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WARNING: EXACERBATIONS OF HEPATITIS B and DIFFERENT FORMULATIONS OF EPIVIR Exacerbations of Hepatitis B Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued EPIVIR. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue EPIVIR and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions ( 5.1 )]. Important Differences among Lamivudine-Containing Products EPIVIR tablets and oral solution (used to treat HIV-1 infection) contain a higher dose of the active ingredient (lamivudine) than EPIVIR-HBV tablets and oral solution (used to treat chronic HBV infection). Patients with HIV-1 infection should receive only dosage forms appropriate for treatment of HIV-1 [see Warnings and Precautions ( 5.1 )]. WARNING: EXACERBATIONS OF HEPATITIS B and DIFFERENT FORMULATIONS OF EPIVIR See full prescribing information for complete boxed warning • Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued EPIVIR. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.1 ) • Patients with HIV-1 infection should receive only dosage forms of EPIVIR appropriate for treatment of HIV-1. ( 5.1 )

1 INDICATIONS AND USAGE EPIVIR is 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. EPIVIR is 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 )

2 DOSAGE AND ADMINISTRATION • Adults: 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily. ( 2.1 ) • Pediatric Patients Aged 3 Months and Older: Administered either once or twice daily. Dose should be calculated on body weight (kg) and should not exceed 300 mg daily. ( 2.2 ) • Patients with Renal Impairment: Doses of EPIVIR must be adjusted in accordance with renal function. ( 2.3 ) 2.1 Recommended Dosage for Adult Patients The recommended dosage of EPIVIR in HIV-1–infected adults is 300 mg daily, administered as either 150 mg taken orally twice daily or 300 mg taken orally once daily with or without food. If lamivudine is administered to a patient infected with HIV‑1 and HBV, the dosage indicated for HIV‑1 therapy should be used as part of an appropriate combination regimen [see Warnings and Precautions ( 5.1 )] . 2.2 Recommended Dosage for Pediatric Patients EPIVIR scored tablet is the preferred formulation for HIV-1–infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Before prescribing EPIVIR scored tablets, pediatric patients should be assessed for the ability to swallow tablets. For patients unable to safely and reliably swallow EPIVIR tablets, the oral solution formulation may be prescribed [see Warnings and Precautions ( 5.5 )] . The recommended oral dosage of EPIVIR tablets for HIV-1–infected pediatric patients is presented in Table 1 . Table 1. Dosing Recommendations for EPIVIR Scored (150-mg) Tablets in Pediatric Patients a Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment [see Clinical Studies ( 14.2 )] . b Patients may alternatively take one 300-mg tablet, which is not scored. Weight (kg) Once-Daily Dosing Regimen a Twice-Daily Dosing Regimen Using Scored 150-mg Tablet AM Dose PM Dose Total Daily Dose 14 to <20 1 tablet (150 mg) ½ tablet (75 mg) ½ tablet (75 mg) 150 mg ≥20 to <25 1½ tablets (225 mg) ½ tablet (75 mg) 1 tablet (150 mg) 225 mg ≥25 2 tablets (300 mg) b 1 tablet (150 mg) 1 tablet (150 mg) 300 mg Oral Solution The recommended dosage of EPIVIR oral solution in HIV-1–infected pediatric patients aged 3 months and older is 5 mg per kg taken orally twice daily or 10 mg per kg taken orally once daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents [see Clinical Pharmacology ( 12.3 )] . Consider HIV-1 viral load and CD4+ cell count/percentage when selecting the dosing interval for patients initiating treatment with oral solution [see Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.3 )] . 2.3 Patients with Renal Impairment Dosing of EPIVIR is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2 [see Clinical Pharmacology ( 12.3 )] . Table 2. Adjustment of Dosage of EPIVIR in Adults and Adolescents (Greater than or Equal to 25 kg) in Accordance with Creatinine Clearance Creatinine Clearance (mL/min) Recommended Dosage of EPIVIR ≥50 150 mg twice daily or 300 mg once daily 30-49 150 mg once daily 15-29 150 mg first dose, then 100 mg once daily 5-14 150 mg first dose, then 50 mg once daily <5 50 mg first dose, then 25 mg once daily No additional dosing of EPIVIR is required after routine (4-hour) hemodialysis or peritoneal dialysis.

ge of EPIVIR ≥50 150 mg twice daily or 300 mg once daily 30-49 150 mg once daily 15-29 150 mg first dose, then 100 mg once daily 5-14 150 mg first dose, then 50 mg once daily <5 50 mg first dose, then 25 mg once daily No additional dosing of EPIVIR is required after routine (4-hour) hemodialysis or peritoneal dialysis. Although there are insufficient data to recommend a specific dose adjustment of EPIVIR in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.

3 DOSAGE FORMS AND STRENGTHS • EPIVIR Scored Tablets EPIVIR scored tablets contain 150 mg of lamivudine. The tablets are white, diamond-shaped, scored, film-coated tablets debossed with “GX CJ7” on both sides. • EPIVIR Tablets EPIVIR tablets contain 300 mg of lamivudine. The tablets are gray, modified diamond-shaped, film-coated, and engraved with “GX EJ7” on one side and plain on the reverse side. • EPIVIR Oral Solution EPIVIR oral solution contains 10 mg of lamivudine per 1 mL. The solution is a clear, colorless to pale yellow, strawberry-banana flavored liquid. • Tablets: 150 mg, scored ( 3 ) • Tablets: 300 mg ( 3 ) • Oral Solution: 10 mg per mL ( 3 )

4 CONTRAINDICATIONS EPIVIR is contraindicated in patients with a previous hypersensitivity reaction to lamivudine. EPIVIR is contraindicated in patients with previous hypersensitivity reaction to lamivudine. ( 4 )

5 WARNINGS AND PRECAUTIONS • Co-infected HIV‑1/HBV Patients: Emergence of lamivudine-resistant HBV variants associated with lamivudine‑containing antiretroviral regimens has been reported. ( 5.1 ) • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. ( 5.2 ) • Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. ( 5.3 ) • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. ( 5.4 ) • Lower virologic suppression rates and increased risk of viral resistance were observed in pediatric subjects who received EPIVIR oral solution concomitantly with other antiretroviral oral solutions compared with those who received tablets. An all-tablet regimen should be used when possible. ( 5.5 ) 5.1 Patients with Hepatitis B Virus Co-Infection Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re‑emergence of HBV DNA. Although most events appear to have been self‑limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine‑containing HIV‑1 treatment regimens to non‑lamivudine–containing regimens in patients infected with both HIV‑1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow‑up for at least several months after stopping treatment. Important Differences among Lamivudine ‑ Containing Products EPIVIR tablets and oral solution contain a higher dose of the same active ingredient (lamivudine) than EPIVIR‑HBV tablets and EPIVIR‑HBV oral solution. EPIVIR‑HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in EPIVIR‑HBV are not appropriate for patients co-infected with HIV‑1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co‑infected with HIV‑1 and HBV. If treatment with EPIVIR‑HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV‑1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV‑1 treatment. If a decision is made to administer lamivudine to patients co‑infected with HIV‑1 and HBV, EPIVIR tablets, EPIVIR oral solution, or another product containing the higher dose of lamivudine should be used as part of an appropriate combination regimen. Emergence of Lamivudine-Resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV (see full prescribing information for EPIVIR-HBV). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1–infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

-1 and HBV (see full prescribing information for EPIVIR-HBV). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1–infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. 5.2 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including EPIVIR. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with EPIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations. 5.3 Pancreatitis In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, EPIVIR should be used with caution. Treatment with EPIVIR should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions ( 6.1 )] . 5.4 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EPIVIR. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.5 Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution Pediatric subjects who received EPIVIR oral solution (at weight band-based doses approximating 8 mg per kg per day) concomitantly with other antiretroviral oral solutions at any time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving EPIVIR tablets [see Clinical Pharmacology ( 12.3 ), Microbiology ( 12.4 ), Clinical Studies ( 14.2 )] . EPIVIR scored tablet is the preferred formulation for HIV-1‑infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol [see Clinical Pharmacology ( 12.3 )] . Consider more frequent monitoring of HIV-1 viral load when treating with EPIVIR oral solution.

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 ViiV Healthcare at 1-877-844-8872 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 EPIVIR 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 EPIVIR 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) a Either zidovudine monotherapy or zidovudine in combination with zalcitabine. Adverse Reaction EPIVIR 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% Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received EPIVIR in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions ( 5.3 )]. EPIVIR 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving EPIVIR 300 mg once daily or EPIVIR 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 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007) a The median duration on study was 12 months. b Either zidovudine monotherapy or zidovudine in combination with zalcitabine.

4. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007) 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. Test (Threshold Level) 24-Week Surrogate Endpoint Trials a Clinical Endpoint Trial a EPIVIR plus RETROVIR RETROVIR b EPIVIR 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% The frequencies of selected laboratory abnormalities reported in subjects receiving EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar. Clinical Trials Experience in Pediatric Subjects EPIVIR 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 EPIVIR 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 a Includes pain, discharge, erythema, or swelling of an ear. Adverse Reaction EPIVIR 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% Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside‑experienced pediatric subjects receiving EPIVIR 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 EPIVIR. 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 EPIVIR plus RETROVIR. Pancreatitis was observed in 1 subject in this trial who received open‑label EPIVIR in combination with RETROVIR and ritonavir following discontinuation of didanosine monotherapy [see Warnings and Precautions ( 5.3 )]. 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 3-4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300 ULN = Upper limit of normal.

%) 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 3-4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300 ULN = Upper limit of normal. Test (Threshold Level) EPIVIR 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% Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of EPIVIR 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 EPIVIR. 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.

<table ID="_Ref511894849" width="98.22%"><caption>Table 3. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)</caption><col width="50%"/><col width="25%"/><col width="25%"/><tfoot><tr><td align="left" colspan="3" valign="top">^aEither zidovudine monotherapy or zidovudine in combination with zalcitabine.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR 150 mg</content></paragraph><paragraph><content styleCode="bold">Twice Daily </content></paragraph><paragraph><content styleCode="bold">plus RETROVIR</content></paragraph><paragraph><content styleCode="bold">(n = 251)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">RETROVIR^a</content></paragraph><paragraph><content styleCode="bold">(n = 230)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>35%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Malaise &amp; fatigue</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Fever or chills</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Digestive</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>33%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>29%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nausea &amp; vomiting</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Anorexia and/or decreased appetite</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Abdominal pain</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>

><td align="center" styleCode="Rrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Abdominal pain</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph> 9%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Abdominal cramps</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Dyspepsia</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Neuropathy</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Insomnia &amp; other sleep disorders</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Dizziness</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Depressive disorders</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Respiratory</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nasal signs &amp; symptoms</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Cough</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Skin</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Skin rashes</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Musculoskeletal pain</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10%</paragraph></td></tr><t

lign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Musculoskeletal pain</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10%</paragraph></td></tr><t r><td styleCode="Rrule Lrule " valign="top"><paragraph> Myalgia</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Arthralgia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr></tbody></table> <table ID="_Ref511894897" width="100%"><caption>Table 4. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007)</caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tfoot><tr><td align="left" colspan="5" valign="top">^aThe median duration on study was 12 months. ^bEither zidovudine monotherapy or zidovudine in combination with zalcitabine. ^cCurrent therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine. ULN = Upper limit of normal.

="left" colspan="5" valign="top">^aThe median duration on study was 12 months. ^bEither zidovudine monotherapy or zidovudine in combination with zalcitabine. ^cCurrent therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine. ULN = Upper limit of normal. ND = Not done.</td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Test</content></paragraph><paragraph><content styleCode="bold">(Threshold Level)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">24-Week Surrogate Endpoint</content></paragraph><paragraph><content styleCode="bold">Trials^a</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Clinical Endpoint</content></paragraph><paragraph><content styleCode="bold">Trial^a</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR plus RETROVIR</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">RETROVIR^b</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR </content></paragraph><paragraph><content styleCode="bold">plus</content></paragraph><paragraph><content styleCode="bold">Current Therapy^c</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Placebo </content></paragraph><paragraph><content styleCode="bold">plus</content></paragraph><paragraph><content styleCode="bold">Current Therapy^c</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Absolute neutrophil count (&lt;750/mm³)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7.2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5.4%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Hemoglobin (&lt;8.0 g/dL)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.9%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Platelets (&lt;50,000/mm³)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.4%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>ALT (&gt;5.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.7%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.6%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>AST (&gt;5.0 x ULN)</paragraph></td>

e="Rrule " valign="top"><paragraph>3.6%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>AST (&gt;5.0 x ULN)</paragraph></td> <td align="center" styleCode="Rrule " valign="top"><paragraph>1.7%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4.0%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Bilirubin (&gt;2.5 x ULN)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.4%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>ND</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>ND</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Amylase (&gt;2.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.2%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.5%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.2%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.1%</paragraph></td></tr></tbody></table> <table ID="_Ref511894940" width="100%"><caption>Table 5.

<td align="center" styleCode="Rrule " valign="top"><paragraph>1.7%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1.8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4.0%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Bilirubin (&gt;2.5 x ULN)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0.4%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>ND</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>ND</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Amylase (&gt;2.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.2%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.5%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.2%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.1%</paragraph></td></tr></tbody></table> <table ID="_Ref511894940" width="100%"><caption>Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG300</caption><col width="46%"/><col width="27%"/><col width="27%"/><tfoot><tr><td align="left" colspan="3" valign="top">^aIncludes pain, discharge, erythema, or swelling of an ear.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR plus </content> <content styleCode="bold">RETROVIR</content></paragraph><paragraph><content styleCode="bold">(n = 236)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Didanosine</content></paragraph><paragraph><content styleCode="bold">(n = 235)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Fever</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>32%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Digestive</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Hepatomegaly</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nausea &amp; vomiting</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Stomatitis</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Splenomegaly </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Respiratory</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Cough</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Abnormal breath sounds/wheezing</paragraph></td><td align="center" styleCode="Rr

ragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Abnormal breath sounds/wheezing</paragraph></td><td align="center" styleCode="Rr ule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Ear, Nose, and Throat </content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Signs or symptoms of ears^a</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nasal discharge or congestion</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Other</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Skin rashes</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Lymphadenopathy</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11%</paragraph></td></tr></tbody></table>

</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Lymphadenopathy</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11%</paragraph></td></tr></tbody></table> <table ID="_Ref511894987" width="97.68%"><caption>Table 6. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300</caption><col width="57%"/><col width="23%"/><col width="20%"/><tfoot><tr><td align="left" colspan="3" valign="top">ULN = Upper limit of normal.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Test</content></paragraph><paragraph><content styleCode="bold">(Threshold Level)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR plus </content></paragraph><paragraph><content styleCode="bold">RETROVIR</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Didanosine</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Absolute neutrophil count (&lt;400/mm³)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Hemoglobin (&lt;7.0 g/dL)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Platelets (&lt;50,000/mm³)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>ALT (&gt;10 x ULN)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>AST (&gt;10 x ULN)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Lipase (&gt;2.5 x ULN)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Total Amylase (&gt;2.5 x ULN)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration. ( 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 Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS • Lactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPIVIR 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 difference in the overall risk of birth defects for lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data) . The APR uses the MACDP as the 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 occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, 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 development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose ( see Data ). Data Human Data: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of 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. Lamivudine pharmacokinetics were studied in pregnant women 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 with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. 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 concentration (n = 8).

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 concentration (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 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C max ) 35 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. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommends that HIV-1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Lamivudine is present in human milk. There is no information on the effects of lamivudine on the breastfed infant or the effects of the drugs on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving EPIVIR. 8.4 Pediatric Use The safety and effectiveness of EPIVIR in combination with other antiretroviral agents have been established in pediatric patients aged 3 months and older. EPIVIR scored tablet is the preferred formulation for HIV-1‑infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate because pediatric subjects who received EPIVIR oral solution had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving EPIVIR tablets in the ARROW trial [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] . 8.5 Geriatric Use Clinical trials of EPIVIR 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 EPIVIR 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 ( 2.3 ), Clinical Pharmacology ( 12.3 )] . 8.6 Patients with Impaired Renal Function Reduction of the dosage of EPIVIR is recommended for patients with impaired renal function [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPIVIR 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 difference in the overall risk of birth defects for lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data) . The APR uses the MACDP as the 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 occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, 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 development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose ( see Data ). Data Human Data: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of 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. Lamivudine pharmacokinetics were studied in pregnant women 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 with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. 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 concentration (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 7 through 16 [rat] and 8 through 20 [rabbit]).

nal serum concentration (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 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C max ) 35 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.

8.4 Pediatric Use The safety and effectiveness of EPIVIR in combination with other antiretroviral agents have been established in pediatric patients aged 3 months and older. EPIVIR scored tablet is the preferred formulation for HIV-1‑infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate because pediatric subjects who received EPIVIR oral solution had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving EPIVIR tablets in the ARROW trial [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] .

8.5 Geriatric Use Clinical trials of EPIVIR 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 EPIVIR 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 ( 2.3 ), Clinical Pharmacology ( 12.3 )] .

10 OVERDOSAGE There is no known specific treatment for overdose with EPIVIR. 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.

11 DESCRIPTION EPIVIR (also known as 3TC) is a brand name for lamivudine, 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. EPIVIR tablets are for oral administration. Each scored 150-mg film-coated tablet contains 150 mg of lamivudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide. Each 300-mg film-coated tablet contains 300 mg of lamivudine and the inactive ingredients black iron oxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide. EPIVIR oral solution is for oral administration. One milliliter (1 mL) of EPIVIR oral solution contains 10 mg of lamivudine (10 mg per mL) in an aqueous solution and the inactive ingredients artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg). lamivudine structural formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lamivudine is an antiretroviral agent [see Microbiology ( 12.4 )]. 12.3 Pharmacokinetics Pharmacokinetics in Adults The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1–infected adult subjects after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg per kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg per kg. The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg per day administered to HBV-infected subjects. The steady-state pharmacokinetic properties of the EPIVIR 300-mg tablet once daily for 7 days compared with the EPIVIR 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma AUC 24,ss ; however, C max,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC 24,ss and C max24,ss ; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The pharmacokinetics of lamivudine was evaluated in 12 adult HIV-1–infected subjects dosed with lamivudine 150 mg twice daily in combination with other antiretroviral agents. The geometric mean (95% CI) for AUC (0-12) was 5.53 (4.58, 6.67) mcg•h per mL and for C max was 1.40 (1.17, 1.69) mcg per mL. Absorption and Bioavailability: Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg per kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (C max ) was 1.5 ± 0.5 mcg per mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and C max increased in proportion to oral dose over the range from 0.25 to 10 mg per kg. The accumulation ratio of lamivudine in HIV-1–positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg per kg twice daily. Effects of Food on Oral Absorption: EPIVIR tablets and oral solution may be administered with or without food. An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1–infected subjects on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (T max : 3.2 ± 1.3 hours) compared with the fasted state (T max : 0.9 ± 0.3 hours); C max in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. 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 subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight. Binding of lamivudine to human plasma proteins is less than 36%.

nt volume of distribution after IV administration of lamivudine to 20 subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight. Binding of lamivudine to human plasma proteins is less than 36%. In vitro studies showed that over the concentration range of 0.1 to 100 mcg per mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration. Metabolism: Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (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 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL per min (mean ± SD). In 20 HIV-1–infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine. In most single-dose trials in HIV-1–infected subjects, HBV‑infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-1–infected subjects, total clearance was 398.5 ± 69.1 mL per min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg per kg. Specific Populations Patients with Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-1‑infected adults with impaired renal function ( Table 7 ). Table 7. Pharmacokinetic Parameters (Mean ± SD) after a Single 300-mg Oral Dose of Lamivudine in 3 Groups of Adults with Varying Degrees of Renal Function Parameter Creatinine Clearance Criterion (Number of Subjects) >60 mL/min (n = 6) 10-30 mL/min (n = 4) <10 mL/min (n = 6) Creatinine clearance (mL/min) 111 ± 14 28 ± 8 6 ± 2 C max (mcg/mL) 2.6 ± 0.5 3.6 ± 0.8 5.8 ± 1.2 AUC∞ (mcg•h/mL) 11.0 ± 1.7 48.0 ± 19 157 ± 74 Cl/F (mL/min) 464 ± 76 114 ± 34 36 ± 11 T max 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 ( 2.3 )] . Based on a trial in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL per min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis. The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known. Patients with Hepatic Impairment: The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease. Pregnant Women: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa.

tion. Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease. Pregnant Women: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. 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: The pharmacokinetics of lamivudine have been studied after either single or repeat doses of EPIVIR in 210 pediatric subjects. Pediatric subjects receiving lamivudine oral solution (dosed at approximately 8 mg per kg per day) achieved approximately 25% lower plasma concentrations of lamivudine compared with HIV-1–infected adults. Pediatric subjects receiving lamivudine oral tablets achieved plasma concentrations comparable to or slightly higher than those observed in adults. The absolute bioavailability of both EPIVIR tablets and oral solution are lower in children than adults. The relative bioavailability of EPIVIR oral solution is approximately 40% lower than tablets containing lamivudine in pediatric subjects despite no difference in adults. Lower lamivudine exposures in pediatric patients receiving EPIVIR oral solution is likely due to the interaction between lamivudine and concomitant solutions containing sorbitol (such as ZIAGEN). Modeling of pharmacokinetic data suggests increasing the dosage of EPIVIR oral solution to 5 mg per kg taken orally twice daily or 10 mg per kg taken orally once daily (up to a maximum of 300 mg daily) is needed to achieve sufficient concentrations of lamivudine [see Dosage and Administration ( 2.2 )] . There are no clinical data in HIV-1‑infected pediatric patients coadministered with sorbitol-containing medicines at this dose. The pharmacokinetics of lamivudine dosed once daily in HIV-1‑infected pediatric subjects aged 3 months through 12 years was evaluated in 3 trials (PENTA-15 [n = 17], PENTA 13 [n = 19], and ARROW PK [n = 35]). All 3 trials were 2-period, crossover, open-label pharmacokinetic trials of twice- versus once-daily dosing of abacavir and lamivudine. These 3 trials demonstrated that once-daily dosing provides similar AUC 0-24 to twice-daily dosing of lamivudine at the same total daily dose when comparing the dosing regimens within the same formulation (i.e., either the oral solution or the tablet formulation). The mean C max was approximately 80% to 90% higher with lamivudine once-daily dosing compared with twice-daily dosing. Table 8. Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat Dosing of Lamivudine in 3 Pediatric Trials a n = 16 for PENTA-15 C max . b Solution was dosed at 8 mg per kg per day. c Five subjects in PENTA-13 received lamivudine tablets. Trial (Number of Subjects) ARROW PK (n = 35) PENTA-13 (n = 19) PENTA-15 (n = 17) a Age Range 3-12 years 2-12 years 3-36 months Formulation Tablet Solution b and Tablet c Solution b Parameter Once Daily Twice Daily Once Daily Twice Daily Once Daily Twice Daily C max (mcg/mL) 3.17 (2.76, 3.64) 1.80 (1.59, 2.04) 2.09 (1.80, 2.42) 1.11 (0.96, 1.29) 1.87 (1.65, 2.13) 1.05 (0.88, 1.26) AUC (0-24) (mcg•h/mL) 13.0 (11.4, 14.9) 12.0 (10.7, 13.4) 9.80 (8.64, 11.1) 8.88 (7.67, 10.3) 8.66 (7.46, 10.1) 9.48 (7.89, 11.4) Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose.

4) (mcg•h/mL) 13.0 (11.4, 14.9) 12.0 (10.7, 13.4) 9.80 (8.64, 11.1) 8.88 (7.67, 10.3) 8.66 (7.46, 10.1) 9.48 (7.89, 11.4) Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg per kg per day, CSF lamivudine concentrations in 8 subjects ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg per mL. Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants aged up to 1 week in 2 trials in South Africa. In these trials, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric subjects (aged over 3 months) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges over 3 months old [see Adverse Reactions ( 6.1 )] . Geriatric Patients: The pharmacokinetics of lamivudine after administration of EPIVIR 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 1 (MATE)1, MATE2-K, organic cation transporter 1 (OCT)1, OCT2, or OCT3. Effect of Other Agents on the Pharmacokinetics of Lamivudine: Lamivudine is a 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 as no dose adjustment of lamivudine is needed. Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a 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 a 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 a 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 a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution.

ine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a 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 (0-24) , 14%, 32%, and 36% in the AUC (∞) , and 28%, 52%, and 55% in the C max ; of lamivudine, respectively. Trimethoprim/Sulfamethoxazole: Lamivudine and TMP/SMX were coadministered to 14 HIV‑1–positive subjects in a single‑center, open‑label, randomized, crossover trial. Each subject received treatment with a single 300‑mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used in treat PCP. Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1–infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours). 12.4 Microbiology Mechanism of Action Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. Antiviral Activity The antiviral activity of lamivudine against HIV‑1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC 50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC 50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV‑1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC 50 values against HIV‑2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Lamivudine was not antagonistic to all tested anti-HIV agents. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV‑1 activity of lamivudine by 3.5‑fold in MT‑4 cells. Resistance Lamivudine‑resistant variants of HIV‑1 have been selected in cell culture. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV‑1 reverse transcriptase at codon 184 changing the methionine to either valine or isoleucine (M184V/I). HIV‑1 strains resistant to both lamivudine and zidovudine have been isolated from subjects. Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV‑1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks.

ptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV‑1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks. Genotypic and Phenotypic Analysis of On ‑ Therapy HIV ‑ 1 Isolates from Subjects with Virologic Failure Trial EPV20001: Fifty‑three of 554 (10%) subjects enrolled in EPV20001 were identified as virological failures (plasma HIV‑1 RNA level greater than or equal to 400 copies per mL) by Week 48. Twenty-eight subjects were randomized to the lamivudine once‑daily treatment group and 25 to the lamivudine twice‑daily treatment group. The median baseline plasma HIV‑1 RNA levels of subjects in the lamivudine once‑daily group and lamivudine twice‑daily group were 4.9 log 10 copies per mL and 4.6 log 10 copies per mL, respectively. Genotypic analysis of on‑therapy isolates from 22 subjects identified as virologic failures in the lamivudine once‑daily group showed that isolates from 8 of 22 subjects contained a treatment‑emergent lamivudine resistance‑associated substitution (M184V or M184I), isolates from 0 of 22 subjects contained treatment‑emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), and isolates from 10 of 22 subjects contained treatment‑emergent amino acid substitutions associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C). Genotypic analysis of on‑therapy isolates from subjects (n = 22) in the lamivudine twice‑daily treatment group showed that isolates from 5 of 22 subjects contained treatment‑emergent lamivudine resistance substitutions, isolates from 1 of 22 subjects contained treatment‑emergent zidovudine resistance substitutions, and isolates from 7 of 22 subjects contained treatment‑emergent efavirenz resistance substitutions. Phenotypic analysis of baseline‑matched on‑therapy HIV‑1 isolates from subjects (n = 13) receiving lamivudine once daily showed that isolates from 7 of 13 subjects showed an 85- to 299‑fold decrease in susceptibility to lamivudine, isolates from 12 of 13 subjects were susceptible to zidovudine, and isolates from 8 of 13 subjects exhibited a 25- to 295‑fold decrease in susceptibility to efavirenz. Phenotypic analysis of baseline‑matched on‑therapy HIV‑1 isolates from subjects (n = 13) receiving lamivudine twice daily showed that isolates from 4 of 13 subjects exhibited a 29- to 159‑fold decrease in susceptibility to lamivudine, isolates from all 13 subjects were susceptible to zidovudine, and isolates from 3 of 13 subjects exhibited a 21- to 342‑fold decrease in susceptibility to efavirenz. Trial EPV40001: Fifty subjects received lamivudine 300 mg once daily plus zidovudine 300 mg twice daily plus abacavir 300 mg twice daily and 50 subjects received lamivudine 150 mg plus zidovudine 300 mg plus abacavir 300 mg all twice-daily. The median baseline plasma HIV‑1 RNA levels for subjects in the 2 groups were 4.79 log 10 copies per mL and 4.83 log 10 copies per mL, respectively. Fourteen of 50 subjects in the lamivudine once‑daily treatment group and 9 of 50 subjects in the lamivudine twice‑daily group were identified as virologic failures. Genotypic analysis of on‑therapy HIV‑1 isolates from subjects (n = 9) in the lamivudine once‑daily treatment group showed that isolates from 6 subjects had an abacavir and/or lamivudine resistance‑associated substitution M184V alone.

50 subjects in the lamivudine twice‑daily group were identified as virologic failures. Genotypic analysis of on‑therapy HIV‑1 isolates from subjects (n = 9) in the lamivudine once‑daily treatment group showed that isolates from 6 subjects had an abacavir and/or lamivudine resistance‑associated substitution M184V alone. On‑therapy isolates from subjects (n = 6) receiving lamivudine twice daily showed that isolates from 2 subjects had M184V alone, and isolates from 2 subjects harbored the M184V substitution in combination with zidovudine resistance‑associated amino acid substitutions. Phenotypic analysis of on‑therapy isolates from subjects (n = 6) receiving lamivudine once daily showed that HIV‑1 isolates from 4 subjects exhibited a 32- to 53‑fold decrease in susceptibility to lamivudine. HIV‑1 isolates from these 6 subjects were susceptible to zidovudine. Phenotypic analysis of on‑therapy isolates from subjects (n = 4) receiving lamivudine twice daily showed that HIV‑1 isolates from 1 subject exhibited a 45‑fold decrease in susceptibility to lamivudine and a 4.5‑fold decrease in susceptibility to zidovudine. Pediatrics: Pediatric subjects receiving lamivudine oral solution concomitantly with other antiretroviral oral solutions (abacavir, nevirapine/efavirenz, or zidovudine) in ARROW developed viral resistance more frequently than those receiving tablets. At randomization to once-daily or twice-daily dosing of EPIVIR plus abacavir, 13% of subjects who started on tablets and 32% of subjects who started on solution had resistance substitutions. The resistance profile observed in pediatrics is similar to that observed in adults in terms of the genotypic substitutions detected and relative frequency, with the most commonly detected substitutions at M184 (V or I) [see Clinical Studies ( 14.2 )] . Cross-Resistance Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (NRTIs). Lamivudine-resistant HIV-1 mutants were cross-resistant in cell culture to didanosine (ddI). Cross-resistance is also expected with abacavir and emtricitabine as these select M184V substitutions.

12.3 Pharmacokinetics Pharmacokinetics in Adults The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1–infected adult subjects after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg per kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg per kg. The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg per day administered to HBV-infected subjects. The steady-state pharmacokinetic properties of the EPIVIR 300-mg tablet once daily for 7 days compared with the EPIVIR 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma AUC 24,ss ; however, C max,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC 24,ss and C max24,ss ; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The pharmacokinetics of lamivudine was evaluated in 12 adult HIV-1–infected subjects dosed with lamivudine 150 mg twice daily in combination with other antiretroviral agents. The geometric mean (95% CI) for AUC (0-12) was 5.53 (4.58, 6.67) mcg•h per mL and for C max was 1.40 (1.17, 1.69) mcg per mL. Absorption and Bioavailability: Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg per kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (C max ) was 1.5 ± 0.5 mcg per mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and C max increased in proportion to oral dose over the range from 0.25 to 10 mg per kg. The accumulation ratio of lamivudine in HIV-1–positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg per kg twice daily. Effects of Food on Oral Absorption: EPIVIR tablets and oral solution may be administered with or without food. An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1–infected subjects on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (T max : 3.2 ± 1.3 hours) compared with the fasted state (T max : 0.9 ± 0.3 hours); C max in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. 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 subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight. Binding of lamivudine to human plasma proteins is less than 36%.

ine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a 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 (0-24) , 14%, 32%, and 36% in the AUC (∞) , and 28%, 52%, and 55% in the C max ; of lamivudine, respectively. Trimethoprim/Sulfamethoxazole: Lamivudine and TMP/SMX were coadministered to 14 HIV‑1–positive subjects in a single‑center, open‑label, randomized, crossover trial. Each subject received treatment with a single 300‑mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used in treat PCP. Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1–infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).

<table ID="_Ref511895273" width="100.28%"><caption>Table 7. Pharmacokinetic Parameters (Mean &#xB1; SD) after a Single 300-mg Oral Dose of Lamivudine in 3 Groups of Adults with Varying Degrees of Renal Function</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Parameter</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Creatinine Clearance Criterion</content></paragraph><paragraph><content styleCode="bold">(Number of Subjects)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">&gt;60 mL/min</content></paragraph><paragraph><content styleCode="bold">(n = 6)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">10-30 mL/min</content></paragraph><paragraph><content styleCode="bold">(n = 4)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">&lt;10 mL/min</content></paragraph><paragraph><content styleCode="bold">(n = 6)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Creatinine clearance (mL/min)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>111 &#xB1; 14</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>28 &#xB1; 8</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6 &#xB1; 2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>C_max (mcg/mL)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.6 &#xB1; 0.5</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.6 &#xB1; 0.8</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5.8 &#xB1; 1.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>AUC&#x221E; (mcg&#x2022;h/mL)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11.0 &#xB1; 1.7</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>48.0 &#xB1; 19</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>157 &#xB1; 74</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Cl/F (mL/min)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>464 &#xB1; 76</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>114 &#xB1; 34</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>36 &#xB1; 11</paragraph></td></tr></tbody></table>

<td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>464 &#xB1; 76</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>114 &#xB1; 34</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>36 &#xB1; 11</paragraph></td></tr></tbody></table> <table ID="_RefID0EPCAI" width="99.2%"><caption>Table 8. Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat Dosing of Lamivudine in 3 Pediatric Trials</caption><col width="16%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><tfoot><tr><td align="left" colspan="7" valign="top">^a n = 16 for PENTA-15 C_max. ^bSolution was dosed at 8 mg per kg per day.

ne in 3 Pediatric Trials</caption><col width="16%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><tfoot><tr><td align="left" colspan="7" valign="top">^a n = 16 for PENTA-15 C_max. ^bSolution was dosed at 8 mg per kg per day. ^cFive subjects in PENTA-13 received lamivudine tablets.</td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"/><td align="center" colspan="6" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Trial</content></paragraph><paragraph><content styleCode="bold">(Number of Subjects)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">ARROW PK</content></paragraph><paragraph><content styleCode="bold">(n = 35)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">PENTA-13</content></paragraph><paragraph><content styleCode="bold">(n = 19)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">PENTA-15</content></paragraph><paragraph><content styleCode="bold">(n = 17)^a</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Age Range</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">3-12 years</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">2-12 years</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">3-36 months</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Formulation</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Tablet</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Solution^b and Tablet^c</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Solution^b</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Parameter</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Once </content></paragraph><paragraph><content styleCode="bold">Daily</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Twice </content></paragraph><paragraph><content styleCode="bold">Daily</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Once Daily</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Twice </content></paragraph><paragraph><content styleCode="bold">Daily</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Once Daily</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Twice </content></paragraph><pa

tyleCode="bold">Daily</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Once Daily</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Twice </content></paragraph><pa ragraph><content styleCode="bold">Daily</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>C_max</paragraph><paragraph>(mcg/mL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.17 (2.76, 3.64)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.80 (1.59, 2.04)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.09 (1.80, 2.42)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.11 (0.96, 1.29)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.87 (1.65, 2.13)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.05 (0.88, 1.26)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>AUC_(0-24)</paragraph><paragraph>(mcg&#x2022;h/mL)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>13.0 (11.4, 14.9)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>12.0 (10.7, 13.4)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>9.80 (8.64, 11.1)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>8.88 (7.67, 10.3)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>8.66 (7.46, 10.1)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>9.48 (7.89, 11.4)</paragraph></td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long‑term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg. Mutagenesis Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV‑1 infection. Impairment of Fertility In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long‑term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg. Mutagenesis Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV‑1 infection. Impairment of Fertility In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

14 CLINICAL STUDIES The use of EPIVIR is based on the results of clinical trials in HIV-1–infected subjects in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials. 14.1 Adult Subjects Clinical Endpoint Trial NUCB3007 (CAESAR) was a multicenter, double‑blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-1–infected adults with 25 to 250 CD4+ cells per mm 3 (median = 122 cells per mm 3 ) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on trial was 12 months. Results are summarized in Table 9 . Table 9. Number of Subjects (%) with at Least One HIV-1 Disease Progression Event or Death a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States. Endpoint Current Therapy (n = 460) EPIVIR plus Current Therapy (n = 896) EPIVIR plus an NNRTI a plus Current Therapy (n = 460) HIV-1 progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%) Death 27 (5.9%) 23 (2.6%) 14 (3.0%) Surrogate Endpoint Trials Dual Nucleoside Analogue Trials: Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These trials demonstrated the antiviral effect of lamivudine in a 2-drug combination. More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression. Dose Regimen Comparison Surrogate Endpoint Trials in Therapy-Naive Adults: EPV20001 was a multicenter, double‑blind, controlled trial in which subjects were randomized 1:1 to receive EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral treatment-naive HIV-1–infected adults enrolled: male (79%), white (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells per mm 3 (median = 362 cells per mm 3 ), and median baseline plasma HIV-1 RNA of 4.66 log 10 copies per mL. Outcomes of treatment through 48 weeks are summarized in Figure 1 and Table 10 . Figure 1. Virologic Response through Week 48, EPV20001 a,b (Intent-to-Treat) a Roche AMPLICOR HIV-1 MONITOR. b Responders at each visit are subjects who had achieved and maintained HIV-1 RNA less than 400 copies per mL without discontinuation by that visit. Table 10. Outcomes of Randomized Treatment through 48 Weeks (Intent-to-Treat) a Achieved confirmed plasma HIV-1 RNA less than 400 copies per mL and maintained through 48 weeks. b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48. c Includes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment.

ion but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48. c Includes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment. Outcome EPIVIR 300 mg Once Daily plus RETROVIR plus Efavirenz (n = 278) EPIVIR 150 mg Twice Daily plus RETROVIR plus Efavirenz (n = 276) Responder a 67% 65% Virologic failure b 8% 8% Discontinued due to clinical progression <1% 0% Discontinued due to adverse events 6% 12% Discontinued due to other reasons c 18% 14% The proportions of subjects with HIV-1 RNA less than 50 copies per mL (via Roche Ultrasensitive assay) through Week 48 were 61% for subjects receiving EPIVIR 300 mg once daily and 63% for subjects receiving EPIVIR 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells per mm 3 at Week 48 in subjects receiving EPIVIR 300 mg once daily and 146 cells per mm 3 for subjects receiving EPIVIR 150 mg twice daily. A small, randomized, open‑label pilot trial, EPV40001, was conducted in Thailand. A total of 159 treatment‑naive adult subjects (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells per mm 3 , median plasma HIV‑1 RNA 4.8 log 10 copies per mL) were enrolled. Two of the treatment arms in this trial provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily. In intent‑to‑treat analyses of 48‑week data, the proportions of subjects with HIV‑1 RNA below 400 copies per mL were 61% (33 of 54) in the group randomized to once‑daily lamivudine and 75% (39 of 52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV‑1 RNA below 50 copies per mL were 54% (29 of 54) in the once‑daily lamivudine group and 67% (35 of 52) in the all‑twice‑daily group; and the median increases in CD4+ cell counts were 166 cells per mm 3 in the once‑daily lamivudine group and 216 cells per mm 3 in the all‑twice‑daily group. Figure 1. Virologic Response Through Week 48, EPV20001ab (Intent-to-Treat 14.2 Pediatric Subjects Clinical Endpoint Trial ACTG300 was a multicenter, randomized, double‑blind trial that provided for comparison of EPIVIR plus RETROVIR (zidovudine) with didanosine monotherapy. A total of 471 symptomatic, HIV-1–infected therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-white. The mean baseline CD4+ cell count was 868 cells per mm 3 (mean: 1,060 cells per mm 3 and range: 0 to 4,650 cells per mm 3 for subjects aged less than or equal to 5 years; mean: 419 cells per mm 3 and range: 0 to 1,555 cells per mm 3 for subjects aged over 5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log 10 copies per mL. The median duration on trial was 10.1 months for the subjects receiving EPIVIR plus RETROVIR and 9.2 months for subjects receiving didanosine monotherapy. Results are summarized in Table 11 . Table 11. Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death) Endpoint EPIVIR plus RETROVIR (n = 236) Didanosine (n = 235) HIV-1 disease progression or death (total) 15 (6.4%) 37 (15.7%) Physical growth failure 7 (3.0%) 6 (2.6%) Central nervous system deterioration 4 (1.7%) 12 (5.1%) CDC Clinical Category C 2 (0.8%) 8 (3.4%) Death 2 (0.8%) 11 (4.7%) Once-Daily Dosing ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects.

re 7 (3.0%) 6 (2.6%) Central nervous system deterioration 4 (1.7%) 12 (5.1%) CDC Clinical Category C 2 (0.8%) 8 (3.4%) Death 2 (0.8%) 11 (4.7%) Once-Daily Dosing ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1–infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing EPIVIR and abacavir, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks on treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of EPIVIR and abacavir, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Virologic suppression was not a requirement for participation: at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort. The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks is shown in Table 12 . The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age. Table 12. Virologic Outcome of Randomized Treatment at Week 96 a (ARROW Randomization 3) a Analyses were based on the last observed viral load data within the Week 96 window. b Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96. c Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol. d Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing). Outcome EPIVIR plus Abacavir Twice-Daily Dosing (n = 333) EPIVIR plus Abacavir Once-Daily Dosing (n = 336) HIV-1 RNA <80 copies/mL b 70% 67% HIV-1 RNA ≥80 copies/mL c 28% 31% No virologic data Discontinued due to adverse event or death 1% <1% Discontinued study for other reasons d 0% <1% Missing data during window but on study 1% 1% Analyses by formulation demonstrated the proportion of subjects with HIV-1 RNA of less than 80 copies per mL at randomization and Week 96 was higher in subjects who had received tablet formulations of EPIVIR and abacavir (75% [458/610] and 72% [434/601]) than in those who had received solution formulation(s) (with EPIVIR solution given at weight band-based doses approximating 8 mg per kg per day) at any time (52% [29/56] and 54% [30/56]), respectively [see Warnings and Precautions ( 5.5 )] . These differences were observed in each different age group evaluated.

<table ID="_Ref511895485" width="101.48%"><caption>Table 9. Number of Subjects (%) with at Least One HIV-1 Disease Progression Event or Death</caption><col width="37%"/><col width="17%"/><col width="20%"/><col width="26%"/><tfoot><tr><td align="left" colspan="4" valign="top">^aAn investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Endpoint</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Current </content></paragraph><paragraph><content styleCode="bold">Therapy</content></paragraph><paragraph><content styleCode="bold">(n = 460)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR plus</content></paragraph><paragraph><content styleCode="bold">Current </content></paragraph><paragraph><content styleCode="bold">Therapy</content></paragraph><paragraph><content styleCode="bold">(n = 896)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR plus an</content></paragraph><paragraph><content styleCode="bold">NNRTI^a plus</content></paragraph><paragraph><content styleCode="bold">Current Therapy</content></paragraph><paragraph><content styleCode="bold">(n = 460)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>HIV-1 progression or death</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>90 (19.6%)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>86 (9.6%)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>41 (8.9%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Death</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>27 (5.9%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>23 (2.6%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>14 (3.0%)</paragraph></td></tr></tbody></table>

gn="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>27 (5.9%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>23 (2.6%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>14 (3.0%)</paragraph></td></tr></tbody></table> <table ID="_Ref511895588" width="100%"><caption>Table 10. Outcomes of Randomized Treatment through 48 Weeks (Intent-to-Treat)</caption><col width="50%"/><col width="25%"/><col width="25%"/><tfoot><tr><td align="left" colspan="3" valign="top">^aAchieved confirmed plasma HIV-1 RNA less than 400 copies per mL and maintained through 48 weeks. ^bAchieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48. ^cIncludes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Outcome</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR 300 mg </content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">plus RETROVIR</content></paragraph><paragraph><content styleCode="bold"> plus Efavirenz</content></paragraph><paragraph><content styleCode="bold">(n = 278)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR 150 mg </content></paragraph><paragraph><content styleCode="bold">Twice Daily</content></paragraph><paragraph><content styleCode="bold">plus RETROVIR </content></paragraph><paragraph><content styleCode="bold">plus Efavirenz</content></paragraph><paragraph><content styleCode="bold">(n = 276)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Responder^a</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>67%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>65%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Virologic failure^b</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Discontinued due to clinical progression</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Discontinued due to adverse events</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Discontinued due to other reasons^c</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>14%</paragraph></td></tr></tbody></table>

styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Discontinued due to other reasons^c</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>14%</paragraph></td></tr></tbody></table> <table ID="_Ref511895632" width="95.76%"><caption>Table 11. Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)</caption><col width="59%"/><col width="22%"/><col width="19%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Endpoint</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR plus </content></paragraph><paragraph><content styleCode="bold">RETROVIR</content></paragraph><paragraph><content styleCode="bold">(n = 236)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Didanosine</content></paragraph><paragraph><content styleCode="bold">(n = 235)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>HIV-1 disease progression or death (total)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>15 (6.4%)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>37 (15.7%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Physical growth failure</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7 (3.0%)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6 (2.6%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Central nervous system deterioration</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4 (1.7%)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12 (5.1%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> CDC Clinical Category C</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2 (0.8%)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8 (3.4%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Death</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2 (0.8%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11 (4.7%)</paragraph></td></tr></tbody></table>

paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Death</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2 (0.8%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11 (4.7%)</paragraph></td></tr></tbody></table> <table ID="_Ref511895682" width="96.56%"><caption>Table 12. Virologic Outcome of Randomized Treatment at Week 96^a (ARROW Randomization 3)</caption><col width="50%"/><col width="26%"/><col width="25%"/><tfoot><tr><td align="left" colspan="3" valign="top">^aAnalyses were based on the last observed viral load data within the Week 96 window. ^bPredicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96. ^cIncludes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol. ^dOther includes reasons such as withdrew consent, loss to follow-up, etc.

r loss of efficacy or for reasons other than an adverse event or death and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol. ^dOther includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Outcome</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR plus </content></paragraph><paragraph><content styleCode="bold">Abacavir </content></paragraph><paragraph><content styleCode="bold">Twice-Daily Dosing</content></paragraph><paragraph><content styleCode="bold">(n = 333)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">EPIVIR plus </content></paragraph><paragraph><content styleCode="bold">Abacavir </content></paragraph><paragraph><content styleCode="bold">Once-Daily Dosing</content></paragraph><paragraph><content styleCode="bold">(n = 336)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">HIV-1 RNA &lt;80 copies/mL^b</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>70%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>67%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">HIV-1 RNA &#x2265;80 copies/mL^c</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>31%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">No virologic data</content></paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Discontinued due to adverse event or death</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Discontinued study for other reasons^d</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Missing data during window but on study</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1%</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING EPIVIR scored tablets contain 150 mg of lamivudine, are white, diamond-shaped, film-coated, and debossed with “GX CJ7” on both sides. Packaged as follows: Bottle of 60 tablets (NDC 49702-203-18) with child-resistant closure. EPIVIR tablets contain 300 mg of lamivudine, are gray, modified diamond-shaped, film-coated, and engraved with “GX EJ7” on one side and plain on the reverse side. Packaged as follows: Bottle of 30 tablets (NDC 49702-204-13) with child-resistant closure. Recommended Storage: Store EPIVIR tablets at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. EPIVIR oral solution is a clear, colorless to pale yellow, strawberry‑banana-flavored liquid. Each mL of the solution contains 10 mg of lamivudine. Packaged as follows: Plastic bottle of 240 mL (NDC 49702-205-48) with child-resistant closure. This product does not require reconstitution. Store in tightly closed bottles at 25°C (77°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients with Hepatitis B or C Co-Infection Inform patients co‑infected with HIV‑1 and HBV that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see Warnings and Precautions ( 5.1 )] . Differences in Formulations of EPIVIR Advise patients that EPIVIR tablets and oral solution contain a higher dose of the same active ingredient (lamivudine) as EPIVIR‑HBV tablets and oral solution. If a decision is made to include lamivudine in the HIV‑1 treatment regimen of a patient co‑infected with HIV‑1 and HBV, the formulation and dosage of lamivudine in EPIVIR (not EPIVIR‑HBV) should be used [see Warnings and Precautions ( 5.1 )] . Lactic Acidosis/Hepatomegaly with Steatosis Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking EPIVIR if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions ( 5.2 )] . Risk of Pancreatitis Advise parents or guardians to monitor pediatric patients for signs and symptoms of pancreatitis [see Warnings and Precautions ( 5.3 )] . Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when EPIVIR is started [see Warnings and Precautions ( 5.4 )]. Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution Advise patients that an all-tablet regimen should be used when possible due to an increased rate of treatment failure among pediatric subjects who received EPIVIR oral solution concomitantly with other antiretroviral oral solutions [see Warnings and Precautions ( 5.5 )] . Sucrose Content of EPIVIR Oral Solution Advise diabetic patients that each 15‑mL dose of EPIVIR oral solution contains 3 grams of sucrose (1 mL = 200 mg of sucrose) [see Description ( 11 )] . Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPIVIR during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Instruct women with HIV-1 infection not to breastfeed because HIV‑1 can be passed to the baby in the breast milk [see Use in Specific Populations ( 8.2 )] . Missed Dosage Instruct patients that if they miss a dose of EPIVIR, 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 )] . EPIVIR, ZIAGEN, and RETROVIR are trademarks owned by or licensed to the ViiV Healthcare group of companies. EPIVIR-HBV is a trademark owned by or licensed to the GSK group of companies. Manufactured for: ViiV Healthcare Durham, NC 27701 ©2024 ViiV Healthcare group of companies or its licensor. EPV:14PI PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _

PATIENT INFORMATION EPIVIR (EP-i-veer) EPIVIR (EP-i-veer) (lamivudine) (lamivudine) tablets oral solution What is the most important information I should know about EPIVIR? EPIVIR can cause serious side effects, including: • Worsening of hepatitis B virus in people who have HIV-1 infection. If you have HIV-1 (Human Immunodeficiency Virus type 1) and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking EPIVIR. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease can be serious and may lead to death. • Do not run out of EPIVIR. Refill your prescription or talk to your healthcare provider before your EPIVIR is all gone. • Do not stop EPIVIR without first talking to your healthcare provider. • If you stop taking EPIVIR, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver. • Resistant Hepatitis B Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with EPIVIR and become harder to treat (resistant). What is EPIVIR? EPIVIR is a prescription medicine used together with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). EPIVIR tablets and oral solution (used to treat HIV-1 infection) contain a higher dose of the same active ingredient (lamivudine) than is in the medicine EPIVIR-HBV tablets and oral solution (used to treat HBV). If you have both HIV-1 and HBV, you should not use EPIVIR-HBV to treat your infections. The safety and effectiveness of EPIVIR have not been established in children under 3 months of age. Who should not take EPIVIR? Do not take EPIVIR if you are allergic to lamivudine or any of the ingredients in EPIVIR. See the end of this Patient Information leaflet for a complete list of ingredients in EPIVIR. What should I tell my healthcare provider before taking EPIVIR? Before you take EPIVIR, tell your healthcare provider if you: • have or have had liver problems, including hepatitis B or C virus infection. • have kidney problems. • have diabetes. Each 15-mL dose (150 mg) of EPIVIR oral solution contains 3 grams of sucrose. • are pregnant or plan to become pregnant. Taking EPIVIR during pregnancy has not been associated with an increased risk of birth defects. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral 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. Do not breastfeed if you take EPIVIR. o You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medications interact with EPIVIR. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with EPIVIR. Do not start taking a new medicine without telling your healthcare provider.

tions interact with EPIVIR. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with EPIVIR. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take EPIVIR with other medicines. How should I take EPIVIR? • Take EPIVIR exactly as your healthcare provider tells you to take it. • If you miss a dose of EPIVIR, take it as soon as you remember. Do not take 2 doses at the same time or take more than what your healthcare provider tells you to take. • Stay under the care of a healthcare provider during treatment with EPIVIR. • EPIVIR may be taken with or without food. • For children 3 months and older, your healthcare provider will prescribe a dose of EPIVIR based on your child’s body weight. • Tell your healthcare provider if you or your child has trouble swallowing tablets. EPIVIR also comes as a liquid (oral solution). • Do not run out of EPIVIR. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy. • If you take too much EPIVIR, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of EPIVIR? • EPIVIR can cause serious side effects including: • See “What is the most important information I should know about EPIVIR?” • Build-up of an acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take EPIVIR. Lactic acidosis is a serious medical emergency that can cause 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 ○unusual (not normal) muscle pain ○trouble breathing ○stomach pain with nausea and vomiting ○feel cold, especially in your arms and legs ○feel dizzy or light-headed ○have a fast or irregular heartbeat • Serious liver problems can happen in people who take EPIVIR. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). 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) ○dark or “tea-colored” urine ○light-colored stools (bowel movements) ○loss of appetite for several days or longer ○nausea ○pain, aching, or tenderness on the right side of your stomach area You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese). • Risk of inflammation of the pancreas (pancreatitis). Children may be at risk for developing pancreatitis during treatment with EPIVIR if they: ○have taken nucleoside analogue medicines in the past ○have a history of pancreatitis ○have other risk factors for pancreatitis Call your healthcare provider right away if your child develops signs and symptoms of pancreatitis including severe upper stomach-area pain, with or without nausea and vomiting. Your healthcare provider may tell you to stop giving EPIVIR to your child if their symptoms and blood test results show that your child may have pancreatitis. • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking EPIVIR.

immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking EPIVIR. The most common side effects of EPIVIR in adults include: • headache • nausea • generally not feeling well • tiredness • nasal signs and symptoms • diarrhea • cough The most common side effects of EPIVIR in children include fever and cough. 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 EPIVIR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store EPIVIR? • Store EPIVIR tablets and oral solution at room temperature between 68°F to 77°F (20°C to 25°C). • Keep bottles of EPIVIR oral solution tightly closed. Keep EPIVIR and all medicines out of the reach of children. General information about the safe and effective use of EPIVIR. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use EPIVIR for a condition for which it was not prescribed. Do not give EPIVIR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about EPIVIR that is written for health professionals. For more information, go to www.viivhealthcare.com or call 1-877-844-8872. What are the ingredients in EPIVIR? Active ingredient: lamivudine Inactive ingredients: EPIVIR scored 150-mg film-coated tablets: hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide. EPIVIR 300-mg film-coated tablets: black iron oxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide. EPIVIR oral solution: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg per mL). Manufactured for: ViiV Healthcare Durham, NC 27701 EPIVIR is a trademark owned by or licensed to the ViiV Healthcare group of companies. EPIVIR-HBV is a trademark owned by or licensed to the GSK group of companies. ©2024 ViiV Healthcare group of companies or its licensor. EPV:8PIL This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: August 2024

<table width="100%"><col width="3%"/><col width="49%"/><col width="49%"/><tbody><tr><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">PATIENT INFORMATION</content></paragraph><paragraph><content styleCode="bold"> EPIVIR (EP-i-veer) EPIVIR (EP-i-veer)</content></paragraph><paragraph><content styleCode="bold">(lamivudine) (lamivudine)</content></paragraph><paragraph><content styleCode="bold"> tablets oral solution</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about EPIVIR?</content></paragraph><paragraph><content styleCode="bold">EPIVIR can cause serious side effects, including:</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Worsening of hepatitis B virus in people who have HIV-1 infection.</content> If you have HIV-1 (Human Immunodeficiency Virus type 1) and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking EPIVIR. A &#x201C;flare-up&#x201D; is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease can be serious and may lead to death.<list listType="unordered"><item><caption>&#x2022;</caption>Do not run out of EPIVIR. Refill your prescription or talk to your healthcare provider before your EPIVIR is all gone.</item><item><caption>&#x2022;</caption>Do not stop EPIVIR without first talking to your healthcare provider.</item><item><caption>&#x2022;</caption>If you stop taking EPIVIR, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver.</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">Resistant Hepatitis B Virus (HBV).</content> If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with EPIVIR and become harder to treat (resistant).</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is EPIVIR?</content></paragraph><paragraph>EPIVIR is a prescription medicine used together with other antiretroviral medicines to treat HIV-1 infection. </paragraph><paragraph>HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).</paragraph><paragraph>EPIVIR tablets and oral solution (used to treat HIV-1 infection) contain a higher dose of the same active ingredient (lamivudine) than is in the medicine EPIVIR-HBV tablets and oral solution (used to treat HBV). If you have both HIV-1 and HBV, you should not use EPIVIR-HBV to treat your infections.</paragraph><paragraph>The safety and effectiveness of EPIVIR have not been established in children under 3 months of age.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Who should not take EPIVIR?</content></paragraph><paragraph><content styleCode="bold">Do not take EPIVIR</content> if you are allergic to lamivudine or any of the ingredients in EPIVIR.

hs of age.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Who should not take EPIVIR?</content></paragraph><paragraph><content styleCode="bold">Do not take EPIVIR</content> if you are allergic to lamivudine or any of the ingredients in EPIVIR. See the end of this Patient Information leaflet for a complete list of ingredients in EPIVIR.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I tell my healthcare provider before taking EPIVIR?</content></paragraph><paragraph><content styleCode="bold">Before you take EPIVIR, tell your healthcare provider if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have or have had liver problems, including hepatitis B or C virus infection.</item><item><caption>&#x2022;</caption>have kidney problems.</item><item><caption>&#x2022;</caption>have diabetes. Each 15-mL dose (150 mg) of EPIVIR oral solution contains 3 grams of sucrose.</item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant. Taking EPIVIR during pregnancy has not been associated with an increased risk of birth defects. Talk to your healthcare provider if you are pregnant or plan to become pregnant.</item><item><caption> </caption><content styleCode="bold">Pregnancy Registry.</content> There is a pregnancy registry for women who take antiretroviral 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.</item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. <content styleCode="bold">Do not breastfeed if you take EPIVIR.</content><list listType="unordered"><item><caption>o</caption>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.</item></list></item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph><paragraph>Some medications interact with EPIVIR. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with EPIVIR. </paragraph><paragraph><content styleCode="bold">Do not start taking a new medicine without telling your healthcare provider.</content> Your healthcare provider can tell you if it is safe to take EPIVIR with other medicines.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take EPIVIR?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Take EPIVIR exactly as your healthcare provider tells you to take it.</content></item><item><caption>&#x2022;</caption>If you miss a dose of EPIVIR, take it as soon as you remember. Do not take 2 doses at the same time or take more than what your healthcare provider tells you to take. </item><item><caption>&#x2022;</caption>Stay under the care of a healthcare provider during treatment with EPIVIR.</item><item><caption>&#x2022;</caption>EPIVIR may be taken with or without food.</item><item><caption>&#x2022;</caption>For children 3 months and older, your healthcare provider will prescribe a dose of EPIVIR based on your child&#x2019;s body weight.</item><item><caption>&#x2022;</caption>Tell your healthcare provider if you or your child has trouble swallowing tablets.

taken with or without food.</item><item><caption>&#x2022;</caption>For children 3 months and older, your healthcare provider will prescribe a dose of EPIVIR based on your child&#x2019;s body weight.</item><item><caption>&#x2022;</caption>Tell your healthcare provider if you or your child has trouble swallowing tablets. EPIVIR also comes as a liquid (oral solution).</item><item><caption>&#x2022;</caption>Do not run out of EPIVIR. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.</item><item><caption>&#x2022;</caption>If you take too much EPIVIR, call your healthcare provider or go to the nearest hospital emergency room right away.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of EPIVIR?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">EPIVIR can cause serious side effects including:</content></item><item><caption>&#x2022;</caption><content styleCode="bold">See &#x201C;What is the most important information I should know about EPIVIR?&#x201D;</content></item><item><caption>&#x2022;</caption><content styleCode="bold">Build-up of an acid in your blood (lactic acidosis).</content> Lactic acidosis can happen in some people who take EPIVIR. Lactic acidosis is a serious medical emergency that can cause death. <content styleCode="bold">Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:</content></item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption>&#x25CB;feel very weak or tired</item><item><caption> </caption>&#x25CB;unusual (not normal) muscle pain</item><item><caption> </caption>&#x25CB;trouble breathing</item><item><caption> </caption>&#x25CB;stomach pain with nausea and vomiting</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption> </caption>&#x25CB;feel cold, especially in your arms and legs</item><item><caption> </caption>&#x25CB;feel dizzy or light-headed</item><item><caption> </caption>&#x25CB;have a fast or irregular heartbeat</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Serious liver problems</content> can happen in people who take EPIVIR. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis).

="top"><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Serious liver problems</content> can happen in people who take EPIVIR. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). <content styleCode="bold">Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:</content></item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption>&#x25CB;your skin or the white part of your eyes turns yellow (jaundice)</item><item><caption> </caption>&#x25CB;dark or &#x201C;tea-colored&#x201D; urine</item><item><caption> </caption>&#x25CB;light-colored stools (bowel movements)</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption> </caption>&#x25CB;loss of appetite for several days or longer</item><item><caption> </caption>&#x25CB;nausea</item><item><caption> </caption>&#x25CB;pain, aching, or tenderness on the right side of your stomach area</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese).</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Risk of inflammation of the pancreas (pancreatitis). </content>Children may be at risk for developing pancreatitis during treatment with EPIVIR if they:</item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption>&#x25CB;have taken nucleoside analogue medicines in the past</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption> </caption>&#x25CB;have a history of pancreatitis</item><item><caption> </caption>&#x25CB;have other risk factors for pancreatitis</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Call your healthcare provider right away if your child develops signs and symptoms of pancreatitis including severe upper stomach-area pain, with or without nausea and vomiting. </content>Your healthcare provider may tell you to stop giving EPIVIR to your child if their symptoms and blood test results show that your child may have pancreatitis.</paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Changes in your immune system (Immune Reconstitution Syndrome)</content> can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time.

listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Changes in your immune system (Immune Reconstitution Syndrome)</content> can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking EPIVIR.</item></list><paragraph><content styleCode="bold">The most common side effects of EPIVIR in adults include:</content></paragraph></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>headache</item><item><caption>&#x2022;</caption>nausea</item><item><caption>&#x2022;</caption>generally not feeling well</item><item><caption>&#x2022;</caption>tiredness</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>nasal signs and symptoms</item><item><caption>&#x2022;</caption>diarrhea</item><item><caption>&#x2022;</caption>cough</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">The most common side effects of EPIVIR in children include fever and cough.</content></paragraph><paragraph>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</paragraph><paragraph>These are not all the possible side effects of EPIVIR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store EPIVIR?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Store EPIVIR tablets and oral solution at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item><item><caption>&#x2022;</caption>Keep bottles of EPIVIR oral solution tightly closed.</item></list><paragraph><content styleCode="bold">Keep EPIVIR and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of EPIVIR.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use EPIVIR for a condition for which it was not prescribed. Do not give EPIVIR to other people, even if they have the same symptoms that you have.

and effective use of EPIVIR.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use EPIVIR for a condition for which it was not prescribed. Do not give EPIVIR to other people, even if they have the same symptoms that you have. It may harm them.</paragraph><paragraph>You can ask your healthcare provider or pharmacist for information about EPIVIR that is written for health professionals.</paragraph><paragraph>For more information, go to <linkHtml href="http://www.viivhealthcare.com">www.viivhealthcare.com</linkHtml> or call 1-877-844-8872.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in EPIVIR?</content></paragraph><paragraph>Active ingredient: lamivudine</paragraph><paragraph>Inactive ingredients: </paragraph><paragraph>EPIVIR scored 150-mg film-coated tablets: hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.</paragraph><paragraph>EPIVIR 300-mg film-coated tablets: black iron oxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.</paragraph><paragraph>EPIVIR oral solution: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg per mL). </paragraph></td></tr><tr><td colspan="2" styleCode="Lrule " valign="top"><paragraph>Manufactured for: ViiV Healthcare Durham, NC 27701</paragraph></td><td styleCode="Rrule " valign="top"/></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>EPIVIR is a trademark owned by or licensed to the ViiV Healthcare group of companies. EPIVIR-HBV is a trademark owned by or licensed to the GSK group of companies.</paragraph><paragraph>&#xA9;2024 ViiV Healthcare group of companies or its licensor.</paragraph><paragraph>EPV:8PIL</paragraph></td></tr><tr><td colspan="2" styleCode="Botrule " valign="top"><paragraph>This Patient Information has been approved by the U.S. Food and Drug Administration.</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Revised: August 2024</paragraph></td></tr></tbody></table>

WARNING: EXACERBATIONS OF HEPATITIS B, AND DIFFERENT FORMULATIONS OF LAMIVUDINE TABLETS. Exacerbations of Hepatitis B Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions ( 5.1 )]. Important Differences among Lamivudine-Containing Products Lamivudine tablets (used to treat HIV-1 infection) contain a higher dose of the active ingredient (lamivudine) than lamivudine-HBV tablets (used to treat chronic HBV infection). Patients with HIV-1 infection should receive only dosage forms appropriate for treatment of HIV-1 [see Warnings and Precautions ( 5.1 )]. WARNING: EXACERBATIONS OF HEPATITIS B, and DIFFERENT FORMULATIONS OF LAMIVUDINE TABLETS See full prescribing information for complete boxed warning. • Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine tablets. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.1 ) • Patients with HIV-1 infection should receive only dosage forms of lamivudine tablets appropriate for treatment of HIV-1. ( 5.1 )

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 )

2 DOSAGE AND ADMINISTRATION • Adults: 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily. ( 2.1 ) • Pediatric Patients Aged 3 Months and Older: Administered either once or twice daily. Dose should be calculated on body weight (kg) and should not exceed 300 mg daily. ( 2.2 ) • Patients with Renal Impairment: Doses of lamivudine tablets must be adjusted in accordance with renal function. ( 2.3 ) 2.1 Recommended Dosage for Adult Patients The recommended dosage of lamivudine tablets in HIV-1-infected adults is 300 mg daily, administered as either 150 mg taken orally twice daily or 300 mg taken orally once daily with or without food. If lamivudine is administered to a patient infected with HIV-1 and HBV, the dosage indicated for HIV-1 therapy should be used as part of an appropriate combination regimen [see Warnings and Precautions ( 5.1 )] . 2.2 Recommended Dosage for Pediatric Patients Lamivudine scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Before prescribing lamivudine scored tablets, pediatric patients should be assessed for the ability to swallow tablets. For patients unable to safely and reliably swallow lamivudine tablets, the oral solution formulation may be prescribed [see Warnings and Precautions (5.6)] . The recommended oral dosage of lamivudine tablets for HIV-1-infected pediatric patients is presented in Table 1. Table 1. Dosing Recommendations for Lamivudine Scored (150-mg) Tablets in Pediatric Patients Weight (kg) Once-Daily Dosing Regimen a Twice-Daily Dosing Regimen Using Scored 150-mg Tablet AM Dose PM Dose Total Daily Dose 14 to <20 1 tablet (150 mg) ½ tablet (75 mg) ½ tablet (75 mg) 150 mg ≥20 to <25 1½ tablets (225 mg) ½ tablet (75 mg) 1 tablet (150 mg) 225 mg ≥25 2 tablets (300 mg) b 1 tablet (150 mg) 1 tablet (150 mg) 300 mg a Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment [see Clinical Studies ( 14.2 )] . b Patients may alternatively take one 300-mg tablet, which is not scored. 2.3 Patients with Renal Impairment Dosing of lamivudine tablets are adjusted in accordance with renal function. Dosage adjustments are listed in Table 2 [see Clinical Pharmacology ( 12.3 )] . Table 2. Adjustment of Dosage of Lamivudine Tablets in Adults and Adolescents (Greater than or Equal to 25 kg) in Accordance with Creatinine Clearance Creatinine Clearance (mL/min) Recommended Dosage of Lamivudine ≥50 150 mg twice daily or 300 mg once daily 30 - 49 150 mg once daily 15 - 29 150 mg first dose, then 100 mg once daily 5 - 14 150 mg first dose, then 50 mg once daily <5 50 mg first dose, then 25 mg once daily No additional dosing of lamivudine is required after routine (4-hour) hemodialysis or peritoneal dialysis. Although there are insufficient data to recommend a specific dose adjustment of lamivudine in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.

3 DOSAGE FORMS AND STRENGTHS Lamivudine tablets, USP 150 mg are white to off-white, diamond shaped, biconvex film-coated tablets, engraved “APO” on one side, “LMV” score “150” on the other side. Lamivudine tablets, USP 300 mg are grey, diamond shaped, biconvex film-coated tablets, engraved “APO” on one side, “LMV 300” on the other side. • Tablets: 150 mg, scored ( 3 ) • Tablets: 300 mg ( 3 )

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

5 WARNINGS AND PRECAUTIONS • Co-infected HIV-1/HBV Patients: Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. ( 5.1 ) • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. ( 5.2 ) • Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. ( 5.3 ) • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. ( 5.4 ) • Lower virologic suppression rates and increased risk of viral resistance were observed in pediatric subjects who received lamivudine oral solution concomitantly with other antiretroviral oral solutions compared with those who received tablets. An all-tablet regimen should be used when possible. ( 5.5 ) 5.1 Patients with Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Important Differences among Lamivudine-Containing Products Lamivudine tablets contain a higher dose of the same active ingredient (lamivudine) than lamivudine-HBV tablets. Lamivudine-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in lamivudine-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. If treatment with lamivudine-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment. If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, lamivudine tablets, lamivudine oral solution, or another product containing the higher dose of lamivudine should be used as part of an appropriate combination regimen. Emergence of Lamivudine-Resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV (see full prescribing information for lamivudine-HBV). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

nd HBV (see full prescribing information for lamivudine-HBV). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. 5.2 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including Lamivudine. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with lamivudine tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations. 5.3 Pancreatitis In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, lamivudine should be used with caution. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions ( 6.1 )]. 5.4 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine tablets. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.5 Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution Pediatric subjects who received lamivudine oral solution (at weight band-based doses approximating 8 mg per kg per day) concomitantly with other antiretroviral oral solutions at any time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving lamivudine tablets [see Clinical Pharmacology (12.3), Microbiology (12.4), Clinical Studies (14.2)] . Lamivudine scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol [see Clinical Pharmacology ( 12.3 )]. Consider more frequent monitoring of HIV-1 viral load when treating with lamivudine oral solution.

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.

es 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.

europathies 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.

<table ID="_RefID0EUOAE" width="100%"><caption>Table 3. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)</caption><col width="50%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Lamivudine 150 mg Twice Daily plus RETROVIR</content></paragraph><paragraph><content styleCode="bold">(n = 251)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">RETROVIR^a</content></paragraph><paragraph><content styleCode="bold">(n = 230)</content></paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>35%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Malaise &amp; fatigue</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Fever or chills</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>12%</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Digestive</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>33%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>29%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nausea &amp; vomiting</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Anorexia and/or decreased appetite</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Abdominal pain</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Abdominal cramps</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrul

h>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Abdominal cramps</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrul e " valign="top"><paragraph> Dyspepsia</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>5%</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Neuropathy</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>10%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Insomnia &amp; other sleep disorders</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Dizziness</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Depressive disorders</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>4%</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Respiratory</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nasal signs &amp; symptoms</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Cough</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>18%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>13%</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Skin</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Skin rashes</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>6%</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Musculoskeletal</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Musculoskeletal pain</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>10%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Myalgia</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Arthralgia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>5%</paragraph></td></tr></tbody></table>

</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Arthralgia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>5%</paragraph></td></tr></tbody></table> <table ID="_RefID0EE2AE" width="100%"><caption>Table 4.

</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Arthralgia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>5%</paragraph></td></tr></tbody></table> <table ID="_RefID0EE2AE" width="100%"><caption>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)</caption><col width="29%"/><col width="18%"/><col width="18%"/><col width="18%"/><col width="18%"/><tbody><tr><td styleCode="Toprule " valign="top"/><td align="center" colspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">24-Week Surrogate Endpoint Trials^a</content></paragraph></td><td align="center" colspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Clinical Endpoint Trial^a</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Test (Threshold Level)</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Lamivudine plus RETROVIR</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">RETROVIR^b</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Lamivudine plus Current Therapy^c</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Placebo plus Current Therapy^c</content></paragraph></td></tr><tr><td valign="top"><paragraph>Absolute neutrophil count (&lt;750/mm³) </paragraph></td><td align="center" valign="top"><paragraph>7.2% </paragraph></td><td align="center" valign="top"><paragraph>5.4% </paragraph></td><td align="center" valign="top"><paragraph>15% </paragraph></td><td align="center" valign="top"><paragraph>13% </paragraph></td></tr><tr><td valign="top"><paragraph>Hemoglobin (&lt;8.0 g/dL) </paragraph></td><td align="center" valign="top"><paragraph>2.9% </paragraph></td><td align="center" valign="top"><paragraph>1.8% </paragraph></td><td align="center" valign="top"><paragraph>2.2% </paragraph></td><td align="center" valign="top"><paragraph>3.4% </paragraph></td></tr><tr><td valign="top"><paragraph>Platelets (&lt;50,000/mm³) </paragraph></td><td align="center" valign="top"><paragraph>0.4% </paragraph></td><td align="center" valign="top"><paragraph>1.3% </paragraph></td><td align="center" valign="top"><paragraph>2.8% </paragraph></td><td align="center" valign="top"><paragraph>3.8% </paragraph></td></tr><tr><td valign="top"><paragraph>ALT (&gt;5.0 x ULN) </paragraph></td><td align="center" valign="top"><paragraph>3.7% </paragraph></td><td align="center" valign="top"><paragraph>3.6% </paragraph></td><td align="center" valign="top"><paragraph>3.8% </paragraph></td><td align="center" valign="top"><paragraph>1.9% </paragraph></td></tr><tr><td valign="top"><paragraph>AST (&gt;5.0 x ULN) </paragraph></td><td align="center" valign="top"><paragraph>1.7% </paragraph></td><td align="center" valign="top"><paragraph>1.8% </paragraph></td><td align="center" valign="top"><paragraph>4.0% </paragraph></td><td align="center" valign="top"><paragraph>2.1% </paragraph></td></tr><tr><td valign="top"><paragraph>Bilirubin (&gt;2.5 x ULN) </paragraph></td><td align="center" valign="top"><paragraph>0.8% </paragraph></td><td align="center" valign="top"><paragraph>0.4% </paragraph></td><td align="center" valign="top"><paragraph>ND </paragraph></td><td align="center" valign="top"><paragraph>ND </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Amylase (&gt;2.0 x ULN) </paragraph></td><td align="center" styleCode="Botru

lign="center" valign="top"><paragraph>0.4% </paragraph></td><td align="center" valign="top"><paragraph>ND </paragraph></td><td align="center" valign="top"><paragraph>ND </paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Amylase (&gt;2.0 x ULN) </paragraph></td><td align="center" styleCode="Botru le " valign="top"><paragraph>4.2% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.5% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2.2% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.1% </paragraph></td></tr></tbody></table> <table ID="_RefID0EL6AE" width="100%"><caption>Table 5.

le " valign="top"><paragraph>4.2% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.5% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2.2% </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1.1% </paragraph></td></tr></tbody></table> <table ID="_RefID0EL6AE" width="100%"><caption>Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG300</caption><col width="50%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Lamivudine plus </content> <content styleCode="bold">RETROVIR</content> <content styleCode="bold">(n = 236) </content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Didanosine </content> <content styleCode="bold">(n = 235)</content></paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td></tr><tr><td valign="top"><paragraph>Fever</paragraph></td><td align="center" valign="top"><paragraph>25%</paragraph></td><td align="center" valign="top"><paragraph>32%</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Digestive</content></paragraph></td></tr><tr><td valign="top"><paragraph>Hepatomegaly</paragraph></td><td align="center" valign="top"><paragraph>11%</paragraph></td><td align="center" valign="top"><paragraph>11%</paragraph></td></tr><tr><td valign="top"><paragraph>Nausea &amp; vomiting</paragraph></td><td align="center" valign="top"><paragraph>8%</paragraph></td><td align="center" valign="top"><paragraph>7%</paragraph></td></tr><tr><td valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" valign="top"><paragraph>8%</paragraph></td><td align="center" valign="top"><paragraph>6%</paragraph></td></tr><tr><td valign="top"><paragraph>Stomatitis</paragraph></td><td align="center" valign="top"><paragraph>6%</paragraph></td><td align="center" valign="top"><paragraph>12%</paragraph></td></tr><tr><td valign="top"><paragraph>Splenomegaly</paragraph></td><td align="center" valign="top"><paragraph>5%</paragraph></td><td align="center" valign="top"><paragraph>8%</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Respiratory</content></paragraph></td></tr><tr><td valign="top"><paragraph>Cough</paragraph></td><td align="center" valign="top"><paragraph>15%</paragraph></td><td align="center" valign="top"><paragraph>18%</paragraph></td></tr><tr><td valign="top"><paragraph>Abnormal breath sounds/wheezing</paragraph></td><td align="center" valign="top"><paragraph>7%</paragraph></td><td align="center" valign="top"><paragraph>9%</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Ear, Nose, and Throat</content></paragraph></td></tr><tr><td valign="top"><paragraph>Signs or symptoms of ears^a</paragraph></td><td align="center" valign="top"><paragraph>7%</paragraph></td><td align="center" valign="top"><paragraph>6%</paragraph></td></tr><tr><td valign="top"><paragraph>Nasal discharge or congestion</paragraph></td><td align="center" valign="top"><paragraph>8%</paragraph></td><td align="center" valign="top"><paragraph>11%</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">Other</content></paragraph></td></tr><tr><td valign="top"><paragraph>Skin rashes</paragraph></td><td align="center" valign="top"><paragraph>12%</paragraph></td><td align="center" valign="top"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Botrule " val

lspan="3" valign="top"><paragraph><content styleCode="bold">Other</content></paragraph></td></tr><tr><td valign="top"><paragraph>Skin rashes</paragraph></td><td align="center" valign="top"><paragraph>12%</paragraph></td><td align="center" valign="top"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Botrule " val ign="top"><paragraph>Lymphadenopathy</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>11%</paragraph></td></tr></tbody></table>

lspan="3" valign="top"><paragraph><content styleCode="bold">Other</content></paragraph></td></tr><tr><td valign="top"><paragraph>Skin rashes</paragraph></td><td align="center" valign="top"><paragraph>12%</paragraph></td><td align="center" valign="top"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Botrule " val ign="top"><paragraph>Lymphadenopathy</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>11%</paragraph></td></tr></tbody></table> <table ID="_RefID0EDEAG" width="100%"><caption>Table 6. Frequencies of Selected Grade 3 to 4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Test</content></paragraph><paragraph><content styleCode="bold">(Threshold Level)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Lamivudine plus</content></paragraph><paragraph><content styleCode="bold">RETROVIR</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Didanosine</content></paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Absolute neutrophil count (&lt;400/mm³)</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>8%</paragraph></td><td align="center" valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Hemoglobin (&lt;7.0 g/dL)</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>4%</paragraph></td><td align="center" valign="bottom"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Platelets (&lt;50,000/mm³)</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>1%</paragraph></td><td align="center" valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>ALT (&gt;10 x ULN)</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>1%</paragraph></td><td align="center" valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>AST (&gt;10 x ULN)</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>2%</paragraph></td><td align="center" valign="bottom"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Lipase (&gt;2.5 x ULN)</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>3%</paragraph></td><td align="center" valign="bottom"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Total Amylase (&gt;2.5 x ULN)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>3%</paragraph></td><td align="center" styleCode="Botrule " valign="bottom"><paragraph>3%</paragraph></td></tr></tbody></table>

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 Warnings and Precautions ( 5.6 ), Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS • Lactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine tablets 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 difference in the overall risk of birth defects for lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the 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 occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, 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 development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose (see Data). Data Human Data Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of 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. Lamivudine pharmacokinetics were studied in pregnant women 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 with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. 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 concentration (n = 8).

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 concentration (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 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C max ) 35 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. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Lamivudine is present in human milk. There is no information on the effects of lamivudine on the breastfed infant or the effects of the drugs on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving lamivudine. 8.4 Pediatric Use The safety and effectiveness of lamivudine tablets in combination with other antiretroviral agents have been established in pediatric patients aged 3 months and older. Lamivudine scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate because pediatric subjects who received lamivudine oral solution had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving lamivudine tablets in the ARROW trial [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] . 8.5 Geriatric Use Clinical trials of lamivudine tablets 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 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 ( 2.3 ), Clinical Pharmacology ( 12.3 )]. 8.6 Patients with Impaired Renal Function Reduction of the dosage of lamivudine tablets are recommended for patients with impaired renal function [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine tablets 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 difference in the overall risk of birth defects for lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the 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 occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, 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 development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose (see Data). Data Human Data Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of 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. Lamivudine pharmacokinetics were studied in pregnant women 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 with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. 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 concentration (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 7 through 16 [rat] and 8 through 20 [rabbit]).

rnal serum concentration (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 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C max ) 35 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.

8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Lamivudine is present in human milk. There is no information on the effects of lamivudine on the breastfed infant or the effects of the drugs on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving lamivudine.

8.4 Pediatric Use The safety and effectiveness of lamivudine tablets in combination with other antiretroviral agents have been established in pediatric patients aged 3 months and older. Lamivudine scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate because pediatric subjects who received lamivudine oral solution had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving lamivudine tablets in the ARROW trial [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] .

8.5 Geriatric Use Clinical trials of lamivudine tablets 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 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 ( 2.3 ), Clinical Pharmacology ( 12.3 )].

10 OVERDOSAGE There is no known specific treatment for overdose with lamivudine. 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.

11 DESCRIPTION Lamivudine is a synthetic nucleoside analogue with activity against HIV-1 and HBV. The drug substance used in lamivudine tablets, USP 150 mg and 300 mg is lamivudine in the form of lamivudine methanol solvate. The chemical name of lamivudine methanol solvate is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinone methanol solvate. It has a molecular formula of C 8 H 11 N 3 O 3 S·0.2CH 4 O and a molecular weight of 235.66 g/mol. It has the following structural formula: Lamivudine methanol solvate is a white to off-white powder. It is highly soluble in water. Lamivudine tablets, USP are for oral administration. Each scored 150-mg film-coated tablet contains lamivudine methanol solvate equivalent to 150 mg of lamivudine and the inactive ingredients colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, polyethylene glycol and titanium dioxide. Each 300-mg film-coated tablet contains lamivudine methanol solvate equivalent to 300 mg of lamivudine, and the inactive ingredients colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide black, lactose anhydrous, magnesium stearate, polyethylene glycol and titanium dioxide. Meets USP Dissolution Test 2. chemical-structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lamivudine is an antiretroviral agent [see Microbiology ( 12.4 )]. 12.3 Pharmacokinetics Pharmacokinetics in Adults The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult subjects after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg per kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg per kg. The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg per day administered to HBV-infected subjects. The steady-state pharmacokinetic properties of the lamivudine 300-mg tablet once daily for 7 days compared with the lamivudine 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects. Lamivudine tablets 300 mg once daily resulted in lamivudine exposures that were similar to lamivudine tablets 150 mg twice daily with respect to plasma AUC 24,ss ; however, C max,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC 24,ss and C max24,ss ; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The pharmacokinetics of lamivudine was evaluated in 12 adult HIV-1-infected subjects dosed with lamivudine 150 mg twice daily in combination with other antiretroviral agents. The geometric mean (95% CI) for AUC (0-12) was 5.53 (4.58, 6.67) mcg.h per mL and for C max was 1.40 (1.17, 1.69) mcg per mL. Absorption and Bioavailability Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg per kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (C max ) was 1.5 ± 0.5 mcg per mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and C max increased in proportion to oral dose over the range from 0.25 to 10 mg per kg. The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg per kg twice daily. Effects of Food on Oral Absorption Lamivudine tablets may be administered with or without food. An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected subjects on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (T max : 3.2 ± 1.3 hours) compared with the fasted state (T max : 0.9 ± 0.3 hours); C max in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. 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 subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight. Binding of lamivudine to human plasma proteins is less than 36%.

nt volume of distribution after IV administration of lamivudine to 20 subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight. Binding of lamivudine to human plasma proteins is less than 36%. In vitro studies showed that over the concentration range of 0.1 to 100 mcg per mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration. Metabolism Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (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 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL per min (mean ± SD). In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine. In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-1-infected subjects, total clearance was 398.5 ± 69.1 mL per min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg per kg. Specific Populations Patients with Renal Impairment The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-1-infected adults with impaired renal function (Table 7). Table 7. Pharmacokinetic Parameters (Mean ± SD) after a Single 300-mg Oral Dose of Lamivudine in 3 Groups of Adults with Varying Degrees of Renal Function Parameter Creatinine Clearance Criterion (Number of Subjects) >60 mL/min (n = 6) 1 0-30 mL/min (n = 4) <10 mL/min (n = 6) Creatinine clearance (mL/min) 111 ± 14 28 ± 8 6 ± 2 C max (mcg/mL) 2.6 ± 0.5 3.6 ± 0.8 5.8 ± 1.2 AUC∞ (mcg•h/mL) 11.0 ± 1.7 48.0 ± 19 157 ± 74 Cl/F (mL/min) 464 ± 76 114 ± 34 36 ± 11 T max 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 ( 2.3 )] . Based on a trial in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL per min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis. The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known. Patients with Hepatic Impairment The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease. Pregnant Women Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa.

ction. Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease. Pregnant Women Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. 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 The pharmacokinetics of lamivudine have been studied after either single or repeat doses of lamivudine in 210 pediatric subjects. Pediatric subjects receiving lamivudine oral solution (dosed at approximately 8 mg per kg per day) achieved approximately 25% lower plasma concentrations of lamivudine compared with HIV-1-infected adults. Pediatric subjects receiving lamivudine oral tablets achieved plasma concentrations comparable to or slightly higher than those observed in adults. The absolute bioavailability of both lamivudine tablets and oral solution are lower in children than adults. The relative bioavailability of lamivudine oral solution is approximately 40% lower than tablets containing lamivudine in pediatric subjects despite no difference in adults. Lower lamivudine exposures in pediatric patients receiving lamivudine oral solution is likely due to the interaction between lamivudine and concomitant solutions containing sorbitol (such as ZIAGEN). Modeling of pharmacokinetic data suggests increasing the dosage of lamivudine oral solution to 5 mg per kg taken orally twice daily or 10 mg per kg taken orally once daily (up to a maximum of 300 mg daily) is needed to achieve sufficient concentrations of lamivudine [see Dosage and Administration ( 2.2 )] . There are no clinical data in HIV-1 infected pediatric patients coadministered with sorbitol-containing medicines at this dose. The pharmacokinetics of lamivudine dosed once daily in HIV-1-infected pediatric subjects aged 3 months through 12 years was evaluated in 3 trials (PENTA-15 [n = 17], PENTA 13 [n = 19], and ARROW PK [n = 35]). All 3 trials were 2-period, crossover, open-label pharmacokinetic trials of twice- versus once-daily dosing of abacavir and lamivudine. These 3 trials demonstrated that once-daily dosing provides similar AUC 0-24 to twice-daily dosing of lamivudine at the same total daily dose when comparing the dosing regimens within the same formulation (i.e., either the oral solution or the tablet formulation). The mean C max was approximately 80% to 90% higher with lamivudine once-daily dosing compared with twice-daily dosing. Table 8. Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat Dosing of Lamivudine in 3 Pediatric Trials Trial (Number of Subjects) ARROW PK (n = 35) PENTA-13 (n = 19) PENTA-15 (n = 17) a Age Range 3-12 years 2-12 years 3-36 months Formulation Tablet Solution b and Tablet c Solution b Parameter Once Daily Twice Daily Once Daily Twice Daily Once Daily Twice Daily Cmax (mcg/mL) 3.17 (2.76, 3.64) 1.80 (1.59, 2.04) 2.09 (1.80, 2.42) 1.11 (0.96, 1.29) 1.87 (1.65, 2.13) 1.05 (0.88, 1.26) AUC (0-24) (mcg•h/mL) 13.0 (11.4, 14.9) 12.0 (10.7, 13.4) 9.80 (8.64, 11.1) 8.88 (7.67, 10.3) 8.66 (7.46, 10.1) 9.48 (7.89, 11.4) a n = 16 for PENTA-15 C max. b Solution was dosed at 8 mg per kg per day. c Five subjects in PENTA-13 received lamivudine tablets. Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose.

for PENTA-15 C max. b Solution was dosed at 8 mg per kg per day. c Five subjects in PENTA-13 received lamivudine tablets. Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg per kg per day, CSF lamivudine concentrations in 8 subjects ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg per mL. Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants aged up to 1 week in 2 trials in South Africa. In these trials, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric subjects (aged over 3 months) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges over 3 months old [see Adverse Reactions ( 6.1 )] . Geriatric Patients The pharmacokinetics of lamivudine after administration of lamivudine tablets 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 Interactions 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 1 (MATE)1, MATE2-K, organic cation transporter 1 (OCT)1, OCT2, or OCT3. Effect of Other Agents on the Pharmacokinetics of Lamivudine Lamivudine is a 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 as no dose adjustment of lamivudine is needed. Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a 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 a 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 a 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 a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution.

ine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a 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 (0-24), 14%, 32%, and 36% in the AUC (∞) , and 28%, 52%, and 55% in the C max of lamivudine, respectively. Trimethoprim/Sulfamethoxazole Lamivudine and TMP/SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used in treat PCP. Zidovudine No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours). 12.4 Microbiology Mechanism of Action Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. Antiviral Activity The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC 50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC 50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC 50 values against HIV-2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Lamivudine was not antagonistic to all tested anti-HIV agents. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells. Resistance Lamivudine-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either valine or isoleucine (M184V/I). HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects. Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks.

ptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks. Genotypic and Phenotypic Analysis of On-Therapy HIV-1 Isolates from Subjects with Virologic Failure Trial EPV20001 Fifty-three of 554 (10%) subjects enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level greater than or equal to 400 copies per mL) by Week 48. Twenty-eight subjects were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-1 RNA levels of subjects in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log 10 copies per mL and 4.6 log 10 copies per mL, respectively. Genotypic analysis of on-therapy isolates from 22 subjects identified as virologic failures in the lamivudine once-daily group showed that isolates from 8 of 22 subjects contained a treatment-emergent lamivudine resistance-associated substitution (M184V or M184I), isolates from 0 of 22 subjects contained treatment-emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), and isolates from 10 of 22 subjects contained treatment-emergent amino acid substitutions associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C). Genotypic analysis of on-therapy isolates from subjects (n = 22) in the lamivudine twice-daily treatment group showed that isolates from 5 of 22 subjects contained treatment-emergent lamivudine resistance substitutions, isolates from 1 of 22 subjects contained treatment-emergent zidovudine resistance substitutions, and isolates from 7 of 22 subjects contained treatment-emergent efavirenz resistance substitutions. Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from subjects (n = 13) receiving lamivudine once daily showed that isolates from 7 of 13 subjects showed an 85- to 299-fold decrease in susceptibility to lamivudine, isolates from 12 of 13 subjects were susceptible to zidovudine, and isolates from 8 of 13 subjects exhibited a 25- to 295-fold decrease in susceptibility to efavirenz. Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from subjects (n = 13) receiving lamivudine twice daily showed that isolates from 4 of 13 subjects exhibited a 29- to 159-fold decrease in susceptibility to lamivudine, isolates from all 13 subjects were susceptible to zidovudine, and isolates from 3 of 13 subjects exhibited a 21- to 342-fold decrease in susceptibility to efavirenz. Trial EPV40001 Fifty subjects received lamivudine 300 mg once daily plus zidovudine 300 mg twice daily plus abacavir 300 mg twice daily and 50 subjects received lamivudine 150 mg plus zidovudine 300 mg plus abacavir 300 mg all twice-daily. The median baseline plasma HIV-1 RNA levels for subjects in the 2 groups were 4.79 log 10 copies per mL and 4.83 log 10 copies per mL, respectively. Fourteen of 50 subjects in the lamivudine once-daily treatment group and 9 of 50 subjects in the lamivudine twice-daily group were identified as virologic failures. Genotypic analysis of on-therapy HIV-1 isolates from subjects (n = 9) in the lamivudine once-daily treatment group showed that isolates from 6 subjects had an abacavir and/or lamivudine resistance-associated substitution M184V alone.

50 subjects in the lamivudine twice-daily group were identified as virologic failures. Genotypic analysis of on-therapy HIV-1 isolates from subjects (n = 9) in the lamivudine once-daily treatment group showed that isolates from 6 subjects had an abacavir and/or lamivudine resistance-associated substitution M184V alone. On-therapy isolates from subjects (n = 6) receiving lamivudine twice daily showed that isolates from 2 subjects had M184V alone, and isolates from 2 subjects harbored the M184V substitution in combination with zidovudine resistance-associated amino acid substitutions. Phenotypic analysis of on-therapy isolates from subjects (n = 6) receiving lamivudine once daily showed that HIV-1 isolates from 4 subjects exhibited a 32- to 53-fold decrease in susceptibility to lamivudine. HIV-1 isolates from these 6 subjects were susceptible to zidovudine. Phenotypic analysis of on-therapy isolates from subjects (n = 4) receiving lamivudine twice daily showed that HIV-1 isolates from 1 subject exhibited a 45-fold decrease in susceptibility to lamivudine and a 4.5-fold decrease in susceptibility to zidovudine. Pediatrics Pediatric subjects receiving lamivudine oral solution concomitantly with other antiretroviral oral solutions (abacavir, nevirapine/efavirenz, or zidovudine) in ARROW developed viral resistance more frequently than those receiving tablets. At randomization to once-daily or twice-daily dosing of lamivudine plus abacavir, 13% of subjects who started on tablets and 32% of subjects who started on solution had resistance substitutions. The resistance profile observed in pediatrics is similar to that observed in adults in terms of the genotypic substitutions detected and relative frequency, with the most commonly detected substitutions at M184 (V or I) [see Clinical Studies ( 14.2 )] . Cross-Resistance Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (NRTIs). Lamivudine-resistant HIV-1 mutants were cross-resistant in cell culture to didanosine (ddI). Cross-resistance is also expected with abacavir and emtricitabine as these select M184V substitutions.

12.3 Pharmacokinetics Pharmacokinetics in Adults The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult subjects after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg per kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg per kg. The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg per day administered to HBV-infected subjects. The steady-state pharmacokinetic properties of the lamivudine 300-mg tablet once daily for 7 days compared with the lamivudine 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects. Lamivudine tablets 300 mg once daily resulted in lamivudine exposures that were similar to lamivudine tablets 150 mg twice daily with respect to plasma AUC 24,ss ; however, C max,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC 24,ss and C max24,ss ; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The pharmacokinetics of lamivudine was evaluated in 12 adult HIV-1-infected subjects dosed with lamivudine 150 mg twice daily in combination with other antiretroviral agents. The geometric mean (95% CI) for AUC (0-12) was 5.53 (4.58, 6.67) mcg.h per mL and for C max was 1.40 (1.17, 1.69) mcg per mL. Absorption and Bioavailability Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg per kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (C max ) was 1.5 ± 0.5 mcg per mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and C max increased in proportion to oral dose over the range from 0.25 to 10 mg per kg. The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg per kg twice daily. Effects of Food on Oral Absorption Lamivudine tablets may be administered with or without food. An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected subjects on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (T max : 3.2 ± 1.3 hours) compared with the fasted state (T max : 0.9 ± 0.3 hours); C max in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. 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 subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight. Binding of lamivudine to human plasma proteins is less than 36%.

ine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a 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 (0-24), 14%, 32%, and 36% in the AUC (∞) , and 28%, 52%, and 55% in the C max of lamivudine, respectively. Trimethoprim/Sulfamethoxazole Lamivudine and TMP/SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used in treat PCP. Zidovudine No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).

<table ID="_RefID0EXYAG" width="100%"><caption>Table 7. Pharmacokinetic Parameters (Mean &#xB1; SD) after a Single 300-mg Oral Dose of Lamivudine in 3 Groups of Adults with Varying Degrees of Renal Function</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Parameter</content></paragraph></td><td align="center" colspan="3" styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Creatinine Clearance Criterion</content></paragraph><paragraph><content styleCode="bold">(Number of Subjects)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">&gt;60 mL/min</content></paragraph><paragraph><content styleCode="bold">(n = 6)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>1<content styleCode="bold">0-30 mL/min</content></paragraph><paragraph><content styleCode="bold">(n = 4)</content></paragraph></td><td align="center" styleCode="Botrule " valign="bottom"><paragraph><content styleCode="bold">&lt;10 mL/min</content></paragraph><paragraph><content styleCode="bold">(n = 6)</content></paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Creatinine clearance (mL/min)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>111 &#xB1; 14</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>28 &#xB1; 8</paragraph></td><td align="center" valign="top"><paragraph>6 &#xB1; 2 </paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>C_max (mcg/mL)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2.6 &#xB1; 0.5</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3.6 &#xB1; 0.8</paragraph></td><td align="center" valign="top"><paragraph>5.8 &#xB1; 1.2</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>AUC&#x221E; (mcg&#x2022;h/mL)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11.0 &#xB1; 1.7</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>48.0 &#xB1; 19</paragraph></td><td align="center" valign="top"><paragraph>157 &#xB1; 74</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Cl/F (mL/min)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>464 &#xB1; 76</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>114 &#xB1; 34</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>36 &#xB1; 11</paragraph></td></tr></tbody></table>

></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>464 &#xB1; 76</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>114 &#xB1; 34</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>36 &#xB1; 11</paragraph></td></tr></tbody></table> <table ID="_RefID0EP5AG" width="100%"><caption>Table 8.

></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>464 &#xB1; 76</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>114 &#xB1; 34</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>36 &#xB1; 11</paragraph></td></tr></tbody></table> <table ID="_RefID0EP5AG" width="100%"><caption>Table 8. Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat Dosing of Lamivudine in 3 Pediatric Trials</caption><col width="31%"/><col width="10%"/><col width="13%"/><col width="10%"/><col width="14%"/><col width="10%"/><col width="13%"/><tbody><tr><td rowspan="2" styleCode="Toprule " valign="top"/><td align="center" colspan="6" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Trial (Number of Subjects)</content></paragraph></td></tr><tr><td align="center" colspan="2" valign="top"><paragraph><content styleCode="bold">ARROW PK</content> <content styleCode="bold">(n = 35)</content></paragraph></td><td align="center" colspan="2" valign="top"><paragraph><content styleCode="bold">PENTA-13</content> <content styleCode="bold">(n = 19)</content></paragraph></td><td align="center" colspan="2" valign="top"><paragraph><content styleCode="bold">PENTA-15</content> <content styleCode="bold">(n = 17)^a</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Age Range</content></paragraph></td><td align="center" colspan="2" valign="top"><paragraph><content styleCode="bold">3-12 years</content></paragraph></td><td align="center" colspan="2" valign="top"><paragraph><content styleCode="bold">2-12 years</content></paragraph></td><td align="center" colspan="2" valign="top"><paragraph><content styleCode="bold">3-36 months</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Formulation</content></paragraph></td><td align="center" colspan="2" valign="top"><paragraph><content styleCode="bold">Tablet</content></paragraph></td><td align="center" colspan="2" valign="top"><paragraph><content styleCode="bold">Solution^b and Tablet^c</content></paragraph></td><td align="center" colspan="2" valign="top"><paragraph><content styleCode="bold">Solution^b</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Parameter</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Once Daily</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Twice Daily</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Once Daily</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Twice Daily</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Once Daily</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Twice Daily</content></paragraph></td></tr><tr><td valign="top"><paragraph>Cmax (mcg/mL)</paragraph></td><td align="center" valign="top"><paragraph>3.17 (2.76, 3.64)</paragraph></td><td align="center" valign="top"><paragraph>1.80 (1.59, 2.04)</paragraph></td><td align="center" valign="top"><paragraph>2.09 (1.80, 2.42)</paragraph></td><td align="center" valign="top"><paragraph>1.11 (0.96, 1.29)</paragraph></td><td align="center" valign="top"><paragraph>1.87 (1.65, 2.13)</paragraph></td><td align="center" valign="top"><paragraph>1.05 (0.88, 1.26)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>AUC_(0-24) (mcg&#x2022;h/mL)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>13.0 (11.4, 14.9)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>

<paragraph>1.05 (0.88, 1.26)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>AUC_(0-24) (mcg&#x2022;h/mL)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>13.0 (11.4, 14.9)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph> 12.0 (10.7, 13.4)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>9.80 (8.64, 11.1)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>8.88 (7.67, 10.3)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>8.66 (7.46, 10.1)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>9.48 (7.89, 11.4)</paragraph></td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg. Mutagenesis Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection. Impairment of Fertility In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg. Mutagenesis Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection. Impairment of Fertility In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

14 CLINICAL STUDIES The use of lamivudine tablets is based on the results of clinical trials in HIV-1-infected subjects in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials. 14.1 Adult Subjects Clinical Endpoint Trial NUCB3007 (CAESAR) was a multicenter, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of lamivudine or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells per mm 3 (median = 122 cells per mm 3 ) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on trial was 12 months. Results are summarized in Table 9. Table 9. Number of Subjects (%) with at Least One HIV-1 Disease Progression Event or Death Endpoint Current Therapy (n = 460) Lamivudine plus Current Therapy (n = 896) Lamivudine plus an NNRTI a plus Current Therapy (n = 460) HIV-1 progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%) Death 27 (5.9%) 23 (2.6%) 14 (3.0%) a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States. Surrogate Endpoint Trials Dual Nucleoside Analogue Trials Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These trials demonstrated the antiviral effect of lamivudine in a 2-drug combination. More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression. Dose Regimen Comparison Surrogate Endpoint Trials in Therapy- Naive Adults EPV20001 was a multicenter, double-blind, controlled trial in which subjects were randomized 1:1 to receive lamivudine 300 mg once daily or lamivudine 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), white (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells per mm 3 (median = 362 cells per mm 3 ), and median baseline plasma HIV-1 RNA of 4.66 log 10 copies per mL. Outcomes of treatment through 48 weeks are summarized in Figure 1 and Table 10. Figure 1. Virologic Response through Week 48, EPV20001 a,b (Intent-to-Treat) a Roche AMPLICOR HIV-1 MONITOR. b Responders at each visit are subjects who had achieved and maintained HIV-1 RNA less than 400 copies per mL without discontinuation by that visit. Table 10. Outcomes of Randomized Treatment through 48 Weeks (Intent-to-Treat) Outcome Lamivudine 300 mg Once Daily plus RETROVIR plus Efavirenz (n = 278) Lamivudine 150 mg Twice Daily plus RETROVIR plus Efavirenz (n = 276) Responder a 67% 65% Virologic failure b 8% 8% Discontinued due to clinical progression <1% 0% Discontinued due to adverse events 6% 12% Discontinued due to other reasons c 18% 14% a Achieved confirmed plasma HIV-1 RNA less than 400 copies per mL and maintained through 48 weeks.

ly plus RETROVIR plus Efavirenz (n = 276) Responder a 67% 65% Virologic failure b 8% 8% Discontinued due to clinical progression <1% 0% Discontinued due to adverse events 6% 12% Discontinued due to other reasons c 18% 14% a Achieved confirmed plasma HIV-1 RNA less than 400 copies per mL and maintained through 48 weeks. b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48. c Includes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment. The proportions of subjects with HIV-1 RNA less than 50 copies per mL (via Roche Ultrasensitive assay) through Week 48 were 61% for subjects receiving lamivudine tablets 300 mg once daily and 63% for subjects receiving lamivudine tablets 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells per mm 3 at Week 48 in subjects receiving lamivudine tablets 300 mg once daily and 146 cells per mm 3 for subjects receiving lamivudine tablets 150 mg twice daily. A small, randomized, open-label pilot trial, EPV40001, was conducted in Thailand. A total of 159 treatment-naive adult subjects (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells per mm 3 , median plasma HIV-1 RNA 4.8 log 10 copies per mL) were enrolled. Two of the treatment arms in this trial provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily. In intent-to-treat analyses of 48-week data, the proportions of subjects with HIV-1 RNA below 400 copies per mL were 61% (33 of 54) in the group randomized to once-daily lamivudine and 75% (39 of 52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies per mL were 54% (29 of 54) in the once-daily lamivudine group and 67% (35 of 52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells per mm 3 in the once-daily lamivudine group and 216 cells per mm 3 in the all-twice-daily group. figure1 14.2 Pediatric Subjects Clinical Endpoint Trial ACTG300 was a multicenter, randomized, double-blind trial that provided for comparison of lamivudine plus RETROVIR (zidovudine) with didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-white. The mean baseline CD4+ cell count was 868 cells per mm 3 (mean: 1,060 cells per mm 3 and range: 0 to 4,650 cells per mm 3 for subjects aged less than or equal to 5 years; mean: 419 cells per mm 3 and range: 0 to 1,555 cells per mm 3 for subjects aged over 5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log 10 copies per mL. The median duration on trial was 10.1 months for the subjects receiving lamivudine tablets plus RETROVIR and 9.2 months for subjects receiving didanosine monotherapy. Results are summarized in Table 11. Table 11.

r mm 3 for subjects aged over 5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log 10 copies per mL. The median duration on trial was 10.1 months for the subjects receiving lamivudine tablets plus RETROVIR and 9.2 months for subjects receiving didanosine monotherapy. Results are summarized in Table 11. Table 11. Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death) Endpoint Lamivudine plus RETROVIR (n = 236) Didanosine (n = 235) HIV-1 disease progression or death (total) 15 (6.4%) 37 (15.7%) Physical growth failure 7 (3.0%) 6 (2.6%) Central nervous system deterioration 4 (1.7%) 12 (5.1%) CDC Clinical Category C 2 (0.8%) 8 (3.4%) Death 2 (0.8%) 11 (4.7%) Once-Daily Dosing ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1-infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing Lamivudine and abacavir, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks on treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of Lamivudine and abacavir, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Virologic suppression was not a requirement for participation: at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort. The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks is shown in Table 12. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age. Table 12. Virologic Outcome of Randomized Treatment at Week 96 a (ARROW Randomization 3) Outcome Lamivudine plus Abacavir Twice-Daily Dosing (n = 333) Lamivudine plus Abacavir Once-Daily Dosing (n = 336) HIV-1 RNA <80 copies/mL b 70% 67% HIV-1 RNA ≥80 copies/mL c 28% 31% No virologic data Discontinued due to adverse event or death 1% <1% Discontinued study for other reasons d 0% <1% Missing data during window but on study 1% 1% a Analyses were based on the last observed viral load data within the Week 96 window. b Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96. c Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol. d Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing). Analyses by formulation demonstrated the proportion of subjects with HIV-1 RNA of less than 80 copies per mL at randomization and Week 96 was higher in subjects who had received tablet formulations of lamivudine and abacavir (75% [458/610] and 72% [434/601]) than in those who had received solution formulation(s) (with lamivudine solution given at weight band-based doses approximating 8 mg per kg per day) at any time (52% [29/56] and 54% [30/56]), respectively [see Warnings and Precautions ( 5.6 )] . These differences were observed in each different age group evaluated.

<table ID="_RefID0EMLBG" width="100%"><caption>Table 9. Number of Subjects (%) with at Least One HIV-1 Disease Progression Event or Death</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" styleCode="Toprule " valign="bottom"><paragraph><content styleCode="bold">Endpoint</content></paragraph></td><td align="center" styleCode="Toprule " valign="bottom"><paragraph><content styleCode="bold">Current Therapy</content></paragraph><paragraph><content styleCode="bold">(n = 460)</content></paragraph></td><td align="center" styleCode="Toprule " valign="bottom"><paragraph><content styleCode="bold">Lamivudine plus</content></paragraph><paragraph><content styleCode="bold">Current Therapy</content></paragraph><paragraph><content styleCode="bold">(n = 896)</content></paragraph></td><td align="center" styleCode="Toprule " valign="bottom"><paragraph><content styleCode="bold">Lamivudine plus an</content></paragraph><paragraph><content styleCode="bold">NNRTI^a plus</content></paragraph><paragraph><content styleCode="bold">Current Therapy</content></paragraph><paragraph><content styleCode="bold">(n = 460)</content></paragraph></td></tr><tr><td valign="top"><paragraph>HIV-1 progression or death</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>90 (19.6%)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>86 (9.6%)</paragraph></td><td align="center" valign="top"><paragraph>41 (8.9%)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Death</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27 (5.9%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>23 (2.6%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>14 (3.0%)</paragraph></td></tr></tbody></table>

</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27 (5.9%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>23 (2.6%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>14 (3.0%)</paragraph></td></tr></tbody></table> <table ID="_RefID0ESPBG" width="100%"><caption>Table 10. Outcomes of Randomized Treatment through 48 Weeks (Intent-to-Treat)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Outcome</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Lamivudine 300 mg</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">plus RETROVIR</content></paragraph><paragraph><content styleCode="bold">plus Efavirenz</content></paragraph><paragraph><content styleCode="bold">(n = 278)</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Lamivudine 150 mg</content></paragraph><paragraph><content styleCode="bold">Twice Daily</content></paragraph><paragraph><content styleCode="bold">plus RETROVIR</content></paragraph><paragraph><content styleCode="bold">plus Efavirenz</content></paragraph><paragraph><content styleCode="bold">(n = 276)</content></paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Responder^a</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>67%</paragraph></td><td align="center" valign="top"><paragraph>65%</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Virologic failure^b</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8%</paragraph></td><td align="center" valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Discontinued due to clinical progression</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" valign="top"><paragraph>0%</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Discontinued due to adverse events</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6%</paragraph></td><td align="center" valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Discontinued due to other reasons^c</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>14%</paragraph></td></tr></tbody></table>

/tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Discontinued due to other reasons^c</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18%</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>14%</paragraph></td></tr></tbody></table> <table ID="_RefID0EQVBG" width="100%"><caption>Table 11. Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Endpoint</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Lamivudine plus RETROVIR</content></paragraph><paragraph><content styleCode="bold">(n = 236)</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Didanosine</content></paragraph><paragraph><content styleCode="bold">(n = 235)</content></paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>HIV-1 disease progression or death (total)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>15 (6.4%)</paragraph></td><td align="center" valign="top"><paragraph>37 (15.7%)</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Physical growth failure</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7 (3.0%)</paragraph></td><td align="center" valign="top"><paragraph>6 (2.6%)</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>Central nervous system deterioration</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4 (1.7%)</paragraph></td><td align="center" valign="top"><paragraph>12 (5.1%)</paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph>CDC Clinical Category C</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2 (0.8%)</paragraph></td><td align="center" valign="top"><paragraph>8 (3.4%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Death</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2 (0.8%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>11 (4.7%)</paragraph></td></tr></tbody></table>

ph>8 (3.4%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Death</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2 (0.8%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>11 (4.7%)</paragraph></td></tr></tbody></table> <table ID="_RefID0EDZBG" width="100%"><caption>Table 12. Virologic Outcome of Randomized Treatment at Week 96^a (ARROW Randomization 3)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Outcome</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Lamivudine plus Abacavir</content> <content styleCode="bold">Twice-Daily Dosing</content> <content styleCode="bold">(n = 333)</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Lamivudine plus Abacavir</content> <content styleCode="bold">Once-Daily Dosing</content> <content styleCode="bold">(n = 336)</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">HIV-1 RNA &lt;80 copies/mL^b</content> </paragraph></td><td align="center" valign="top"><paragraph>70%</paragraph></td><td align="center" valign="top"><paragraph>67%</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">HIV-1 RNA &#x2265;80 copies/mL^c</content></paragraph></td><td align="center" valign="top"><paragraph>28%</paragraph></td><td align="center" valign="top"><paragraph>31%</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph><content styleCode="bold">No virologic data</content></paragraph></td></tr><tr><td valign="top"><paragraph>Discontinued due to adverse event or death</paragraph></td><td align="center" valign="top"><paragraph>1%</paragraph></td><td align="center" valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td valign="top"><paragraph>Discontinued study for other reasons^d</paragraph></td><td align="center" valign="top"><paragraph>0%</paragraph></td><td align="center" valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Missing data during window but on study</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1%</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Lamivudine tablets, USP 150 mg are white to off-white, diamond shaped, biconvex film-coated tablets, engraved “APO” on one side, “LMV” score “150” on the other side. They are supplied as follows: Cartons of 30 film-coated tablets (10 film-coated tablets each blister pack x 3), NDC 0904-6583-04 WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Recommended Storage Store lamivudine tablets at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients with Hepatitis B or C Co-infection Inform patients co-infected with HIV-1 and HBV that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see Warnings and Precautions ( 5.1 )] . Differences in Formulations of Lamivudine Advise patients that lamivudine tablets contain a higher dose of the same active ingredient (lamivudine) as lamivudine-HBV tablets and oral solution. If a decision is made to include lamivudine in the HIV-1 treatment regimen of a patient co-infected with HIV-1 and HBV, the formulation and dosage of lamivudine in lamivudine tablets (not lamivudine-HBV) should be used [see Warnings and Precautions ( 5. 1)] . Lactic Acidosis/Hepatomegaly with Steatosis Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking lamivudine tablets if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions ( 5.2 )] . Risk of Pancreatitis Advise parents or guardians to monitor pediatric patients for signs and symptoms of pancreatitis [see Warnings and Precautions ( 5.3 )] . Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when lamivudine tablets is started [see Warnings and Precautions ( 5.4 )]. Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution Advise patients that an all-tablet regimen should be used when possible due to an increased rate of treatment failure among pediatric subjects who received lamivudine oral solution concomitantly with other antiretroviral oral solutions [see Warnings and Precautions ( 5.5 )]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine tablets during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations ( 8.2 )] . Missed Dosage Instruct patients that if they miss a dose of lamivudine, 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 registered trademarks in this document are the property of their respective owners. APOTEX INC. LAMIVUDINE TABLETS, USP 150 mg and 300 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 USA 33326 Packaged and Distributed by: MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA Refer to package label for Distributor's NDC Number Revised: May 2019 Revision: 13

<table width="45%"><col width="29%"/><col width="23%"/><tbody><tr><td styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Manufactured by</content></paragraph></td><td styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Manufactured for</content></paragraph></td></tr><tr><td valign="top"><paragraph>Apotex Inc. </paragraph></td><td valign="top"><paragraph>Apotex Corp.</paragraph></td></tr><tr><td valign="top"><paragraph>Toronto, Ontario</paragraph></td><td valign="top"><paragraph>Weston, Florida</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Canada M9L 1T9</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>USA 33326</paragraph></td></tr></tbody></table>

PATIENT INFORMATION Lamivudine Tablets, USP (la miv' ue deen) What is the most important information I should know about lamivudine tablets? Lamivudine tablets can cause serious side effects, including: • Worsening of hepatitis B virus in people who have HIV-1 infection. If you have HIV-1 (Human Immunodeficiency Virus type 1) and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking lamivudine tablets. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease can be serious and may lead to death. o Do not run out of lamivudine tablets. Refill your prescription or talk to your healthcare provider before your lamivudine tablets is all gone. o Do not stop lamivudine tablets without first talking to your healthcare provider. o If you stop taking lamivudine tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver. • Resistant Hepatitis B Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with lamivudine tablets and become harder to treat (resistant). What is lamivudine? Lamivudine is a prescription medicine used together with other antiretroviral medicines to treat Human Immunodeficiency Virus (HIV-1) infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). Lamivudine tablets (used to treat HIV-1 infection) contain a higher dose of the same active ingredient (lamivudine) than is in the medicine lamivudine -HBV tablets (used to treat HBV). If you have both HIV-1 and HBV, you should not use lamivudine -HBV to treat your infections. The safety and effectiveness of lamivudine tablets have not been established in children under 3 months of age. Who should not take lamivudine tablets? Do not take lamivudine tablets if you are allergic to lamivudine or any of the ingredients in lamivudine tablets. See the end of this Patient Information leaflet for a complete list of ingredients in lamivudine tablets. What should I tell my healthcare provider before taking lamivudine tablets? Before you take lamivudine tablets, tell your healthcare provider if you: • have or have had liver problems, including hepatitis B or C virus infection. • have kidney problems. • have diabetes. • are pregnant or plan to become pregnant. Taking lamivudine tablets during pregnancy has not been associated with an increased risk of birth defects. Talk to your healthcare provider if you are pregnant or plan to become pregnant. • Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral 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. Do not breastfeed if you take lamivudine tablets. o You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medications interact with lamivudine. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with lamivudine.

-the-counter medicines, vitamins, and herbal supplements. Some medications interact with lamivudine. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with lamivudine. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take lamivudine tablets with other medicines. How should I take lamivudine tablets? • Take lamivudine tablets exactly as your healthcare provider tells you to take it. • If you miss a dose of lamivudine tablets, take it as soon as you remember. Do not take 2 doses at the same time or take more than what your healthcare provider tells you to take. • Stay under the care of a healthcare provider during treatment with lamivudine tablets. • Lamivudine tablets may be taken with or without food. • For children 3 months and older, your healthcare provider will prescribe a dose of lamivudine tablets based on your child’s body weight. • Tell your healthcare provider if you or your child has trouble swallowing tablets. • Do not run out of lamivudine tablets. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy. • If you take too much lamivudine tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of lamivudine tablets? • Lamivudine tablets can cause serious side effects including: • See "What is the most important information I should know about lamivudine tablets?" • Build-up of an acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take lamivudine tablets. Lactic acidosis is a serious medical emergency that can cause 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 • unusual (not normal) muscle pain • trouble breathing • stomach pain with nausea and vomiting • feel cold, especially in your arms and legs • feel dizzy or light-headed • have a fast or irregular heartbeat • Serious liver problems can happen in people who take lamivudine tablets. In some cases these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). 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) • dark or “tea-colored” urine • light-colored stools (bowel movements) • loss of appetite for several days or longer • nausea • pain, aching, or tenderness on the right side of your stomach area You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese). • Risk of inflammation of the pancreas (pancreatitis). Children may be at risk for developing pancreatitis during treatment with lamivudine tablets if they: • have taken nucleoside analogue medicines in the past • have a history of pancreatitis • have other risk factors for pancreatitis Call your healthcare provider right away if your child develops signs and symptoms of pancreatitis including severe upper stomach-area pain, with or without nausea and vomiting. Your healthcare provider may tell you to stop giving lamivudine tablets to your child if their symptoms and blood test results show that your child may have pancreatitis. • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines.

th or without nausea and vomiting. Your healthcare provider may tell you to stop giving lamivudine tablets to your child if their symptoms and blood test results show that your child may have pancreatitis. • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking lamivudine tablets. The most common side effects of lamivudine tablets in adults include: • headache • nasal signs and symptoms • nausea • diarrhea • generally not feeling well • cough • tiredness The most common side effects of lamivudine tablets in children include fever and cough. 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. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store lamivudine tablets? • Store lamivudine tablets at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Keep lamivudine tablets and all medicines out of the reach of children. General information about the safe and effective use of lamivudine tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use lamivudine tablets for a condition for which it was not prescribed. Do not give lamivudine tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about lamivudine tablets that is written for health professionals. To report Suspected Adverse Reactions, contact Apotex Corp., at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. What are the ingredients in lamivudine tablets? Active ingredient : lamivudine Inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide black, lactose anhydrous, magnesium stearate, polyethylene glycol, and titanium dioxide. This Patient Information has been approved by the U.S. Food and Drug Administration. All registered trademarks in this document are the property of their respective owners. APOTEX INC. LAMIVUDINE TABLETS, USP 150 mg and 300 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 USA 33326 Packaged and Distributed by: MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA Refer to package label for Distributor's NDC Number Revised: May 2019 Rev. 13

<table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td styleCode="Botrule Toprule " valign="top"><paragraph>&#x2022; feel very weak or tired &#x2022; unusual (not normal) muscle pain &#x2022; trouble breathing &#x2022; stomach pain with nausea and vomiting </paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph>&#x2022; feel cold, especially in your arms and legs &#x2022; feel dizzy or light-headed &#x2022; have a fast or irregular heartbeat </paragraph></td></tr></tbody></table> <table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td styleCode="Botrule Toprule " valign="top"><paragraph>&#x2022; your skin or the white part of your eyes turns yellow (jaundice) &#x2022; dark or &#x201C;tea-colored&#x201D; urine &#x2022; light-colored stools (bowel movements) </paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph>&#x2022; loss of appetite for several days or longer &#x2022; nausea &#x2022; pain, aching, or tenderness on the right side of your stomach area </paragraph></td></tr></tbody></table> <table width="90%"><col width="56%"/><col width="44%"/><tbody><tr><td styleCode="Toprule " valign="top"><paragraph>&#x2022; have taken nucleoside analogue medicines in the past</paragraph></td><td styleCode="Toprule " valign="top"><paragraph>&#x2022; have a history of pancreatitis</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"/><td styleCode="Botrule " valign="top"><paragraph>&#x2022; have other risk factors for pancreatitis</paragraph></td></tr></tbody></table> <table width="90%"><col width="56%"/><col width="44%"/><tbody><tr><td styleCode="Toprule " valign="top"><paragraph>&#x2022; headache</paragraph></td><td styleCode="Toprule " valign="top"><paragraph>&#x2022; nasal signs and symptoms</paragraph></td></tr><tr><td valign="top"><paragraph>&#x2022; nausea</paragraph></td><td valign="top"><paragraph>&#x2022; diarrhea</paragraph></td></tr><tr><td valign="top"><paragraph>&#x2022; generally not feeling well</paragraph></td><td valign="top"><paragraph>&#x2022; cough</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>&#x2022; tiredness</paragraph></td><td styleCode="Botrule " valign="top"/></tr></tbody></table>

ea</paragraph></td></tr><tr><td valign="top"><paragraph>&#x2022; generally not feeling well</paragraph></td><td valign="top"><paragraph>&#x2022; cough</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>&#x2022; tiredness</paragraph></td><td styleCode="Botrule " valign="top"/></tr></tbody></table> <table width="45%"><col width="29%"/><col width="23%"/><tbody><tr><td styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Manufactured by</content></paragraph></td><td styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Manufactured for</content></paragraph></td></tr><tr><td valign="top"><paragraph>Apotex Inc.</paragraph></td><td valign="top"><paragraph>Apotex Corp.</paragraph></td></tr><tr><td valign="top"><paragraph>Toronto, Ontario</paragraph></td><td valign="top"><paragraph>Weston, Florida</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Canada M9L 1T9</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>USA 33326</paragraph></td></tr></tbody></table>

WARNING: EXACERBATIONS OF HEPATITIS B, AND RISK OF HIV-1 RESISTANCE IF LAMIVUDINE TABLETS (HBV) IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy [including lamivudine tablets (HBV)]. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted [ see Warnings and Precautions ( 5.1 )] Lamivudine tablets (HBV) is not approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection because the lamivudine dosage in lamivudine tablets (HBV) is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with lamivudine tablets (HBV) and periodically during treatment [see Warnings and Precaution ( 5.1 ) ] W A RN I N G: EXACERBATIONS OF HEPATITIS B, and RISK OF HIV-1 RESISTANCE IF LAMIVUDINE TABLETS (HBV) I S USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION See full prescribing information for complete boxed warning S e v er e acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy [including lamivudine tablets (HBV)]. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.1 ) Lamivudine tablets (HBV) contain a lower dose of the same active ingredient (lamivudine) as Epivir tablets and oral solution used to treat human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 resistance may emerge in chronic hepatitis B patients with unrecognized or untreated HIV-1 infection because the lamivudine dosage in lamivudine tablets (HBV) is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with lamivudine tablets (HBV) and periodically during treatment. ( 5.2 )

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 withhuman 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 resistanthuman 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 Creatinine Clearance (mL/min) Recommended Dosage of Lamivudine Tablets (HBV) ≥50 100 mg once daily 30-49 100 mg first dose, then 50 mg once daily 15-29 100 mg first dose, then 25 mg once daily 5-14 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).

n 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 Lamivudine tablets (HBV): 100 mg, are orange-brown, capsule shaped, biconvex film-coated tablets engraved “APO” on one side, “LMV 100” on the other side. Tablets: 100 mg ( 3 )

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

5 WARNINGS AND PRECAUTIONS Emergence of Resistance-Associated HBV Substitutions: Consider a switch to an alternative regimen if serum HBV DNA remains detectable after 24 weeks of treatment. ( 2.6 , 5.3 ) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. ( 5.4 ) 5.1 Exacerbations of Hepatitis after Discontinuation of Treatment Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA commonly observed after stopping treatment; see Table 4 for more information regarding frequency of posttreatment ALT elevations [ see Adverse Reactions ( 6.1 ) ]. Although most events appear to have been self-limited, fatalities have been reported in some cases. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with lamivudine tablets (HBV). There is insufficient evidence to determine whether re-initiation of lamivudine tablets (HBV) alters the course of posttreatment exacerbations of hepatitis. 5.2 Risk of HIV-1 Resistance if Lamivudine Tablets (HBV) is Used in Patients with Unrecognized or Untreated HIV-1 Infection Lamivudine tablets (HBV) contain a lower lamivudine dose than the lamivudine dose used to treat HIV-1 infection with Epivir 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 a 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 B in a patient who has unrecognized or untreated HIV-1 infection or who acquires HIV-1 infection during treatment. 5.3 Emergence of Resistance-Associated HBV Substitutions In controlled clinical trials, YMDD-mutant HBV was detected in subjects with on–lamivudine tablets (HBV) re-appearance of HBV DNA after an initial decline below the assay limit [see Microbiology ( 12.4 )]. Subjects treated with lamivudine tablets (HBV) (adults and children) with YMDD-mutant HBV at 52 weeks showed diminished treatment responses in comparison with subjects treated with lamivudine tablets (HBV) without evidence of YMDD substitutions, including the following: lower rates of HBeAg seroconversion and HBeAg loss (no greater than placebo recipients), more frequent return of positive HBV DNA, and more frequent ALT elevations. In the controlled trials, when subjects developed YMDD-mutant HBV, they had a rise in HBV DNA and ALT from their previous on-treatment levels. Progression of hepatitis B, including death, has been reported in some subjects with YMDD-mutant HBV, including subjects from the liver transplant setting and from other clinical trials.

ntrolled trials, when subjects developed YMDD-mutant HBV, they had a rise in HBV DNA and ALT from their previous on-treatment levels. Progression of hepatitis B, including death, has been reported in some subjects with YMDD-mutant HBV, including subjects from the liver transplant setting and from other clinical trials. In order to reduce the risk of resistance in patients receiving monotherapy with lamivudine tablets (HBV), a switch to an alternative regimen should be considered if serum HBV DNA remains detectable after 24 weeks of treatment. Optimal therapy should be guided by resistance testing. 5.4 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine tablets (HBV). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Most of these reports have described patients receiving nucleoside analogues for treatment of HIV infection, but there have been reports of lactic acidosis in patients receiving lamivudine for hepatitis B. Treatment with lamivudine tablets (HBV) should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Exacerbations of hepatitis B after discontinuation of treatment [ see Warnings and Precautions ( 5.1 ) ]. Risk of emergence of resistant HIV-1 infection [ see Warnings and Precautions ( 5.2 ) ]. Risk of emergence of resistant HBV infection [ see Warnings and Precautions ( 5.3) ]. Lactic acidosis and severe hepatomegaly with steatosis [ see Warnings and Precautions ( 5.4 ) ]. The most common reported adverse reactions in those receiving lamivudine tablets (HBV) (incidence greater than or equal to 10% and reported at a rate greater than placebo) were ear, nose, and throat infections; sore throat; and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 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 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. Clinical Trials Experience in Adult Subjects with Chronic HBV Infection Clinical adverse reactions (regardless of investigator’s causality assessment) reported in greater than or equal to 10% of subjects who received lamivudine tablets (HBV) and reported at a rate greater than in subjects who received placebo are listed in Table 2. Table 2. Clinical Adverse Reactions a 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 1 to 3) a Includes adverse events regardless of severity and causality assessment. Adverse Event Lamivudine Tablets (HBV) (n = 332) Placebo (n = 200) Ear, Nose, and Throat Ear, nose, and throat infections 25% 21% Sore throat 13% 8% Gastrointestinal Diarrhea 14% 12% Specified laboratory abnormalities reported in subjects who received lamivudine tablets (HBV) and reported at a rate greater than in subjects who received placebo are listed in Table 3. Table 3. Frequencies of Specified Laboratory Abnormalities Reported during Treatment at a Greater Frequency in Subjects Treated with Lamivudine Tablets (HBV) than with Placebo (Trials 1 to 3) a a Includes subjects treated for 52 to 68 weeks. b Includes observations during and after treatment in the 2 placebo-controlled trials that collected this information. ULN = Upper limit of normal. Test (Abnormal Level) Subjects with Abnormality/Subjects with Observations Lamivudine Tabglets (HBV) Placebo Serum Lipase ≥2.5 x ULN b 10% 7% Creatine Phosphokinase (CPK) ≥7 x baseline 9% 5% Platelets <50,000/mm 3 4% 3% In subjects followed for up to 16 weeks after discontinuation of treatment, posttreatment ALT elevations were observed more frequently in subjects who had received lamivudine tablets (HBV) than in subjects who had received placebo. A 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 1 and 3) a Each subject may be represented in one or more category. b During treatment phase. c Comparable to a Grade 3 toxicity in accordance with modified WHO criteria. ULN = Upper limit of normal.

e treatment course is shown in Table 4. Table 4. Posttreatment ALT Elevations with No-Active-Treatment Follow-up (Trials 1 and 3) a Each subject may be represented in one or more category. b During treatment phase. c Comparable to a Grade 3 toxicity in accordance with modified WHO criteria. ULN = Upper limit of normal. Abnormal Value Subjects with ALT Elevation/ Subjects with Observations a Lamivudine Tablets (HBV) b Placebo b ALT ≥2 x baseline value 27% 19% ALT ≥3 x baseline value c 21% 8% ALT ≥2 x baseline value and absolute ALT >500 IU/L 15% 7% ALT ≥2 x baseline value; and bilirubin >2 x ULN and ≥2 x baseline value 0.7% 0.9% 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 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. Blood and Lymphatic Anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia. Digestive Stomatitis. Endocrine and Metabolic Hyperglycemia. General Weakness. Hepatic and Pancreatic Lactic acidosis and steatosis [see Warnings and Precautions ( 5.4 ) ], posttreatment exacerbations of hepatitis [see Warnings and Precautions ( 5.1 )] , pancreatitis. Hypersensitivity Anaphylaxis, urticaria. Musculoskeletal Cramps, rhabdomyolysis. Nervous Paresthesia, peripheral neuropathy. Respiratory Abnormal breath sounds/wheezing. Skin Alopecia, pruritus, rash.

<table width="503.000"><caption>Table 2. Clinical Adverse Reactions ^aReported 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 1 to 3) </caption><col span="1" width="45.5%"/><col span="1" width="25.8%"/><col span="1" width="28.6%"/><tfoot><tr><td align="left" colspan="3" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">^aIncludes adverse events regardless of severity and causality assessment. </td></tr></tfoot><tbody><tr><td align="center" colspan="1" rowspan="1" styleCode="Botrule Toprule Rrule Lrule" valign="bottom">Adverse Event</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom"><paragraph>Lamivudine Tablets (HBV)</paragraph>(n = 332) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom"><paragraph>Placebo</paragraph>(n = 200) </td></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Ear, Nose, and Throat</content></td><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom"/><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom"/></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Rrule" valign="top">Ear, nose, and throat infections</td><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom">25%</td><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom">21%</td></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Rrule" valign="top">Sore throat</td><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom">13%</td><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom">8%</td></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Gastrointestinal</content></td><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom"/><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom"/></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Rrule" valign="top">Diarrhea</td><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom">14%</td><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom">12%</td></tr></tbody></table>

ode="Rrule" valign="bottom"/></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Rrule" valign="top">Diarrhea</td><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom">14%</td><td align="center" colspan="1" rowspan="1" styleCode="Rrule" valign="bottom">12%</td></tr></tbody></table> <table width="0.000"><caption>Table 3. Frequencies of Specified Laboratory Abnormalities Reported during Treatment at a Greater Frequency in Subjects Treated with Lamivudine Tablets (HBV) than with Placebo (Trials 1 to 3) ^a</caption><col span="1"/><col span="1"/><col span="1"/><tfoot><tr><td align="left" colspan="3" rowspan="1" styleCode="Lrule Rrule" valign="top">^aIncludes subjects treated for 52 to 68 weeks. </td></tr><tr><td align="left" colspan="3" rowspan="1" styleCode="Lrule Rrule" valign="top">^bIncludes observations during and after treatment in the 2 placebo-controlled trials that collected this information. </td></tr><tr><td align="left" colspan="3" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">ULN = Upper limit of normal.</td></tr></tfoot><tbody><tr><td align="center" colspan="1" rowspan="2" styleCode="Botrule Toprule Rrule Lrule" valign="bottom"><paragraph>Test</paragraph>(Abnormal Level) </td><td align="center" colspan="2" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Subjects with Abnormality/Subjects with Observations</td></tr><tr><td align="center" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="bottom">Lamivudine Tabglets (HBV)</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Placebo</td></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">Serum Lipase &#x2265;2.5 x ULN ^b</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">10%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">7%</td></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">Creatine Phosphokinase (CPK) &#x2265;7 x baseline</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">9%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">5%</td></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">Platelets &lt;50,000/mm ³</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">4%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">3%</td></tr></tbody></table>

eft" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">Platelets &lt;50,000/mm ³</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">4%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">3%</td></tr></tbody></table> <table width="0.000"><caption>Table 4. Posttreatment ALT Elevations with No-Active-Treatment Follow-up (Trials 1 and 3)</caption><col span="1"/><col span="1"/><col span="1"/><tfoot><tr><td align="left" colspan="3" rowspan="1" styleCode="Lrule Rrule" valign="top">^aEach subject may be represented in one or more category. </td></tr><tr><td align="left" colspan="3" rowspan="1" styleCode="Lrule Rrule" valign="top">^b During treatment phase. ^cComparable to a Grade 3 toxicity in accordance with modified WHO criteria. </td></tr><tr><td align="left" colspan="3" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">ULN = Upper limit of normal.</td></tr></tfoot><tbody><tr><td align="center" colspan="1" rowspan="2" styleCode="Botrule Toprule Rrule Lrule" valign="bottom">Abnormal Value</td><td align="center" colspan="2" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Subjects with ALT Elevation/ Subjects with Observations ^a</td></tr><tr><td align="center" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="bottom">Lamivudine Tablets (HBV) ^b</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Placebo ^b</td></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">ALT &#x2265;2 x baseline value</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">27%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">19%</td></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">ALT &#x2265;3 x baseline value ^c</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">21%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">8%</td></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">ALT &#x2265;2 x baseline value and absolute ALT &gt;500 IU/L</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">15%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">7%</td></tr><tr><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">ALT &#x2265;2 x baseline value; and bilirubin &gt;2 x ULN and &#x2265;2 x baseline value</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">0.7%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">0.9%</td></tr></tbody></table>

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials Experience in Adult Subjects with Chronic HBV Infection Clinical adverse reactions (regardless of investigator’s causality assessment) reported in greater than or equal to 10% of subjects who received lamivudine tablets (HBV) and reported at a rate greater than in subjects who received placebo are listed in Table 2. Table 2. Clinical Adverse Reactions a 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 1 to 3) a Includes adverse events regardless of severity and causality assessment. Adverse Event Lamivudine Tablets (HBV) (n = 332) Placebo (n = 200) Ear, Nose, and Throat Ear, nose, and throat infections 25% 21% Sore throat 13% 8% Gastrointestinal Diarrhea 14% 12% Specified laboratory abnormalities reported in subjects who received lamivudine tablets (HBV) and reported at a rate greater than in subjects who received placebo are listed in Table 3. Table 3. Frequencies of Specified Laboratory Abnormalities Reported during Treatment at a Greater Frequency in Subjects Treated with Lamivudine Tablets (HBV) than with Placebo (Trials 1 to 3) a a Includes subjects treated for 52 to 68 weeks. b Includes observations during and after treatment in the 2 placebo-controlled trials that collected this information. ULN = Upper limit of normal. Test (Abnormal Level) Subjects with Abnormality/Subjects with Observations Lamivudine Tabglets (HBV) Placebo Serum Lipase ≥2.5 x ULN b 10% 7% Creatine Phosphokinase (CPK) ≥7 x baseline 9% 5% Platelets <50,000/mm 3 4% 3% In subjects followed for up to 16 weeks after discontinuation of treatment, posttreatment ALT elevations were observed more frequently in subjects who had received lamivudine tablets (HBV) than in subjects who had received placebo. A 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 1 and 3) a Each subject may be represented in one or more category. b During treatment phase. c Comparable to a Grade 3 toxicity in accordance with modified WHO criteria. ULN = Upper limit of normal. Abnormal Value Subjects with ALT Elevation/ Subjects with Observations a Lamivudine Tablets (HBV) b Placebo b ALT ≥2 x baseline value 27% 19% ALT ≥3 x baseline value c 21% 8% ALT ≥2 x baseline value and absolute ALT >500 IU/L 15% 7% ALT ≥2 x baseline value; and bilirubin >2 x ULN and ≥2 x baseline value 0.7% 0.9% 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).

e value 0.7% 0.9% 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). 14 CLINICAL STUDIES 14.1 Adult Subjects The safety and efficacy of lamivudine tablets (HBV) once daily versus placebo were evaluated in 3 controlled trials in subjects with compensated chronic hepatitis B virus infection. All subjects were aged 16 years or older and had chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of HBV replication (serum HBeAg-positive and positive for serum HBV DNA) and persistently elevated ALT levels and/or chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The results of these trials are summarized below. Trial 1 was a randomized, double-blind trial of lamivudine tablets (HBV) once daily versus placebo for 52 weeks followed by a 16-week no-treatment period in 141 treatment-naive U.S subjects. Trial 2 was a randomized, double-blind, 3-arm trial that compared lamivudine tablets (HBV) 25 mg once daily versus lamivudine tablets (HBV) once daily versus placebo for 52 weeks in 358 Asian subjects. Trial 3 was a randomized, partially-blind trial conducted primarily in North America and Europe in 238 subjects who had ongoing evidence of active chronic hepatitis B despite previous treatment with interferon alfa. The trial compared lamivudine 100 mg once daily for 52 weeks, followed by either lamivudine tablets (HBV) or matching placebo once daily for 16 weeks (Arm 1), versus placebo once daily for 68 weeks (Arm 2). Principal endpoint comparisons for the histologic and serologic outcomes in subjects receiving lamivudine tablets (HBV) (100 mg daily) or placebo in these trials are shown in the following tables. Table 7. Histologic Response at Week 52 among Adult Subjects Receiving Lamivudine Tablets (HBV) 100 mg Once Daily or Placebo a Improvement was defined as a greater than or equal to 2-point decrease in the Knodell Histologic Activity Index (HAI) at Week 52 compared with pretreatment HAI. Subjects with missing data at baseline were excluded. Assessment Trial 1 Trial 2 Trial 3 Lamivudine Tablets (HBV) 100 mg (n = 62) Placebo (n = 63) Lamivudine Tablets (HBV) 100 mg (n = 131) Placebo (n = 68) Lamivudine Tablets (HBV) 100 mg (n = 110) Placebo (n = 54) Improvement a 55% 25% 56% 26% 56% 26% No Improvement 27% 59% 36% 62% 25% 54% Missing Data 18% 16% 8% 12% 19% 20% Table 8. HBeAg Seroconverters a at Week 52 among Adult Subjects Receiving Lamivudine Tablets (HBV) 100 mg Once Daily or Placebo a Three-component seroconversion was defined as Week 52 values showing loss of HBeAg, gain of HBeAb, and reduction of HBV DNA to below the solution-hybridization assay limit. Subjects with negative baseline HBeAg or HBV DNA assay were excluded from the analysis. Seroconversion Trial 1 Trial 2 Trial 3 Lamivudine Tablets (HBV) 100 mg (n = 63) Placebo (n = 69) Lamivudine Tablets (HBV) 100 mg (n = 140) Placebo (n = 70) Lamivudine Tablets (HBV) 100 mg (n = 108) Placebo (n = 53) Seroconverters 17% 6% 16% 4% 15% 13% Normalization of serum ALT levels was more frequent with treatment of lamivudine tablets (HBV) compared with placebo in Trials 1, 2, and 3. The majority of subjects treated with lamivudine tablets (HBV) showed a decrease of HBV DNA to below the assay limit early in the course of therapy. However, reappearance of assay-detectable HBV DNA during treatment with lamivudine tablets (HBV) was observed in approximately one-third of subjects after this initial response.

jority of subjects treated with lamivudine tablets (HBV) showed a decrease of HBV DNA to below the assay limit early in the course of therapy. However, reappearance of assay-detectable HBV DNA during treatment with lamivudine tablets (HBV) was observed in approximately one-third of subjects after this initial response. 14.2 Pediatric Subjects The safety and efficacy of lamivudine tablets (HBV) were evaluated in a double-blind clinical trial in 286 subjects aged 2 to 17 years, who were randomized (2:1) to receive 52 weeks of lamivudine tablets (HBV) (3 mg per kg once daily to a maximum of 100 mg once daily) or placebo. All subjects had compensated chronic hepatitis B accompanied by evidence of hepatitis B virus replication (positive serum HBeAg and positive for serum HBV DNA by a research branched-chain DNA assay) and persistently elevated serum ALT levels. The combination of loss of HBeAg and reduction of HBV DNA to below the assay limit of the research assay, evaluated at Week 52, was observed in 23% of subjects treated with lamivudine tablets (HBV) and 13% of placebo-treated subjects. Normalization of serum ALT was achieved and maintained to Week 52 more frequently in subjects treated with lamivudine compared with placebo (55% versus 13%). As in the adult controlled trials, most subjects treated with lamivudine tablets (HBV) had decreases in HBV DNA below the assay limit early in treatment, but about one-third of subjects with this initial response had reappearance of assay-detectable HBV DNA during treatment. Adolescents (aged 13 to 17 years) showed less evidence of treatment effect than younger pediatric subjects.

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

ule" valign="top">ALT &#x2265;2 x baseline value; and bilirubin &gt;2 x ULN and &#x2265;2 x baseline value</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">0.7%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">0.9%</td></tr></tbody></table> <table ID="id_067b85c2-303e-4153-82ae-d08415493e4d" width="547.000"><caption ID="id_b44a3e28-0e89-4293-bd0e-53c20dbd2fd8">Table 7. Histologic Response at Week 52 among Adult Subjects Receiving Lamivudine Tablets (HBV) 100 mg Once Daily or Placebo</caption><col span="1" width="23.8%"/><col span="1" width="14.1%"/><col span="1" width="12.2%"/><col span="1" width="13.9%"/><col span="1" width="12.2%"/><col span="1" width="13.9%"/><col span="1" width="9.9%"/><tfoot ID="id_e41b9758-5665-40cb-81ef-522dbccd780a"><tr><td align="left" colspan="7" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">^aImprovement was defined as a greater than or equal to 2-point decrease in the Knodell Histologic Activity Index (HAI) at Week 52 compared with pretreatment HAI. Subjects with missing data at baseline were excluded.

0a"><tr><td align="left" colspan="7" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">^aImprovement was defined as a greater than or equal to 2-point decrease in the Knodell Histologic Activity Index (HAI) at Week 52 compared with pretreatment HAI. Subjects with missing data at baseline were excluded. </td></tr></tfoot><tbody><tr ID="id_d957bd55-5403-419e-a963-3b41003a858b"><td align="center" colspan="1" rowspan="2" styleCode="Botrule Toprule Rrule Lrule" valign="bottom">Assessment</td><td align="center" colspan="2" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Trial 1</td><td align="center" colspan="2" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Trial 2</td><td align="center" colspan="2" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Trial 3</td></tr><tr ID="id_faf71ba2-125d-45f0-bf6a-2619589778ff"><td align="center" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="bottom">Lamivudine Tablets (HBV) 100 mg (n = 62) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom"><paragraph>Placebo</paragraph>(n = 63) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Lamivudine Tablets (HBV) 100 mg (n = 131) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom"><paragraph>Placebo</paragraph>(n = 68) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Lamivudine Tablets (HBV) 100 mg (n = 110) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom"><paragraph>Placebo </paragraph>(n = 54) </td></tr><tr ID="id_f2599753-dbdf-4d6d-a986-eef24c528d97"><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">Improvement ^a</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">55%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">25%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">56%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">26%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">56%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">26%</td></tr><tr ID="id_b77a3420-0c74-4f6c-b47d-7acb6cdef1b8"><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">No Improvement</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">27%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">59%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">36%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">62%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">25%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">54%</td></tr><tr ID="id_b38115dd-e0e9-4444-8652-3f10f736a0c1"><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">Missing Data</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">18%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">16%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">8%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">12%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">19%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">20%</td></tr></tbody></table

lign="bottom">8%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">12%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">19%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">20%</td></tr></tbody></table >

lign="bottom">8%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">12%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">19%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">20%</td></tr></tbody></table > <table ID="id_f1a59bef-9ac5-49f7-82f8-9dfae891b8c4" width="476.000"><caption ID="id_c1f687f3-54d4-4f27-83ce-a7757b1785c2">Table 8. HBeAg Seroconverters ^aat Week 52 among Adult Subjects Receiving Lamivudine Tablets (HBV) 100 mg Once Daily or Placebo </caption><col span="1" width="18.9%"/><col span="1" width="14.1%"/><col span="1" width="11.3%"/><col span="1" width="13.2%"/><col span="1" width="13.2%"/><col span="1" width="14.1%"/><col span="1" width="15.1%"/><tfoot ID="id_ae271520-84b2-4497-a71b-74ffec08ac66"><tr><td align="left" colspan="7" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">^aThree-component seroconversion was defined as Week 52 values showing loss of HBeAg, gain of HBeAb, and reduction of HBV DNA to below the solution-hybridization assay limit. Subjects with negative baseline HBeAg or HBV DNA assay were excluded from the analysis. </td></tr></tfoot><tbody><tr ID="id_284d9b22-52e7-4a37-9f7d-6277211cab22"><td align="center" colspan="1" rowspan="2" styleCode="Botrule Toprule Rrule Lrule" valign="bottom">Seroconversion</td><td align="center" colspan="2" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Trial 1</td><td align="center" colspan="2" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Trial 2</td><td align="center" colspan="2" rowspan="1" styleCode="Botrule Rrule" valign="bottom">Trial 3</td></tr><tr ID="id_d20e3a43-ddc3-4fd7-96d9-2d02c072fb96"><td align="center" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="bottom"><paragraph>Lamivudine Tablets (HBV) 100 mg</paragraph>(n = 63) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom"><paragraph>Placebo</paragraph>(n = 69) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom"><paragraph>Lamivudine Tablets (HBV) 100 mg</paragraph>(n = 140) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom"><paragraph>Placebo</paragraph>(n = 70) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom"><paragraph>Lamivudine Tablets (HBV) 100 mg</paragraph>(n = 108) </td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom"><paragraph>Placebo</paragraph>(n = 53) </td></tr><tr ID="id_19b4b98b-1520-41f0-8ad6-d1e0894405ac"><td align="left" colspan="1" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">Seroconverters</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">17%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">6%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">16%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">4%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">15%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">13%</td></tr></tbody></table>

ign="bottom">16%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">4%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">15%</td><td align="center" colspan="1" rowspan="1" styleCode="Botrule Rrule" valign="bottom">13%</td></tr></tbody></table> <table ID="id_067b85c2-303e-4153-82ae-d08415493e4d" width="547.000"><caption ID="id_b44a3e28-0e89-4293-bd0e-53c20dbd2fd8">Table 7. Histologic Response at Week 52 among Adult Subjects Receiving Lamivudine Tablets (HBV) 100 mg Once Daily or Placebo</caption><col span="1" width="23.8%"/><col span="1" width="14.1%"/><col span="1" width="12.2%"/><col span="1" width="13.9%"/><col span="1" width="12.2%"/><col span="1" width="13.9%"/><col span="1" width="9.9%"/><tfoot ID="id_e41b9758-5665-40cb-81ef-522dbccd780a"><tr><td align="left" colspan="7" rowspan="1" styleCode="Lrule Botrule Rrule" valign="top">^aImprovement was defined as a greater than or equal to 2-point decrease in the Knodell Histologic Activity Index (HAI) at Week 52 compared with pretreatment HAI. Subjects with missing data at baseline were excluded.

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.

y (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 Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) 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 (C max ) 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 (C max ) 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 3 or 6 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 a breastfed infant of a mother being treated for HIV-1 infection was estimated to be approximately 6% of the recommended daily lamivudine dose for HBV in children over 2 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 mother’s 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 2 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 6 months despite constant milk concentrations.

e recommended 3-mg-per-kg daily lamivudine dose for treatment of HBV in children over 2 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 6 months despite constant milk concentrations. This is consistent with increased lamivudine renal clearance in the first 6 months of life. 8.4 Pediatric Use Lamivudine tablets (HBV) is indicated for the treatment of chronic hepatitis B virus infection in pediatric patients aged 2 to 17 years [ see Indications and Usage ( 1 ) , Clinical Pharmacology ( 12.3 ) , Clinical Studies ( 14.2 ) ]. The safety and efficacy of lamivudine tablets (HBV) in pediatric patients younger than 2 years have not been established. 8.5 Geriatric Use Clinical trials of lamivudine tablets (HBV) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of lamivudine tablets (HBV) in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Dosage and Administration ( 2.4 ), Clinical Pharmacology ( 12.3 )] . 8.6 Patients with Impaired Renal Function Reduction of the dosage of lamivudine tablets (HBV) is recommended for patients with impaired renal function [ see Dosage and Administration ( 2.4 ) , Clinical Pharmacology ( 12.3 ) ]. 8.7 Patients with Impaired Liver Function No dose adjustment for lamivudine is required for patients with impaired hepatic function.

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.

y (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 Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) 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 (C max ) 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 (C max ) 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 3 or 6 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 a breastfed infant of a mother being treated for HIV-1 infection was estimated to be approximately 6% of the recommended daily lamivudine dose for HBV in children over 2 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 mother’s 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 2 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 6 months despite constant milk concentrations. This is consistent with increased lamivudine renal clearance in the first 6 months of life.

8.4 Pediatric Use Lamivudine tablets (HBV) is indicated for the treatment of chronic hepatitis B virus infection in pediatric patients aged 2 to 17 years [ see Indications and Usage ( 1 ) , Clinical Pharmacology ( 12.3 ) , Clinical Studies ( 14.2 ) ]. The safety and efficacy of lamivudine tablets (HBV) in pediatric patients younger than 2 years have not been established.

8.5 Geriatric Use Clinical trials of lamivudine 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 )] .

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.

11 DESCRIPTION Lamivudine tablets (HBV) is a synthetic nucleoside analogue with activity against HBV. The drug substance used in lamivudine tablets (HBV) is lamivudine in the form of lamivudine methanol solvate. The chemical name of lamivudine methanol solvate is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)­ )­2(1H)-pyrimidinone methanol solvate. It has a molecular formula of C 8 H 11 N 3 O 3 S• O.2 CH 4 O C 8 H 11 N 3 O 3 S and a molecular weight of 235.66 g/mol. It has the following structural formula: Lamivudine is a white to off-white powder. It is highly soluble in water. Lamivudine tablets (HBV) are for oral administration. Each tablet contains lamivudine methanol solvate equivalent to 100 mg of lamivudine and the inactive ingredients anhydrous lactose, colloidal silicon dioxide, crospovidone, ferric oxide red, ferric oxide yellow, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol and titanium dioxide. Meets with USP dissolution test # 2 chemical-structure.jpg

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lamivudine is an antiviral agent with activity against HBV [ see Microbiology ( 12.4 ) ] . 12.3 Pharmacokinetics Pharmacokinetics in Adults The pharmacokinetic properties of lamivudine have been studied as single and multiple oral doses ranging from 5 mg to 600 mg per day administered to HBV-infected subjects. Absorption and Bioavailability : Following single oral doses of 100 mg, the peak serum lamivudine concentration (C max ) in HBV-infected patients (steady state) and healthy subjects (single dose) was 1.28 ± 0.56 mcg per mL and 1.05 ± 0.32 mcg per mL (mean ± SD), respectively, which occurred between 0.5 and 2 hours after administration. The area under the plasma concentration versus time curve (AUC[0-24 h]) following 100-mg lamivudine oral single and repeated daily doses to steady state was 4.3 ± 1.4 (mean ± SD) and 4.7 ± 1.7 mcg•hour per mL, respectively. The relative bioavailability of the tablet and oral solution were demonstrated in healthy subjects. Although the solution demonstrated a slightly higher peak serum concentration (C max ), there was no significant difference in systemic exposure (AUC) between the oral solution and the tablet. Therefore, the oral solution and the tablet may be used interchangeably. After oral administration of lamivudine once daily to HBV-infected adults, the AUC and C max increased in proportion to dose over the range from 5 mg to 600 mg once daily. Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the 10-mg per mL oral solution. Effects of Food on Oral Absorption: Lamivudine tablets (HBV) may be administered with or without food. The 100-mg tablet was administered orally to 24 healthy subjects on 2 occasions, once in the fasted state and once with food (standard meal: 967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There was no significant difference in systemic exposure (AUC) in the fed and fasted states. Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 HIV-1-infected subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight. Binding of lamivudine to human plasma proteins is less than 36%. In vitro studies showed that over the concentration range of 0.1 to 100 mcg per mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration. Metabolism: Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (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 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL per min (mean ± SD). In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine. In most single-dose trials with plasma sampling for up to 48 or 72 hours after dosing, the observed mean elimination half-life (t½) ranged from 13 to 19 hours.

d subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine. In most single-dose trials with plasma sampling for up to 48 or 72 hours after dosing, the observed mean elimination half-life (t½) ranged from 13 to 19 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. Spe cific Populations Patients with Renal Impairmen t 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 a Single 100-mg Oral Dose of Lamivudine in Adults with Varying Degrees of Renal Function P arameter Creatinine Clearance Criterion ( Number of Subjects) ≥ 80 mL/min ( n = 9) 20-59 mL/min ( n = 8) <20 mL/min ( n = 6) Creatinine clearance (mL/min) 97 (range 82-117) 39 (range 25-49) 15 (range 13-19) C max (mcg/mL) 1.31 ± 0.35 1.85 ± 0.40 1.55 ± 0.31 AUC (mcg•h/mL) 5.28 ± 1.01 14.67 ± 3.74 27.33 ± 6.56 Cl/F (mL/min) 326.4 ± 63.8 120.1 ± 29.5 64.5 ± 18.3 T max was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment [see Dosage and Administration ( 2.4 )] . Hemodialysis increases lamivudine clearance from a mean of 64 to 88 mL per min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis. The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients with chronic hepatitis B 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 a Single 100-mg Dose of Lamivudine in Adults with Normal or Impaired Hepatic Function P arameter Normal ( n = 8) Impairment a M oderate ( n = 8) S e vere ( n = 8) C max (mcg/mL) 0.92 ± 0.31 1.06 ± 0.58 1.08 ± 0.27 AUC (mcg•h/mL) 3.96 ± 0.58 3.97 ± 1.36 4.30 ± 0.63 T max (h) 1.3 ± 0.8 1.4 ± 0.8 1.4 ± 1.2 Cl/F (mL/min) 424.7 ± 61.9 456.9 ± 129.8 395.2 ± 51.8 Clr (mL/min) 279.2 ± 79.2 323.5 ± 100.9 216.1 ± 58.0 a Hepatic impairment assessed by aminopyrine breath test. Pharmacokinetic parameters were not altered by diminishing hepatic impairment. Safety and efficacy of lamivudine tablets (HBV) have not been established in the presence of decompensated liver disease [see Indications and Usage ( 1 )] . Patients Post-Hepatic Transplant Fourteen HBV-infected adult subjects received liver transplant following lamivudine therapy and completed pharmacokinetic assessments at enrollment, 2 weeks after 100-mg once-daily dosing (pre-transplant), and 3 months following transplant; there were no significant differences in pharmacokinetic parameters. The overall exposure of lamivudine is primarily affected by renal impairment; consequently, transplant patients with renal impairment had generally higher exposure than patients with normal renal function. Safety and efficacy of lamivudine tablets (HBV) have not been established in this population [see Indications and Usage ( 1 )] .

posure 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 2 clinical trials conducted in South Africa (3 to 6 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 a 28-day dose-ranging trial in 53 pediatric subjects with chronic hepatitis B. Subjects aged 2 to 12 years were randomized to receive lamivudine 0.35 mg per kg twice daily, 3 mg per kg once daily, 1.5 mg per kg twice daily, or 4 mg per kg twice daily. Subjects aged 13 to 17 years received lamivudine 100 mg once daily. Lamivudine T max was 0.5 to 1 hour. In general, both C max and exposure (AUC) showed dose proportionality in the dosing range studied. Weight-corrected oral clearance was highest at age 2 and declined from 2 to 12 years, where values were then similar to those seen in adults. A dose of 3 mg per kg given once daily produced a steady-state lamivudine AUC (mean 5,953 ng•hour per mL ± 1,562 SD) similar to that associated with a dose of 100 mg per day in adults. 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 1 (MATE1), MATE2-K, organic cation transporter 1 (OCT1), OCT2 or OCT3. Effect of Other Agents on the Pharmacokinetics of Lamivudine Lamivudine is a 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 a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a 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 a trial of 19 healthy male subjects. Ribavirin In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine.

likely to affect the disposition and elimination of lamivudine. Interferon Alfa There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a 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 a 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 a single 300-mg dose of lamivudine oral solution alone or coadministered with a 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 (0-24) , 14%, 32%, and 36% in the AUC (∞) , and 28%, 52%, and 55% in the C max of lamivudine. Trimethoprim/Sulfamethoxazole Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC ∞ , a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine. Zidovudine No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours). 12.4 Microbiology Mechanism of Action Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of the RNA- and DNA-­dependent polymerase activities of HBV reverse transcriptase (rt) via DNA chain termination after incorporation of the nucleotide analogue. Antiviral Activity Activity of lamivudine against HBV in cell culture was assessed in HBV DNA-transfected 2.2.15 cells, HB611 cells, and infected human primary hepatocytes. EC50 values (the concentration of drug needed to reduce the level of extracellular HBV DNA by 50%) varied from 0.01 microM (2.3 ng per mL) to 5.6 microM (1,288 ng per mL) depending upon the duration of exposure of cells to lamivudine, the cell model system, and the protocol used. See the prescribing information for lamivudine tablets regarding activity of lamivudine against HIV. The anti-HBV activity of lamivudine in combination with adefovir or tenofovir in cell culture was not antagonistic. Resistance Lamivudine-resistant isolates have been identified in subjects with virologic breakthrough. Lamivudine-resistant HBV isolates develop rtM204V/I substitutions in the YMDD motif of the catalytic domain of the viral reverse transcriptase.

bination with adefovir or tenofovir in cell culture was not antagonistic. Resistance Lamivudine-resistant isolates have been identified in subjects with virologic breakthrough. Lamivudine-resistant HBV isolates develop rtM204V/I substitutions in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory substitutions improving replication efficiency. Other substitutions reported in lamivudine-resistant HBV isolates include rtH55R, rtL80I/V, rtV173M, rtA181T/V, rtT184S, rtF219Y, rtL229F/M/V/W, and rtQ267H. In 4 controlled clinical trials evaluating lamivudine tablets (HBV) in adults with HBeAg-positive chronic hepatitis B virus infection (CHB), YMDD-mutant HBV was detected in 81 of 335 subjects receiving lamivudine tablets (HBV) once daily for 52 weeks. The prevalence of YMDD substitutions was less than 10% in each of these trials for subjects studied at 24 weeks and increased to an average of 24% (range in 4 trials: 16% to 32%) at 52 weeks. A similar prevalence of YMDD substitutions has been reported in large controlled Phase 3 clinical trials utilizing lamivudine tablets (HBV) as a comparator arm in adults with HBeAg-positive CHB for 48 weeks (range in 4 trials: 11% to 27%) and in adults with HBeAg-negative CHB for 48 weeks (range in 3 clinical trials: 6% to 18%). Long-term follow up in subjects who continued 100 mg per day of lamivudine tablets (HBV) demonstrated that the prevalence of YMDD substitutions further increased from 23% (211 of 998) in Year 1, to 46% (368 of 796), 55% (378 of 688), 71% (421 of 592), and 65% (103 of 159) in Years 2, 3, 4, and 5, respectively. In a controlled trial, treatment-naive subjects with HBeAg-positive CHB were treated with lamivudine tablets (HBV) or lamivudine tablets (HBV) plus adefovir dipivoxil combination therapy. Following 104 weeks of therapy, YMDD-mutant HBV was detected in 7 of 40 (18%) subjects receiving combination therapy compared with 15 of 35 (43%) subjects receiving therapy with only lamivudine tablets (HBV). In 2 controlled clinical trials, treatment-naive subjects who received 48 weeks of therapy with lamivudine tablets (HBV) in combination with pegylated interferon developed YMDD substitutions less frequently than subjects treated with lamivudine tablets (HBV) alone (1 of 173 [1%] versus 32 of 179 [18%] in HBeAg-negative subjects; 9 of 256 [4%] versus 69 of 254 [27%] in HBeAgpositive subjects). Several clinical studies have evaluated alternative regimens in subjects who failed lamivudine tablets (HBV) due to development of lamivudine resistance. These studies demonstrated a higher rate of viral suppression and decreased development of viral resistance compared with continuation of monotherapy with lamivudine tablets (HBV). Pediatric Subjects In a controlled trial in pediatric subjects, YMDD-mutant HBV was detected in 31 of 166 (19%) subjects receiving lamivudine tablets (HBV) for 52 weeks. For a subgroup that remained on therapy with lamivudine tablets (HBV) in a follow-up trial, YMDD substitutions increased from 24% (29 of 121) at 12 months to 59% (68 of 115) at 24 months and 64% (66 of 103) at 36 months of treatment with lamivudine tablets (HBV). Cross-Resistance HBV containing lamivudine resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M and rtM204V, rtV173L and rtL180M and rtM204V) retain susceptibility to adefovir dipivoxil but have reduced susceptibility to entecavir (greater than 30-fold) and telbivudine (greater than 100-fold). The lamivudine resistance-associated substitution rtA181T results in diminished response to adefovir and telbivudine.

80M and rtM204V, rtV173L and rtL180M and rtM204V) retain susceptibility to adefovir dipivoxil but have reduced susceptibility to entecavir (greater than 30-fold) and telbivudine (greater than 100-fold). The lamivudine resistance-associated substitution rtA181T results in diminished response to adefovir and telbivudine. Similarly, HBV with entecavir resistance-associated substitutions (rtI169T and rtM250V, rtT184G and rtS202I) have greater than 1,000-fold reductions in susceptibility to lamivudine.

12.4 Microbiology Mechanism of Action Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of the RNA- and DNA-­dependent polymerase activities of HBV reverse transcriptase (rt) via DNA chain termination after incorporation of the nucleotide analogue. Antiviral Activity Activity of lamivudine against HBV in cell culture was assessed in HBV DNA-transfected 2.2.15 cells, HB611 cells, and infected human primary hepatocytes. EC50 values (the concentration of drug needed to reduce the level of extracellular HBV DNA by 50%) varied from 0.01 microM (2.3 ng per mL) to 5.6 microM (1,288 ng per mL) depending upon the duration of exposure of cells to lamivudine, the cell model system, and the protocol used. See the prescribing information for lamivudine tablets regarding activity of lamivudine against HIV. The anti-HBV activity of lamivudine in combination with adefovir or tenofovir in cell culture was not antagonistic. Resistance Lamivudine-resistant isolates have been identified in subjects with virologic breakthrough. Lamivudine-resistant HBV isolates develop rtM204V/I substitutions in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory substitutions improving replication efficiency. Other substitutions reported in lamivudine-resistant HBV isolates include rtH55R, rtL80I/V, rtV173M, rtA181T/V, rtT184S, rtF219Y, rtL229F/M/V/W, and rtQ267H. In 4 controlled clinical trials evaluating lamivudine tablets (HBV) in adults with HBeAg-positive chronic hepatitis B virus infection (CHB), YMDD-mutant HBV was detected in 81 of 335 subjects receiving lamivudine tablets (HBV) once daily for 52 weeks. The prevalence of YMDD substitutions was less than 10% in each of these trials for subjects studied at 24 weeks and increased to an average of 24% (range in 4 trials: 16% to 32%) at 52 weeks. A similar prevalence of YMDD substitutions has been reported in large controlled Phase 3 clinical trials utilizing lamivudine tablets (HBV) as a comparator arm in adults with HBeAg-positive CHB for 48 weeks (range in 4 trials: 11% to 27%) and in adults with HBeAg-negative CHB for 48 weeks (range in 3 clinical trials: 6% to 18%). Long-term follow up in subjects who continued 100 mg per day of lamivudine tablets (HBV) demonstrated that the prevalence of YMDD substitutions further increased from 23% (211 of 998) in Year 1, to 46% (368 of 796), 55% (378 of 688), 71% (421 of 592), and 65% (103 of 159) in Years 2, 3, 4, and 5, respectively. In a controlled trial, treatment-naive subjects with HBeAg-positive CHB were treated with lamivudine tablets (HBV) or lamivudine tablets (HBV) plus adefovir dipivoxil combination therapy. Following 104 weeks of therapy, YMDD-mutant HBV was detected in 7 of 40 (18%) subjects receiving combination therapy compared with 15 of 35 (43%) subjects receiving therapy with only lamivudine tablets (HBV).

treated with lamivudine tablets (HBV) or lamivudine tablets (HBV) plus adefovir dipivoxil combination therapy. Following 104 weeks of therapy, YMDD-mutant HBV was detected in 7 of 40 (18%) subjects receiving combination therapy compared with 15 of 35 (43%) subjects receiving therapy with only lamivudine tablets (HBV). In 2 controlled clinical trials, treatment-naive subjects who received 48 weeks of therapy with lamivudine tablets (HBV) in combination with pegylated interferon developed YMDD substitutions less frequently than subjects treated with lamivudine tablets (HBV) alone (1 of 173 [1%] versus 32 of 179 [18%] in HBeAg-negative subjects; 9 of 256 [4%] versus 69 of 254 [27%] in HBeAgpositive subjects). Several clinical studies have evaluated alternative regimens in subjects who failed lamivudine tablets (HBV) due to development of lamivudine resistance. These studies demonstrated a higher rate of viral suppression and decreased development of viral resistance compared with continuation of monotherapy with lamivudine tablets (HBV). Pediatric Subjects In a controlled trial in pediatric subjects, YMDD-mutant HBV was detected in 31 of 166 (19%) subjects receiving lamivudine tablets (HBV) for 52 weeks. For a subgroup that remained on therapy with lamivudine tablets (HBV) in a follow-up trial, YMDD substitutions increased from 24% (29 of 121) at 12 months to 59% (68 of 115) at 24 months and 64% (66 of 103) at 36 months of treatment with lamivudine tablets (HBV). Cross-Resistance HBV containing lamivudine resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M and rtM204V, rtV173L and rtL180M and rtM204V) retain susceptibility to adefovir dipivoxil but have reduced susceptibility to entecavir (greater than 30-fold) and telbivudine (greater than 100-fold). The lamivudine resistance-associated substitution rtA181T results in diminished response to adefovir and telbivudine. Similarly, HBV with entecavir resistance-associated substitutions (rtI169T and rtM250V, rtT184G and rtS202I) have greater than 1,000-fold reductions in susceptibility to lamivudine.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 34 times (mice), and 113 and 187 times (male and female rats, respectively) those observed in humans at the recommended therapeutic dose for chronic hepatitis B. Mutagenesis Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Impairment of Fertility Lamivudine did not affect male or female fertility in rats at oral doses up to 4,000 mg per kg per day, associated with concentrations approximately 70 times (male) or 104 times (females) higher than the concentrations (C max ) in humans at the dose of 100 mg [see Use in Specific Populations ( 8.1 )] .

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 34 times (mice), and 113 and 187 times (male and female rats, respectively) those observed in humans at the recommended therapeutic dose for chronic hepatitis B. Mutagenesis Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Impairment of Fertility Lamivudine did not affect male or female fertility in rats at oral doses up to 4,000 mg per kg per day, associated with concentrations approximately 70 times (male) or 104 times (females) higher than the concentrations (C max ) in humans at the dose of 100 mg [see Use in Specific Populations ( 8.1 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Lamivudine tablets (HBV), 100 mg, are orange-brown, capsule shaped, biconvex film-coated tablets engraved “APO” on one side, “LMV 100” on the other side. Bottles of 60 tablets (NDC 51407-866-60) with child-resistant closures. Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Severe Acute Exacerbation of Hepatitis after Discontinuation of Treatment Inform patients that discontinuation of anti-hepatitis B therapy, including lamivudine tablets (HBV), may result in severe acute exacerbations of hepatitis B including decompensation of liver disease. Advise patients not to discontinue lamivudine tablets (HBV) without first informing their healthcare provider [see Warnings and Precautions ( 5.1 ) ] . Risk of Development of HIV-1 Resistance in Patients with HIV-1 Co-infection Counsel patients on the importance of testing for HIV to avoid inappropriate therapy and development of resistance to HIV. HIV counseling and testing should be offered before starting lamivudine tablets (HBV) and periodically during therapy. Inform patients that if they have or develop HIV infection and are not receiving effective HIV treatment, lamivudine tablets (HBV) may increase the risk of development of resistance to HIV medications. Advise patients that lamivudine tablets (HBV) contains a lower dose of the same active ingredient (lamivudine) as HIV drugs containing lamivudine [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.2 ) ] . Emergence of HBV Resistance Inform patients that emergence of resistant hepatitis B virus and worsening of disease can occur during treatment. Patients should promptly report any new or worsening symptoms to their physician [see Warnings and Precautions ( 5.3 ) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking lamivudine tablets (HBV) if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions ( 5.4 )]. Hepatitis B Transmission Advise patients that treatment with lamivudine tablets (HBV) has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination. Drug Interactions Inform patients that lamivudine tablets (HBV) may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription or non-prescription medication, or herbal products. Advise patients to avoid chronic use of sorbitol-containing prescription and over-the-counter medicines when possible. Taking lamivudine tablets (HBV) with chronically administered sorbitol-containing medicines may decrease the concentrations of lamivudine [see Drug Interactions ( 7.2 )] . Pregnancy Registry Advise patients that there is a 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 a 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 registered trademarks in this document are the property of their respective owners. APOTEX INC. LAMIVUDINE TABLETS (HBV) 100 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Totonto, Ontario Weston, Florida Canada M9L 1T9 USA 33326 Revised: February 2022 Revision: 7 Marketed by: GSMS, Inc. Camarillo, CA 93012 USA

PATIENT INFORMATION Lamivudine Tablets (HBV) (la miv′ ue deen) What is the most important information I should know about lamivudine tablets (HBV)? Lamivudine tablets (HBV) can cause serious side effects, including: Worsening liver disease. Your hepatitis B 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 B with lamivudine tablets (HBV) and during treatment. Lamivudine tablets (HBV) contain a lower dose of lamivudine than other medicines that contain lamivudine and are used to treat HIV-1 infection. Resistant Hepatitis B Virus (HBV). The hepatitis B 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. For more information about side effects, see “What are the possible side effects of lamivudine tablets (HBV) ?” What is lamivudine tablets (HBV)? Lamivudine tablets (HBV) is a prescription medicine used to treat long-term (chronic) hepatitis B 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 a severely damaged liver that is unable to work properly (decompensated liver disease) people with HIV-1, hepatitis C virus, or hepatitis D (delta) virus people who have had a liver transplant children with chronic HBV less than 2 years of age Lamivudine tablets (HBV) does not stop you from spreading HBV to others by sex, sharing needles, or being exposed to your blood. Avoid doing things that can spread HBV infection to others. Do not take lamivudine tablets (HBV): If you are allergic to lamivudine or any of the ingredients in lamivudine tablets (HBV). See the end of this Patient Information leaflet for a complete list of ingredients in 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 a 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.

e 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 a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with lamivudine tablets (HBV). Do not start taking a 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 I take lamivudine tablets (HBV)? Take lamivudine tablets (HBV) exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking lamivudine tablets (HBV) without talking with your healthcare provider If you miss a dose of lamivudine tablets (HBV) , take it as soon as you remember. Do not take 2 doses at the same time or take more than what your healthcare provider tells you to take. Stay under the care of a healthcare provider during treatment with lamivudine tablets (HBV) Lamivudine tablets (HBV) may be taken with or without food. Your healthcare provider may prescribe a lower dose if you have problems with your kidneys. For children 2 to 17 years of age, your healthcare provider will prescribe a dose of lamivudine tablets (HBV) based on your child’s 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 I should know about lamivudine tablets (HBV)?" Too much lactic acid in your blood (lactic acidosis). Lactic acidosis is a 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 unusual (not normal) muscle pain trouble breathing stomach pain with nausea and vomiting feel cold, especially in your arms and legs feel dizzy or light-headed have a fast or irregular heartbeat Severe liver problems. Severe liver problems can happen in people who take lamivudine tablets (HBV) or similar medicines. In some cases, these severe 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) dark or “tea-colored” urine light-colored stools (bowel movements) loss of appetite for several days or longer nausea pain, aching, or tenderness on the right side of your stomach area You may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese). The most common side effects of lamivudine tablets (HBV) include ear, nose, and throat infections; sore throat; and diarrhea. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

to get lactic acidosis or severe liver problems if you are female or very overweight (obese). The most common side effects of lamivudine tablets (HBV) include ear, nose, and throat infections; sore throat; and 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 I store lamivudine tablets (HBV)? Store lamivudine tablets (HBV) at room temperature between 68°F to 77°F (20°C to 25°C). 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 a Patient Information leaflet. Do not use lamivudine tablets (HBV) for a 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 Inactive ingredients: anhydrous lactose, crospovidone, colloidal silicon dioxide, ferric oxide red, ferric oxide yellow, hypromellose, hydroxypropyl cellulose, magnesium stearate, polyethylene glycol and titanium dioxide. This Patient Information has been approved by the U.S. Food and Drug Administration All registered trademarks in this document are the property of their respective owners. APOTEX INC. LAMIVUDINE TABLETS (HBV) 100 mg Manufactured by Apotex Inc. Toronto, Ontario Canada M9L 1T9 Manufactured for Apotex Corp. Weston, Florida USA 33326 Revised: February 2022 Revision: 7 Marketed by: GSMS, Inc. Camarillo, CA 93012 USA

<table><tbody><tr><td><content styleCode="bold">Manufactured by </content> Apotex Inc. Toronto, Ontario Canada M9L 1T9 </td><td><content styleCode="bold">Manufactured for </content> Apotex Corp. Weston, Florida USA 33326 </td></tr></tbody></table>