EPIVIR

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

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 )

• 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. 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.

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

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. 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. 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.

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 )] .