1 INDICATIONS AND USAGE Lamivudine tablets are a nucleoside analogue indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.

Limitations of Use: • The dosage of this product is for HIV-1 and not for HBV.

Lamivudine tablets are a nucleoside analogue reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Limitations of Use: The dosage of this product is for HIV-1 and not for HBV.

( 1 )

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 a (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% a Either zidovudine monotherapy or zidovudine in combination with zalcitabine.

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 a Clinical Endpoint Trial a Test (Threshold Level) Lamivudine plus RETROVIR RETROVIR b Lamivudine plus Current Therapy c Placebo plus Current Therapy c Absolute neutrophil count (<750/mm 3 ) 7.2% 5.4% 15% 13% Hemoglobin (<8.0 g/dL) 2.9% 1.8% 2.2% 3.4% Platelets (<50,000/mm 3 ) 0.4% 1.3% 2.8% 3.8% ALT (>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% a The median duration on study was 12 months.

b Either zidovudine monotherapy or zidovudine in combination with zalcitabine.

c Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.

ULN = Upper limit of normal.

ND = Not done.

The frequencies of selected laboratory abnormalities reported in subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.

Clinical Trials Experience in Pediatric Subjects Lamivudine oral solution has been studied in 638 pediatric subjects aged 3 months to 18 years in 3 clinical trials.

Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with lamivudine 4 mg per kg twice daily plus RETROVIR 160 mg per m 2 3 times daily in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.

Table 5.

Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG300 Adverse Reaction Lamivudine plus RETROVIR (n = 236) Didanosine (n = 235) Body as a Whole Fever 25% 32% Digestive Hepatomegaly 11% 11% Nausea & vomiting 8% 7% Diarrhea 8% 6% Stomatitis 6% 12% Splenomegaly 5% 8% Respiratory Cough 15% 18% Abnormal breath sounds/wheezing 7% 9% Ear, Nose, and Throat Signs or symptoms of ears a 7% 6% Nasal discharge or congestion 8% 11% Other Skin rashes 12% 14% Lymphadenopathy 9% 11% a Includes pain, discharge, erythema, or swelling of an ear.

Pancreatitis Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving lamivudine alone or in combination with other antiretroviral agents.

In an open-label dose-escalation trial (NUCA2002), 14 subjects (14%) developed pancreatitis while receiving monotherapy with lamivudine.

Three of these subjects died of complications of pancreatitis.

In a second open-label trial (NUCA2005), 12 subjects (18%) developed pancreatitis.

In Trial ACTG300, pancreatitis was not observed in 236 subjects randomized to lamivudine plus RETROVIR.

Pancreatitis was observed in 1 subject in this trial who received open-label lamivudine in combination with RETROVIR and ritonavir following discontinuation of didanosine monotherapy [see Warnings and Precautions ( 5.4 )].

Paresthesias and Peripheral Neuropathies Paresthesias and peripheral neuropathies were reported in 15 subjects (15%) in Trial NUCA2002, 6 subjects (9%) in Trial NUCA2005, and 2 subjects (less than 1%) in Trial ACTG300.

Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6.

Table 6.

Frequencies of Selected Grade 3 to 4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300 Test (Threshold Level) Lamivudine plus RETROVIR Didanosine Absolute neutrophil count (<400/mm 3 ) 8% 3% Hemoglobin (<7.0 g/dL) 4% 2% Platelets (<50,000/mm 3 ) 1% 3% ALT (>10 x ULN) 1% 3% AST (>10 x ULN) 2% 4% Lipase (>2.5 x ULN) 3% 3% Total Amylase (>2.5 x ULN) 3% 3% ULN = Upper limit of normal.

Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of lamivudine was assessed in the ARROW trial.

Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events.

The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing.

One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator.

Neonates Limited short-term safety information is available from 2 small, uncontrolled trials in South Africa in neonates receiving lamivudine with or without zidovudine for the first week of life following maternal treatment starting at Week 38 or 36 of gestation [see Clinical Pharmacology ( 12.3 )] .

Selected adverse reactions reported in these neonates included increased liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, and sepsis; 3 neonates died (1 from gastroenteritis with acidosis and convulsions, 1 from traumatic injury, and 1 from unknown causes).

Two other nonfatal gastroenteritis or diarrhea cases were reported, including 1 with convulsions; 1 infant had transient renal insufficiency associated with dehydration.

The absence of control groups limits assessments of causality, but it should be assumed that perinatally exposed infants may be at risk for adverse reactions comparable to those reported in pediatric and adult HIV-1-infected patients treated with lamivudine-containing combination regimens.

Long-term effects of in utero and infant lamivudine exposure are not known.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of lamivudine tablets.

Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.

Body as a Whole Redistribution/accumulation of body fat .

Endocrine and Metabolic Hyperglycemia.

General Weakness.

Hemic and Lymphatic Anemia (including pure red cell aplasia and severe anemias progressing on therapy).

Hepatic and Pancreatic Lactic acidosis and hepatic steatosis [see Warnings and Precautions ( 5.2 )] , posttreatment exacerbations of hepatitis B [see Warnings and Precautions ( 5.1 )] .

Hypersensitivity Anaphylaxis, urticaria.

Musculoskeletal Muscle weakness, CPK elevation, rhabdomyolysis.

Skin Alopecia, pruritus.