PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetics in Adults The pharmacokinetic properties of lamivudine have been studied as single and multiple oral doses ranging from mg to 600 mg per day administered to HBV-infected subjects.Absorption and Bioavailability: Following single oral doses of 100 mg, the peak serum lamivudine concentration (Cmax) in HBV-infected patients (steady state) and healthy subjects (single dose) was 1.28 +- 0.56 mcg per mL and 1.05 +- 0.32 mcg per mL (mean +- SD), respectively, which occurred between 0.5 and hours after administration. The area under the plasma concentration versus time curve (AUC[0 to 24h]) following 100-mg lamivudine oral single and repeated daily doses to steady state was 4.3 +- 1.4 (mean +- SD) and 4.7 +- 1.7 mcgohour per mL, respectively. The relative bioavailability of the tablet and oral solution were demonstrated in healthy subjects. Although the solution demonstrated slightly higher peak serum concentration (Cmax), there was no significant difference in systemic exposure (AUC) between the oral solution and the tablet. Therefore, the oral solution and the tablet may be used interchangeably. After oral administration of lamivudine once daily to HBV-infected adults, the AUC and Cmax increased in proportion to dose over the range from mg to 600 mg once daily. Absolute bioavailability in 12 adult subjects was 86% +- 16% (mean +- SD) for the 150-mg tablet and 87% +- 13% for the 10-mg-per mL oral solution. Effects of Food on Oral Absorption: Lamivudine tablets (HBV) may be administered with or without food. The 100-mg tablet was administered orally to 24 healthy subjects on occasions, once in the fasted state and once with food (standard meal: 967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There was no significant difference in systemic exposure (AUC) in the fed and fasted states. Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 HIV-1-infected subjects was 1.3 +- 0.4 per 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 less than 36%. In vitro studies showed that over the concentration range of 0.1 to 100 mcg per 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 humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). Serum concentrations of this metabolite have not been determined. Lamivudine is not significantly metabolized by cytochrome P450 enzymes. 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 per min (mean +- SD). In 20 HIV-1-infected subjects given single IV dose, renal clearance was 280.4 +- 75.2 mL per min (mean +- SD), representing 71% +- 16% (mean +- SD) of total clearance of lamivudine. In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, 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 subjects, total clearance was 398.5 +- 69.1 mL per 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 per kg. Specific Populations Patients with Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in healthy adults and in adults with impaired renal function, with and without hemodialysis (Table 5). Table 5. Pharmacokinetic Parameters (Mean +- SD) Dose-Normalized to Single 100-mg Oral Dose of Lamivudine in Adults with Varying Degrees of Renal Function Parameter Creatinine Clearance Criterion(Number of Subjects) >=80 mL/min (n 9)20-59 mL/min(n 8)<20 mL/min(n 6)Creatinine clearance (mL/min) 97(range 82-117) 39(range 25-49) 15(range 13-19) Cmax (mcg/mL) 1.31 +- 0.35 1.85 +- 0.40 1.55 +- 0.31 AUC (mcgoh/mL) 5.28 +- 1.01 14.67 +- 3.74 27.33 +- 6.56 Cl/F (mL/min) 326.4 +- 63.8 120.1 +- 29.5 64.5 +- 18.3 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 (2.4)]. Hemodialysis increases lamivudine clearance from mean of 64 to 88 mL per 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. The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients with chronic hepatitis is not known. Patients with Hepatic Impairment: The pharmacokinetic properties of lamivudine in adults with hepatic impairment are shown in Table 6. Subjects were stratified by severity of hepatic impairment. Table 6. Pharmacokinetic Parameters (Mean +- SD) Dose-Normalized to Single 100-mg Dose of Lamivudine in Adults with Normal or Impaired Hepatic Function Parameter Normal (n 8) Impairmenta Moderate (n 8)Severe (n 8)Cmax (mcg/mL) 0.92 +- 0.31 1.06 +- 0.58 1.08 +- 0.27 AUC (mcgoh/mL) 3.96 +- 0.58 3.97 +- 1.36 4.30 +- 0.63 Tmax (h) 1.3 +- 0.8 1.4 +- 0.8 1.4 +- 1.2 Cl/F (mL/min) 424.7 +- 61.9 456.9 +- 129.8 395.2 +- 51.8 Clr (mL/min) 279.2 +- 79.2 323.5 +- 100.9 216.1 +- 58.0 Hepatic impairment assessed by aminopyrine breath test. Pharmacokinetic parameters were not altered by diminishing hepatic impairment. Safety and efficacy of lamivudine tablets (HBV) have not been established in the presence of decompensated liver disease [see Indications and Usage (1)]. Patients Post-Hepatic Transplant: Fourteen HBV-infected adult subjects received liver transplant following lamivudine therapy and completed pharmacokinetic assessments at enrollment, weeks after 100-mg once-daily dosing (pre-transplant), and months following transplant; there were no significant differences in pharmacokinetic parameters. The overall exposure of lamivudine is primarily affected by renal impairment; consequently, transplant patients with renal impairment had generally higher exposure than patients with normal renal function. Safety and efficacy of lamivudine tablets (HBV) have not been established in this population [see Indications and Usage (1)]. Pregnant Women: The pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in healthy volunteers were similar at similar doses. Lamivudine pharmacokinetics were studied in 36 pregnant women with HIV during clinical trials conducted in South Africa (3 to times the recommended daily dosage for HBV). 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. Pediatric Patients: Lamivudine pharmacokinetics were evaluated in 28-day dose-ranging trial in 53 pediatric subjects with chronic hepatitis B. Subjects aged to 12 years were randomized to receive lamivudine 0.35 mg per kg twice daily, mg per kg once daily, 1.5 mg per kg twice daily, or mg per kg twice daily. Subjects aged 13 to 17 years received lamivudine 100 mg once daily. Lamivudine Tmax was 0.5 to hour. In general, both Cmax and exposure (AUC) showed dose proportionality in the dosing range studied. Weight-corrected oral clearance was highest at age and declined from to 12 years, where values were then similar to those seen in adults. dose of mg per kg given once daily produced steady-state lamivudine AUC (mean 5,953 ngohour per mL +- 1,562 SD) similar to that associated with dose of 100 mg per day in adults. Geriatric Patients: The pharmacokinetics of lamivudine after administration of lamivudine tablets (HBV) to subjects over 65 years have not been studied [see Use in Specific Populations (8.5)]. Male and Female Patients: There are no significant or clinically relevant gender differences in lamivudine pharmacokinetics. Racial Groups: There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics. Drug Interaction Studies Effect of Lamivudine on the Pharmacokinetics of Other Agents: Based on in vitro study results, lamivudine at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein (MATE1), MATE2-K, organic cation transporter (OCT1), OCT2, or OCT3. Effect of Other Agents on the Pharmacokinetics of Lamivudine: Lamivudine is substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant, and no dose adjustment of lamivudine is needed. Lamivudine is substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine. 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 to 24), 14%, 32%, and 36% in the AUC(), and 28%, 52%, and 55% in the Cmax of lamivudine. Trimethoprim/Sulfamethoxazole: Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-1-positive subjects in single-center, open-label, randomized, crossover trial. Each subject 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. 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).

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine 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 substantial difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects of 2.7% reported in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The APR uses the MACDP as 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 occur at less than 20 weeks gestation. Of over 11,000 women exposed to lamivudine in the APR, less than 1% were treated for HBV. The majority of women exposed to lamivudine in the APR were HIV-1-infected and were treated with higher doses of lamivudine compared with HBV mono-infected women. In addition to lamivudine, HIV-1-infected women were also treated with other concomitant medications for HIV-1 infection (see Data). The estimated rate of miscarriage for women exposed to lamivudine in the indicated population is unknown. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. 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 developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 60 times the recommended clinical dose (see Data). Data Human Data: Based on prospective reports from the APR of over 11,000 exposures to lamivudine (including over 4,600 exposed in the first trimester) during pregnancy resulting in live births, less than 1% of which were patients with HBV, there was no substantial difference in birth defects with lamivudine compared with the birth defect rate of 2.7% observed in the comparator 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. The pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in healthy volunteers are similar at similar doses. Lamivudine pharmacokinetics were studied in pregnant women with HIV-1 infection during clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg lamivudine twice daily (3 times the recommended daily dosage for HBV) with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily (3 times the recommended daily dosage for HBV) with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily (6 times the recommended daily dosage for HBV) without other antiretrovirals. 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 concentrations (n 8). Animal Data: 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 53 or more times higher than human exposure at the recommended daily dose. Evidence of early embryolethality in the absence of maternal toxicity was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 60 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 at plasma concentrations (Cmax) 104 times higher than human exposure.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine 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 substantial difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects of 2.7% reported in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The APR uses the MACDP as 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 occur at less than 20 weeks gestation. Of over 11,000 women exposed to lamivudine in the APR, less than 1% were treated for HBV. The majority of women exposed to lamivudine in the APR were HIV-1-infected and were treated with higher doses of lamivudine compared with HBV mono-infected women. In addition to lamivudine, HIV-1-infected women were also treated with other concomitant medications for HIV-1 infection (see Data). The estimated rate of miscarriage for women exposed to lamivudine in the indicated population is unknown. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. 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 developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 60 times the recommended clinical dose (see Data). Data Human Data: Based on prospective reports from the APR of over 11,000 exposures to lamivudine (including over 4,600 exposed in the first trimester) during pregnancy resulting in live births, less than 1% of which were patients with HBV, there was no substantial difference in birth defects with lamivudine compared with the birth defect rate of 2.7% observed in the comparator 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. The pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in healthy volunteers are similar at similar doses. Lamivudine pharmacokinetics were studied in pregnant women with HIV-1 infection during clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg lamivudine twice daily (3 times the recommended daily dosage for HBV) with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily (3 times the recommended daily dosage for HBV) with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily (6 times the recommended daily dosage for HBV) without other antiretrovirals. 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 concentrations (n 8). Animal Data: 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 53 or more times higher than human exposure at the recommended daily dose. Evidence of early embryolethality in the absence of maternal toxicity was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 60 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 at plasma concentrations (Cmax) 104 times higher than human exposure.. 8.2 Lactation. Risk Summary Lamivudine is present in human milk. There is no information available regarding lamivudine concentrations in milk from lactating women receiving lamivudine for treatment of HBV infection. However, in lactating women with HIV-1 infection being treated with lamivudine at or times the recommended daily dose for HBV, lamivudine concentrations in milk were similar to those observed in serum (see Data). The lamivudine dose received by breastfed infant of mother being treated for HIV-1 infection was estimated to be approximately 6% of the recommended daily lamivudine dose for HBV in children over years of age. There is no information available regarding the effects of the drug on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for lamivudine tablets (HBV) and any potential adverse effects on the breastfed infant from lamivudine or from the underlying maternal condition. Data In mothers with HIV receiving lamivudine monotherapy (300 mg twice daily [6 times the recommended daily dosage for HBV]) or combination therapy (150 mg lamivudine twice daily [3 times the recommended daily dosage for HBV] with 300 mg zidovudine twice daily), the median breast milk to plasma lamivudine concentration ratio was 0.6 to 3.3, and the estimated infant daily dose was approximately 6% of the recommended 3-mg-per-kg daily lamivudine dose for treatment of HBV in children over years of age. In breastfed infants of mothers with HIV-1 infection receiving lamivudine therapy, the blood concentrations of lamivudine decreased after delivery and were undetectable at months despite constant milk concentrations. This is consistent with increased lamivudine renal clearance in the first months of life.. 8.4 Pediatric Use. Lamivudine tablets (HBV) is indicated for the treatment of chronic hepatitis virus infection in pediatric patients aged to 17 years [see Indications and Usage (1), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. The safety and efficacy of lamivudine tablets (HBV) in pediatric patients younger than years have not been established.. 8.5 Geriatric Use. Clinical trials of lamivudine tablets (HBV) 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 tablets (HBV) in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. 8.6 Patients with Impaired Renal Function. Reduction of the dosage of lamivudine tablets (HBV) is recommended for patients with impaired renal function [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. 8.7 Patients with Impaired Liver Function. No dose adjustment for lamivudine is required for patients with impaired hepatic function.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Emergence of Resistance-Associated HBV Substitutions: Consider switch to an alternative regimen if serum HBV DNA remains detectable after 24 weeks of treatment. (2.6,5.3) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. (5.4). 5.1 Exacerbations of Hepatitis after Discontinuation of Treatment. Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA commonly observed after stopping treatment; see Table for more information regarding frequency of posttreatment ALT elevations [see Adverse Reactions (6.1)]. Although most events appear to have been self-limited, fatalities have been reported in some cases. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with lamivudine tablets (HBV). There is insufficient evidence to determine whether re-initiation of lamivudine tablets (HBV) alters the course of posttreatment exacerbations of hepatitis.. 5.2 Risk of HIV-1 Resistance if Lamivudine Tablets (HBV) is Used in Patients with Unrecognized or Untreated HIV-1 Infection. Lamivudine tablets (HBV) contain lower lamivudine dose than the lamivudine dose used to treat HIV-1 infection with lamivudine tablets and oral solution or with lamivudine-containing antiretroviral fixed-dose combination products. Lamivudine tablets (HBV) is not appropriate for patients co-infected with HBV and HIV-1. If patient with unrecognized or untreated HIV-1 infection is prescribed lamivudine tablets (HBV) for the treatment of HBV, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriate use of monotherapy for HIV-1 treatment. HIV counseling and testing should be offered to all patients before beginning treatment with lamivudine tablets (HBV) and periodically during treatment because of the risk of rapid emergence of resistant HIV-1 and limitation of treatment options if lamivudine tablets (HBV) is prescribed to treat chronic hepatitis in patient who has unrecognized or untreated HIV-1 infection or who acquires HIV-1 infection during treatment.. 5.3 Emergence of Resistance-Associated HBV Substitutions. In controlled clinical trials, YMDD-mutant HBV was detected in subjects with on- lamivudine tablets (HBV) re-appearance of HBV DNA after an initial decline below the assay limit [see Microbiology (12.4)]. Subjects treated with lamivudine tablets (HBV) (adults and children) with YMDD-mutant HBV at 52 weeks showed diminished treatment responses in comparison with subjects treated with lamivudine tablets (HBV) without evidence of YMDD substitutions, including the following: lower rates of HBeAg seroconversion and HBeAg loss (no greater than placebo recipients), more frequent return of positive HBV DNA, and more frequent ALT elevations. In the controlled trials, when subjects developed YMDD-mutant HBV, they had rise in HBV DNA and ALT from their previous on-treatment levels. Progression of hepatitis B, including death, has been reported in some subjects with YMDD-mutant HBV, including subjects from the liver transplant setting and from other clinical trials. In order to reduce the risk of resistance in patients receiving monotherapy with lamivudine tablets (HBV), switch to an alternative regimen should be considered if serum HBV DNA remains detectable after 24 weeks of treatment. Optimal therapy should be guided by resistance testing.. 5.4 Lactic Acidosis and Severe Hepatomegaly with Steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine tablets (HBV). majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Most of these reports have described patients receiving nucleoside analogues for treatment of HIV infection, but there have been reports of lactic acidosis in patients receiving lamivudine for hepatitis B. Treatment with lamivudine tablets (HBV) should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling: Exacerbations of hepatitis after discontinuation of treatment [see Warnings and Precautions (5.1)]. Risk of emergence of resistant HIV-1 infection [see Warnings and Precautions (5.2)]. Risk of emergence of resistant HBV infection [see Warnings and Precautions (5.3)]. Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.4)]. The most common reported adverse reactions in those receiving lamivudine tablets (HBV) (incidence greater than or equal to 10% and reported at rate greater than placebo) were ear, nose, and throat infections; sore throat; and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials Experience in Adult Subjects with Chronic HBV Infection Clinical adverse reactions (regardless of investigators causality assessment) reported in greater than or equal to 10% of subjects who received lamivudine tablets (HBV) and reported at rate greater than in subjects who received placebo are listed in Table 2. Table 2. Clinical Adverse Reactionsa Reported in Greater than or Equal to 10% of Subjects Who Received Lamivudine Tablets (HBV) for 52 to 68 Weeks and at an Incidence Greater than Placebo (Trials to 3) Adverse EventLamivudine Tablets (HBV) (n 332)Placebo (n 200)Ear, Nose, and Throat Ear, nose, and throat infections 25% 21% Sore throat 13% 8% Gastrointestinal Diarrhea 14% 12% aIncludes adverse events regardless of severity and causality assessment. Specified laboratory abnormalities reported in subjects who received lamivudine tablets (HBV) and reported at rate greater than in subjects who received placebo are listed in Table 3. Table 3. Frequencies of Specified Laboratory Abnormalities Reported during Treatment at Greater Frequency in Subjects Treated with Lamivudine Tablets (HBV) than with Placebo (Trials to 3)a Test (Abnormal Level)Subjects with Abnormality/Subjects with ObservationsLamivudine Tablets (HBV)PlaceboSerum Lipase >=2.5 ULNb 10% 7% CPK >=7 baseline 9% 5% Platelets <50,000/mm3 4% 3% Includes subjects treated for 52 to 68 weeks. Includes observations during and after treatment in the placebo-controlled trials that collected this information. ULN Upper limit of normal. In subjects followed for up to 16 weeks after discontinuation of treatment, posttreatment ALT elevations were observed more frequently in subjects who had received lamivudine tablets (HBV) than in subjects who had received placebo. comparison of ALT elevations between Weeks 52 and 68 in subjects who discontinued lamivudine tablets (HBV) at Week 52 and subjects in the same trials who received placebo throughout the treatment course is shown in Table 4. Table 4. Posttreatment ALT Elevations with No-Active-Treatment Follow-up (Trials and 3) Abnormal Value Subjects with ALT Elevation/ Subjects with Observationsa Lamivudine Tablets (HBV)bPlacebobALT >=2 baseline value 27% 19% ALT >=3 baseline valuec 21% 8% ALT >=2 baseline value and absolute ALT >500 IU/L 15% 7% ALT >=2 baseline value; and bilirubin >2 ULN and >=2 baseline value 0.7% 0.9% Each subject may be represented in one or more category.b During treatment phase.c Comparable to Grade toxicity in accordance with modified WHO criteria. ULN Upper limit of normal. Clinical Trials Experience in Pediatric Subjects with Chronic HBV Infection Most commonly observed adverse reactions in the pediatric trials were similar to those in adult trials. Posttreatment transaminase elevations were observed in some subjects followed after cessation of lamivudine tablets (HBV).. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of lamivudine tablets (HBV). Because these reactions are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have been chosen for inclusion due to combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.Blood and Lymphatic Anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia. Digestive Stomatitis. Endocrine and Metabolic Hyperglycemia. General Weakness. Hepatic and Pancreatic Lactic acidosis and steatosis [see Warnings and Precautions (5.4)], posttreatment exacerbations of hepatitis [see Warnings and Precautions (5.1)], pancreatitis.Hypersensitivity Anaphylaxis, urticaria. Musculoskeletal Cramps, rhabdomyolysis. Nervous Paresthesia, peripheral neuropathy. Respiratory Abnormal breath sounds/wheezing. Skin Alopecia, pruritus, rash.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Lamivudine is an antiviral agent with activity against HBV [see Microbiology (12.4)]. 12.3 Pharmacokinetics. Pharmacokinetics in Adults The pharmacokinetic properties of lamivudine have been studied as single and multiple oral doses ranging from mg to 600 mg per day administered to HBV-infected subjects.Absorption and Bioavailability: Following single oral doses of 100 mg, the peak serum lamivudine concentration (Cmax) in HBV-infected patients (steady state) and healthy subjects (single dose) was 1.28 +- 0.56 mcg per mL and 1.05 +- 0.32 mcg per mL (mean +- SD), respectively, which occurred between 0.5 and hours after administration. The area under the plasma concentration versus time curve (AUC[0 to 24h]) following 100-mg lamivudine oral single and repeated daily doses to steady state was 4.3 +- 1.4 (mean +- SD) and 4.7 +- 1.7 mcgohour per mL, respectively. The relative bioavailability of the tablet and oral solution were demonstrated in healthy subjects. Although the solution demonstrated slightly higher peak serum concentration (Cmax), there was no significant difference in systemic exposure (AUC) between the oral solution and the tablet. Therefore, the oral solution and the tablet may be used interchangeably. After oral administration of lamivudine once daily to HBV-infected adults, the AUC and Cmax increased in proportion to dose over the range from mg to 600 mg once daily. Absolute bioavailability in 12 adult subjects was 86% +- 16% (mean +- SD) for the 150-mg tablet and 87% +- 13% for the 10-mg-per mL oral solution. Effects of Food on Oral Absorption: Lamivudine tablets (HBV) may be administered with or without food. The 100-mg tablet was administered orally to 24 healthy subjects on occasions, once in the fasted state and once with food (standard meal: 967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There was no significant difference in systemic exposure (AUC) in the fed and fasted states. Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 HIV-1-infected subjects was 1.3 +- 0.4 per 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 less than 36%. In vitro studies showed that over the concentration range of 0.1 to 100 mcg per 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 humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). Serum concentrations of this metabolite have not been determined. Lamivudine is not significantly metabolized by cytochrome P450 enzymes. 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 per min (mean +- SD). In 20 HIV-1-infected subjects given single IV dose, renal clearance was 280.4 +- 75.2 mL per min (mean +- SD), representing 71% +- 16% (mean +- SD) of total clearance of lamivudine. In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, 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 subjects, total clearance was 398.5 +- 69.1 mL per 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 per kg. Specific Populations Patients with Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in healthy adults and in adults with impaired renal function, with and without hemodialysis (Table 5). Table 5. Pharmacokinetic Parameters (Mean +- SD) Dose-Normalized to Single 100-mg Oral Dose of Lamivudine in Adults with Varying Degrees of Renal Function Parameter Creatinine Clearance Criterion(Number of Subjects) >=80 mL/min (n 9)20-59 mL/min(n 8)<20 mL/min(n 6)Creatinine clearance (mL/min) 97(range 82-117) 39(range 25-49) 15(range 13-19) Cmax (mcg/mL) 1.31 +- 0.35 1.85 +- 0.40 1.55 +- 0.31 AUC (mcgoh/mL) 5.28 +- 1.01 14.67 +- 3.74 27.33 +- 6.56 Cl/F (mL/min) 326.4 +- 63.8 120.1 +- 29.5 64.5 +- 18.3 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 (2.4)]. Hemodialysis increases lamivudine clearance from mean of 64 to 88 mL per 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. The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients with chronic hepatitis is not known. Patients with Hepatic Impairment: The pharmacokinetic properties of lamivudine in adults with hepatic impairment are shown in Table 6. Subjects were stratified by severity of hepatic impairment. Table 6. Pharmacokinetic Parameters (Mean +- SD) Dose-Normalized to Single 100-mg Dose of Lamivudine in Adults with Normal or Impaired Hepatic Function Parameter Normal (n 8) Impairmenta Moderate (n 8)Severe (n 8)Cmax (mcg/mL) 0.92 +- 0.31 1.06 +- 0.58 1.08 +- 0.27 AUC (mcgoh/mL) 3.96 +- 0.58 3.97 +- 1.36 4.30 +- 0.63 Tmax (h) 1.3 +- 0.8 1.4 +- 0.8 1.4 +- 1.2 Cl/F (mL/min) 424.7 +- 61.9 456.9 +- 129.8 395.2 +- 51.8 Clr (mL/min) 279.2 +- 79.2 323.5 +- 100.9 216.1 +- 58.0 Hepatic impairment assessed by aminopyrine breath test. Pharmacokinetic parameters were not altered by diminishing hepatic impairment. Safety and efficacy of lamivudine tablets (HBV) have not been established in the presence of decompensated liver disease [see Indications and Usage (1)]. Patients Post-Hepatic Transplant: Fourteen HBV-infected adult subjects received liver transplant following lamivudine therapy and completed pharmacokinetic assessments at enrollment, weeks after 100-mg once-daily dosing (pre-transplant), and months following transplant; there were no significant differences in pharmacokinetic parameters. The overall exposure of lamivudine is primarily affected by renal impairment; consequently, transplant patients with renal impairment had generally higher exposure than patients with normal renal function. Safety and efficacy of lamivudine tablets (HBV) have not been established in this population [see Indications and Usage (1)]. Pregnant Women: The pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in healthy volunteers were similar at similar doses. Lamivudine pharmacokinetics were studied in 36 pregnant women with HIV during clinical trials conducted in South Africa (3 to times the recommended daily dosage for HBV). 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. Pediatric Patients: Lamivudine pharmacokinetics were evaluated in 28-day dose-ranging trial in 53 pediatric subjects with chronic hepatitis B. Subjects aged to 12 years were randomized to receive lamivudine 0.35 mg per kg twice daily, mg per kg once daily, 1.5 mg per kg twice daily, or mg per kg twice daily. Subjects aged 13 to 17 years received lamivudine 100 mg once daily. Lamivudine Tmax was 0.5 to hour. In general, both Cmax and exposure (AUC) showed dose proportionality in the dosing range studied. Weight-corrected oral clearance was highest at age and declined from to 12 years, where values were then similar to those seen in adults. dose of mg per kg given once daily produced steady-state lamivudine AUC (mean 5,953 ngohour per mL +- 1,562 SD) similar to that associated with dose of 100 mg per day in adults. Geriatric Patients: The pharmacokinetics of lamivudine after administration of lamivudine tablets (HBV) to subjects over 65 years have not been studied [see Use in Specific Populations (8.5)]. Male and Female Patients: There are no significant or clinically relevant gender differences in lamivudine pharmacokinetics. Racial Groups: There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics. Drug Interaction Studies Effect of Lamivudine on the Pharmacokinetics of Other Agents: Based on in vitro study results, lamivudine at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein (MATE1), MATE2-K, organic cation transporter (OCT1), OCT2, or OCT3. Effect of Other Agents on the Pharmacokinetics of Lamivudine: Lamivudine is substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant, and no dose adjustment of lamivudine is needed. Lamivudine is substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine. 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 to 24), 14%, 32%, and 36% in the AUC(), and 28%, 52%, and 55% in the Cmax of lamivudine. Trimethoprim/Sulfamethoxazole: Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-1-positive subjects in single-center, open-label, randomized, crossover trial. Each subject 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. 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).. 12.4 Microbiology. Mechanism of Action 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 the RNA- and DNA- dependent polymerase activities of HBV reverse transcriptase (rt) via DNA chain termination after incorporation of the nucleotide analogue. Antiviral Activity Activity of lamivudine against HBV in cell culture was assessed in HBV DNA-transfected 2.2.15 cells, HB611 cells, and infected human primary hepatocytes. EC50 values (the concentration of drug needed to reduce the level of extracellular HBV DNA by 50%) varied from 0.01 microM (2.3 ng per mL) to 5.6 microM (1.3 mcg per mL) depending upon the duration of exposure of cells to lamivudine, the cell model system, and the protocol used. See the prescribing information for lamivudine regarding activity of lamivudine against HIV. The anti-HBV activity of lamivudine in combination with adefovir or tenofovir in cell culture was not antagonistic.Resistance Lamivudine-resistant isolates have been identified in subjects with virologic breakthrough. Lamivudine-resistant HBV isolates develop rtM204V/I substitutions 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 substitutions improving replication efficiency. Other substitutions reported in lamivudine-resistant HBV isolates include rtH55R, rtL80I/V, rtV173M, rtA181T/V, rtT184S, rtF219Y, rtL229F/M/V/W, and rtQ267H. In controlled clinical trials evaluating lamivudine tablets (HBV) in adults with HBeAg-positive chronic hepatitis virus infection (CHB), YMDD-mutant HBV was detected in 81 of 335 subjects receiving lamivudine tablets (HBV) 100 mg once daily for 52 weeks. The prevalence of YMDD substitutions was less than 10% in each of these trials for subjects studied at 24 weeks and increased to an average of 24% (range in trials: 16% to 32%) at 52 weeks. similar prevalence of YMDD substitutions has been reported in large controlled Phase clinical trials utilizing lamivudine tablets (HBV) as comparator arm in adults with HBeAg-positive CHB for 48 weeks (range in trials: 11% to 27%) and in adults with HBeAg-negative CHB for 48 weeks (range in clinical trials: 6% to 18%).Long-term follow up in subjects who continued 100 mg per day of lamivudine tablets (HBV) demonstrated that the prevalence of YMDD substitutions further increased from 23% (211 of 998) in Year 1, to 46% (368 of 796), 55% (378 of 688), 71% (421 of 592), and 65% (103 of 159) in Years 2, 3, 4, and 5, respectively.In controlled trial, treatment-naive subjects with HBeAg-positive CHB were treated with lamivudine tablets (HBV) or lamivudine tablets (HBV) plus adefovir dipivoxil combination therapy. Following 104 weeks of therapy, YMDD-mutant HBV was detected in of 40 (18%) subjects receiving combination therapy compared with 15 of 35 (43%) subjects receiving therapy with only lamivudine tablets (HBV). In controlled clinical trials, treatment-naive subjects who received 48 weeks of therapy with lamivudine tablets (HBV) in combination with pegylated interferon developed YMDD substitutions less frequently than subjects treated with lamivudine tablets (HBV) alone (1 of 173 [1%] versus 32 of 179 [18%] in HBeAg-negative subjects; of 256 [4%] versus 69 of 254 [27%] in HBeAg-positive subjects). Several clinical studies have evaluated alternative regimens in subjects who failed lamivudine tablets (HBV) due to development of lamivudine resistance. These studies demonstrated higher rate of viral suppression and decreased development of viral resistance compared with continuation of monotherapy with lamivudine tablets (HBV).Pediatric Subjects: In controlled trial in pediatric subjects, YMDD-mutant HBV was detected in 31 of 166 (19%) subjects receiving lamivudine tablets (HBV) for 52 weeks. For subgroup that remained on therapy with lamivudine tablets (HBV) in follow-up trial, YMDD substitutions increased from 24% (29 of 121) at 12 months to 59% (68 of 115) at 24 months and 64% (66 of 103) at 36 months of treatment with lamivudine tablets (HBV). Cross-Resistance HBV containing lamivudine resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M and rtM204V, rtV173L and rtL180M and rtM204V) retain susceptibility to adefovir dipivoxil but have reduced susceptibility to entecavir (greater than 30-fold) and telbivudine (greater than 100-fold). The lamivudine resistance-associated substitution rtA181T results in diminished response to adefovir and telbivudine. Similarly, HBV with entecavir resistance-associated substitutions (rtI169T and rtM250V, rtT184G and rtS202I) have greater than 1,000-fold reductions in susceptibility to lamivudine.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adult Subjects. The safety and efficacy of lamivudine tablets (HBV) 100 mg once daily versus placebo were evaluated in controlled trials in subjects with compensated chronic hepatitis virus infection. All subjects were aged 16 years or older and had chronic hepatitis virus infection (serum HBsAg-positive for at least months) accompanied by evidence of HBV replication (serum HBeAg-positive and positive for serum HBV DNA) and persistently elevated ALT levels and/or chronic inflammation on liver biopsy compatible with diagnosis of chronic viral hepatitis. The results of these trials are summarized below. Trial was randomized, double-blind trial of lamivudine tablets (HBV) 100 mg once daily versus placebo for 52 weeks followed by 16-week no-treatment period in 141 treatment-naive U.S. subjects. Trial was randomized, double-blind, 3-arm trial that compared lamivudine tablets (HBV) 25 mg once daily versus lamivudine tablets (HBV) 100 mg once daily versus placebo for 52 weeks in 358 Asian subjects. Trial was randomized, partially-blind trial conducted primarily in North America and Europe in 238 subjects who had ongoing evidence of active chronic hepatitis despite previous treatment with interferon alfa. The trial compared lamivudine tablets (HBV) 100 mg once daily for 52 weeks, followed by either lamivudine tablets (HBV) 100 mg or matching placebo once daily for 16 weeks (Arm 1), versus placebo once daily for 68 weeks (Arm 2). Principal endpoint comparisons for the histologic and serologic outcomes in subjects receiving lamivudine tablets (HBV) (100 mg daily) or placebo in these trials are shown in the following tables.Table 7. Histologic Response at Week 52 among Adult Subjects Receiving Lamivudine Tablets (HBV) 100 mg Once Daily or PlaceboAssessmentTrial 1Trial 2Trial 3Lamivudine Tablets (HBV)(n 62)Placebo(n 63)Lamivudine Tablets (HBV)(n 131)Placebo(n 68)Lamivudine Tablets (HBV)(n 110)Placebo(n 54)Improvementa No ImprovementMissing Data 55%27%18% 25%59%16% 56%36%8% 26%62%12% 56%25%19% 26%54%20% Improvement was defined as greater than or equal to 2-point decrease in the Knodell Histologic Activity Index (HAI) at Week 52 compared with pretreatment HAI. Subjects with missing data at baseline were excluded. Table 8. HBeAg Seroconvertersa at Week 52 among Adult Subjects Receiving Lamivudine Tablets (HBV) 100 mg Once Daily or Placebo SeroconversionTrial 1Trial 2Trial 3Lamivudine Tablets (HBV)(n 63)Placebo(n 69)Lamivudine Tablets (HBV)(n 140)Placebo(n 70)Lamivudine Tablets (HBV)(n 108)Placebo(n 53)Seroconverters 17% 6% 16% 4% 15% 13% Three-component seroconversion was defined as Week 52 values showing loss of HBeAg, gain of HBeAb, and reduction of HBV DNA to below the solution-hybridization assay limit. Subjects with negative baseline HBeAg or HBV DNA assay were excluded from the analysis. Normalization of serum ALT levels was more frequent with treatment of lamivudine tablets (HBV) compared with placebo in Trials 1, 2, and 3. The majority of subjects treated with lamivudine tablets (HBV) showed decrease of HBV DNA to below the assay limit early in the course of therapy. However, reappearance of assay-detectable HBV DNA during treatment with lamivudine tablets (HBV) was observed in approximately one-third of subjects after this initial response.. 14.2 Pediatric Subjects. The safety and efficacy of lamivudine tablets (HBV) were evaluated in double-blind clinical trial in 286 subjects aged from to 17 years, who were randomized (2:1) to receive 52 weeks of lamivudine tablets (HBV) (3 mg per kg once daily to maximum of 100 mg once daily) or placebo. All subjects had compensated chronic hepatitis accompanied by evidence of hepatitis virus replication (positive serum HBeAg and positive for serum HBV DNA by research branched-chain DNA assay) and persistently elevated serum ALT levels. The combination of loss of HBeAg and reduction of HBV DNA to below the assay limit of the research assay, evaluated at Week 52, was observed in 23% of subjects treated with lamivudine tablets (HBV) and 13% of placebo-treated subjects. Normalization of serum ALT was achieved and maintained to Week 52 more frequently in subjects treated with lamivudine tablets (HBV) compared with placebo (55% versus 13%). As in the adult controlled trials, most subjects treated with lamivudine tablets (HBV) had decreases in HBV DNA below the assay limit early in treatment, but about one-third of subjects with this initial response had reappearance of assay-detectable HBV DNA during treatment. Adolescents (aged 13 to 17 years) showed less evidence of treatment effect than younger pediatric subjects.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE ADMINISTRATION. Adults: 100 mg, once daily. (2.2) Pediatric Patients aged to 17 years: mg per kg once daily up to 100 mg once daily. Prescribe oral solution for pediatric patients requiring less than 100 mg daily. (2.3) Patients with Renal Impairment: Doses of lamivudine tablets (HBV) must be adjusted in accordance with renal function. (2.4) Lamivudine tablets (HBV) should not be used with other medications that contain lamivudine or emtricitabine. (2.5). 2.1 HIV Counseling and Testing. HIV counseling and testing should be offered to all patients before beginning treatment with lamivudine tablets (HBV) and periodically during treatment because of the risk of emergence of resistant HIV-1 and limitation of treatment options if lamivudine tablets (HBV) is prescribed to treat chronic hepatitis infection in patient who has unrecognized HIV-1 infection or acquires HIV-1 infection during treatment [see Warnings and Precautions (5.2)]. 2.2 Recommended Dosage for Adult Patients. The recommended oral dosage of lamivudine tablets (HBV) is 100 mg once daily.. 2.3 Recommended Dosage for Pediatric Patients. The recommended oral dosage of lamivudine tablets (HBV) for pediatric patients aged to 17 years is mg per kg once daily up to maximum daily dosage of 100 mg. The oral solution formulation should be prescribed for patients requiring dosage less than 100 mg or if unable to swallow tablets.. 2.4 Patients with Renal Impairment. Dosage recommendations for adult patients with reduced renal function are provided in Table [see Clinical Pharmacology (12.3)]. Table 1. Dosage of Lamivudine Tablets (HBV) in Adult Patients with Renal Impairment Creatinine Clearance(mL/min)Recommended Dosage of Lamivudine Tablets (HBV)>=5030-4915-295-14<5 100 mg once daily100 mg first dose, then 50 mg once daily100 mg first dose, then 25 mg once daily35 mg first dose, then 15 mg once daily35 mg first dose, then 10 mg once daily Following correction of the dosage for renal impairment, no additional dosage modification of lamivudine tablets (HBV) is required after routine (4-hour) hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3)]. There are insufficient data to recommend specific dosage of lamivudine tablets (HBV) in pediatric patients with renal impairment.. 2.5 Important Administration Instructions. Lamivudine tablets (HBV) may be administered with or without food. The tablets and oral solution may be used interchangeably [see Clinical Pharmacology (12.3)]. The oral solution should be used for doses less than 100 mg. Lamivudine tablets (HBV) should not be used with other medications that contain lamivudine or medications that contain emtricitabine.. 2.6 Assessing Patients during Treatment. Patients should be monitored regularly during treatment by physician experienced in the management of chronic hepatitis B. During treatment, combinations of events such as return of persistently elevated ALT, increasing levels of HBV DNA over time after an initial decline below assay limit, progression of clinical signs or symptoms of hepatic disease, and/or worsening of hepatic necroinflammatory findings may be considered as potentially reflecting loss of therapeutic response. Such observations should be taken into consideration when determining the advisability of continuing therapy with lamivudine tablets (HBV). The optimal duration of treatment, the durability of HBeAg seroconversions occurring during treatment, and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Severe Acute Exacerbation of Hepatitis after Discontinuation of Treatment Inform patients that discontinuation of anti-hepatitis therapy, including lamivudine tablets (HBV), may result in severe acute exacerbations of hepatitis including decompensation of liver disease. Advise patients not to discontinue lamivudine tablets (HBV) without first informing their healthcare provider [see Warnings and Precautions (5.1)]. Risk of Development of HIV-1 Resistance in Patients with HIV-1 Co-infection Counsel patients on the importance of testing for HIV to avoid inappropriate therapy and development of resistance to HIV. HIV counseling and testing should be offered before starting lamivudine tablets (HBV) and periodically during therapy. Inform patients that if they have or develop HIV infection and are not receiving effective HIV treatment, lamivudine tablets (HBV) may increase the risk of development of resistance to HIV medications. Advise patients that lamivudine tablets (HBV) contains lower dose of the same active ingredient (lamivudine) as HIV drugs containing lamivudine [see Dosage and Administration (2.1), Warnings and Precautions (5.2)]. Emergence of HBV Resistance Inform patients that emergence of resistant hepatitis virus and worsening of disease can occur during treatment. Patients should promptly report any new or worsening symptoms to their physician [see Warnings and Precautions (5.3)]. Lactic Acidosis/Severe 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 tablets (HBV) if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.4)]. Hepatitis Transmission Advise patients that treatment with lamivudine tablets (HBV) has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination. Drug Interactions Inform patients that lamivudine tablets (HBV) may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription or non-prescription medication, or herbal products. Advise patients to avoid chronic use of sorbitol-containing prescription and over-the-counter medicines when possible. Taking lamivudine tablets (HBV) with chronically administered sorbitol-containing medicines may decrease the concentrations of lamivudine [see Drug Interactions (7.2)]. Pregnancy Registry Advise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine tablets (HBV) during pregnancy [see Use in Specific Populations (8.1)]. Missed Dosage Instruct patients that if they miss dose of lamivudine tablets (HBV), 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)]. All brands listed are trademarks of their respective owners and are not trademarks of Annora Pharma Private Limited. The makers of these brands are not affiliated with and do not endorse Annora Pharma Private Limited or its products. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 By: Annora Pharma Pvt. Ltd. Sangareddy 502313, Telangana, India. Revised: 08/2019 PATIENT INFORMATION Lamivudine Tablets, USP (HBV) (la miv ue deen) What is the most important information should know about lamivudine tablets (HBV) Lamivudine tablets (HBV) can cause serious side effects, including:o Worsening liver disease. Your hepatitis infection may become worse after stopping treatment with lamivudine tablets (HBV). Worsening liver disease can be serious and may lead to death. If you stop treatment with lamivudine tablets (HBV), your healthcare provider will need to check your health and do blood tests to check your liver for at least several months after you stop taking lamivudine tablets (HBV). Risk of HIV-1 resistance in people with unknown HIV-1 infection or in people with untreated HIV-1 infection. If you have or get HIV-1 (Human Immunodeficiency Virus type 1) that is not being treated with medicines while taking lamivudine tablets (HBV), the HIV-1 virus may develop resistance to certain HIV-1 medicines and become harder to treat. Your healthcare provider should offer you counseling and testing for HIV-1 infection before you start treatment for hepatitis with lamivudine tablets (HBV) and during treatment. Lamivudine tablets (HBV) contain lower dose of lamivudine than other medicines that contain lamivudine and are used to treat HIV-1 infection.o Resistant Hepatitis Virus (HBV). The hepatitis virus can change (mutate) during your treatment with lamivudine tablets (HBV) and become harder to treat (resistant). If this happens, your liver disease can become worse and may lead to death. Tell your healthcare provider right away if you have any new symptoms. What are lamivudine tablets (HBV) Lamivudine tablet (HBV) is prescription medicine used to treat long-term (chronic) hepatitis virus (HBV) when the disease is progressing and there is liver swelling (inflammation). It is not known if lamivudine tablets (HBV) are safe and effective in: people with chronic HBV who have severely damaged liver that is unable to work properly (decompensated liver disease) people with HIV-1, hepatitis virus, or hepatitis (delta) virus people who have had liver transplant children with chronic HBV less than years of age Lamivudine tablets (HBV) does not stop you from spreading HBV to others by sex, sharing needles, or being exposed to your blood. Avoid doing things that can spread HBV infection to others. Do not take lamivudine tablets (HBV): if you are allergic to lamivudine or any of the ingredients in lamivudine tablets (HBV). See the end of this Patient Information leaflet for complete list of ingredients in lamivudine tablets (HBV). What should tell my healthcare provider before taking lamivudine tablets (HBV) Before taking lamivudine tablets (HBV), tell your healthcare provider about all of your medical conditions, including if you: have HIV-1 infection have kidney problems are pregnant or plan to become pregnant. It is not known if lamivudine tablets (HBV) will harm your unborn baby. Pregnancy Registry. There is pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. Lamivudine can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take lamivudine tablets (HBV) or breastfeed. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with lamivudine tablets (HBV). Keep list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for list of medicines that interact with lamivudine tablets (HBV). Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take lamivudine tablets (HBV) with other medicines. Lamivudine tablets (HBV) should not be taken if you also take other medicines that contain lamivudine or emtricitabine. How should take lamivudine tablets (HBV) Take lamivudine tablets (HBV) exactly as your healthcare provider tells you to take them. If you miss dose of lamivudine tablets (HBV), take it as soon as you remember. Do not take doses at the same time or take more than what your healthcare provider tells you to take. Stay under the care of healthcare provider during treatment with lamivudine tablets (HBV). Lamivudine tablets (HBV) may be taken with or without food. Your healthcare provider may prescribe lower dose if you have problems with your kidneys. For children to 17 years of age, your healthcare provider will prescribe dose of lamivudine tablets (HBV) based on your childs body weight. Tell your healthcare provider if you or your child has trouble swallowing tablets. If you take too much lamivudine tablets (HBV), call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of lamivudine tablets (HBV)Lamivudine tablets (HBV) may cause serious side effects, including: See What is the most important information should know about Lamivudine tablets (HBV) Build-up of lactic acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take lamivudine tablets (HBV). Lactic acidosis is serious medical emergency that can lead to death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis: feel very weak or tired feel cold, especially in your arms and legs unusual (not normal) muscle pain feel dizzy or light-headed trouble breathing have fast or irregular heartbeat stomach pain with nausea and vomiting Severe liver problems. Severe liver problems can happen in people who take lamivudine tablets (HBV) or similar medicines. In some cases these liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis) when you take lamivudine tablets (HBV). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems: your skin or the white part of your eyes turns yellow (jaundice) loss of appetite for several days or longer dark or tea-colored urine nausea light-colored stools (bowel movements) pain, aching, or tenderness on the right side of your stomach area You may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese).The most common side effects of lamivudine tablets (HBV) include ear, nose, and throat infections; sore throat; and diarrheaTell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of lamivudine tablets (HBV). Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store lamivudine tablets (HBV) Store lamivudine tablets (HBV) at room temperature between 68F to 77F (20C to 25C). Keep lamivudine tablets (HBV) and all medicines out of the reach of children. General information about the safe and effective use of lamivudine tablets (HBV) Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use lamivudine tablets (HBV) for condition for which it was not prescribed. Do not give lamivudine tablets (HBV) to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about lamivudine tablets (HBV) that is written for health professionals. For more information, call 1-866-495-1995. What are the ingredients in lamivudine tablets (HBV) Active ingredient: lamivudine USP Inactive ingredients: magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The tablets are coated with opadry white containing hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide.All brands listed are trademarks of their respective owners and are not trademarks of Annora Pharma Private Limited. The makers of these brands are not affiliated with and do not endorse Annora Pharma Private Limited or its products. This Patient Information has been approved by the U.S. Food and Drug Administration. Patient Information available at http://camberpharma.com/medication-guides Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 By: Annora Pharma Pvt. Ltd. Sangareddy 502313, Telangana, India. Revised: 08/2019. logocamber. logocamber2.