1.3%2.8%3.8%ALT (>5.0 ULN)3.7%3.6%3.8%1.9%AST (>5.0 ULN)1.7%1.8%4.0%2.1%Bilirubin (>2.5 ULN)0.8%0.4%NDNDAmylase (>2.0 ULN)4.2%1.5%2.2%1.1%a The median duration on study was 12 months.b Either zidovudine monotherapy or zidovudine in combination with zalcitabine.c Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.ULN Upper limit of normal.ND Not done. The frequencies of selected laboratory abnormalities reported in patients receiving Lamivudine 300 mg once daily or Lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.Pediatric Patients Clinical Trials in HIV-1: Lamivudine Oral Solution has been studied in 638 pediatric patients months to 18 years of age in clinical trials.Selected clinical adverse reactions and physical findings with >=5% frequency during therapy with Lamivudine mg/kg twice daily plus Zidovudine 160 mg/m times daily in therapy-naive (<=56 days of antiretroviral therapy) pediatric patients are listed in Table 4.Table 4. Selected Clinical Adverse Reactions and Physical Findings (>=5% Frequency) in Pediatric Patients in Study ACTG300Adverse ReactionLamivudine plus Zidovudine (n=236)Didanosine (n=235)Body as Whole Fever25%32%Digestive Hepatomegaly11%11% Nausea and vomiting8%7% Diarrhea8%6% Stomatitis6%12% Splenomegaly5%8%Respiratory Cough15%18% Abnormal breath sounds/wheezing 7%9%Ear, Nose, and Throat Signs or symptoms of earsa 7%6% Nasal discharge or congestion8%11%Other Skin rashes12%14% Lymphadenopathy9%11%a Includes pain, discharge, erythema, or swelling of an ear.Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric patients receiving lamivudine alone or in combination with other antiretroviral agents. In an open-label dose-escalation study (NUCA2002), 14 patients (14%) developed pancreatitis while receiving monotherapy with lamivudine. Three of these patients died of complications of pancreatitis. In second open-label study (NUCA2005), 12 patients (18%) developed pancreatitis. In Study ACTG300, pancreatitis was not observed in 236 patients randomized to Lamivudine plus Zidovudine. Pancreatitis was observed in patient in this study who received open-label Lamivudine in combination with Zidovudine and ritonavir following discontinuation of didanosine monotherapy [see Warnings and Precautions (5.5)].Paresthesias and Peripheral Neuropathies: Paresthesias and peripheral neuropathies were reported in 15 patients (15%) in Study NUCA2002, patients (9%) in Study NUCA2005, and patients (less than 1%) in Study ACTG300.Selected laboratory abnormalities experienced by therapy-naive (<=56 days of antiretroviral therapy) pediatric patients are listed in Table 5.Table 5. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Pediatric Patients in Study ACTG300Test (Threshold Level)Lamivudine plus ZidovudineDidanosineAbsolute neutrophil count (less than 400/mm3)8%3%Hemoglobin (less than 7.0 g/dL)4%2%Platelets (less than 50,000/mm3)1%3%ALT (>10 ULN)1%3%AST (>10 ULN)2%4%Lipase (>2.5 ULN)3%3%Total Amylase (>2.5 ULN)3%3%ULN Upper limit of normalNeonates Clinical Trials in HIV-1: Limited short-term safety information is available from small, uncontrolled studies in South Africa in neonates receiving lamivudine with or without zidovudine for the first week of life following maternal treatment starting at Week 38 or 36 of gestation [see Clinical Pharmacology (12.3)]. Selected adverse reactions reported in these neonates included increased liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, and sepsis; neonates died (1 from gastroenteritis with acidosis and convulsions, from traumatic injury, and from unknown causes). Two other nonfatal gastroenteritis or diarrhea cases were reported, including with convulsions; infant had transient renal insufficiency associated with dehydration. The absence of control groups limits assessments of causality, but it should be assumed that perinatally exposed infants may be at risk for adverse reactions comparable to those reported in pediatric and adult HIV-1-infected patients treated with lamivudine-containing combination regimens. Long-term effects of in utero and infant lamivudine exposure are not known.. 6.2 Postmarketing Experience. In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported during postmarketing use of lamivudine. Because these reactions are reported voluntarily from population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.Body as Whole: Redistribution/accumulation of body fat [see Warnings and Precautions (5.7)].Endocrine and Metabolic: Hyperglycemia.General: Weakness.Hemic and Lymphatic: Anemia (including pure red cell aplasia and severe anemias progressing on therapy).Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, posttreatment exacerbation of hepatitis [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].Hypersensitivity: Anaphylaxis, urticaria. Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis. Skin: Alopecia, pruritus.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. Figure 1. Systemic Clearance (L/hrokg) of Lamivudine in Relation to 12.1 Mechanism of Action. Lamivudine is an antiviral agent [see Clinical Pharmacology (12.4)].. 12.3 Pharmacokinetics. Pharmacokinetics in Adults: The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult patients after administration of single intravenous (IV) doses ranging from 0.25 to mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg.The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from mg to 600 mg/day administered to HBV-infected patients.The steady-state pharmacokinetic properties of the Lamivudine 300-mg tablet once daily for days compared with the Lamivudine 150-mg tablet twice daily for days were assessed in crossover study in 60 healthy volunteers. Lamivudine 300 mg once daily resulted in lamivudine exposures that were similar to Lamivudine 150 mg twice daily with respect to plasma AUC24,ss however, Cmax,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen.Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.Absorption and Bioavailability: Lamivudine was rapidly absorbed after oral administration in HIV-1- infected patients. Absolute bioavailability in 12 adult patients was 86% +-16% (mean +-SD) for the 150- mg tablet and 87% +-13% for the oral solution. After oral administration of mg/kg twice day to adults with HIV-1, the peak serum lamivudine concentration (Cmax) was 1.5 +- 0.5 mcg/mL (mean +- SD).The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kgThe accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of mg/kg twice daily.Effects of Food on Oral Absorption: An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected patients on occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax 3.2 +- 1.3 hours) compared with the fasted state (Tmax 0.9 +- 0.3 hours); Cmax in the fed state was 40% +- 23% (mean +- SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC) in the fed and fasted states; therefore, Lamivudine Oral Solution may be administered with or without food.Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 patients was 1.3 +- 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.Binding of lamivudine to human plasma proteins is low (less than 36%). In vitro studies showed that over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.Metabolism: Metabolism of lamivudine is minor route of elimination. In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within 12 hours after single oral dose of lamivudine in HIV-1-infected adults, 5.2% +- 1.4% (mean +- SD) of the dose was excreted as the transsulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.Elimination: The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In healthy subjects given single 300-mg oral dose of lamivudine, renal clearance was 199.7 +- 56.9 mL/min (mean +- SD). In 20 HIV-1-infected patients given single IV dose, renal clearance was 280.4 +- 75.2 mL/min (mean +- SD), representing 71% +- 16% (mean +- SD) of total clearance of lamivudine.In most single-dose studies in HIV-1-infected patients, HBV-infected patients, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t1/2) ranged from to hours. In HIV-1-infected patients, total clearance was 398.5 +- 69.1 mL/min (mean +- SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg/kg.Special Populations: Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in small group of HIV-1-infected adults with impaired renal function (Table 6).Table 6. Pharmacokinetic Parameters (Mean +- SD) After Single 300-mg Oral Dose of Lamivudine in Groups of Adults With Varying Degrees of Renal FunctionParameterCreatinine Clearance Criterion (Number of Subjects)>60 mL/min (n=6)10-30 mL/min (n=4)<10 mL/min (n=6)Creatinine clearance (mL/min) Cmax (mcg/mL) AUC (mcgohr/mL) Cl/F (mL/min)111 +- 14 2.6 +- 0.5 11.0 +- 1.7 464 +- 76 28 +- 3.6 +- 0.8 48.0 +- 19 114 +- 34 +- 5.8 +- 1.2 157 +- 74 36 +- 11 Exposure (AUC), Cmax, and half-life increased with diminishing renal function (as expressed by creatinine clearance). Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment [see Dosage and Administration (2.3)].Based on study in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis.The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.Hepatic Impairment: The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.Pediatric Patients: In Study NUCA2002, pharmacokinetic properties of lamivudine were assessed in subset of 57 HIV-1-infected pediatric patients (age range: 4.8 months to 16 years, weight range: to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg/day. In the infants and children (range: months to 12 years of age) receiving oral solution mg/kg twice daily (the usual recommended pediatric dose), absolute bioavailability was 66% +- 26% (mean +- SD), which was less than the 86% +- 16% (mean +- SD) observed in adults. The mechanism for the diminished absolute bioavailability of lamivudine in infants and children is unknown.Systemic clearance decreased with increasing age in pediatric patients, as shown in Figure 1. Figure 1. Systemic Clearance (L/hrokg) of Lamivudine in Relation to After oral administration of lamivudine mg/kg twice daily to 11 pediatric patients ranging from months to 14 years of age, Cmax was 1.1 +- 0.6 mcg/mL and half-life was 2.0 +- 0.6 hours. (In adults with similar blood sampling, the half-life was 3.7 +- hours.) Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric patients receiving an 8-mg/kg/day dose and adults receiving 4-mg/kg/day dose.Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric patients after multiple oral dosing with lamivudine. CSF samples were collected between and hours postdose. At the dose of mg/kg/day, CSF lamivudine concentrations in patients ranged from 5.6% to 30.9% (mean +- SD of 14.2% +- 7.9%) of the concentration in simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL.Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants up to week of age in studies in South Africa. In these studies, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric patients (>3 months of age) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old [see Adverse Reactions (6.1)].Geriatric Patients: The pharmacokinetics of lamivudine after administration of lamivudine to patients over 65 years of age have not been studied [see Use in Specific Populations (8.5)].Gender: There are no significant gender differences in lamivudine pharmacokinetics.Race: There are no significant racial differences in lamivudine pharmacokinetics.Drug Interactions: Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in study of 19 healthy male subjects [see Warnings and Precautions (5.4)]. 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 coinfected patients [see Warnings and Precautions (5.4)].Trimethoprim/Sulfamethoxazole: Lamivudine and TMP/SMX were coadministered to 14 HIV-1-positive patients in single-center, open-label, randomized, crossover study. Each patient received treatment with single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once day for days with concomitant administration of lamivudine 300 mg with the fifth dose in crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% +- 23% (mean +- SD) in lamivudine AUC, decrease of 29% +- 13% in lamivudine oral clearance, and decrease of 30% +- 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine [see Drug Interactions (7.3)].Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg 12 hr) [see Drug Interactions (7.4)].. 12.4 Microbiology. Mechanism of Action: Intracellularly, lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is weak inhibitor of mammalian DNA polymerases , and Antiviral Activity: The antiviral activity of lamivudine against HIV-1 was assessed in number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC50 values (50% effective concentrations) were in the range of 0.003 to 15 uM (1 uM 0.23 mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.429 uM (range: 0.200 to 2.007 uM) from Virco (n 92 baseline samples from COLA40263) and 2.35 uM (1.37 to 3.68 uM) from Monogram Biosciences (n 135 baseline samples from ESS30009). The EC50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 uM, and against HIV-2 isolates from 0.003 to 0.120 uM in peripheral blood mononuclear cells. Ribavirin (50 uM) decreased the anti-HIV-1 activity of lamivudine by 3.5 fold in MT-4 cells. In HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity. Please see the full prescribing information for Epivir-HBV for information regarding the inhibitory activity of lamivudine against HBV.Resistance: Lamivudine-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis 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 isoleucine or valine (M184V/I).HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients.Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.Lamivudine-resistant HBV isolates develop substitutions (rtM204V/I) in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory mutations improving replication efficiency. Other substitutions detected in lamivudine-resistant HBV isolates include: rtL80I and rtA181T. Similar HBV mutants have been reported in HIV-1- infected patients who received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis virus [see Warnings and Precautions (5.2)].Cross-Resistance: Lamivudine-resistant HIV-1 mutants were cross-resistant to didanosine (ddI) and zalcitabine (ddC). In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged.Genotypic and Phenotypic Analysis of On-Therapy HIV-1 Isolates From Patients With Virologic Failure: Study EPV20001: Fifty-three of 554 (10%) patients enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level >=400 copies/mL) by Week 48. Twenty-eight patients were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-1 RNA levels of patients in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log10 copies/mL and 4.6 log10 copies/mL, respectively.Genotypic analysis of on-therapy isolates from 22 patients identified as virologic failures in the lamivudine once-daily group showed that isolates from 0/22 patients contained treatment-emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), isolates from 10/22 patients contained treatment-emergent amino acid substitutions associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C), and isolates from 8/22 patients contained treatment-emergent lamivudine resistance-associated substitution (M184I or M184V).Genotypic analysis of on-therapy isolates from patients (n 22) in the lamivudine twice-daily treatment group showed that isolates from 1/22 patients contained treatment-emergent zidovudine resistance substitutions, isolates from 7/22 contained treatment-emergent efavirenz resistance substitutions, and isolates from 5/22 contained treatment-emergent lamivudine resistance substitutions.Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n 13) receiving lamivudine once daily showed that isolates from 12/13 patients were susceptible to zidovudine; isolates from 8/13 patients exhibited 25- to 295-fold decrease in susceptibility to efavirenz, and isolates from 7/13 patients showed an 85- to 299-fold decrease in susceptibility to lamivudine.Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n 13) receiving lamivudine twice daily showed that isolates from all 13 patients were susceptible to zidovudine; isolates from 3/13 patients exhibited 21- to 342-fold decrease in susceptibility to efavirenz, and isolates from 4/13 patients exhibited 29- to 159-fold decrease in susceptibility to lamivudine.Study EPV40001: Fifty patients received zidovudine 300 mg twice daily plus abacavir 300 mg twice daily plus lamivudine 300 mg once daily and 50 patients received zidovudine 300 mg plus abacavir 300 mg plus lamivudine 150 mg all twice daily. The median baseline plasma HIV-1 RNA levels for patients in the groups were 4.79 log10 copies/mL and 4.83 log10 copies/mL, respectively. Fourteen of 50 patients in the lamivudine once-daily treatment group and of 50 patients in the lamivudine twice-daily group were identified as virologic failures.Genotypic analysis of on-therapy HIV-1 isolates from patients (n 9) in the lamivudine once-daily treatment group showed that isolates from patients had an abacavir and/or lamivudine resistance-associated substitution M184V alone. On-therapy isolates from patients (n 6) receiving lamivudine twice daily showed that isolates from patients had M184V alone, and isolates from patients harbored the M184V substitution in combination with zidovudine resistance-associated amino acid substitutions.Phenotypic analysis of on-therapy isolates from patients (n 6) receiving lamivudine once daily showed that HIV-1 isolates from patients exhibited 32- to 53-fold decrease in susceptibility to lamivudine.HIV-1 isolates from these patients were susceptible to zidovudine.Phenotypic analysis of on-therapy isolates from patients (n 4) receiving lamivudine twice daily showed that HIV-1 isolates from patient exhibited 45-fold decrease in susceptibility to lamivudine and 4.5-fold decrease in susceptibility to zidovudine.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The use of Lamivudine is based on the results of clinical studies in HIV-1-infected patients in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to combination regimen in controlled trials.. Figure 2. Virologic Response Through Week 48, EPV20001 (Intent-to-Treat). 14.1 Adults. Clinical Endpoint Study: NUCB3007 (CAESAR) was multi-center, double-blind, placebo-controlled study comparing continued current therapy (zidovudine alone [62% of patients] or zidovudine with didanosine or zalcitabine [38% of patients]) to the addition of lamivudine or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells/mm (median 122 cells/mm 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 study was 12 months. Results are summarized in Table 7.Table 7. Number of Patients (%) With at Least One HIV-1 Disease Progression Event or DeathEndpointCurrent Therapy (n=460)Lamivudine plus Current Therapy (n=896)Lamivudine plus an NNRTIa plus Current Therapy (n=460)HIV-1 progression or death90 (19.6%)86 (9.6%)41 (8.9%)Death27 (5.9%)23 (2.6%)14 (3.0%)a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.Surrogate Endpoint Studies: Dual Nucleoside Analogue Studies: Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These studies demonstrated the antiviral effect of lamivudine in 2-drug combination. More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least antiretroviral drugs for enhanced viral suppression.Dose Regimen Comparison Surrogate Endpoint Studies in Therapy-Naive Adults: EPV20001 was multi-center, double-blind, controlled study in which patients were randomized 1:1 to receive Lamivudine 300 mg once daily or Lamivudine 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm3 (median 362 cells/mm3 ), and median baseline plasma HIV-1 RNA of 4.66 log10 copies/mL. Outcomes of treatment through 48 weeks are summarized in Figure and Table 8.Figure 2. Virologic Response Through Week 48, EPV20001 (Intent-to-Treat)a Roche AMPLICOR HIV-1 MONITOR.b Responders at each visit are patients who had achieved and maintained HIV-1 RNA less than 400 copies/mL without discontinuation by that visit.Table 8. Outcomes of Randomized Treatment Through 48 Weeks (Intent-to-Treat)OutcomeLamivudine 300mgOnce Dailyplus Zidovudineplus Efavirenz(n 278)Lamivudine 150mgTwice Dailyplus Zidovudineplus Efavirenz(n 276)Respondera Virologic failureb Discontinued due to clinicalprogressionDiscontinued due to adverse eventsDiscontinued due to other reasonsc 67%8%less than 1%6%18%65%8%0%12%14%a Achieved confirmed plasma HIV-1 RNA less than 400 copies/mL and maintained through 48 weeks.b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48.c Includes consent withdrawn, lost to follow-up, protocol violation, data outside the study-defined schedule, and randomized but never initiated treatment.The proportions of patients with HIV-1 RNA less than 50 copies/mL (via Roche Ultrasensitive assay) through Week 48 were 61% for patients receiving Lamivudine 300 mg once daily and 63% for patients receiving Lamivudine 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells/mm3 at Week 48 in patients receiving Lamivudine 300 mg once daily and 146 cells/mm3 for patients receiving Lamivudine 150 mg twice daily. small, randomized, open-label pilot study, EPV40001, was conducted in Thailand. total of 159 treatment-naive adult patients (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm3, median plasma HIV-1 RNA 4.8 log10 copies/mL) were enrolled. Two of the treatment arms in this study provided comparison between lamivudine 300 mg once daily (n 54) and lamivudine 150 mg twice daily (n 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily. In intent-to-treat analyses of 48-week data, the proportions of patients with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75% (39/52) in the group randomized to receive all drugs twice daily; the proportions with HIV-1 RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells/mm3 in the once-daily lamivudine group and 216 cells/mm3 in the all-twice-daily group.. 14.2 Pediatric Patients. Clinical Endpoint Study: ACTG300 was multi-center, randomized, double-blind study that provided for comparison of Lamivudine plus Zidovudine with didanosine monotherapy. total of 471 symptomatic, HIV-1-infected therapy-naive (<=56 days of antiretroviral therapy) pediatric patients were enrolled in these treatment arms. The median age was 2.7 years (range: weeks to 14 years), 58% were female, and 86% were non-Caucasian. The mean baseline CD4+ cell count was 868 cells/mm3 (mean: 1,060 cells/mm3 and range: to 4,650 cells/mm3 for patients <=5 years of age; mean: 419 cells/mm3 and range: to 1,555 cells/mm3 for patients >5 years of age) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration on study was 10.1 months for the patients receiving Lamivudine plus Zidovudine and 9.2 months for patients receiving didanosine monotherapy. Results are summarized in Table 9. Table 9. Number of Patients (%) Reaching Primary Clinical Endpoint (Disease Progression or DeathEndpointLamivudine plus Zidovudine (n=236)Didanosine (n=235)HIV-1 disease progression or death (total)Physical growth failureCentral nervous system deteriorationCDC Clinical Category CDeath15 (6.4%)7 (3.0%)4 (1.7%)2 (0.8%)2 (0.8%)37 (15.7%)6 (2.6%)12 (5.1%)8 (3.4%)11 (4.7%).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetics in Adults: The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult patients after administration of single intravenous (IV) doses ranging from 0.25 to mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg.The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from mg to 600 mg/day administered to HBV-infected patients.The steady-state pharmacokinetic properties of the Lamivudine 300-mg tablet once daily for days compared with the Lamivudine 150-mg tablet twice daily for days were assessed in crossover study in 60 healthy volunteers. Lamivudine 300 mg once daily resulted in lamivudine exposures that were similar to Lamivudine 150 mg twice daily with respect to plasma AUC24,ss however, Cmax,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen.Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.Absorption and Bioavailability: Lamivudine was rapidly absorbed after oral administration in HIV-1- infected patients. Absolute bioavailability in 12 adult patients was 86% +-16% (mean +-SD) for the 150- mg tablet and 87% +-13% for the oral solution. After oral administration of mg/kg twice day to adults with HIV-1, the peak serum lamivudine concentration (Cmax) was 1.5 +- 0.5 mcg/mL (mean +- SD).The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kgThe accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of mg/kg twice daily.Effects of Food on Oral Absorption: An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected patients on occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax 3.2 +- 1.3 hours) compared with the fasted state (Tmax 0.9 +- 0.3 hours); Cmax in the fed state was 40% +- 23% (mean +- SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC) in the fed and fasted states; therefore, Lamivudine Oral Solution may be administered with or without food.Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 patients was 1.3 +- 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.Binding of lamivudine to human plasma proteins is low (less than 36%). In vitro studies showed that over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.Metabolism: Metabolism of lamivudine is minor route of elimination. In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within 12 hours after single oral dose of lamivudine in HIV-1-infected adults, 5.2% +- 1.4% (mean +- SD) of the dose was excreted as the transsulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.Elimination: The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In healthy subjects given single 300-mg oral dose of lamivudine, renal clearance was 199.7 +- 56.9 mL/min (mean +- SD). In 20 HIV-1-infected patients given single IV dose, renal clearance was 280.4 +- 75.2 mL/min (mean +- SD), representing 71% +- 16% (mean +- SD) of total clearance of lamivudine.In most single-dose studies in HIV-1-infected patients, HBV-infected patients, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t1/2) ranged from to hours. In HIV-1-infected patients, total clearance was 398.5 +- 69.1 mL/min (mean +- SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg/kg.Special Populations: Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in small group of HIV-1-infected adults with impaired renal function (Table 6).Table 6. Pharmacokinetic Parameters (Mean +- SD) After Single 300-mg Oral Dose of Lamivudine in Groups of Adults With Varying Degrees of Renal FunctionParameterCreatinine Clearance Criterion (Number of Subjects)>60 mL/min (n=6)10-30 mL/min (n=4)<10 mL/min (n=6)Creatinine clearance (mL/min) Cmax (mcg/mL) AUC (mcgohr/mL) Cl/F (mL/min)111 +- 14 2.6 +- 0.5 11.0 +- 1.7 464 +- 76 28 +- 3.6 +- 0.8 48.0 +- 19 114 +- 34 +- 5.8 +- 1.2 157 +- 74 36 +- 11 Exposure (AUC), Cmax, and half-life increased with diminishing renal function (as expressed by creatinine clearance). Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment [see Dosage and Administration (2.3)].Based on study in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis.The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.Hepatic Impairment: The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.Pediatric Patients: In Study NUCA2002, pharmacokinetic properties of lamivudine were assessed in subset of 57 HIV-1-infected pediatric patients (age range: 4.8 months to 16 years, weight range: to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg/day. In the infants and children (range: months to 12 years of age) receiving oral solution mg/kg twice daily (the usual recommended pediatric dose), absolute bioavailability was 66% +- 26% (mean +- SD), which was less than the 86% +- 16% (mean +- SD) observed in adults. The mechanism for the diminished absolute bioavailability of lamivudine in infants and children is unknown.Systemic clearance decreased with increasing age in pediatric patients, as shown in Figure 1. Figure 1. Systemic Clearance (L/hrokg) of Lamivudine in Relation to After oral administration of lamivudine mg/kg twice daily to 11 pediatric patients ranging from months to 14 years of age, Cmax was 1.1 +- 0.6 mcg/mL and half-life was 2.0 +- 0.6 hours. (In adults with similar blood sampling, the half-life was 3.7 +- hours.) Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric patients receiving an 8-mg/kg/day dose and adults receiving 4-mg/kg/day dose.Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric patients after multiple oral dosing with lamivudine. CSF samples were collected between and hours postdose. At the dose of mg/kg/day, CSF lamivudine concentrations in patients ranged from 5.6% to 30.9% (mean +- SD of 14.2% +- 7.9%) of the concentration in simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL.Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants up to week of age in studies in South Africa. In these studies, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric patients (>3 months of age) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old [see Adverse Reactions (6.1)].Geriatric Patients: The pharmacokinetics of lamivudine after administration of lamivudine to patients over 65 years of age have not been studied [see Use in Specific Populations (8.5)].Gender: There are no significant gender differences in lamivudine pharmacokinetics.Race: There are no significant racial differences in lamivudine pharmacokinetics.Drug Interactions: Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in study of 19 healthy male subjects [see Warnings and Precautions (5.4)]. 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 coinfected patients [see Warnings and Precautions (5.4)].Trimethoprim/Sulfamethoxazole: Lamivudine and TMP/SMX were coadministered to 14 HIV-1-positive patients in single-center, open-label, randomized, crossover study. Each patient received treatment with single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once day for days with concomitant administration of lamivudine 300 mg with the fifth dose in crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% +- 23% (mean +- SD) in lamivudine AUC, decrease of 29% +- 13% in lamivudine oral clearance, and decrease of 30% +- 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine [see Drug Interactions (7.3)].Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg 12 hr) [see Drug Interactions (7.4)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Physicians are encouraged to register patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263. (8.1)(8). 8.1 Pregnancy. Teratogenic Effects Pregnancy Category C. There are no adequate and well-controlled studies of lamivudine in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity.Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans.Lamivudine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Lamivudine pharmacokinetics were studied in pregnant women during clinical studies conducted in South Africa. The study 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 studies were not designed or powered to provide efficacy information. 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. In subset of subjects, lamivudine amniotic fluid specimens were collected following natural rupture of membranes. Amniotic fluid concentrations of lamivudine were typically times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily). It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients.Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus [see Nonclinical Toxicology (13.2)].Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.. 8.3 Nursing Mothers. The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for serious adverse reactions in nursing infants and HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving lamivudine.Lamivudine is excreted into human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.. 8.4 Pediatric Use. The safety and effectiveness of twice-daily Lamivudine in combination with other antiretroviral agents have been established in pediatric patients months and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].. 8.5 Geriatric Use. Clinical studies of lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].. 8.6 Patients With Impaired Renal Function. Reduction of the dosage of lamivudine is recommended for patients with impaired renal function [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. (5) Lactic acidosis and severe hepatomegaly with steatosis: Reported with the use of nucleoside analogues. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatoxicity occur. (5.1) Severe acute exacerbations of hepatitis: Reported in patients who are co-infected with hepatitis virus and HIV-1 and discontinued lamivudine. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis treatment. (5.2) Patients with HIV-1 infection should receive only dosage forms of lamivudine appropriate for treatment of HIV-1. (5.2) Co-infected HIV-1/HBV Patients: Emergence of lamivudine-resistant HBV variants associated with lamivudine- containing antiretroviral regimens has been reported. (5.2) Emtricitabine should not be administered concomitantly with lamivudine-containing products. (5.3) Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving interferon and ribavirin based regimens. Monitor for treatment-associated toxicities. Discontinue lamivudine as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.4) Pancreatitis: Use with caution in pediatric patients with history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.5) Immune reconstitution syndrome (5.6) and redistribution/accumulation of body fat (5.7) have been reported in patients treated with combination antiretroviral therapy. Lactic acidosis and severe hepatomegaly with steatosis: Reported with the use of nucleoside analogues. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatoxicity occur. (5.1) Severe acute exacerbations of hepatitis: Reported in patients who are co-infected with hepatitis virus and HIV-1 and discontinued lamivudine. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis treatment. (5.2) Patients with HIV-1 infection should receive only dosage forms of lamivudine appropriate for treatment of HIV-1. (5.2) Co-infected HIV-1/HBV Patients: Emergence of lamivudine-resistant HBV variants associated with lamivudine- containing antiretroviral regimens has been reported. (5.2) Emtricitabine should not be administered concomitantly with lamivudine-containing products. (5.3) Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving interferon and ribavirin based regimens. Monitor for treatment-associated toxicities. Discontinue lamivudine as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.4) Pancreatitis: Use with caution in pediatric patients with history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.5) Immune reconstitution syndrome (5.6) and redistribution/accumulation of body fat (5.7) have been reported in patients treated with combination antiretroviral therapy. 5.1 Lactic Acidosis/Severe Hepatomegaly With Steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering lamivudine to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. Treatment with lamivudine 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).. 5.2 Patients With HIV-1 and Hepatitis Virus Co-infection. Posttreatment Exacerbations of Hepatitis: In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The casual relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis. Important Differences Among Lamivudine-Containing Products: Lamivudine Oral Solution contains higher dose of the same active ingredient (lamivudine) than in EPIVIR-HBV Oral Solution. EPIVIRHBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in EPIVIR-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis in patients co-infected with HIV-1 and HBV. If treatment with EPIVIR-HBV is prescribed for chronic hepatitis for patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIVo1 treatment. If decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, lamivudine tablets, lamivudine oral solution, COMBIVIR(R) (lamivudine/zidovudine) Tablets, EPZICOM(R) (abacavir sulfate and lamivudine) Tablets or TRIZIVIR(R) (abacavir sulfate, lamivudine and zidovudine) Tablets should be used as part of an appropriate combination regimen.Emergence of Lamivudine-Resistant HBV: In non-HIV-1-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response(see full prescribing information for EPIVIR-HBV for additional information). Emergence of hepatitis virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis virus.. 5.3 Use With Other Lamivudine- and Emtricitabine-Containing Products. Lamivudine Oral Solution should not be administered concomitantly with other lamivudine-containing products including EPIVIR(R)-HBV Tablets, EPIVIR(R) Oral Solution, COMBIVIR(R) (lamivudine/zidovudine) Tablets, EPZICOM(R) (abacavir sulfate and lamivudine) Tablets, or TRIZIVIR(R) (abacavir sulfate, lamivudine, and zidovudine) or emtricitabine-containing products, including ATRIPLA(R) (efavirenz, emtricitabine, and tenofovir), EMTRIVA(R) (emtricitabine), TRUVADA(R) (emtricitabine and tenofovir) or COMPLERA(R) (rilpivirine/emtricitabine/tenofovir).. 5.4 Use With Interferon- and Ribavirin-Based Regimens. In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of pharmacokinetic or pharmacodynamics interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3)], 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. Patients receiving interferon alfa with or without ribavirin and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine 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 >6). See the complete prescribing information for interferon and ribavirin.. 5.5 Pancreatitis. In pediatric patients with history of prior antiretroviral nucleoside exposure, history of pancreatitis, or other significant risk factors for the development of pancreatitis, lamivudine should be used with caution. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)].. 5.6 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds 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.. 5.7 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. causal relationship has not been established.