ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the labeling: Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.1)]. Exacerbations of hepatitis after discontinuation of treatment [see Warnings and Precautions (5.2)]. Risk of emergence of resistant HIV-1 infection [see Warnings and Precautions (5.3)]. Risk of emergence of resistant HBV infection [see Warnings and Precautions (5.4)]. o 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 Hetero Labs Limited at 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 of 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 ThroatEar, nose, and throat infections 25% 21% Sore throat 13% 8% GastrointestinalDiarrhea 14% 12% Includes 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 ValueSubjects with ALT Elevation/ Subjects with Observationsa Lamivudine Tablets (HBV)b Placebob ALT >=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. During treatment phase. 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 Lympatic 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 5.1)] ,posttreatment exacerbations of hepatitis [see Warnings and Precautions 5.2)] 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. amivudine is an antivi ral g ent with activity against HBV [s ee Mi crobiology (12. ) ]. 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 asymptomatic 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% 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 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 ParameterCreatinine Clearance Criterion (Number of Subjects)>=80 mL/min (n 9)20-59 mL/min (n 8)<20 mL/min (n 6)Creatinine Clerance (mL/min)97 (range 82-117)39 (range 25-49)15 (range 13-19)Cmax (mcg/mL)1.31 +- 0.351.85 +- 0.401.55 +- 0.31AUC (mcg.h/mL)5.28 +- 1.0114.67 +- 3.7427.33 +- 6.56Cl/F (mL/min)326.4 +- 63.8120.1 +- 29.564.5 +- 18.3 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 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. 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 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 ParameterNormal (n 8) ImpairmentaModerate (n 8)Severe (n 8)Cmax (mcg/mL) 0.92 +- 0.31 1.06 +- 0.581.08 +- 0.27AUC (mcg.h/mL) 3.96 +- 0.58 3.97+- 1.364.30 +- 0.63Tmax (h) 1.3 +- 0.8 1.4 +- 0.81.4 +- 1.2Cl/F (mL/min) 424.7 +- 61.9 456.9 +- 129.8395.2 +- 51.8Clr (mL/min) 279.2 +- 79.2 323.5 +- 100.9 216.1 +- 58.0a Hepatic impairment assessed by aminopyrine breath test. 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 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. Mechan sm of Act on amivudine is s ynth et ic nu cl eoside n al gu e. nt racellul ar y, amivudine is phospho y at ed to its active -t riphosph ate et abolit e, amivudine riphosph at e, TC -TP. The rin cip al mode of action of TC TP is the inhibition of the NA- and NA- ep end ent po ym r ase activiti es of BV re erse r ans cript ase (rt) via NA ch ain ermin ation aft er in o rpo ration of the nu cl eotide an al g ue into vi ral DNA. TC -TP is weak inhibitor of amm ali an , and -DNA po y era es.Ant v iral Act v t A ctivi ty of amivudine ag ainst BV in ell cultu re as ass ess ed in BV NA-t ans e ct ed 2.2.15 cells, B611 cells, and in fect ed hu an ri a ry ep at c t es. EC 50 alu es (the co cent ation of r ug ee ed to red ce the ev el of xt racellul ar BV NA by 50 %) ari ed from 0.01 uM (2 .3 ng er L) to 5.6 uM (1.3 cg er L) e end ing upon the u ration of xposu re of cells to amivudin e, the cell mod el yst em, and the roto col us ed. ee the P V IR res cribi ng in fo rm ation for in fo rm ation eg ardi ng activi ty of amivudine ag ainst I V. Res istance amivudin e-resist ant isol at es ere id enti fi ed in subj ects with vi rolo gic reakth ro gh, efin ed wh en using solution y ri di ation ass ay as the et ction of BV NA in erum on or mo re cc asions aft er faili ng to et ct BV DNA on or o re c asions and efin ed wh en using PCR ass ay as g rea er th an lo g10 (10 -fold) in r ease in erum HBV DNA from adir du ri ng r atm ent in subj ect who ad an initi al vi rolo gic resp ons e. amivudin -resist ant HBV isol at es ev elop rtM2 04 /I substitutions in the YM DD motif of the cat l ytic dom ain of the vi ral re erse rans cript as e. rtM204 /I substitutions are r equ ent ly accomp an ed by oth er ubstitutions (rt V173 L, t L180M) whi ch enh n ce he ev el of amivudine resist an ce or act as com ens ato ry substitutions mp roving epli cation f fi i en y. Oth er substitutions et ect ed in amivudin e-resist ant HBV isol at es in clude t L8 0I and rt A181 T. In cont roll ed clini cal r als in adults with B Ag -positive ch ronic e atitis vi rus in fection (C HB ), YM D -mut ant BV as et ct ed in 81 of 335 subj ects eceivi ng lamivudine tablets (HBV) 100 mg on ce ai ly for 52 e eks. The r ev l en ce of YM DD substitutions was ess th an 10% in each of th ese ri ls for subj ects studi ed at 24 weeks and n cr as ed to an av ra ge of 24% (ra ge in t ri als: 16% to 32 %) at 52 e eks. In limit ed ata from lo g t rm follo w-up ri al in subj ects who continu ed 100 mg er ay lamivudine tablets (HBV) aft er ne of th se ri als, YM DD substitutions fu rth er in creas ed rom 18% (10 of 57) at y ear to 41% (20 of 49 ), 53% (27 of 51 ), and 69% (31 of 5) af er 2, 3, and y ea rs of r atm ent, resp ectiv l y. v er the - ear reatm ent eriod, the ropo rtion of subj ects who ev elop ed YM DD-mut ant BV at ny time was 9% (40 of 58 ). In cont roll ed ri al, r ea tm ent -n aive subj ects with B eA -positive HB ere r eat ed with lamivudine tablets (HBV) or lamivudine tablets (HBV) plus ad fovir dipivoxil combin ation h era y. Follo wing 104 weeks of th ra y, YM DD-mut ant HBV was et ect ed in of 40 (18 %) subj ects re eiving combin ation th era py co mp ared with 15 of 35 (4 %) subj ects e ceivi ng th ra py with on ly lamivudine tablets (HBV). In anoth er cont roll ed ri al, combi ation th era py was ev alu t ed in adult subj ects with B Ag -positive HB who ad YM DD-mut ant BV and diminish ed clini cal and vi rolo gic response to lamivudine tablets (HBV). Follo wing 52 weeks of lamivudine tablets (HBV) plus ad efovir dipivoxil combin ation th era py (n 46) or th era py with on ly lamivudine tablets (HBV) (n 49 ), YM DD-mut ant BV was et ec ed ess r equ nt ly in subj ects e ceivi ng combin ation th era y, 2% ersus 96 %.A publish ed ri al sug es ed th at the rat es of amivudine resist an ce in subj cts reat ed or B eA -n eg ative HB app ear to be mo re ar able (0% to 27% at y ar nd 10% to 56% at y ars ).Ped iat ric Sub je cts: In cont roll ed ri al in edi at ric subj ects, YM DD-mut ant BV was et ec ed in 31 of 66 (19 %) subj ects e eiving lamivudine tablets (HBV) for 52 eeks. or su g roup th at rem ain ed on th ra py with lamivudine tablets (HBV) in follo w-up ri al, YM DD ubstitutions in creas ed from 24% (29 of 12 1) at 12 months to 59% (68 of 115) at 24 months and 64% (66 of 103) at 36 months of reatm ent 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 (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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Clinical Studies of Lamivudine Tablets (HBV) in Adult Patients. The afe ty and f fi a cy of lamivudine tablets (HBV) 100 mg on ce ai ly ersus pl ce bo were ev alu at ed in cont roll ed ri als in subj ects with comp ens at ed ch ron ic ep at itis vi rus in fection. All subj ects were g ed 16 e ars or ol er and ad ch ronic e atitis vi rus in fection (s erum Bs g -positive or at e ast months) accomp an ed by evid en ce of BV epli cation (s erum B eA -positive and pos itive for erum BV DN A) and e rsist ent ly l ev at ed LT ev els and/or ch ronic in fl amm ation on liv er biop sy com atible with di gnosis of ch ro nic vi ral ep atitis. The results of th ese ri als re summ ari ed elo w. Tri al was randomi ed, doubl e-blind ri al of lamivudine tablets (HBV) 100 mg on ce ai ly e rsus pl acebo or 52 e eks follo wed by 16 week o -t eatm ent eriod in 141 r atm ent -n aive US subj ects. Tri al was randomi ed, doubl e-blind, -arm ri al th at comp ared lamivudine tablets (HBV) 25 mg on ce ai ly e rsus lamivudine tablets (HBV) 100 mg on ce ai ly e rsus pl acebo for 52 weeks in 358 Asi an subj ects. Tri al was randomi ed, arti al y -blind ri al co ndu ct ed rim ari ly in No th Am eri ca and Eu rope in 238 subj ects who ad on goi ng evid en ce of active h ronic e atitis d espite revious reatm ent with int erferon al fa. he ri al comp ared lamivudine tablets (HBV) 100 mg on ce ai ly for 52 e eks, follo wed by eith er lamivudine tablets (HBV) 00 mg or at chi ng pl ce bo on ce ai ly for 16 weeks A rm ), e rsus pl acebo on ce ai ly for 68 weeks A rm ).P rin cip al endpoint comp arisons for the histolo ic and erol gic out com es in subj ects receivi ng lamivudine tablets (HBV) (100 mg ai y) or l acebo in th ese ri als are sho wn in the follo wing abl es.Table 7. His tologic Response at eek 52 m ong Adult Sub jects Re eiving Lamivudine Tablets (HBV)100 mg On ce Daily or Pla cebo Ass es m entT rial 1T rial 2T rial 3Lamivudine Tablets (HBV) (n 62)Placebo(n 63)Lamivudine Tablets (HBV) (n 131)Placebo(n 68)Lamivudine Tablets (HBV) (n 110)Placebo(n 54) Imp ro em enta 55% 25% 56% 26% 56% 26% No Im rov em ent 27% 59% 36% 62% 25% 54% Missing Data 18% 16% 8% 12% 19% 20% Imp ro em ent was efin ed as g e at er th an or eq al to -point ecr ase in the Knod ell Histolo gic Activi ty Ind ex (H I) at eek 52 com ared with r et reatm ent HA I. Subj ects with missing ata at a eline were x clud ed. Table 8. HB eAg ero conv ert rsa at eek 52 mong Adult Sub jects eceiving Lamivudine Tablets (HBV) 100 mg On ce Daily or Pla cebo SeroconversionT rial 1T rial 2T rial 3Lamivudine Tablets (HBV) (n 63)Placebo(n 69)Lamivudine Tablets (HBV) (n 140)Placebo(n 70)Lamivudine Tablets (HBV) (n 108)Placebo(n 53)S ero conv er ers 17% 6% 16% 4% 15% 13% Th ree compon ent er c onv ersion was e fin ed as eek 52 alu es sho wi ng loss of B A g, ain of HB eAb, and redu ction of BV DNA to elow the solution h yb ridi ation ass ay limit. Subj ects with e ative as eline B Ag or HBV DNA ass ay we re x clud ed from the an l ysis.Normalization of serum ALT levels was more frequent with treatment of lamivudine tablets (HBV) compared with placebo in Trials 1, 2, and 3. The ajo ri ty of subj ects reat ed with lamivudine tablets (HBV) sho wed d ec ease of BV NA to elow the ass ay limit ear ly in the co rse of th ra y. Ho wev r, e app a ran ce of ass y d et ect ab le BV NA du ri ng r atm ent with lamivudine tablets (HBV) was obs erv ed in app ro xi at ly n e-thi rd of subj ects aft er this initi al respons e.. Tri al was randomi ed, doubl e-blind ri al of lamivudine tablets (HBV) 100 mg on ce ai ly e rsus pl acebo or 52 e eks follo wed by 16 week o -t eatm ent eriod in 141 r atm ent -n aive US subj ects.. Tri al was randomi ed, doubl e-blind, -arm ri al th at comp ared lamivudine tablets (HBV) 25 mg on ce ai ly e rsus lamivudine tablets (HBV) 100 mg on ce ai ly e rsus pl acebo for 52 weeks in 358 Asi an subj ects.. Tri al was randomi ed, arti al y -blind ri al co ndu ct ed rim ari ly in No th Am eri ca and Eu rope in 238 subj ects who ad on goi ng evid en ce of active h ronic e atitis d espite revious reatm ent with int erferon al fa. he ri al comp ared lamivudine tablets (HBV) 100 mg on ce ai ly for 52 e eks, follo wed by eith er lamivudine tablets (HBV) 00 mg or at chi ng pl ce bo on ce ai ly for 16 weeks A rm ), e rsus pl acebo on ce ai ly for 68 weeks A rm ).. 14.2 Clinical Studies of Lamivudine Tablets (HBV) in Pediatric Subjects. The afe ty and f fi a cy of lamivudine tablets (HBV) ere ev alu at ed in doubl e-blind clini cal ri al in 286 subj ects g ed rom to 17 e ars, who ere andomi ed (2:1) to recei ve 52 weeks of lamivudine tablets (HBV) (3 mg er kg on ce ai ly to m ximum of 100 mg on ce ai y) or pl c ebo. All subj ects ad comp ens t ed ch ronic e atitis a ccomp ani ed by evid en ce of ep atitis vi rus repli cation (positive er um B Ag and positive for erum BV NA by res arch ran ch d -c ain DNA as a y) and e rsist ent ly el ev at ed erum LT e els. The combin ation of loss of B Ag and edu ction of BV NA to e low the ass ay limit of the res a rch as a y, ev alu at ed at eek 52, as obs erv ed in 23% of ubj ects reat ed with lamivudine tablets (HBV) and 3% of pl acebo -t eat ed subj cts. No rm ali ation of erum LT was chi ev ed and aint ain ed to eek 52 mo re freq ent ly in subj cts reat ed with lamivudine tablets (HBV) comp ared with pl acebo (55% ersus 13 %). As in the adult co nt roll ed ri als, most subj ects reat ed with lamivudine tablets (HBV) ad e rea es in BV NA elow the as ay limit ear ly in r atm nt, but about on e-thi rd of subj ects with this initi al response ad e pp eara ce of ass y d et ec able BV DNA du ri ng re atm ent. Adol es cents a ed 13 to 17 e ars) sh wed ess evid n ce of r atm ent eff ct th an you g er edi at ric subj cts.

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. IV couns eli ng and esting should be f fe ed to all ati ents efo re e ginn ing r atm ent with lamivudine tablets (HBV) and eriodi cal ly du ri ng r atm ent ecau se of the risk of em r e ce of resist ant H V -1 and limit ation of reatm ent options if lamivudine tablets (HBV) is re crib ed to r at ch ronic ep atitis in fection in p ati ent who as un e ogni ed I -1 in fection or acqui res I V-1 in fection du ri ng reatm nt [s ee Warnings and Pr cautions (5. ) ].. 2.2 Recommended Dosage for Adult Patients. The e comm end ed r al dos age of lamivudine tablets (HBV) is 100 mg on ce ai y.. 2.3 Recommended Dosage for Pediatric Patients. The e comm end ed r al dos age of lamivudine tablets (HBV) for edi at ric ati ents g ed to 17 e ars is mg er kg n ce ai ly up to m ximum ai ly dos age of 100 g. The ral solution fo rmul ation should be r es crib ed or ati ents eq ui ring do a ge ess th an 100 mg or if n able to wallow abl ets.. 2.4 Patients with Renal Impairment. Dos ge ecomm end atio ns for adult ati ents with edu ced en al fu ction are rovid ed in Table [s ee Clini cal har ma cology (12. ) ]. Table 1. Dosage of Lamivudine Tablets (HBV) in Adult Pa ti en ts wi th Renal mpai ment Crea tinine Cl ea ran ce mL/ min) Rec mmend ed Dosage of Lamivudine Tablets (HBV)>=50 100 mg on ce ai ly 30 -49 100 mg fi rst dos e, th en 50 mg on ce ai ly 15 -29 100 mg fi rst dos e, th en 25 mg on ce ai ly -14 35 mg fi rst dos e, th en 15 mg on ce ai ly <5 35 mg fi rst dos e, th en 10 mg on ce ai ly Follo wing co r ection of the dos ge or re al imp ai rm ent, no addition al dos ge modi fi cation of lamivudine tablets (HBV) is equi red ft er outine (4 -hou r) emodi l ysis or eriton eal di l ysis [s ee Clini cal har ma cology (12. ) ]. Th ere are insu fi ci ent a ta to recomm end sp eci ic dos ge of lamivudine tablets (HBV) in edi at ric ati ents with ren al imp ai rm ent.. 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. Ad vise the pati ent to e ad the FDA-appro ed pati ent lab eling Pati ent Inf or mation ).Lactic Acidosis and Severe Hepatomegaly with SteatosisAdvise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of lamivudine tablets (HBV). Advise patients to contact their healthcare provider immediately and stop lamivudine tablets (HBV) if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions 5.1)]. 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 (5.2)]. 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 (5.3)]. 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 (5.4)]. 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, 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 Hetero Labs Limited. The makers of these brands are not affiliated with and do not endorse Hetero Labs Limited or its products. Manufactured for: Camber Pharmaceuticals, Inc.,Piscataway, NJ 08854By:HETEROTM Hetero Labs LimitedUnit V, Polepally, Jadcherla, Mahabubnagar-509 301, India. Revised: December 2017. address.jpg.

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 asymptomatic 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% 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 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 ParameterCreatinine Clearance Criterion (Number of Subjects)>=80 mL/min (n 9)20-59 mL/min (n 8)<20 mL/min (n 6)Creatinine Clerance (mL/min)97 (range 82-117)39 (range 25-49)15 (range 13-19)Cmax (mcg/mL)1.31 +- 0.351.85 +- 0.401.55 +- 0.31AUC (mcg.h/mL)5.28 +- 1.0114.67 +- 3.7427.33 +- 6.56Cl/F (mL/min)326.4 +- 63.8120.1 +- 29.564.5 +- 18.3 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 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. 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 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 ParameterNormal (n 8) ImpairmentaModerate (n 8)Severe (n 8)Cmax (mcg/mL) 0.92 +- 0.31 1.06 +- 0.581.08 +- 0.27AUC (mcg.h/mL) 3.96 +- 0.58 3.97+- 1.364.30 +- 0.63Tmax (h) 1.3 +- 0.8 1.4 +- 0.81.4 +- 1.2Cl/F (mL/min) 424.7 +- 61.9 456.9 +- 129.8395.2 +- 51.8Clr (mL/min) 279.2 +- 79.2 323.5 +- 100.9 216.1 +- 58.0a Hepatic impairment assessed by aminopyrine breath test. 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 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. Teratogenic Effects: 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.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENTS ATIENT INFORMATION (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: 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, very overweight (obese), or have been taking nucleoside analogue medicines for long time. 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. 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) is 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. Who should not take lamivudine tablets (HBV) 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 it. 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) The most common side effects of lamivudine tablets (HBV) include ear, nose, and throat infections; sore throat; and diarrhea Tell 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. What are the ingredients in lamivudine tablets (HBV) Active ingredient: lamivudine, USP Inactive ingredients: crospovidone, isomalt, isopropyl alcohol, magnesium stearate and methylene chloride. The tablets are coated with Opadry Pink containing hypromellose, iron oxide red, polyethylene glycol, polysorbate 80, titanium dioxide and yellow iron oxide. All brands listed are trademarks of their respective owners and are not trademarks of Hetero Labs Limited. The makers of these brands are not affiliated with and do not endorse Hetero Labs Limited or its products. This Patient Information has been approved by the U.S. Food and Drug Administration.Manufactured for: Camber Pharmaceuticals, Inc.,Piscataway, NJ 08854By:HETEROTM Hetero Labs Limited Unit V, Polepally, Jadcherla, Mahabubnagar-509 301, India.Revised:December 2017. addrtess.jpg.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Teratogenic Effects: 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 indi cat ed for the r atm ent of ch ronic ep atitis vi rus in ection in edi at ric ati ents ag ed to 17 e ars [s ee Indi cations and Usage (1 ), Clini cal Phar ma cology (12. ), Clini cal Studi es (14.2 ]. The afe ty and f fi ca cy of lamivudine tablets (HBV) in edi at ric ati ents ou g er th an y ars a ve not een est ablish ed.. 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. edu ction of the dos ge of lamivudine tablets (HBV) is e omm end ed for ati ents ith imp ai red ren al fu ction [s ee Dos age and Ad ministration (2.4 ), Clini cal Phar ma col ogy (12. ) ].. 8.7 Patients With Impaired Liver Function. No dose adjustm ent for amivudine is requi red or ati ents with imp ai red ep atic fun ction.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Emergence of Resistance-Associated HBV Substitutions: Monitor ALT and HBV DNA levels during lamivudine treatment to aid in treatment decisions if emergence of viral mutants or loss of therapeutic response is suspected. (2.6,5.4). 5.1 Lactic Acidosis and Severe Hepatomegaly with Steatosis. a ctic cidosis and ev re ep atom eg ly with st atosis, in cluding fat al as es, ave een repo rt ed with the use of nu cl eoside an al g es al one or in combin ation, in cluding lamivudine tablets (HBV) and oth er anti et rovi rals. m ajo ri ty of h ese as es ave e en in wom en. b esi ty and rolong ed nu cl eoside xposu re ay be risk fact rs. Most of th ese rep rts ave es cri ed ati ents e ceivi ng nu cl eoside an al g es for reatm ent of IV in e ction, but th ere ave een epo rts of actic acidosis in ati ents re eiving amivudine for ep atitis B. aution should be x ercis ed wh en administ eri ng lamivudine tablets (HBV) to ny ati ent with kno wn risk facto rs for liv er dis eas e; ho wev er, cas es also have een rep rt ed in ati ents with no kno wn risk fac to rs. Treatm ent with lamivudine tablets (HBV) should be susp end ed in ny ati ent who ev elops clini cal or abo rato ry findi gs sug estive of actic cid osis or ronoun ced e at oto xi ci ty (whi ch ay n clude ep atom eg ly and st eatosis ev en in the abs en ce of a rk ed ran amin ase el v ations ).. 5.2 Exacerbations of Hepatitis after Discontinuation of Treatment. Clini cal and abo rato ry evid en ce of x acer ations of ep atitis ave c cu red aft er dis continu ation of lamivudine tablets (HBV) (t ese a ve e en rim ari ly et ect ed by e rum LT el ev ations, in addition to the re-em r e ce of HBV DNA common ly obs er ed aft er stopping r atm ent; ee Table for mo re in fo rm ation reg ardi ng r equ n cy of postt reatm ent LT l ev ations) [s ee Ad verse ea ctions (6. ) ]. Althou gh most ev ents pp ear to a ve een el f-l imit ed, fat aliti es ave een rep rt ed in some cas es. The cau al rel ations hip of ep atitis x acerb at ion aft er dis continu ation of lamivudine tablets (HBV) as not een l a ly es ablish ed. ati ents should be clos ly monito red with both clin cal and abo ato ry follo -up for at e ast ev r al months aft er stopping reatm ent with lamivudine tablets (HBV). h ere is insu ff ci ent evid en ce to e ermine wh eth er e-initi ation of lamivudine tablets (HBV) alt ers the cou rse of postt eatm ent x acerb ations of ep atitis.. 5.3 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.. 5.4 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 solution-hybridization 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 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.