Lamivudine

Dosage and Administration (2.2) 07/2016 Warnings and Precautions, Related Products that are Recommended (5.3) Removed-Not 07/2016 Warnings and Precautions, Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution (5.6) 07/2016

1 INDICATIONS AND USAGE LAMIVUDINE 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. LAMIVUDINE is a nucleoside analogue reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Limitation 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 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 must be adjusted in accordance with renal function. (2.3) 2.1 Recommended Dosage for Adult Patients The recommended dosage of LAMIVUDINE 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 (5.2) ]. 2.2 Recommended Dosage for Pediatric Patients The recommended dosage of EPIVIR oral solution in HIV-1-infected pediatric patients aged 3 months and older is 4 mg per kg taken orally twice daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents. Once daily dosing in pediatric patients 3 months of age and older in combination with other antiretroviral agents for the treatment of HIV-1 infection. 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 should be prescribed [see Warnings and Precautions (5.6) ] . The recommended oral dosage of LAMIVUDINE tablets for HIV-l-infected pediatric patients is presented in Table 1. Table 1. Dosing Recommendations for LAMIVUDINE Scored (150-mg) Tablets in Pediatric Patients Weight (kg) Twice-daily Dosing Regimen Using Scored 150-mg Tablet AM Dose PM Dose Total Daily Dose 14 to <20 1⁄2 tablet (75 mg) 1⁄2 tablet (75 mg) 150 mg ≥20to <25 1⁄2 tablet (75 mg) 1 tablet (150 mg) 225 mg ≥25 1 tablet (150 mg) 1 tablet (150 mg) 300 mg Additional pediatric use information for patients aged 3 months and above is approved for ViiV Healthcare Company’s EPIVIR® (lamivudine) tablets and oral solution. However, due to ViiV Healthcare Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.3 Patients with Renal Impairment Dosing of LAMIVUDINE 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 LAMIVUDINE in Adults and Adolescents (Greater than or Equal to 25 kg) in Accordance with Creatinine Clearance Creatinine Clearance (mL/min) Recommended Dosage of ≥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.

2.1 Recommended Dosage for Adult Patients The recommended dosage of LAMIVUDINE 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 (5.2) ].

2.2 Recommended Dosage for Pediatric Patients The recommended dosage of EPIVIR oral solution in HIV-1-infected pediatric patients aged 3 months and older is …

3 DOSAGE FORMS AND STRENGTHS LAMIVUDINE Scored Tablets 150 mg are white to off-white, film-coated, diamond- shaped tablets, debossed with “MCR” and “313” separated by functional score on one side and plain on other side with functional score. LAMIVUDINE Tablets 300 mg are Grey, film-coated, modified diamond-shaped tablets, debossed with “MCR” and “314” on one side and plain on other side. Tablets: 300 mg (3) Tablets: 150 mg scored (3)

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

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning , Warnings and Precautions (5.1) ]. Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.2) ]. Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.3) ]. Pancreatitis [see Warnings and Precautions (5.4) ]. Immune reconstitution syndrome [see Warnings and Precautions (5.5) ]. Fat redistribution [see Warnings and Precautions (5.7) ]. The most common reported adverse reactions (incidence greater than 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 equal to 15%) in pediatric patients subjects were fever and cough. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Clinical Trials Experience in Adult SubjectsBecause 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 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 ReactionLAMIVUDINE 150 mgTwice Dailyplus RETROVIR(n = 251)RETROVIRaEither zidovudine monotherapy or zidovudine in combination with zalcitabine.(n = 230)Body as a WholeHeadache35%27%Malaise & fatigue27%23%Fever or chills10%12%DigestiveNausea33%29%Diarrhea18%22%Nausea & vomiting13%12%Anorexia and/or decreased appetite10%7%Abdominal pain9%11%Abdominal cramps6%3%Dyspepsia5%5%Nervous SystemNeuropathy12%10%Insomnia & other sleep disorders11%7%Dizziness10%4%Depressive disorders9%4%RespiratoryNasal signs & symptoms20%11%Cough18%13%SkinSkin rashes9%6%MusculoskeletalMusculoskeletal pain12%10%Myalgia8%6%Arthralgia5%5%Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received LAMIVUDINE in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions (5.4)].LAMIVUDINE 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving LAMIVUDINE 300 mg once daily or LAMIVUDINE 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)ULN = Upper limit of normal.ND = Not done.Test (Threshold Level)24-Week Surrogate EndpointClinical Endpoint TrialThe median duration on study was 12 months.LAMIVUDINE plus RETROVIREither zidovudine monotherapy or zidovudine in combination with zalcitabine.LAMIVUDINE plus Current TherapyCurrent therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.Placebo plus Current TherapyAbsolute neutrophil count(5.0 x ULN)3.7%3.63.8%1.9%AST (>5.0 x ULN)1.7%1.84.0%2.1%Bilirubin (>2.5 x ULN)0.8%0.4NDNDAmylase (>2.0 x ULN)4.2%1.52.2%1.1%The frequencies of se …

7 DRUG INTERACTIONS 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 Pharmacokinetics (12.3) ]. No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended. (8.2) Additional pediatric use information for patients aged 3 months and above is approved for ViiV Healthcare Company’s EPIVIR ® (lamivudine) tablets and oral solution. However, due to ViiV Healthcare Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LAMIVUDINE during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Lamivudine produced embryonic toxicity in rabbits at a dose that produced similar human exposures as the recommended clinical dose. The relevance of animal findings to human pregnancy registry data is not known. Data Human Data: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population of the MACDP. The prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.7%). 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 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. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg per mL (150 mg twice daily) and 2.1 to 5.2 mcg per mL (300 mg twice daily). Animal Data: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed. 8.4 Pediatric Use The safety and effectiveness of LAMIVUDINE 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 appropr …

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

11 DESCRIPTION LAMIVUDINE (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. LAMIVUDINE 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 Chemical Structure

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.

16 HOW SUPPLIED/STORAGE AND HANDLING LAMIVUDINE Scored Tablets, 150 mg White to off-white, film-coated tablets debossed with “MCR” and “313” separated by functional score on one side and plain on other side with functional score. Bottle of 60 tablets (NDC 50742-623-60) with child-resistant closure. LAMIVUDINE Tablets, 300 mg Gray, modified diamond-shaped, film-coated tablets engraved with “MCR" and "314” on one side and plain on the reverse side. Bottle of 30 tablets (NDC 50742-624-30) with child-resistant closure. Recommended Storage: Store LAMIVUDINE Tablets at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].