EPIVIR-HBV®
(lamivudine)
Tablets
EPIVIR-HBV®
(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).

HUMAN IMMUNODEFICIENCY VIRUS (HIV) COUNSELING AND TESTING SHOULD BE OFFERED TO ALL PATIENTS BEFORE BEGINNING EPIVIR-HBV AND PERIODICALLY DURING TREATMENT (SEE WARNINGS), BECAUSE EPIVIR-HBV TABLETS AND ORAL SOLUTION CONTAIN A LOWER DOSE OF THE SAME ACTIVE INGREDIENT (LAMIVUDINE) AS EPIVIR^® TABLETS AND ORAL SOLUTION USED TO TREAT HIV INFECTION. 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 BECAUSE OF SUBTHERAPEUTIC DOSE AND INAPPROPRIATE MONOTHERAPY.

SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO HAVE DISCONTINUED ANTI-HEPATITIS B THERAPY (INCLUDING EPIVIR-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).

EPIVIR-HBV is a brand name for lamivudine, a synthetic nucleoside analogue with activity against hepatitis B virus (HBV) and HIV. Lamivudine was initially developed for the treatment of HIV infection as EPIVIR. Please see the complete prescribing information for EPIVIR Tablets and Oral Solution for additional information. 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-HBV Tablets are for oral administration. Each tablet contains 100 mg of lamivudine and the inactive ingredients hypromellose, macrogol 400, magnesium stearate, microcrystalline cellulose, polysorbate 80, red iron oxide, sodium starch glycolate, titanium dioxide, and yellow iron oxide.

EPIVIR-HBV Oral Solution is for oral administration. One milliliter (1 mL) of EPIVIR-HBV Oral Solution contains 5 mg of lamivudine (5 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. Lamivudine is phosphorylated intracellularly to lamivudine triphosphate, L-TP. Incorporation of the monophosphate form into viral DNA by HBV polymerase results in DNA chain termination. L-TP also inhibits the RNA- and DNA-dependent DNA polymerase activities of HIV-1 reverse transcriptase (RT). L-TP is a weak inhibitor of mammalian alpha-, beta-, and gamma-DNA polymerases.

In vitroactivity of lamivudine against HBV was assessed in HBV DNA-transfected 2.2.15 cells, HB611 cells, and infected human primary hepatocytes. IC₅₀ values (the concentration of drug needed to reduce the level of extracellular HBV DNA by 50%) varied from 0.01 μM (2.3 ng/mL) to 5.6 μM (1.3 mcg/mL) depending upon the duration of exposure of cells to lamivudine, the cell model system, and the protocol used.See the EPIVIR package insert for information regarding activity of lamivudine against HIV.

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

The pharmacokinetic properties of lamivudine have also 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.

Multiple doses of lamivudine and a single dose of interferon were coadministered to 19 healthy male subjects in a pharmacokinetics study. Results indicated a small (10%) reduction in lamivudine AUC, but no change in interferon pharmacokinetic parameters when the 2 drugs were given in combination. All other pharmacokinetic parameters (C_max, T_max, and t_½) were unchanged. There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in this study.

Lamivudine and zidovudine were coadministered to 12 asymptomatic HIV-positive adult patients in a single-center, open-label, randomized, crossover study. No significant differences were observed in AUC∞ or total clearance for lamivudine or zidovudine when the 2 drugs were administered together. Coadministration of lamivudine with zidovudine resulted in an increase of 39% ± 62% (mean ± SD) in C_max of zidovudine.

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 44% ± 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 (see PRECAUTIONS: Drug Interactions).

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

EPIVIR-HBV is indicated for the treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation. This indication is based on 1-year histologic and serologic responses in adult patients with compensated chronic hepatitis B, and more limited information from a study in pediatric patients ages 2 to 17 years (see Description of Clinical Studies below).

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

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. 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. Particular caution should be exercised when administering EPIVIR or EPIVIR-HBV 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 or EPIVIR-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).

EPIVIR-HBV Tablets and Oral Solution contain a lower dose of the same active ingredient (lamivudine) as EPIVIR Tablets and Oral Solution, COMBIVIR^® (lamivudine/zidovudine) Tablets, and TRIZIVIR^® (abacavir, lamivudine, and zidovudine) Tablets used to treat HIV infection. The formulation and dosage of lamivudine in EPIVIR-HBV are not appropriate for patients dually infected with HBV and HIV. If a decision is made to administer lamivudine to such patients, the higher dosage indicated for HIV therapy should be used as part of an appropriate combination regimen, and the prescribing information for EPIVIR , COMBIVIR, or TRIZIVIR as well as for EPIVIR-HBV should be consulted. HIV counseling and testing should be offered to all patients before beginning EPIVIR-HBV and periodically during treatment because of the risk of rapid emergence of resistant HIV and limitation of treatment options if EPIVIR-HBV is prescribed to treat chronic hepatitis B in a patient who has unrecognized or untreated HIV infection or acquires HIV infection during treatment.

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of EPIVIR-HBV (these have been primarily detected by serum ALT elevations, in addition to the re-emergence of HBV DNA commonly observed after stopping treatment; see Table 7 for more information regarding frequency of posttreatment ALT elevations). 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. There is insufficient evidence to determine whether re-initiation of therapy alters the course of posttreatment exacerbations of hepatitis.

Pancreatitis has been reported in patients receiving lamivudine, particularly in HIV-infected pediatric patients with prior nucleoside exposure.

Patients should be assessed before beginning treatment with EPIVIR-HBV by a physician experienced in the management of chronic hepatitis B.

In controlled clinical trials, YMDD-mutant HBV were detected in patients with on-lamivudine re-appearance of HBV DNA after an initial decline below the solution-hybridization assay limit (see MICROBIOLOGY: Drug Resistance). These mutations can be detected by a research assay and have been associated with reduced susceptibility to lamivudine in vitro. Lamivudine-treated patients (adult and pediatric) with YMDD-mutant HBV at 52 weeks showed diminished treatment responses in comparison to lamivudine-treated patients without evidence of YMDD mutations, including lower rates of HBeAg seroconversion and HBeAg loss (no greater than placebo recipients), more frequent return of positive HBV DNA by solution-hybridization or branched-chain DNA assay, and more frequent ALT elevations. In the controlled trials, when patients developed YMDD-mutant HBV, they had a rise in HBV DNA and ALT from their own previous on-treatment levels. Progression of hepatitis B, including death, has been reported in some patients with YMDD-mutant HBV, including patients from the liver transplant setting and from other clinical trials. The long-term clinical significance of YMDD-mutant HBV is not known. Increased clinical and laboratory monitoring may aid in treatment decisions if emergence of viral mutants is suspected.

Safety and efficacy of EPIVIR-HBV have not been established in patients with decompensated liver disease or organ transplants; pediatric patients <2 years of age; patients dually infected with HBV and HCV, hepatitis delta, or HIV; or other populations not included in the principal phase III controlled studies. There are no studies in pregnant women and no data regarding effect on vertical transmission, and appropriate infant immunizations should be used to prevent neonatal acquisition of HBV.

Patients should be monitored regularly during treatment by a physician experienced in the management of chronic hepatitis B. The safety and effectiveness of treatment with EPIVIR-HBV beyond 1 year have not been established. During treatment, combinations of such 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 EPIVIR-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.

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

A Patient Package Insert (PPI) for EPIVIR-HBV is available for patient information.

Patients should remain under the care of a physician while taking EPIVIR-HBV. They should discuss any new symptoms or concurrent medications with their physician.

Patients should be advised that EPIVIR-HBV is not a cure for hepatitis B, that the long-term treatment benefits of EPIVIR-HBV are unknown at this time, and, in particular, that the relationship of initial treatment response to outcomes such as hepatocellular carcinoma and decompensated cirrhosis is unknown. Patients should be informed that deterioration of liver disease has occurred in some cases when treatment was discontinued. Patients should be advised to discuss any changes in regimen with their physician.

Patients should be informed that emergence of resistant hepatitis B virus and worsening of disease can occur during treatment, and they should promptly report any new symptoms to their physician.

Patients should be counseled on the importance of testing for HIV to avoid inappropriate therapy and development of resistant HIV, and HIV counseling and testing should be offered before starting EPIVIR-HBV and periodically during therapy. Patients should be advised that EPIVIR-HBV Tablets and EPIVIR-HBV Oral Solution contain a lower dose of the same active ingredient (lamivudine) as EPIVIR Tablets, EPIVIR Oral Solution, COMBIVIR Tablets, and TRIZIVIR Tablets. EPIVIR-HBV should not be taken concurrently with EPIVIR, COMBIVIR, or TRIZIVIR (see WARNINGS). Patients infected with both HBV and HIV who are planning to change their HIV treatment regimen to a regimen that does not include EPIVIR, COMBIVIR, or TRIZIVIR should discuss continued therapy for hepatitis B with their physician.

Patients should be advised that treatment with EPIVIR-HBV has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination (see Pregnancy section).

Diabetic patients should be advised that each 20-mL dose of EPIVIR-HBV Oral Solution contains 4 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 44% (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 Pneumocystis carinii pneumonia. 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.

Lamivudine long-term carcinogenicity studies in mice and rats showed no evidence of carcinogenic potential at exposures up to 34 times (mice) and 200 times (rats) those observed in humans at the recommended therapeutic dose for chronic hepatitis B. 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 60 to 70 times those in humans at the recommended dose for chronic hepatitis B. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 80 to 120 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 60 times that for the adult HBV 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 exposures up to 60 times that in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta. There are no adequate and well-controlled studies in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, lamivudine should be used during pregnancy only if the potential benefits outweigh the risks.

Lamivudine has not been shown to affect the transmission of HBV from mother to infant, and appropriate infant immunizations should be used to prevent neonatal acquisition of HBV.

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 the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving lamivudine.

Clinical studies of EPIVIR-HBV 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).

Several serious adverse events reported with lamivudine (lactic acidosis and severe hepatomegaly withsteatosis, posttreatment exacerbations of hepatitis B, pancreatitis, and emergence of viral mutants associated with reduced drug susceptibility and diminished treatment response) are also described in WARNINGS and PRECAUTIONS.

In HIV-infected patients, safety information reflects a higher dose of lamivudine (150 mg b.i.d.) than the dose used to treat chronic hepatitis B in HIV-negative patients. In clinical trials using lamivudine as part of a combination regimen for treatment of HIV infection, several clinical adverse events occurred more often in lamivudine-containing treatment arms than in comparator arms. These included nasal signs and symptoms (20% vs. 11%), dizziness (10% vs. 4%), and depressive disorders (9% vs. 4%). Pancreatitis was observed in 9 of the 2,613 adult patients (<0.5%) who received EPIVIR in controlled clinical trials. Laboratory abnormalities reported more often in lamivudine-containing arms included neutropenia and elevations of liver function tests (also more frequent in lamivudine-containing arms for a retrospective analysis of HIV/HBV dually infected patients in one study), and amylase elevations. Please see the complete prescribing information for EPIVIR Tablets and Oral Solution for more information.

Most commonly observed adverse events in the pediatric trials were similar to those in adult trials; in addition, respiratory symptoms (cough, bronchitis, and viral respiratory infections) were reported in both lamivudine and placebo recipients. Posttreatment transaminase elevations were observed in some patients followed after cessation of lamivudine.

In early open-label studies of lamivudine in children with HIV, peripheral neuropathy and neutropenia were reported, and pancreatitis was observed in 14% to 15% of patients.

The following events have been identified during post-approval use of lamivudine in clinical practice. 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 either their seriousness, frequency of reporting, potential causal connection to lamivudine, or a combination of these factors. Post-marketing experience with lamivudine at this time is largely limited to use in HIV-infected patients.

There is no known antidote for EPIVIR-HBV. 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. 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-HBV for treatment of chronic hepatitis B in adults is 100 mg once daily (see p below and WARNINGS). Safety and effectiveness of treatment beyond 1 year have not been established and the optimum duration of treatment is not known (see PRECAUTIONS).

The formulation and dosage of lamivudine in EPIVIR-HBV are not appropriate for patients dually infected with HBV and HIV. If lamivudine is administered to such patients, the higher dosage indicated for HIV therapy should be used as part of an appropriate combination regimen, and the prescribing information for EPIVIR as well as EPIVIR-HBV should be consulted.

The recommended oral dose of EPIVIR-HBV for pediatric patients 2 to 17 years of age with chronic hepatitis B is 3 mg/kg once daily up to a maximum daily dose of 100 mg. Safety and effectiveness of treatment beyond 1 year have not been established and the optimum duration of treatment is not known (see PRECAUTIONS).

EPIVIR-HBV is available in a 5-mg/mL oral solution when a liquid formulation is needed. (Please see information above regarding distinctions between different lamivudine-containing products.)

It is recommended that doses of EPIVIR-HBV be adjusted in accordance with renal function (Table 8) (see CLINICAL PHARMACOLOGY: Special Populations).

No additional dosing of EPIVIR-HBV is required after routine (4-hour) hemodialysis or peritoneal dialysis.

Although there are insufficient data to recommend a specific dose adjustment of EPIVIR-HBV in pediatric patients with renal impairment, a dose reduction should be considered.

EPIVIR-HBV Tablets, 100 mg, are butterscotch-colored, film-coated, biconvex, capsule-shaped tablets imprinted with “GX CG5” on one side.

Bottles of 60 tablets (NDC 0173-0662-00) with child-resistant closures.

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

EPIVIR-HBV Oral Solution, a clear, colorless to pale yellow, strawberry-banana-flavored liquid, contains 5 mg of lamivudine in each 1 mL in plastic bottles of 240 mL.

Bottles of 240 mL (NDC 0173-0663-00) with child-resistant closures. This product does not require reconstitution.

Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP) in tightly closed bottles.

• Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1982;1:431-435.

GlaxoSmithKline

Research Triangle Park, NC 27709

Manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2004, GlaxoSmithKline

All rights reserved.

December 2004 RL-2153

PHARMACIST DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

EPIVIR -HBV^® (lamivudine) Tablets

EPIVIR-HBV^® (lamivudine) Oral Solution

Please read this information before you start taking EPIVIR-HBV (pronounced EP-i-veer h-b-v). Re-read it each time you get your prescription, in case some information has changed. This information does not take the place of careful discussions with your doctor when you start this medication and at checkups. Stay under a doctor’s care when you take EPIVIR-HBV and do not change or stop treatment without first talking with your doctor.

What is EPIVIR-HBV?

EPIVIR-HBV is the brand name of a product that contains lamivudine, a drug used to treat chronic hepatitis B in patients with actively growing virus and liver inflammation. Hepatitis B can cause damage to cells in the liver. Eventually, this can scar the liver.

The lamivudine in EPIVIR-HBV can reduce the ability of the hepatitis B virus to multiply and infect new liver cells. It may help to lower the amount of hepatitis B virus in your body. EPIVIR-HBV contains a lower dose of lamivudine than the dose in EPIVIR^®, COMBIVIR^®, and TRIZIVIR^®.

Why should I consider HIV testing before starting treatment with EPIVIR-HBV?

Your doctor or healthcare provider should offer you counseling and testing for HIV infection (sometimes called the AIDS virus) before treatment for hepatitis B is started with EPIVIR-HBV, and periodically during treatment. EPIVIR-HBV Tablets and EPIVIR-HBV Oral Solution contain a lower dose of the medicine than other lamivudine-containing drugs, such as EPIVIR, COMBIVIR, and TRIZIVIR which are used to treat HIV. Treatment with EPIVIR-HBV in HIV-infected patients may cause the HIV virus to be less treatable with lamivudine and some other drugs.

If I am HIV-positive, can I take EPIVIR-HBV?

People who have both chronic hepatitis B and HIV should not take EPIVIR-HBV. EPIVIR-HBV Tablets and EPIVIR-HBV Oral Solution contain a lower dose of the same drug (lamivudine) as EPIVIR Tablets, EPIVIR Oral Solution, COMBIVIR Tablets, and TRIZIVIR Tablets. If you have both hepatitis B and HIV, make sure that your doctor or healthcare provider is aware that you have both infections. If you are prescribed lamivudine as part of your combination treatment for HIV, you should use only the products and doses that are intended for treatment of HIV infection, because the lower dose of lamivudine in EPIVIR-HBV could cause the HIV virus to be less responsive to treatment. If you are planning to change your HIV treatment to a regimen that does not include EPIVIR, COMBIVIR, or TRIZIVIR, you should first discuss this change with your doctor or healthcare provider.

Does EPIVIR-HBV cure hepatitis B infection?

EPIVIR-HBV is nota cure for hepatitis B. In studies comparing EPIVIR-HBV with placebo (an inactive sugar pill) for 1 year, more people treated with EPIVIR-HBV had reductions in liver inflammation. It is not known whether EPIVIR-HBV will reduce the risk of getting liver cancer or cirrhosis that may be caused by the hepatitis B virus.

In studies, some patients developed hepatitis B viruses that are resistant to EPIVIR-HBV. These patients generally had less benefit from treatment with EPIVIR-HBV. Some patients have had worsening of hepatitis after resistant virus appears. The long-term importance of a resistant virus is not known.

What happens if I stop taking EPIVIR-HBV?

After stopping treatment with EPIVIR-HBV, some patients have had symptoms or blood tests showing that their hepatitis has gotten worse. Therefore, your doctor should check your health, which may include blood tests, for at least several months after stopping treatment with EPIVIR-HBV. Tell your doctor right away about any new or unusual symptoms that you notice after stopping treatment.

Who should not take EPIVIR-HBV?

You should not take EPIVIR-HBV if you have or may have HIV infection (sometimes called the AIDS virus). EPIVIR-HBV does not contain an appropriate dose of lamivudine for treatment of HIV infection, and using EPIVIR-HBV could cause the HIV virus to become less treatable with lamivudine and some other drugs.

You should not take EPIVIR-HBV if you are also taking EPIVIR, COMBIVIR, or TRIZIVIR. These drugs all contain lamivudine.

You should not take EPIVIR-HBV if you have had an allergic reaction to lamivudine.

EPIVIR-HBV has not been studied in children less than 2 years old.

Can pregnant women and nursing mothers take EPIVIR-HBV?

There are no studies of EPIVIR-HBV in pregnant women. If you are pregnant or if you become pregnant while taking EPIVIR-HBV, notify your doctor or healthcare provider immediately.

EPIVIR-HBV has not been shown to prevent the spread of the hepatitis B virus from mother to infant.

It is not known whether lamivudine is passed to the infant in breast milk. If there is lamivudine in the breast milk, this could cause side effects in nursing infants. Mothers should not breastfeed while taking EPIVIR-HBV or other forms of lamivudine.

How should I take EPIVIR-HBV?

Your doctor will tell you how much EPIVIR-HBV to take. The usual dose is 1 EPIVIR-HBV Tablet orally (by mouth) once a day. Your doctor may prescribe a lower dose if you have problems with your kidneys. EPIVIR-HBV may be taken with food or on an empty stomach. To help you remember to take your EPIVIR-HBV as prescribed, you should try to take EPIVIR-HBV at the same time each day. You must not skip doses or stop treatment without first talking with your doctor or healthcare provider. A strawberry-banana-flavored liquid of EPIVIR-HBV is available for patients who need a liquid.

If you miss your regular time for taking your dose, but then remember it during that same day, take your missed dose immediately. Then, take your next dose at the regularly scheduled time the following day. Do not take 2 doses of EPIVIR-HBV at once to make up for missing a dose. If you are not sure what to do if you miss taking your medication, check with your doctor or healthcare provider for further instructions.

EPIVIR-HBV can usually be taken with many other medications; however, be sure to tell your doctor or healthcare provider about all medications (including over-the-counter and prescription drugs) that you are taking. EPIVIR-HBV Tablets and EPIVIR-HBV Oral Solution contain a lower dose of the same drug (lamivudine) as EPIVIR Tablets, EPIVIR Oral Solution, COMBIVIR Tablets, and TRIZIVIR Tablets; therefore, EPIVIR-HBV should not be taken together with EPIVIR, COMBIVIR, or TRIZIVIR.

You should talk to your doctor about any changes in your treatment.

What are the possible side effects of EPIVIR-HBV?

You should stay under the care of a doctor during treatment so you can be checked for possible serious side effects. Serious side effects such as inflammation of the pancreas can occur with EPIVIR-HBV. Lactic acid buildup in the body and an enlarged liver have been reported with EPIVIR-HBV; this is not common but can result in death.

Hepatitis B virus sometimes becomes resistant to EPIVIR-HBV during treatment, and some people have had tests showing that their hepatitis was getting worse around the time the virus became resistant. Some people also have worsening of hepatitis after stopping EPIVIR-HBV. You should discuss any change in treatment with your doctor.

In studies, the most common side effects seen during treatment with EPIVIR-HBV were ear, nose, and throat infections; malaise and fatigue (feeling tired and run down); headache; abdominal discomfort and pain; nausea and vomiting; diarrhea; muscle pain; sore throat; joint pain; fever or chills; and skin rash.

This ul of possible side effects is not complete. Your doctor or pharmacist can discuss with you a more complete ul of possible side effects with EPIVIR-HBV. Talk to your doctor right away about any side effects or other unusual symptoms that occur when taking EPIVIR-HBV.

Does EPIVIR-HBV reduce the risk of passing hepatitis B to others?

No, EPIVIR-HBV has not been shown to reduce the risk of passing hepatitis B to others through sexual contact or exposure to infected blood. EPIVIR-HBV also has not been shown to reduce the risk of a mother passing hepatitis B to her baby.

What previous or current medical problems or conditions should I discuss with my doctor or healthcare provider?

Talk to your doctor or healthcare provider if:

• You have HIV infection.
• You are pregnant or if you become pregnant while taking EPIVIR-HBV.
• You are breastfeeding.
• You have diabetes. Each 20-mL dose (100 mg) of EPIVIR-HBV Oral Solution contains 4 grams of sucrose.

Also talk to your doctor or healthcare provider about:

• Problems with your blood counts.
• Problems with your muscles.
• Problems with your kidneys.
• Problems with your pancreas.
• Any side effects or unusual symptoms during treatment.

How should I store EPIVIR-HBV Tablets and Oral Solution?

EPIVIR-HBV Tablets and Oral Solution should be stored at room temperature. They do not require refrigeration. Keep EPIVIR-HBV and all medicines out of the reach of children.

Other Information

This medication is prescribed for a particular condition. Do not use it for any other condition or give it to anybody else.

For more complete information about EPIVIR-HBV ask your doctor or pharmacist. You can also ask to read the longer information leaflet that is written for health professionals.

Keep EPIVIR-HBV and all medicines out of the reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.

GlaxoSmithKline

Research Triangle Park, NC 27709

Manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2004, GlaxoSmithKline

All rights reserved.

December 2004 RL-2153