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.

• 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 • Tablets: 300 mg • Oral Solution: 10 mg per mL

• Adults: 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily. • 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. • Patients with Renal Impairment: Doses of EPIVIR must be adjusted in accordance with renal function

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

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 . 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 . 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 . Consider HIV-1 viral load and CD4+ cell count/percentage when selecting the dosing interval for patients initiating treatment with oral solution

Patients with Renal Impairment Dosing of EPIVIR is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2 . 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.

• Co-infected HIV‑1/HBV Patients: Emergence of lamivudine-resistant HBV variants associated with lamivudine‑containing antiretroviral regimens has been reported. • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. • Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. • 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. 5.1 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 . 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

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

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

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

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 . 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 . Consider more frequent monitoring of HIV-1 viral load when treating with EPIVIR oral solution.

Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration

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) . No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine

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 .