EPIVIR® Tablets
(lamivudine tablets)
EPIVIR® Oral Solution
(lamivudine oral solution)

LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING LAMIVUDINE AND OTHER ANTIRETROVIRALS (SEE WARNINGS).

EPIVIR TABLETS AND ORAL SOLUTION (USED TO TREAT HUMAN IMMUNODEFICIENCY VIRUS [HIV] INFECTION) CONTAIN A HIGHER DOSE OF THE ACTIVE INGREDIENT (LAMIVUDINE) THAN EPIVIR-HBV^® TABLETS AND ORAL SOLUTION (USED TO TREAT CHRONIC HEPATITIS B). PATIENTS WITH HIV INFECTION SHOULD RECEIVE ONLY DOSING FORMS APPROPRIATE FOR TREATMENT OF HIV (SEE WARNINGS AND PRECAUTIONS).

SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV 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 AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).

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 C₈H₁₁N₃O₃S and a molecular weight of 229.3. It has the following structural formula:

Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.

EPIVIR Tablets are for oral administration. Each 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/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 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 the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is a weak inhibitor of mammalian DNA polymerases α, β, and γ.

The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC₅₀ values (50% effective concentrations) were in the range of 0.003 to 15 µM (1 μM = 0.23 mcg/mL). HIV from therapy-naive subjects with no mutations associated with resistance gave median EC₅₀ values of 0.426 µM (range: 0.200 to 2.007 µM) from Virco (n = 93 baseline samples from COLA40263) and 2.35 µM (1.44 to 4.08 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC₅₀ values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 µM, and against HIV-2 isolates from 0.003 to 0.120 μM in peripheral blood mononuclear cells. Ribavirin (50 μM) decreased the anti-HIV-1 activity of lamivudine by 3.5 fold in MT-4 cells. In HIV−1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity. Please see the EPIVIR-HBV package insert for information regarding the inhibitory activity of lamivudine against HBV.

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 isoleucine or valine (M184V/I).

HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients. Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.

Mutations in the HBV polymerase YMDD motif have been associated with reduced susceptibility of HBV to lamivudine in cell culture. In studies of non−HIV-infected patients with chronic hepatitis B, HBV isolates with YMDD mutations were detected in some patients who received lamivudine daily for 6 months or more, and were associated with evidence of diminished treatment response; similar HBV mutants have been reported in HIV-infected patients who received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus (see PRECAUTIONS and EPIVIR-HBV package insert).

Lamivudine-resistant HIV-1 mutants were cross-resistant to didanosine (ddI) and zalcitabine (ddC). In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged.

The clinical relevance of genotypic and phenotypic changes associated with lamivudine therapyhas not been fully established.

The steady-state pharmacokinetic properties of the EPIVIR 300-mg tablet once daily for 7 days compared to the EPIVIR 150-mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. 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 to 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 to the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.

The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-infected adult patients after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg.

The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg/day administered to HBV-infected patients.

No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr).

Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-positive patients in a single-center, open-label, randomized, crossover study. Each patient 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.

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.

There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a study of 19 healthy male subjects.

EPIVIR in combination with other antiretroviral agents is indicated for the treatment of HIV infection (see Description of Clinical Studies).

The use of EPIVIR is based on the results of clinical studies in HIV-infected patients 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.

EPV20001 was a multi-center, double-blind, controlled study in which patients 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-infected adults enrolled: male (79%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm³ (median = 362 cells/mm³), and median baseline plasma HIV-1 RNA of 4.66 log₁₀ copies/mL. Outcomes of treatment through 48 weeks are summarized in Figure 1 and Table 3.

Figure 1. Virologic Response Through Week 48, EPV20001^*†(Intent-to-Treat)

EPIVIR Tablets and Oral Solution are contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the products.

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).

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering EPIVIR to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. 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).

EPIVIR Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) than in EPIVIR-HBV Tablets and 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 dually infected with HIV and HBV. Lamivudine has not been adequately studied for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. If treatment with EPIVIR-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV treatment. If a decision is made to administer lamivudine to patients dually infected with HIV and HBV, EPIVIR Tablets, EPIVIR Oral Solution, COMBIVIR^® (lamivudine/zidovudine) Tablets, or EPZICOM^™ (abacavir sulfate and lamivudine) Tablets should be used as part of an appropriate combination regimen. COMBIVIR (a fixed-dose combination tablet of lamivudine and zidovudine) should not be administered concomitantly with EPIVIR, EPIVIR-HBV, EPZICOM, RETROVIR, or TRIZIVIR^®.

In clinical trials in non-HIV-infected patients treated with lamivudine for chronic hepatitis B, 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 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory followup for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions), hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and EPIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of EPIVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh >6) (see the complete prescribing information for interferon and ribavirin).

Reduction of the dosage of EPIVIR is recommended for patients with impaired renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. In non−HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see EPIVIR-HBV package insert for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. Posttreatment exacerbations of hepatitis have also been reported (see WARNINGS).

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 system responds 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.

Trough levels of lamivudine in plasma and of intracellular lamivudine triphosphate were lower with once-daily dosing than with twice-daily dosing (see CLINICAL PHARMACOLOGY). The clinical significance of this observation is not known.

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

EPIVIR is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a physician when using EPIVIR. Patients should be advised that the use of EPIVIR has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.

Patients should be advised 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 treatment regimen of a patient dually infected with HIV and HBV, the formulation and dosage of lamivudine in EPIVIR (not EPIVIR-HBV) should be used.

Patients co-infected with HIV and HBV should be informed that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Patients should be advised to discuss any changes in regimen with their physician.

Patients should be advised that the long-term effects of EPIVIR are unknown at this time.

EPIVIR Tablets and Oral Solution are for oral ingestion only.

Patients should be advised of the importance of taking EPIVIR with combination therapy on a regular dosing schedule and to avoid missing doses.

Parents or guardians should be advised to monitor pediatric patients for signs and symptoms of pancreatitis.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

Diabetic patients should be advised that each 15-mL dose of EPIVIR Oral Solution contains 3 grams of sucrose.

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).

TMP 160 mg/SMX 800 mg once daily has been shown to increase lamivudine exposure (AUC) by 43% (see CLINICAL PHARMACOLOGY). No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP. No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.

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) those observed in humans at the recommended therapeutic dose for HIV infection. Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg/kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV infection. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/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.

Pregnancy Category C. Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the 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. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

In 2 clinical studies conducted in South Africa, pharmacokinetic measurements were performed on samples from pregnant women who received lamivudine beginning at Week 38 of gestation (10 women who received 150 mg twice daily in combination with zidovudine and 10 who received lamivudine 300 mg twice daily without other antiretrovirals) or beginning at Week 36 of gestation (16 women who received lamivudine 150 mg twice daily in combination with zidovudine). These studies were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in the pregnant women were similar to those obtained following birth and in non-pregnant adults. Lamivudine concentrations were generally similar in maternal, neonatal, and cord serum samples. In a subset of subjects from whom amniotic fluid specimens were obtained following natural rupture of membranes, amniotic fluid concentrations of lamivudine ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily) and were typically greater than 2 times the maternal serum levels. See the ADVERSE REACTIONS section for the limited late-pregnancy safety information available from these studies. Lamivudine should be used during pregnancy only if the potential benefits outweigh the risks.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV infection.

A study in lactating rats administered 45 mg/kg of lamivudine showed that lamivudine concentrations in milk were slightly greater than those in plasma. Lamivudine is also excreted in human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.

Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving lamivudine.

Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants up to 1 week of age in 2 studies in South Africa. In these studies, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric patients (>3 months of age) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old. See the ADVERSE REACTIONS section for the limited safety information available from these studies.

The safety and effectiveness of twice-daily EPIVIR in combination with other antiretroviral agents have been established in pediatric patients 3 months of age and older.

In Study A2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-infected pediatric patients (age range: 4.8 months to 16 years, weight range: 5 to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg/day. In the 9 infants and children (range: 5 months to 12 years of age) receiving oral solution 4 mg/kg twice daily (the usual recommended pediatric dose), absolute bioavailability was 66% ± 26% (mean ± SD), which was less than the 86% ± 16% (mean ± SD) observed in adults. The mechanism for the diminished absolute bioavailability of lamivudine in infants and children is unknown.

Systemic clearance decreased with increasing age in pediatric patients, as shown in Figure 2.

Figure 2. Systemic Clearance (L/hr•kg) of Lamivudine in Relation to Age

Clinical studies of EPIVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly (see PRECAUTIONS: Patients with Impaired Renal Function and DOSAGE AND ADMINISTRATION).

Clinical trials in chronic hepatitis B used a lower dose of lamivudine (100 mg daily) than the dose used to treat HIV. The most frequent adverse events with lamivudine versus placebo were ear, nose, and throat infections (25% versus 21%); malaise and fatigue (24% versus 28%); and headache (21% versus 21%), respectively. The most frequent laboratory abnormalities reported with lamivudine were elevated ALT, elevated serum lipase, elevated CPK, and posttreatment elevations of liver function tests. Emergence of HBV viral mutants during lamivudine treatment, associated with reduced drug susceptibility and diminished treatment response, was also reported (also see WARNINGS and PRECAUTIONS). Please see the complete prescribing information for EPIVIR-HBV Tablets and Oral Solution for more information.

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of lamivudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.

There is no known antidote for EPIVIR. One case of an adult ingesting 6 g of EPIVIR was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Two cases of pediatric overdose were reported in ACTG300. One case was a single dose of 7 mg/kg of EPIVIR; the second case involved use of 5 mg/kg of EPIVIR twice daily for 30 days. There were no clinical signs or symptoms noted in either case. 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. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.

The recommended oral dose of EPIVIR for adults is 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily, in combination with other antiretroviral agents (see DESCRIPTION OF CLINICAL STUDIES, PRECAUTIONS, MICROBIOLOGY, and CLINICAL PHARMACOLOGY). If lamivudine is administered to a patient dually infected with HIV and HBV, the dosage indicated for HIV therapy should be used as part of an appropriate combination regimen (see WARNINGS).

It is recommended that doses of EPIVIR be adjusted in accordance with renal function (see Table 9) (see CLINICAL PHARMACOLOGY).

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 Tablets, 150 mg, are white, modified diamond-shaped, film-coated tablets engraved with “GX CJ7” on one side and plain on the reverse side.

Bottle of 60 tablets (NDC 0173-0470-01) with child-resistant closure.

EPIVIR Tablets, 300 mg, are gray, modified diamond-shaped, film-coated tablets engraved with “GX EJ7” on one side and plain on the reverse side.

Bottle of 30 tablets (NDC 0173-0714-00) with child-resistant closure.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

EPIVIR Oral Solution, a clear, colorless to pale yellow, strawberry-banana flavored liquid, contains 10 mg of lamivudine in each 1 mL.

Plastic bottle of 240 mL (NDC 0173-0471-00) 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].

GlaxoSmithKline

Research Triangle Park, NC 27709

Manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2006, GlaxoSmithKline. All rights reserved.

October 2006 RL-2317