Lamivudine

Boxed Warning 11/2018 Warnings and Precautions, Emergence of Resistance- Associated HBV Substitutions ( 5.3 ) 11/2018 Warnings and Precautions, Lactic Acidosis and Severe Hepatomegaly with Steatosis ( 5.4 ) 11/2018 Boxed Warning, Lactic Acidosis and Severe Hepatomegaly with Steatosis (Removed) 11/2018

1 INDICATIONS AND USAGE Lamivudine tablets (HBV) are indicated for the treatment of chronic hepatitis B virus (HBV) infection associated with evidence of hepatitis B viral replication and active liver inflammation [see Clinical Studies ( 14.1 , 14.2 )]. The following points should be considered when initiating therapy with lamivudine tablets (HBV): • Due to high rates of resistance development in treated patients, initiation of treatment with lamivudine tablets (HBV) should only be considered when the use of an alternative antiviral agent with a higher genetic barrier to resistance is not available or appropriate. • Lamivudine tablets (HBV) have not been evaluated in patients co-infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis delta virus. • Lamivudine tablets (HBV) have not been evaluated in liver transplant recipients or in patients with chronic hepatitis B virus infection with decompensated liver disease. Lamivudine tablets (HBV) are a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of chronic hepatitis B virus (HBV) infection associated with evidence of hepatitis B viral replication and active liver inflammation. ( 1 )

2 DOSAGE AND ADMINISTRATION • Adults: 100 mg, once daily. ( 2.2 ) • Pediatric Patients aged 2 to 17 years: 3 mg per kg once daily up to 100 mg once daily. Prescribe oral solution for pediatric patients requiring less than 100 mg daily. ( 2.3) • Patients with Renal Impairment: Doses of lamivudine tablets (HBV) must be adjusted in accordance with renal function. ( 2.4 ) • Lamivudine tablets (HBV) should not be used with other medications that contain lamivudine or emtricitabine. ( 2.5) 2.1 HIV Counseling and Testing HIV counseling and testing should be offered to all patients before beginning treatment with lamivudine tablets (HBV) and periodically during treatment because of the risk of emergence of resistant human immunodeficiency virus type 1 (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 ( 5.2 )] . 2.2 Recommended Dosage for Adult Patients The recommended oral dosage of lamivudine tablets (HBV) is 100 mg once daily. 2.3 Recommended Dosage for Pediatric Patients The recommended oral dosage of lamivudine tablets (HBV) for pediatric patients aged 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 Patients with Renal Impairment Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Clinical Pharmacology ( 12.3 )] . Table 1. Dosage of Lamivudine Tablets (HBV) in Adult Patients with Renal Impairment Cre atinine Clearance ( m L/min) Rec o mme nded Dosage of Lamivudine Tablets (HBV) ≥50 100 mg once daily 30 to 49 100 mg first dose, then 50 mg once daily 15 to 29 100 mg first dose, then 25 mg once daily 5 to 14 35 mg first dose, then 15 mg once daily <5 35 mg first dose, then 10 mg once daily Following correction of the dosage for renal impairment, no additional dosage modification of lamivudine tablets (HBV) is required after routine (4-hour) hemodialysis or peritoneal dialysis [see Clinical Pharmacology ( 12.3) ] . There are insufficient data to recommend 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. 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 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.

3 DOSAGE FORMS AND STRENGTHS Tablets: 150 mg, scored ( 3 ) Tablets: 300 mg ( 3 ) Lamivudine Scored Tablets USP 150 mg, are white to off-white scored capsule shaped, film coated tablets, debossed on both tablet faces, such that, when broken in half "L" and "5" code is present on both halves of the tablet ("L" on one side and " 5" on the opposite face of the tablet). Lamivudine Tablets USP 300 mg, are gray colored capsule shaped, film coated tablets, debossed with "L" on one side and "6" on the other side.

4 CONTRAINDICATIONS Lamivudine tablets (HBV) are contraindicated in patients with a previous hypersensitivity reaction to lamivudine. Lamivudine tablets (HBV) are contraindicated in patients with previous hypersensitivity reaction to lamivudine. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Exacerbations of hepatitis B [see Boxed Warning , Warnings and Precautions (5.1) ]. Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.2) ]. Pancreatitis [see Warnings and Precautions (5.3) ]. Immune reconstitution syndrome [see Warnings and Precautions (5.4) ]. The most common reported adverse reactions (incidence greater than or equal to 15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. (6.1) The most common reported adverse reactions (incidence greater than or equal to 15%) in pediatric subjects were fever and cough. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Inc. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Clinical Trials Experience in Adult Subjects 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 clinical practice. The safety profile of lamivudine tablets in adults is primarily based on 3,568 HIV-1-infected subjects in 7 clinical trials. The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea, and cough. Selected clinical adverse reactions in greater than or equal to 5% of subjects during therapy with lamivudine 150 mg twice daily plus RETROVIR ® 200 mg 3 times daily for up to 24 weeks are listed in Table 3. Table 3. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) Adverse Reaction Lamivudine 150 mg Twice Daily plus RETROVIR (n = 251) RETROVIR Either zidovudine monotherapy or zidovudine in combination with zalcitabine. (n = 230) Body as a Whole Headache 35% 27% Malaise & fatigue 27% 23% Fever or chills 10% 12% Digestive Nausea 33% 29% Diarrhea 18% 22% Nausea & vomiting 13% 12% Anorexia and/or decreased appetite 10% 7% Abdominal pain 9% 11% Abdominal cramps 6% 3% Dyspepsia 5% 5% Nervous System Neuropathy 12% 10% Insomnia & other sleep disorders 11% 7% Dizziness 10% 4% Depressive disorders 9% 4% Respiratory Nasal signs & symptoms 20% 11% Cough 18% 13% Skin Skin rashes 9% 6% Musculoskeletal Musculoskeletal pain 12% 10% Myalgia 8% 6% Arthralgia 5% 5% Pancreatitis Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received lamivudine tablets in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions (5.4) ]. Lamivudine Tablets 300 mg Once Daily The types and frequencies of clinical adverse reactions reported in subjects receiving lamivudine tablets 300 mg once daily or lamivudine tablets 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar. Selected laboratory abnormalities observed during therapy are summarized in Table 4. Table 4. Frequencies of Selected Grade 3 to 4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007) 24-Week Surrogate Endpoint Trials The median duration on study was 12 months. Clinical Endpoint Trial Test (Threshold Level) Lamivudine plus RETROVIR RETROVIR Either zidovudine monotherapy or zidovudine in combination with zalcitabine. Lamivudine plus Current Therapy Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine. Placebo plus Current Therapy Absolute neutrophil count (5.0 x ULN) 3.7% 3.6% 3.8% 1.9% AST (>5.0 x ULN) 1.7% 1.8% 4.0% 2.1% Bilirubin (>2.5 x ULN) 0.8% 0.4% ND ND Amylase (>2.0 x ULN) 4.2% 1.5% 2.2% 1.1% ULN = Upper limit of normal. ND = Not done. The frequencies of selected laboratory abnormaliti …

7 DRUG INTERACTIONS Sorbitol: Coadministration of lamivudine and sorbitol may result in decreased lamivudine concentrations; when possible, avoid chronic coadministration. Consider more frequent monitoring of HBV viral load when chronic coadministration cannot be avoided. ( 7.2 ) 7.1 Drugs Inhibiting Organic Cation Transporters Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim) [see Clinical Pharmacology ( 12.3 )] . No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine. 7.2 Sorbitol Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine [see Clinical Pharmacology ( 12.3 )] . Consider more frequent monitoring of HBV viral load when chronic coadministration cannot be avoided.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a 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 a U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occur at less than 20 weeks’ gestation. Of over 12,900 women exposed to lamivudine in the APR, less than 2% were HBV mono-infected. 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 (C max ) 60 times the recommended clinical dose [see Data] . Data Human Data Based on prospective reports from the APR of over 12,900 exposures to lamivudine during pregnancy resulting in live births (including over 5,400 exposed in the first trimester and over 7,500 exposed in the second/third trimester), there was no difference between the overall risk of birth defects with lamivudine compared with the background birth defect rate of 2.7% observed in the U.S. reference population of the MACDP.The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (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 2 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 a 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 Gestati …

12.1 Mechanism of Action Lamivudine is an antiviral agent with activity against HBV [ see Microbiology ( 12.4 ) ] .

11 DESCRIPTION Lamivudine (also known as 3TC), a synthetic nucleoside analogue with activity against HIV-1 and HBV. The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-) enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.3 g per mol. It has the following structural formula: Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg per mL in water at 20°C. Lamivudine Tablets, USP are for oral administration. Each scored 150-mg film-coated tablet contains 150 mg of lamivudine and the inactive ingredients microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, povidone, magnesium stearate, and opadry white which is composed of Hydroxy Propyl methylcellulose 2910/ Hypromellose 5cP, Titanium dioxide, Polyethylene glycol 400 (Macrogol). Each 300-mg film-coated tablet contains 300 mg of lamivudine and the inactive ingredients microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, povidone, magnesium stearate, and opadry white which is composed of Hydroxy Propyl methylcellulose 2910/ Hypromellose 5cP, Titanium dioxide, Polyethylene glycol 400 (Macrogol). Chemical Structure

10 OVERDOSAGE There is no known specific treatment for overdose with lamivudine tablets (HBV). If overdose occurs, the patient should be monitored and standard supportive treatment applied, as required. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

16 HOW SUPPLIED/STORAGE AND HANDLING Lamivudine Scored Tablets, 150 mg White capsule shaped, biconvex, scored film coated tablets debossed with "J" on one side and "16" on the other side, 1 and 6 seperated by a score line. Bottle of 60 tablets NDC 31722-753-60 Bottle of 600 tablets NDC 31722-753-06 Blister Card of 10 Unit-dose tablets NDC 31722-753-31 Blister pack of 100 (10 x 10) Unit-dose tablets NDC 31722-753-32 Lamivudine Tablets, 300 mg White capsule shaped, biconvex, film coated tablets debossed with "17" on one side and "J" on the other side. Bottle of 30 tablets NDC 31722-754-30 Bottle of 600 tablets NDC 31722-754-06 Blister Card of 10 Unit-dose tablets NDC 31722-754-31 Blister pack of 100 (10 x 10) Unit-dose tablets NDC 31722-754-32 Recommended Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Preserve in well-closed, light-resistant containers.