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 B infection in a patient who has unrecognized HIV-1 infection or acquires HIV-1 infection during treatment [ see Warnings and Precautions ( 5.3) ].

2.2 Dosage in Adult Patients

The recommended oral dosage of Lamivudine Tablets (HBV) is 100 mg once daily.

2.3 Dosage in Pediatric Patients

The recommended oral dosage of Lamivudine Tablets (HBV) for pediatric patients aged 2 to 17 years is 3 mg per kg once daily up to a maximum daily dosage of 100 mg. The oral solution formulation should be prescribed for patients requiring a dosage less than 100 mg or if unable to swallow tablets.

2.4 Dosage Adjustment in Adult Patients With Renal Impairment

Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [ see Clinical Pharmacology ( 12.3) ].

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 a 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 [ see Warnings and Precautions ( 5.4) ].

2.6 Assessing Patients During Treatment

Patients should be monitored regularly during treatment by a physician experienced in the management of chronic hepatitis B. During treatment, combinations of such 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.

5.1 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 alone or in combination, including lamivudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. 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. Particular caution should be exercised when administering Lamivudine Tablets (HBV) to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. 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).

5.2 Exacerbation of Hepatitis After Discontinuation of Treatment

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of Lamivudine Tablets (HBV) (these have been primarily detected by serum ALT elevations, in addition to the re-emergence of HBV DNA commonly observed after stopping treatment; see Table 4 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 of hepatitis exacerbation after discontinuation of lamivudine has not been clearly established. 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 alters the course of posttreatment exacerbations of hepatitis.

5.3 Risk of HIV-1 Resistance if Lamivudine Is Used in Patients With Unrecognized or Untreated HIV-1 Infection

Lamivudine Tablets (HBV) contain a lower lamivudine dose than the lamivudine dose in the following drugs used to treat HIV-1 infection:

• EPIVIR® tablets and oral solution,
• COMBIVIR® (lamivudine/zidovudine) tablets,
• EPZICOM® (abacavir sulfate and lamivudine) tablets, and
• TRIZIVIR® (abacavir, lamivudine, and zidovudine) tablets.

The formulation and dosage of lamivudine in Lamivudine Tablets (HBV) are not approved for patients co-infected with HBV and HIV. If a decision is made to administer lamivudine to such patients, the higher dosage indicated for HIV therapy should be used as part of an appropriate combination regimen, and the prescribing information for EPIVIR®, COMBIVIR®, EPZICOM®, or TRIZIVIR®, as well as for Lamivudine Tablets (HBV), should be consulted. HIV counseling and testing should be offered to all patients before beginning Lamivudine Tablets (HBV) and periodically during treatment because of the risk of rapid emergence of resistant HIV and limitation of treatment options if Lamivudine Tablets (HBV) is prescribed to treat chronic hepatitis B in a patient who has unrecognized or untreated HIV-1 infection or acquires HIV-1 infection during treatment.

5.4 Coadministration With Other Medications Containing Lamivudine or Emtricitabine

Do not coadminister Lamivudine Tablets (HBV) with other lamivudine-containing products including EPIVIR ® (lamivudine), COMBIVIR ® (lamivudine/zidovudine), EPZICOM ® (abacavir/lamivudine), or TRIZIVIR ® (abacavir/lamivudine/zidovudine).

Do not coadminister Lamivudine Tablets (HBV) with emtricitabine-containing products including ATRIPLA ® (efavirenz/emtricitabine/tenofovir disoproxil fumarate), COMPLERA ® (rilpivirine/emtricitabine/tenofovir disoproxil fumarate), EMTRIVA ® (emtricitabine), STRIBILD ® (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate), or TRUVADA ® (emtricitabine/tenofovir disoproxil fumarate).

5.5 Emergence of Resistance-Associated HBV Substitutions

In controlled clinical trials, YMDD-mutant HBV was detected in subjects with on–lamivudine re-appearance of HBV DNA after an initial decline below the solution-hybridization assay limit [ see Microbiology ( 12.4) ]. Subjects treated with lamivudine (adults and children) with YMDD-mutant HBV at 52 weeks showed diminished treatment responses in comparison with subjects treated with lamivudine 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 a rise in HBV DNA and ALT from their own 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 clinical practice, monitoring of ALT and HBV DNA levels during treatment with Lamivudine Tablets (HBV) may aid in treatment decisions if emergence of viral mutants is suspected.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Clinical Trials of Adults With Chronic Hepatitis B Virus Infection: Clinical adverse reactions (regardless of investigator’s causality assessment) reported in greater or equal to 10% of subjects who received lamivudine and reported at a rate greater than placebo are listed in Table 2.

Specified laboratory abnormalities reported in subjects who received lamivudine and reported at a rate greater than in subjects who received placebo are listed in Table 3.

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 100 mg than in subjects who had received placebo. A comparison of ALT elevations between Weeks 52 and 68 in subjects who discontinued lamivudine 100 mg at Week 52 and subjects in the same trials who received placebo throughout the treatment course is shown in Table 4.

Adverse Reactions in Clinical Trials of Pediatric Subjects With Chronic Hepatitis B Virus 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.

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 a population of unknown size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.

            Blood and Lympatic System Disorders: Thrombocytopenia.

            Digestive: Stomatitis.

            Endocrine and Metabolic: Hyperglycemia.

            General: Weakness.

            Blood and Lymphatic: Anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.

            Hepatic and Pancreatic: Lactic acidosis and steatosis, posttreatment exacerbation of hepatitis [see Boxed Warning], pancreatitis.

            Hypersensitivity: Anaphylaxis, urticaria.

            Musculoskeletal: Cramps, rhabdomyolysis.

            Nervous: Paresthesia, peripheral neuropathy.

            Respiratory: Abnormal breath sounds/wheezing.

            Skin: Alopecia, pruritus, rash.

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled trials of lamivudine in pregnant women. Because animal reproduction studies are not always predictive of human response, Lamivudine Tablets (HBV) should be used during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Animal Data: Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity. Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 60 times that for the adult HBV dose. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 60 times those in humans.

Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

8.3 Nursing Mothers

Lamivudine is excreted in human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily, 6 times the recommended dosage for hepatitis B infection) or combination therapy (150 mg lamivudine twice daily [3 times the recommended dosage for hepatitis B infection] and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.

Because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue Lamivudine Tablets (HBV) taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.

8.4 Pediatric Use

Lamivudine Tablets (HBV) is indicated for the treatment of chronic hepatitis B virus infection in pediatric patients aged 2 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 2 years have not been established.

8.5 Geriatric Use

Clinical trials of lamivudine 100 mg did not include sufficient numbers of subjects aged  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 ( 2.4) , 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.

12.1 Mechanism of Action

Lamivudine is an antiviral agent [ 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 5 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 2 hours after administration. The area under the plasma concentration versus time curve (AUC[0-24 h]) 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 mcg•hour per mL, respectively. The relative bioavailability of the tablet and oral solution were demonstrated in healthy subjects. Although the solution demonstrated a slightly higher peak serum concentration (C max), 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 C max increased in proportion to dose over the range from 5 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: The 100-mg tablet was administered orally to 24 healthy subjects on 2 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 asymptomatic HIV-1-infected subjects was 1.3 ± 0.4 L 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% and independent of dose. 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 a minor route of elimination. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. In 9 healthy subjects receiving 300 mg of lamivudine as single oral doses, a total of 4.2% (range: 1.5% to 7.5%) of the dose was excreted as the trans-sulfoxide metabolite in the urine, the majority of which was excreted in the first 12 hours. Serum concentrations of the trans-sulfoxide metabolite have not been determined.

Elimination: The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 9 healthy subjects given a 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 a 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 (t½) ranged from 5 to 7 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.

Special Populations:Adults With Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in healthy subjects and in subjects with impaired renal function, with and without hemodialysis (Table 5).

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 (2.4)].

Hemodialysis increases lamivudine clearance from a 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 a 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.

Pediatric Patients With Renal Impairment: The effect of renal impairment on lamivudine pharmacokinetics in pediatric patients with chronic hepatitis B is not known.

Adults 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.

Pharmacokinetic parameters were not altered by diminishing hepatic impairment. 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 [ see Indications and Usage ( 1) ].

Adults Post-Hepatic Transplant: Fourteen HBV-infected subjects received liver transplant following lamivudine therapy and completed pharmacokinetic assessments at enrollment, 2 weeks after 100 mg once-daily dosing (pre-transplant), and 3 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 have not been established in this population [ see Indications and Usage ( 1) ].

Pediatric Subjects: Lamivudine pharmacokinetics were evaluated in a 28 day dose-ranging trial in 53 pediatric subjects with chronic hepatitis B. Subjects aged 2 to 12 years were randomized to receive lamivudine 0.35 mg per kg twice daily, 3 mg per kg once daily, 1.5 mg per kg twice daily, or 4 mg per kg twice daily. Subjects aged 13 to 17 years received lamivudine 100 mg once daily. Lamivudine Tmax was 0.5 to 1 hour. In general, both Cmax and exposure (AUC) showed dose proportionality in the dosing range studied. Weight-corrected oral clearance was highest at age 2 and declined from 2 to 12 years, where values were then similar to those seen in adults. A dose of 3 mg per kg given once daily produced a steady-state lamivudine AUC (mean 5,953 ng•hour per mL ± 1,562 SD) similar to that associated with a dose of 100 mg per day in adults.

Gender: There are no significant gender differences in lamivudine pharmacokinetics.

Race: There are no significant racial differences in lamivudine pharmacokinetics.

Drug Interactions:Interferon Alfa: Multiple doses of lamivudine and a single dose of interferon were coadministered to 19 healthy male subjects in a pharmacokinetics trial. Results indicated a 10% reduction in lamivudine AUC, but no change in interferon pharmacokinetic parameters when the 2 drugs were given in combination. All other pharmacokinetic parameters (Cmax, Tmax, and t½) were unchanged. There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in this trial.

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 a multi-drug regimen to HIV-1/HCV co-infected subjects.

Trimethoprim/Sulfamethoxazole: Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300 mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 44% ± 23% (mean ± SD) in lamivudine AUC, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine.

Zidovudine: Lamivudine and zidovudine were coadministered to 12 asymptomatic HIV-positive adult subjects in a single-center, open-label, randomized, crossover trial. No significant differences were observed in AUC or total clearance for lamivudine or zidovudine when the 2 drugs were administered together. Coadministration of lamivudine with zidovudine resulted in an increase of 39% ± 62% (mean ± SD) in Cmax of zidovudine.

12.4 Microbiology

Mechanism of Action: Lamivudine is a 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 the inhibition of the RNA- and DNA­ dependent polymerase activities of HBV reverse transcriptase (rt) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is a weak inhibitor of mammalian α, β, and γ-DNA polymerases.

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 EPIVIR ® prescribing information for information regarding activity of lamivudine against HIV.

Resistance: Lamivudine-resistant isolates were identified in subjects with virologic breakthrough, defined when using solution hybridization assay as the detection of HBV DNA in serum on 2 or more occasions after failing to detect HBV DNA on 2 or more occasions and defined when using PCR assay as a greater than 1 log10 (10-fold) increase in serum HBV DNA from nadir during treatment in a subject who had an initial virologic response.

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 detected in lamivudine-resistant HBV isolates include rtL80I and rtA181T.

In 4 controlled clinical trials in adults with HBeAg-positive chronic hepatitis B virus infection (CHB), YMDD-mutant HBV was detected in 81 of 335 subjects receiving lamivudine100 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 4 trials: 16% to 32%) at 52 weeks. In limited data from a long-term follow-up trial in subjects who continued 100 mg per day lamivudine after one of these trials, YMDD substitutions further increased from 18% (10 of 57) at 1 year to 41% (20 of 49), 53% (27 of 51), and 69% (31 of 45) after 2, 3, and 4 years of treatment, respectively. Over the 5-year treatment period, the proportion of subjects who developed YMDD-mutant HBV at any time was 69% (40 of 58).

In a controlled trial, treatment-naive subjects with HBeAg-positive CHB were treated with lamivudine or lamivudine plus adefovir dipivoxil combination therapy. Following 104 weeks of therapy, YMDD-mutant HBV was detected in 7 of 40 (18%) subjects receiving combination therapy compared with 15 of 35 (43%) subjects receiving therapy with only lamivudine. In another controlled trial, combination therapy was evaluated in adult subjects with HBeAg-positive CHB who had YMDD-mutant HBV and diminished clinical and virologic response tolamivudine Following 52 weeks of lamivudine plus adefovir dipivoxil combination therapy (n = 46) or therapy with only lamivudine (n = 49), YMDD-mutant HBV was detected less frequently in subjects receiving combination therapy, 62% versus 96%.

A published trial suggested that the rates of lamivudine resistance in subjects treated for HBeAg-negative CHB appear to be more variable (0% to 27% at 1 year and 10% to 56% at 2 years).

Pediatric Subjects: In a controlled trial in pediatric subjects, YMDD-mutant HBV was detected in 31 of 166 (19%) subjects receiving lamivudine for 52 weeks. For a subgroup that remained on therapy with lamivudine in a 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.

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 (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 (I169T/M250V and T184G/S202I) have greater than 1,000 fold reductions in susceptibility to lamivudine.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 34 times (mice) and 200 times (rats) those observed in humans at the recommended therapeutic dose for chronic hepatitis B.

Mutagenesis: Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg producing plasma levels of 60 to 70 times those in humans at the recommended dose for chronic hepatitis B.

Impairment of Fertility:  In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 80 to 120 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

14.1 Clinical Studies of Lamivudine in Adult Patients

The safety and efficacy of  lamivudine100 mg once daily versus placebo were evaluated in 3 controlled trials in subjects with compensated chronic hepatitis B virus infection. All subjects were aged 16 years or older and had chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 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 a diagnosis of chronic viral hepatitis. The results of these trials are summarized below.

• Trial 1 was a randomized, double-blind trial of  lamivudine 100 mg once daily versus placebo for 52 weeks followed by a 16-week no-treatment period in 141 treatment-naive US subjects.
• Trial 2 was a randomized, double-blind, 3-arm trial that compared lamivudine 25 mg once daily versus lamivudine 100 mg once daily versus placebo for 52 weeks in 358 Asian subjects.
• Trial 3 was a randomized, partially-blind trial conducted primarily in North America and Europe in 238 subjects who had ongoing evidence of active chronic hepatitis B despite previous treatment with interferon alfa. The trial compared lamivudine 100 mg once daily for 52 weeks, followed by either lamivudine 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 (100 mg daily) or placebo in these trials are shown in the following tables.
  

Normalization of serum ALT levels was more frequent with lamivudine treatment compared with placebo in Trials 1-3.

The majority of subjects treated with lamivudine showed a 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 was observed in approximately one-third of subjects after this initial response.

14.2 Clinical Studies of Lamivudine in Pediatric Subjects

The safety and efficacy of lamivudine were evaluated in a double-blind clinical trial in 286 subjects aged from 2 to 17 years, who were randomized (2:1) to receive 52 weeks of lamivudine (3 mg per kg once daily to a maximum of 100 mg once daily) or placebo. All subjects had compensated chronic hepatitis B accompanied by evidence of hepatitis B virus replication (positive serum HBeAg and positive for serum HBV DNA by a 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 and 13% of placebo-treated subjects. Normalization of serum ALT was achieved and maintained to Week 52 more frequently in subjects treated with lamivudine compared with placebo (55% versus13%). As in the adult controlled trials, most subjects treated with lamivudine 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.