BARACLUDE 1mg tablets medication leaflet

Baraclude 0.5 mg film-coated tablets

Baraclude 1 mg film-coated tablets

Baraclude 0.5 mg film-coated tablets

Each tablet contains 0.5 mg entecavir (as monohydrate).

Baraclude 1 mg film-coated tablets

Each tablet contains 1 mg entecavir (as monohydrate).

Each 0.5 mg film-coated tablet contains 120.5 mg lactose.

Each 1 mg film-coated tablet contains 241 mg lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Baraclude 0.5 mg film-coated tablets

White to off-white and triangular-shaped tablet with “BMS” debossed on one side and “1611” on theother.

Baraclude 1 mg film-coated tablets

Pink and triangular-shaped tablet with “BMS” debossed on one side and “1612” on the other.

Baraclude is indicated for the treatment of chronic hepatitis B virus (HBV) infection (see section 5.1)in adults with: compensated liver disease and evidence of active viral replication, persistently elevated serumalanine aminotransferase (ALT) levels and histological evidence of active inflammation and/orfibrosis.

 decompensated liver disease (see section 4.4)

For both compensated and decompensated liver disease, this indication is based on clinical trial data innucleoside naive patients with HBeAg positive and HBeAg negative HBV infection. With respect topatients with lamivudine-refractory hepatitis B, see sections 4.2, pct. 4.4 and 5.1.

Baraclude is also indicated for the treatment of chronic HBV infection in nucleoside naive paediatricpatients from 2 to < 18 years of age with compensated liver disease who have evidence of active viralreplication and persistently elevated serum ALT levels, or histological evidence of moderate to severeinflammation and/or fibrosis. With respect to the decision to initiate treatment in paediatric patients,see sections 4.2, pct. 4.4, and 5.1.

Therapy should be initiated by a physician experienced in the management of chronic hepatitis Binfection.

Compensated liver disease

Nucleoside naïve patients: the recommended dose in adults is 0.5 mg once daily, with or without food.

Lamivudine-refractory patients (i.e. with evidence of viraemia while on lamivudine or the presence oflamivudine resistance [LVDr] mutations) (see sections 4.4 and 5.1): the recommended dose in adults is1 mg once daily, which must be taken on an empty stomach (more than 2 hours before and more than2 hours after a meal) (see section 5.2). In the presence of LVDr mutations, combination use ofentecavir plus a second antiviral agent (which does not share cross-resistance with either lamivudineor entecavir) should be considered in preference to entecavir monotherapy (see section 4.4.).

Decompensated liver disease

The recommended dose for adult patients with decompensated liver disease is 1 mg once daily, whichmust be taken on an empty stomach (more than 2 hours before and more than 2 hours after a meal)(see section 5.2). For patients with lamivudine-refractory hepatitis B, see sections 4.4 and 5.1.

Duration of therapy

The optimal duration of treatment is unknown. Treatment discontinuation may be considered asfollows: In HBeAg positive adult patients, treatment should be administered at least until 12 months afterachieving HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection ontwo consecutive serum samples at least 3-6 months apart) or until HBs seroconversion or thereis loss of efficacy (see section 4.4).

 In HBeAg negative adult patients, treatment should be administered at least until HBsseroconversion or there is evidence of loss of efficacy. With prolonged treatment for more than2 years, regular reassessment is recommended to confirm that continuing the selected therapyremains appropriate for the patient.

In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended.

For appropriate dosing in the paediatric population, Baraclude oral solution or Baraclude 0.5 mg film-coated tablets are available.

The decision to treat paediatric patients should be based on careful consideration of individual patientneeds and with reference to current paediatric treatment guidelines including the value of baselinehistological information. The benefits of long-term virologic suppression with continued therapy mustbe weighed against the risk of prolonged treatment, including the emergence of resistant hepatitis Bvirus.

Serum ALT should be persistently elevated for at least 6 months prior to treatment of paediatricpatients with compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least12 months in patients with HBeAg negative disease.

Paediatric patients with body weight of at least 32.6 kg, should be administered a daily dose of one0.5 mg tablet or 10 ml (0.5 mg) of the oral solution, with or without food. The oral solution should beused for patients with body weight less than 32.6 kg.

Duration of therapy for paediatric patients

The optimal duration of treatment is unknown. In accordance with current paediatric practiceguidelines, treatment discontinuation may be considered as follows: In HBeAg positive paediatric patients, treatment should be administered for at least 12 monthsafter achieving undetectable HBV DNA and HBeAg seroconversion (HBeAg loss and anti-HBedetection on two consecutive serum samples at least 3-6 months apart) or until HBsseroconversion or there is loss of efficacy. Serum ALT and HBV DNA levels should befollowed regularly after treatment discontinuation (see section 4.4).

 In HBeAg negative paediatric patients, treatment should be administered until HBsseroconversion or there is evidence of loss of efficacy.

Pharmacokinetics in paediatric patients with renal or hepatic impairment have not been studied.

Elderly: no dosage adjustment based on age is required. The dose should be adjusted according to thepatient’s renal function (see dosage recommendations in renal impairment and section 5.2).

Gender and race: no dosage adjustment based on gender or race is required.

Renal impairment: the clearance of entecavir decreases with decreasing creatinine clearance (seesection 5.2). Dose adjustment is recommended for patients with creatinine clearance < 50 ml/min,including those on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A reductionof the daily dose using Baraclude oral solution, as detailed in the table, is recommended. As analternative, in case the oral solution is not available, the dose can be adjusted by increasing the dosageinterval, also shown in the table. The proposed dose modifications are based on extrapolation oflimited data, and their safety and effectiveness have not been clinically evaluated. Therefore,virological response should be closely monitored.

Baraclude dosage*

Creatinine clearance Nucleoside naïve patients Lamivudine-refractory or(ml/min) decompensated liver disease≥ 50 0.5 mg once daily 1 mg once daily30 - 49 0.25 mg once daily* 0.5 mg once daily

OR0.5 mg every 48 hours10 - 29 0.15 mg once daily* 0.3 mg once daily*

OR OR0.5 mg every 72 hours 0.5 mg every 48 hours< 10 0.05 mg once daily* 0.1 mg once daily*

Haemodialysis or OR OR

CAPD** 0.5 mg every 5-7 days 0.5 mg every 72 hours

* for doses < 0.5 mg Baraclude oral solution is recommended.

** on haemodialysis days, administer entecavir after haemodialysis.

Hepatic impairment: no dose adjustment is required in patients with hepatic impairment.

Baraclude should be taken orally.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Renal impairment: dosage adjustment is recommended for patients with renal impairment (seesection 4.2). The proposed dose modifications are based on extrapolation of limited data, and theirsafety and effectiveness have not been clinically evaluated. Therefore, virological response should beclosely monitored.

Exacerbations of hepatitis: spontaneous exacerbations in chronic hepatitis B are relatively commonand are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum

ALT may increase in some patients as serum HBV DNA levels decline (see section 4.8). Amongentecavir-treated patients on-treatment exacerbations had a median time of onset of 4-5 weeks. Inpatients with compensated liver disease, these increases in serum ALT are generally not accompaniedby an increase in serum bilirubin concentrations or hepatic decompensation. Patients with advancedliver disease or cirrhosis may be at a higher risk for hepatic decompensation following hepatitisexacerbation, and therefore should be monitored closely during therapy.

Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis Btherapy (see section 4.2). Post-treatment exacerbations are usually associated with rising HBV DNA,and the majority appears to be self-limited. However, severe exacerbations, including fatalities, havebeen reported.

Among entecavir-treated nucleoside naive patients, post-treatment exacerbations had a median time toonset of 23-24 weeks, and most were reported in HBeAg negative patients (see section 4.8). Hepaticfunction should be monitored at repeated intervals with both clinical and laboratory follow-up for atleast 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis Btherapy may be warranted.

Patients with decompensated liver disease: a higher rate of serious hepatic adverse events (regardlessof causality) has been observed in patients with decompensated liver disease, in particular in thosewith Child-Turcotte-Pugh (CTP) class C disease, compared with rates in patients with compensatedliver function. Also, patients with decompensated liver disease may be at higher risk for lactic acidosisand for specific renal adverse events such as hepatorenal syndrome. Therefore, clinical and laboratoryparameters should be closely monitored in this patient population (see also sections 4.8 and 5.1).

Lactic acidosis and severe hepatomegaly with steatosis: occurrences of lactic acidosis (in the absenceof hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis,have been reported with the use of nucleoside analogues. As entecavir is a nucleoside analogue, thisrisk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidlyelevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknownaetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might beindicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associatedwith pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate.

Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obesewomen) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patientsshould be followed closely.

To differentiate between elevations in aminotransferases due to response to treatment and increasespotentially related to lactic acidosis, physicians should ensure that changes in ALT are associated withimprovements in other laboratory markers of chronic hepatitis B.

Resistance and specific precaution for lamivudine-refractory patients: mutations in the HBVpolymerase that encode lamivudine-resistance substitutions may lead to the subsequent emergence ofsecondary substitutions, including those associated with entecavir associated resistance (ETVr). In asmall percentage of lamivudine-refractory patients, ETVr substitutions at residues rtT184, rtS202 orrtM250 were present at baseline. Patients with lamivudine-resistant HBV are at higher risk ofdeveloping subsequent entecavir resistance than patients without lamivudine resistance. Thecumulative probability of emerging genotypic entecavir resistance after 1, 2, 3, 4 and 5 years treatmentin the lamivudine-refractory studies was 6%, 15%, 36%, 47% and 51%, respectively. Virologicalresponse should be frequently monitored in the lamivudine-refractory population and appropriateresistance testing should be performed. In patients with a suboptimal virological response after 24weeks of treatment with entecavir, a modification of treatment should be considered (see sections 4.5and 5.1). When starting therapy in patients with a documented history of lamivudine-resistant HBV,combination use of entecavir plus a second antiviral agent (which does not share cross-resistance witheither lamivudine or entecavir) should be considered in preference to entecavir monotherapy.

Pre-existing lamivudine-resistant HBV is associated with an increased risk for subsequent entecavirresistance regardless of the degree of liver disease; in patients with decompensated liver disease,virologic breakthrough may be associated with serious clinical complications of the underlying liverdisease. Therefore, in patients with both decompensated liver disease and lamivudine-resistant HBV,combination use of entecavir plus a second antiviral agent (which does not share cross-resistance witheither lamivudine or entecavir) should be considered in preference to entecavir monotherapy.

Paediatric population: A lower rate of virologic response (HBV DNA < 50 IU/ml) was observed inpaediatric patients with baseline HBV DNA ≥ 8.0 log10 IU/ml (see section 5.1). Entecavir should beused in these patients only if the potential benefit justifies the potential risk to the child (e.g.resistance). Since some paediatric patients may require long-term or even lifetime management ofchronic active hepatitis B, consideration should be given to the impact of entecavir on future treatmentoptions.

Liver transplant recipients: renal function should be carefully evaluated before and during entecavirtherapy in liver transplant recipients receiving cyclosporine or tacrolimus (see section 5.2).

Co-infection with hepatitis C or D: there are no data on the efficacy of entecavir in patients co-infectedwith hepatitis C or D virus.

Human immunodeficiency virus (HIV)/HBV co-infected patients not receiving concomitantantiretroviral therapy: entecavir has not been evaluated in HIV/HBV co-infected patients notconcurrently receiving effective HIV treatment. Emergence of HIV resistance has been observed whenentecavir was used to treat chronic hepatitis B infection in patients with HIV infection not receivinghighly active antiretroviral therapy (HAART) (see section 5.1). Therefore, therapy with entecavirshould not be used for HIV/HBV co-infected patients who are not receiving HAART. Entecavir hasnot been studied as a treatment for HIV infection and is not recommended for this use.

HIV/HBV co-infected patients receiving concomitant antiretroviral therapy: entecavir has been studiedin 68 adults with HIV/HBV co-infection receiving a lamivudine-containing HAART regimen (seesection 5.1). No data are available on the efficacy of entecavir in HBeAg-negative patients co-infectedwith HIV. There are limited data on patients co-infected with HIV who have low CD4 cell counts(< 200 cells/mm3).

General: patients should be advised that therapy with entecavir has not been proven to reduce the riskof transmission of HBV and therefore appropriate precautions should still be taken.

Lactose: this medicinal product contains 120.5 mg of lactose in each 0.5 mg daily dose or 241 mg oflactose in each 1 mg daily dose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. A lactose-free Baraclude oral solution isavailable for these individuals.

Since entecavir is predominantly eliminated by the kidney (see section 5.2), coadministration withmedicinal products that reduce renal function or compete for active tubular secretion may increaseserum concentrations of either medicinal product. Apart from lamivudine, adefovir dipivoxil andtenofovir disoproxil fumarate, the effects of coadministration of entecavir with medicinal products thatare excreted renally or affect renal function have not been evaluated. Patients should be monitoredclosely for adverse reactions when entecavir is coadministered with such medicinal products.

No pharmacokinetic interactions between entecavir and lamivudine, adefovir or tenofovir wereobserved.

Entecavir is not a substrate, an inducer or an inhibitor of cytochrome P450 (CYP450) enzymes (seesection 5.2). Therefore CYP450 mediated drug interactions are unlikely to occur with entecavir.

Interaction studies have only been performed in adults.

Women of childbearing potential: given that the potential risks to the developing foetus are unknown,women of childbearing potential should use effective contraception.

Pregnancy: there are no adequate data from the use of entecavir in pregnant women. Studies inanimals have shown reproductive toxicity at high doses (see section 5.3). The potential risk forhumans is unknown. Baraclude should not be used during pregnancy unless clearly necessary. Thereare no data on the effect of entecavir on transmission of HBV from mother to newborn infant.

Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.

Breast-feeding: it is unknown whether entecavir is excreted in human milk. Available toxicologicaldata in animals have shown excretion of entecavir in milk (for details see section 5.3). A risk to theinfants cannot be excluded. Breast-feeding should be discontinued during treatment with Baraclude.

Fertility: toxicology studies in animals administered entecavir have shown no evidence of impairedfertility (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. Dizziness,fatigue and somnolence are common side effects which may impair the ability to drive and usemachines.

In clinical studies in patients with compensated liver disease, the most common adverse reactions ofany severity with at least a possible relation to entecavir were headache (9%), fatigue (6%), dizziness(4%) and nausea (3%). Exacerbations of hepatitis during and after discontinuation of entecavir therapyhave also been reported (see section 4.4 and c. Description of selected adverse reactions).

Assessment of adverse reactions is based on experience from postmarketing surveillance and fourclinical studies in which 1,720 patients with chronic hepatitis B infection and compensated liverdisease received double-blind treatment with entecavir (n = 862) or lamivudine (n = 858) for up to107 weeks (see section 5.1). In these studies, the safety profiles, including laboratory abnormalities,were comparable for entecavir 0.5 mg daily (679 nucleoside-naive HBeAg positive or negativepatients treated for a median of 53 weeks), entecavir 1 mg daily (183 lamivudine-refractory patientstreated for a median of 69 weeks), and lamivudine.

Adverse reactions considered at least possibly related to treatment with entecavir are listed by bodysystem organ class. Frequency is defined as very common (≥ 1/10); common (≥ 1/100 to < 1/10);uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping,undesirable effects are presented in order of decreasing seriousness.

Immune system disorders: rare: anaphylactoid reaction

Psychiatric disorders: common: insomnia

Nervous system disorders: common: headache, dizziness, somnolence

Gastrointestinal disorders: common: vomiting, diarrhoea, nausea, dyspepsia

Hepatobiliary disorders common: increased transaminases

Skin and subcutaneous tissue disorders: uncommon: rash, alopecia

General disorders and administration site common: fatigueconditions:

Cases of lactic acidosis have been reported, often in association with hepatic decompensation, otherserious medical conditions or drug exposures (see section 4.4).

Treatment beyond 48 weeks: continued treatment with entecavir for a median duration of 96 weeks didnot reveal any new safety signals.

c. Description of selected adverse reactions

Laboratory test abnormalities: In clinical studies with nucleoside-naive patients, 5% had ALTelevations > 3 times baseline, and < 1% had ALT elevations > 2 times baseline together with totalbilirubin > 2 times upper limit of normal (ULN) and > 2 times baseline. Albumin levels < 2.5 g/dloccurred in < 1% of patients, amylase levels > 3 times baseline in 2%, lipase levels > 3 times baselinein 11% and platelets < 50,000/mm3 in < 1%.

In clinical studies with lamivudine-refractory patients, 4% had ALT elevations > 3 times baseline, and< 1% had ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2 timesbaseline. Amylase levels > 3 times baseline occurred in 2% of patients, lipase levels > 3 times baselinein 18% and platelets < 50,000/mm3 in < 1%.

Exacerbations during treatment: in studies with nucleoside naive patients, on treatment ALT elevations> 10 times ULN and > 2 times baseline occurred in 2% of entecavir treated patients vs 4% oflamivudine treated patients. In studies with lamivudine-refractory patients, on treatment ALTelevations > 10 times ULN and > 2 times baseline occurred in 2% of entecavir treated patients vs 11%of lamivudine treated patients. Among entecavir-treated patients, on-treatment ALT elevations had amedian time to onset of 4-5 weeks, generally resolved with continued treatment, and, in a majority ofcases, were associated with a ≥ 2 log10/ml reduction in viral load that preceded or coincided with the

ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.

Exacerbations after discontinuation of treatment: acute exacerbations of hepatitis have been reportedin patients who have discontinued anti-hepatitis B virus therapy, including therapy with entecavir (seesection 4.4). In studies in nucleoside-naive patients, 6% of entecavir-treated patients and 10% oflamivudine-treated patients experienced ALT elevations (> 10 times ULN and > 2 times reference[minimum of baseline or last end-of-dosing measurement]) during post-treatment follow-up. Amongentecavir-treated nucleoside-naive patients, ALT elevations had a median time to onset of 23-24 weeks, and 86% (24/28) of ALT elevations occurred in HBeAg negative patients. In studies inlamivudine-refractory patients, with only limited numbers of patients being followed up, 11% ofentecavir-treated patients and no lamivudine-treated patients developed ALT elevations during post-treatment follow-up.

In the clinical trials entecavir treatment was discontinued if patients achieved a prespecified response.

If treatment is discontinued without regard to treatment response, the rate of post-treatment ALT flarescould be higher.

d. Paediatric Population

The safety of entecavir in paediatric patients from 2 to < 18 years of age is based on two clinical trialsin subjects with chronic HBV infection; one Phase 2 pharmacokinetic trial (study 028) and one

Phase 3 trial (study 189). These trials provide experience in 195 HBeAg-positive nucleoside-treatment-naïve subjects treated with entecavir for a median duration of 99 weeks. The adversereactions observed in paediatric subjects who received treatment with entecavir were consistent withthose observed in clinical trials of entecavir in adults.(see a. Summary of the safety profile andsection 5.1) with the following exception in the paediatric patients: very common adverse reactions: neutropenia.

e. Other special populations

Experience in patients with decompensated liver disease: the safety profile of entecavir in patientswith decompensated liver disease was assessed in a randomized open-label comparative study inwhich patients received treatment with entecavir 1 mg/day (n = 102) or adefovir dipivoxil 10 mg/day(n = 89) (study 048). Relative to the adverse reactions noted in section b. Tabulated list of adversereactions, one additional adverse reaction [decrease in blood bicarbonate (2%)] was observed inentecavir-treated patients through week 48. The on-study cumulative death rate was 23% (23/102), andcauses of death were generally liver-related, as expected in this population. The on-study cumulativerate of hepatocellular carcinoma (HCC) was 12% (12/102). Serious adverse events were generallyliver-related, with an on-study cumulative frequency of 69%. Patients with high baseline CTP scorewere at higher risk of developing serious adverse events (see section 4.4).

Laboratory test abnormalities: through week 48 among entecavir-treated patients with decompensatedliver disease, none had ALT elevations both > 10 times ULN and > 2 times baseline, and 1% ofpatients had ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2times baseline. Albumin levels < 2.5 g/dl occurred in 30% of patients, lipase levels > 3 times baselinein 10% and platelets < 50,000/mm3 in 20%.

Experience in patients co-infected with HIV: the safety profile of entecavir in a limited number of

HIV/HBV co-infected patients on lamivudine-containing HAART (highly active antiretroviraltherapy) regimens was similar to the safety profile in monoinfected HBV patients (see section 4.4).

Gender/age: there was no apparent difference in the safety profile of entecavir with respect to gender(≈ 25% women in the clinical trials) or age (≈ 5% of patients > 65 years of age).

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation ofthe medicinal product is important. It allows continued monitoring of the benefit/risk balance of themedicinal product. Healthcare professionals are asked to report any suspected adverse reactions via thenational reporting system listed in Appendix V.

There is limited experience of entecavir overdose reported in patients. Healthy subjects who receivedup to 20 mg/day for up to 14 days, and single doses up to 40 mg had no unexpected adverse reactions.

If overdose occurs, the patient must be monitored for evidence of toxicity and given standardsupportive treatment as necessary.

Pharmacotherapeutic group: antivirals for systemic use, nucleoside and nucleotide reversetranscriptase inhibitors

ATC code: J05AF10

Mechanism of action: entecavir, a guanosine nucleoside analogue with activity against HBVpolymerase, is efficiently phosphorylated to the active triphosphate (TP) form, which has anintracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine TP,entecavir-TP functionally inhibits the 3 activities of the viral polymerase: (1) priming of the HBVpolymerase, (2) reverse transcription of the negative strand DNA from the pregenomic messenger

RNA, and (3) synthesis of the positive strand HBV DNA. The entecavir-TP Ki for HBV DNApolymerase is 0.0012 μM. Entecavir-TP is a weak inhibitor of cellular DNA polymerases α, β, and δwith Ki values of 18 to 40 µM. In addition, high exposures of entecavir had no relevant adverse effectson γ polymerase or mitochondrial DNA synthesis in HepG2 cells (Ki > 160 µM).

Antiviral activity: entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentrationof 0.004 µM in human HepG2 cells transfected with wild-type HBV. The median EC50 value forentecavir against LVDr HBV (rtL180M and rtM204V) was 0.026 µM (range 0.010-0.059 µM).

Recombinant viruses encoding adefovir-resistant substitutions at either rtN236T or rtA181V remainedfully susceptible to entecavir.

An analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical HIV-1isolates using a variety of cells and assay conditions yielded EC50 values ranging from 0.026 to> 10 µM; the lower EC50 values were observed when decreased levels of virus were used in the assay.

In cell culture, entecavir selected for an M184I substitution at micromolar concentrations, confirminginhibitory pressure at high entecavir concentrations. HIV variants containing the M184V substitutionshowed loss of susceptibility to entecavir (see section 4.4).

In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir orzidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range ofconcentrations. In HIV antiviral assays, entecavir at micromolar concentrations was not antagonistic tothe anti-HIV activity in cell culture of these six NRTIs or emtricitabine.

Resistance in cell culture: relative to wild-type HBV, LVDr viruses containing rtM204V andrtL180M substitutions within the reverse transcriptase exhibit 8-fold decreased susceptibility toentecavir. Incorporation of additional ETVr amino acid changes rtT184, rtS202 or rtM250 decreasesentecavir susceptibility in cell culture. Substitutions observed in clinical isolates (rtT184A, C, F, G, I,

L, M or S; rtS202 C, G or I; and/or rtM250I, L or V) further decreased entecavir susceptibility 16- to741-fold relative to wild-type virus. Lamivudine-resistant strains harboring rtL180M plus rtM204V incombination with amino acid substitution rtA181C conferred 16- to 122-fold reductions in entecavirphenotypic susceptibility. The ETVr substitutions at residues rtT184, rtS202 and rtM250 alone haveonly a modest effect on entecavir susceptibility, and have not been observed in the absence of LVDrsubstitutions in more than 1000 patient samples sequenced. Resistance is mediated by reducedinhibitor binding to the altered HBV reverse transcriptase, and resistant HBV exhibits reducedreplication capacity in cell culture.

Clinical experience: the demonstration of benefit is based on histological, virological, biochemical,and serological responses after 48 weeks of treatment in active-controlled clinical trials of 1,633 adultswith chronic hepatitis B infection, evidence of viral replication and compensated liver disease. Thesafety and efficacy of entecavir were also evaluated in an active-controlled clinical trial of 191 HBV-infected patients with decompensated liver disease and in a clinical trial of 68 patients co-infected with

HBV and HIV.

In studies in patients with compensated liver disease, histological improvement was defined as a ≥ 2-point decrease in Knodell necro-inflammatory score from baseline with no worsening of the Knodellfibrosis score. Responses for patients with baseline Knodell Fibrosis Scores of 4 (cirrhosis) werecomparable to overall responses on all efficacy outcome measures (all patients had compensated liverdisease). High baseline Knodell necroinflammatory scores (> 10) were associated with greaterhistological improvement in nucleoside-naive patients. Baseline ALT levels ≥ 2 times ULN andbaseline HBV DNA ≤ 9.0 log10 copies/ml were both associated with higher rates of virologic response(Week 48 HBV DNA < 400 copies/ml) in nucleoside-naive HBeAg-positive patients. Regardless ofbaseline characteristics, the majority of patients showed histological and virological responses totreatment.

Experience in nucleoside-naive patients with compensated liver disease:

Results at 48 weeks of randomised, double blind studies comparing entecavir (ETV) to lamivudine(LVD) in HBeAg positive (022) and HBeAg negative (027) patients are presented in the table.

Nucleoside Naive

HBeAg Positive HBeAg Negative(study 022) (study 027)

ETV LVD ETV LVD0.5 mg 100 mg 0.5 mg 100 mgonce daily once daily once daily once dailyn 314a 314a 296a 287a

Histological improvementb 72%* 62% 70%* 61%

Ishak fibrosis score improvement 39% 35% 36% 38%

Ishak fibrosis score worsening 8% 10% 12% 15%n 354 355 325 313

Viral load reduction (log10 copies/ml)c -6.86* -5.39 -5.04* -4.53

HBV DNA undetectable 67%* 36% 90%* 72%(< 300 copies/ml by PCR)c

ALT normalisation (≤ 1 times ULN) 68%* 60% 78%* 71%

HBeAg Seroconversion 21% 18%

*p value vs lamivudine < 0.05a patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2)b a primary endpointc Roche Cobas Amplicor PCR assay (LLOQ = 300 copies/ml)

Experience in lamivudine-refractory patients with compensated liver disease:

In a randomised, double-blind study in HBeAg positive lamivudine-refractory patients (026), with85% of patients presenting LVDr mutations at baseline, patients receiving lamivudine at study entryeither switched to entecavir 1 mg once daily, with neither a washout nor an overlap period (n = 141),or continued on lamivudine 100 mg once daily (n = 145). Results at 48 weeks are presented in thetable.

Lamivudine-refractory

HBeAg positive (study 026)

ETV 1.0 mg once daily LVD 100 mg once dailyn 124a 116a

Histological improvementb 55%* 28%

Ishak fibrosis score improvement 34%* 16%

Ishak fibrosis score worsening 11% 26%n 141 145

Viral load reduction (log c10 copies/ml) -5.11* -0.48

HBV DNA undetectable (< 300 copies/ml 19%* 1%by PCR)c

ALT normalisation (≤ 1 times ULN) 61%* 15%

HBeAg Seroconversion 8% 3%

*p value vs lamivudine < 0.05a patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2)b a primary endpoint.c Roche Cobas Amplicor PCR assay (LLOQ = 300 copies/ml)

Results beyond 48 weeks of treatment:

Treatment was discontinued when prespecified response criteria were met either at 48 weeks or duringthe second year of treatment. Response criteria were HBV virological suppression (HBV DNA< 0.7 MEq/ml by bDNA) and loss of HBeAg (in HBeAg positive patients) or ALT < 1.25 times ULN(in HBeAg negative patients). Patients in response were followed for an additional 24 weeks off-treatment. Patients who met virologic but not serologic or biochemical response criteria continuedblinded treatment. Patients who did not have a virologic response were offered alternative treatment.

Nucleoside-naive:

HBeAg positive (study 022): treatment with entecavir for up to 96 weeks (n = 354) resulted incumulative response rates of 80% for HBV DNA < 300 copies/ml by PCR, 87% for ALTnormalisation, 31% for HBeAg seroconversion and 2% for HBsAg seroconversion (5% for HBsAgloss). For lamivudine (n = 355), cumulative response rates were 39% for HBV DNA < 300 copies/mlby PCR, 79% for ALT normalisation, 26% for HBeAg seroconversion, and 2% for HBsAgseroconversion (3% for HBsAg loss).

At end of dosing, among patients who continued treatment beyond 52 weeks (median of 96 weeks),81% of 243 entecavir-treated and 39% of 164 lamivudine-treated patients had HBV DNA< 300 copies/ml by PCR while ALT normalisation (≤ 1 times ULN) occurred in 79% of entecavir-treated and 68% of lamivudine-treated patients.

HBeAg negative (study 027): treatment with entecavir up to 96 weeks (n = 325) resulted in cumulativeresponse rates of 94% for HBV DNA < 300 copies/ml by PCR and 89% for ALT normalisation versus77% for HBV DNA < 300 copies/ml by PCR and 84% for ALT normalisation for lamivudine-treatedpatients (n = 313).

For 26 entecavir-treated and 28 lamivudine-treated patients who continued treatment beyond 52 weeks(median 96 weeks), 96% of entecavir-treated and 64% of lamivudine-treated patients had HBV DNA< 300 copies/ml by PCR at end of dosing. ALT normalisation (≤ 1 times ULN) occurred in 27% ofentecavir-treated and 21% of lamivudine-treated patients at end of dosing.

For patients who met protocol-defined response criteria, response was sustained throughout the 24-week post-treatment follow-up in 75% (83/111) of entecavir responders vs 73% (68/93) forlamivudine responders in study 022 and 46% (131/286) of entecavir responders vs 31% (79/253) forlamivudine responders in study 027. By 48 weeks of post-treatment follow-up, a substantial number of

HBeAg negative patients lost response.

Liver biopsy results: 57 patients from the pivotal nucleoside-naive studies 022 (HBeAg positive) and027 (HBeAg negative) who enrolled in a long-term rollover study were evaluated for long-term liverhistology outcomes. The entecavir dosage was 0.5 mg daily in the pivotal studies (mean exposure 85weeks) and 1 mg daily in the rollover study (mean exposure 177 weeks), and 51 patients in therollover study initially also received lamivudine (median duration 29 weeks). Of these patients, 55/57(96%) had histological improvement as previously defined (see above), and 50/57 (88%) had a ≥ 1-point decrease in Ishak fibrosis score. For patients with baseline Ishak fibrosis score ≥ 2, 25/43 (58%)had a ≥ 2-point decrease. All (10/10) patients with advanced fibrosis or cirrhosis at baseline (Ishakfibrosis score of 4, 5 or 6) had a ≥ 1 point decrease (median decrease from baseline was 1.5 points). Atthe time of the long-term biopsy, all patients had HBV DNA < 300 copies/ml and 49/57 (86%) hadserum ALT ≤ 1 times ULN. All 57 patients remained positive for HBsAg.

Lamivudine-refractory:

HBeAg positive (study 026): treatment with entecavir for up to 96 weeks (n = 141) resulted incumulative response rates of 30% for HBV DNA < 300 copies/ml by PCR, 85% for ALTnormalisation and 17% for HBeAg seroconversion.

For the 77 patients who continued entecavir treatment beyond 52 weeks (median 96 weeks), 40% ofpatients had HBV DNA < 300 copies/ml by PCR and 81% had ALT normalisation (≤ 1 times ULN) atend of dosing.

Age/gender:

There was no apparent difference in efficacy for entecavir based on gender (≈ 25% women in theclinical trials) or age (≈ 5% of patients > 65 years of age).

Long-Term Follow-Up Study

Study 080 was a randomized, observational open-label Phase 4 study to assess long-term risks ofentecavir treatment (ETV, n=6,216) or other standard of care HBV nucleoside (acid) treatment (non-

ETV) (n=6,162) for up to 10 years in subjects with chronic HBV (CHB) infection. The principalclinical outcome events assessed in the study were overall malignant neoplasms (composite event of

HCC and non-HCC malignant neoplasms), liver related HBV disease progression, non-HCCmalignant neoplasms, HCC, and deaths, including liver related deaths. In this study, ETV was notassociated with an increased risk of malignant neoplasms compared to use of non-ETV, as assessed byeither the composite endpoint of overall malignant neoplasms (ETV n=331, non-ETV n=337;

HR=0.93 [0.8-1.1]), or the individual endpoint of non-HCC malignant neoplasm (ETV n=95, non-

ETV n=81; HR=1.1 [0.82-1.5]). The reported events for liver-related HBV disease progression and

HCC were comparable in both ETV and non-ETV groups. The most commonly reported malignancyin both ETV and non-ETV groups was HCC followed by gastrointestinal malignancies.

Patients with decompensated liver disease: in study 048, 191 patients with HBeAg positive ornegative chronic HBV infection and evidence of hepatic decompensation, defined as a CTP score of 7or higher, received entecavir 1 mg once daily or adefovir dipivoxil 10 mg once daily. Patients wereeither HBV-treatment-naïve or pretreated (excluding pretreatment with entecavir, adefovir dipivoxil,or tenofovir disoproxil fumarate). At baseline, patients had a mean CTP score of 8.59 and 26% ofpatients were CTP class C. The mean baseline Model for End Stage Liver Disease (MELD) score was16.23. Mean serum HBV DNA by PCR was 7.83 log10 copies/ml and mean serum ALT was 100 U/l;54% of patients were HBeAg positive, and 35% of patients had LVDr substitutions at baseline.

Entecavir was superior to adefovir dipivoxil on the primary efficacy endpoint of mean change frombaseline in serum HBV DNA by PCR at week 24. Results for selected study endpoints at weeks 24and 48 are shown in the table.

Week 24 Week 48

ETV Adefovir Adefovir1 mg Dipivoxil ETV1 mg Dipivoxilonce daily 10 mgonce daily once daily 10 mgonce dailyn 100 91 100 91

HBV DNAa

Proportion undetectable (<300 copies/ml)b 49%* 16% 57%* 20%

Mean change from baselinec -4.48* -3.40 -4.66 -3.90(log10 copies/ml)

Stable or improved CTP scoreb,d 66% 71% 61% 67%

MELD score

Mean change from baselinec,e -2.0 -0.9 -2.6 -1.7

HBsAg lossb 1% 0 5% 0

Normalization of:f

ALT (≤1 X ULN)b 46/78 (59%)* 28/71 (39%) 49/78 (63%)* 33/71 (46%)

Albumin (≥1 X LLN)b 20/82 (24%) 14/69 (20%) 32/82 (39%) 20/69 (29%)

Bilirubin (≤1 X ULN)b 12/75 (16%) 10/65 (15%) 15/75 (20%) 18/65 (28%)

Prothrombin time (≤1 X ULN)b 9/95 (9%) 6/82 (7%) 8/95 (8%) 7/82 (9%)a Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/ml).b NC=F (noncompleter=failure), meaning treatment discontinuations before the analysis week, including reasons such asdeath, lack of efficacy, adverse event, noncompliance/loss-to-follow-up, are counted as failures (e.g., HBV

DNA ≥ 300 copies/ml)c NC=M (noncompleters=missing)dDefined as decrease or no change from baseline in CTP score.e Baseline mean MELD score was 17.1 for ETV and 15.3 for adefovir dipivoxil.f Denominator is patients with abnormal values at baseline.

*p<0.05

ULN=upper limit of normal, LLN=lower limit of normal.

The time to onset of HCC or death (whichever occurred first) was comparable in the two treatmentgroups; on-study cumulative death rates were 23% (23/102) and 33% (29/89) for patients treated withentecavir and adefovir dipivoxil, respectively, and on-study cumulative rates of HCC were 12%(12/102) and 20% (18/89) for entecavir and adefovir dipivoxil, respectively.

For patients with LVDr substitutions at baseline, the percentage of patients with HBV DNA<300 copies/ml was 44% for entecavir and 20% for adefovir at week 24 and 50% for entecavir and17% for adefovir at week 48.

HIV/HBV co-infected patients receiving concomitant HAART: study 038 included 67 HBeAg positiveand 1 HBeAg negative patients co-infected with HIV. Patients had stable controlled HIV (HIV RNA< 400 copies/ml) with recurrence of HBV viraemia on a lamivudine-containing HAART regimen.

HAART regimens did not include emtricitabine or tenofovir disoproxil fumarate. At baselineentecavir-treated patients had a median duration of prior lamivudine therapy of 4.8 years and median

CD4 count of 494 cells/mm3 (with only 5 subjects having CD4 count < 200 cells/mm3). Patientscontinued their lamivudine-regimen and were assigned to add either entecavir 1 mg once daily(n = 51) or placebo (n = 17) for 24 weeks followed by an additional 24 weeks where all receivedentecavir. At 24 weeks the reduction in HBV viral load was significantly greater with entecavir (-3.65vs an increase of 0.11 log10 copies/ml). For patients originally assigned to entecavir treatment, thereduction in HBV DNA at 48 weeks was -4.20 log10 copies/ml, ALT normalisation had occurred in37% of patients with abnormal baseline ALT and none achieved HBeAg seroconversion.

HIV/HBV co-infected patients not receiving concomitant HAART: entecavir has not been evaluated in

HIV/HBV co-infected patients not concurrently receiving effective HIV treatment. Reductions in HIV

RNA have been reported in HIV/HBV co-infected patients receiving entecavir monotherapy without

HAART. In some cases, selection of HIV variant M184V has been observed, which has implicationsfor the selection of HAART regimens that the patient may take in the future. Therefore, entecavirshould not be used in this setting due to the potential for development of HIV resistance (see section4.4).

Liver transplant recipients: the safety and efficacy of entecavir 1 mg once daily were assessed in asingle-arm study in 65 patients who received a liver transplant for complications of chronic HBVinfection and had HBV DNA <172 IU/ml (approximately 1000 copies/ml) at the time of transplant.

The study population was 82% male, 39% Caucasian, and 37% Asian, with a mean age of 49 years;89% of patients had HBeAg-negative disease at the time of transplant. Of the 61 patients who wereevaluable for efficacy (received entecavir for at least 1 month), 60 also received hepatitis B immuneglobulin (HBIg) as part of the post-transplant prophylaxis regimen. Of these 60 patients, 49 receivedmore than 6 months of HBIg therapy. At Week 72 post-transplant, none of 55 observed cases hadvirologic recurrence of HBV [defined as HBV DNA ≥50 IU/ml (approximately 300 copies/ml)], andthere was no reported virologic recurrence at time of censoring for the remaining 6 patients. All 61patients had HBsAg loss post-transplantation, and 2 of these later became HBsAg positive despitemaintaining undetectable HBV DNA (<6 IU/ml). The frequency and nature of adverse events in thisstudy were consistent with those expected in patients who have received a liver transplant and theknown safety profile of entecavir.

Paediatric population: Study 189 is a study of the efficacy and safety of entecavir among 180nucleoside-treatment-naïve children and adolescents from 2 to < 18 years of age with HBeAg-positivechronic hepatitis B infection, compensated liver disease, and elevated ALT. Patients were randomized(2:1) to receive blinded treatment with entecavir 0.015 mg/kg up to 0.5 mg/day (N = 120) or placebo(N = 60). The randomization was stratified by age group (2 to 6 years; > 6 to 12 years; and > 12 to< 18 years). Baseline demographics and HBV disease characteristics were comparable between the 2treatment arms and across age cohorts. At study entry, the mean HBV DNA was 8.1 log10 IU/ml andmean ALT was 103 U/l across the study population. Results for the main efficacy endpoints at Week48 and Week 96 are presented in the table below.

Entecavir Placebo*

Week 48 Week 96 Week 48n 120 120 60

HBV DNA < 50 IU/mL and 24.2% 35.8% 3.3%

HBeAg seroconversiona

HBV DNA < 50 IU/mLa 49.2% 64.2% 3.3.%

HBeAg seroconversiona 24.2% 36.7% 10.0%

ALT normalizationa 67.5% 81.7% 23.3%

HBV DNA < 50 IU/mLa

Baseline HBV 82.6% (38/46) 82.6% (38/46) 6.5% (2/31)

DNA < 8 log10 IU/ml

Baseline HBV DNA 28.4% (21/74) 52.7% (39/74) 0% (0/29)≥ 8 log10 IU/mlaNC=F (noncompleter=failure)

* Patients randomized to placebo who did not have HBe- seroconversion by Week 48 rolled over to open-label entecavir forthe second year of the study; therefore randomized comparison data are available only through Week 48.

The paediatric resistance assessment is based on data from nucleoside-treatment-naive paediatricpatients with HBeAg-positive chronic HBV infection in two clinical trials (028 and 189). The twotrials provide resistance data in 183 patients treated and monitored in Year 1 and 180 patients treatedand monitored in Year 2. Genotypic evaluations were performed for all patients with available sampleswho had virologic breakthrough through Week 96 or HBV DNA ≥ 50 IU/ml at Week 48 or Week 96 .

During Year 2, genotypic resistance to ETV was detected in 2 patients (1.1% cumulative probability ofresistance through Year 2).

Clinical resistance in Adults: patients in clinical trials initially treated with entecavir 0.5 mg(nucleoside-naive) or 1.0 mg (lamivudine-refractory) and with an on-therapy PCR HBV DNAmeasurement at or after Week 24 were monitored for resistance.

Through Week 240 in nucleoside-naive studies, genotypic evidence of ETVr substitutions at rtT184,rtS202, or rtM250 was identified in 3 patients treated with entecavir, 2 of whom experienced virologicbreakthrough (see table). These substitutions were observed only in the presence of LVDrsubstitutions (rtM204V and rtL180M).

Emerging Genotypic Entecavir Resistance Through Year 5, Nucleoside-Naive Studies

Year 1 Year 2 Year 3a Year 4a Year 5a

Patients treated and monitored for 663 278 149 121 108resistanceb

Patients in specific year with:

- emerging genotypic ETVrc 1 1 1 0 0

- genotypic ETVrc with virologic 1 0 1 0 0breakthroughd

Cumulative probability of:

- emerging genotypic ETVrc 0.2% 0.5% 1.2% 1.2% 1.2%

- genotypic ETVrc with virologic 0.2% 0.2% 0.8% 0.8% 0.8%breakthroughda Results reflect use of a 1-mg dose of entecavir for 147 of 149 patients in Year 3 and all patients in Years 4 and 5and of combination entecavir-lamivudine therapy (followed by long-term entecavir therapy) for a median of 20weeks for 130 of 149 patients in Year 3 and for 1 week for 1 of 121 patients in Year 4 in a rollover study.

b Includes patients with at least one on-therapy HBV DNA measurement by PCR at or after week 24 through week 58(Year 1), after week 58 through week 102 (Year 2), after week 102 through week 156 (Year 3), after week 156through week 204 (Year 4), or after week 204 through week 252 (Year 5).

c Patients also have LVDr substitutions.d ≥ 1 log10 increase above nadir in HBV DNA by PCR, confirmed with successive measurements or at the end of thewindowed time point.

ETVr substitutions (in addition to LVDr substitutions rtM204V/I ± rtL180M) were observed atbaseline in isolates from 10/187 (5%) lamivudine-refractory patients treated with entecavir andmonitored for resistance, indicating that prior lamivudine treatment can select these resistancesubstitutions and that they can exist at a low frequency before entecavir treatment. Through Week 240,3 of the 10 patients experienced virologic breakthrough (≥ 1 log10 increase above nadir). Emergingentecavir resistance in lamivudine-refractory studies through Week 240 is summarized in the table.

Genotypic Entecavir Resistance Through Year 5, Lamivudine-Refractory Studies

Year 1 Year 2 Year 3a Year 4 a Year 5 a

Patients treated and monitored for 187 146 80 52 33resistanceb

Patients in specific year with:

- emerging genotypic ETVrc 11 12 16 6 2

- genotypic ETVrc with virologic 2e 14e 13e 9e 1ebreakthroughd

Cumulative probability of:

- emerging genotypic ETVrc 6.2% 15% 36.3% 46.6% 51.45%

- genotypic ETVrc with virologic 1.1%e 10.7% e 27% e 41.3% e 43.6% ebreakthroughda Results reflect use of combination entecavir-lamivudine therapy (followed by long-term entecavir therapy) for amedian of 13 weeks for 48 of 80 patients in Year 3, a median of 38 weeks for 10 of 52 patients in Year 4, and for 16weeks for 1 of 33 patients in Year 5 in a rollover study.

b Includes patients with at least one on-therapy HBV DNA measurement by PCR at or after week 24 through week 58(Year 1), after week 58 through week 102 (Year 2), after week 102 through week 156 (Year 3), after week 156 throughweek 204 (Year 4), or after week 204 through week 252 (Year 5).

c Patients also have LVDr substitutions.d ≥ 1 log10 increase above nadir in HBV DNA by PCR, confirmed with successive measurements or at the end of thewindowed time point.e ETVr occurring in any year; virologic breakthrough in specified year.

Among lamivudine-refractory patients with baseline HBV DNA < 107 log10 copies/ml, 64% (9/14)achieved HBV DNA < 300 copies/ml at Week 48. These 14 patients had a lower rate of genotypicentecavir resistance (cumulative probability 18.8% through 5 years of follow-up) than the overallstudy population (see table). Also, lamivudine-refractory patients who achieved HBV DNA < 104 log10copies/ml by PCR at Week 24 had a lower rate of resistance than those who did not (5-year cumulativeprobability 17.6% [n= 50] versus 60.5% [n= 135], respectively).

Integrated Analysis of Phase 2 and 3 Clinical Studies: In a post-approval integrated analysis ofentecavir resistance data from 17 Phase 2 and 3 clinical studies, an emergent entecavir resistance-associated substitution rtA181C was detected in 5 out of 1461 subjects during treatment withentecavir. This substitution was detected only in the presence of lamivudine resistance-associatedsubstitutions rtL180M plus rtM204V.

Absorption: entecavir is rapidly absorbed with peak plasma concentrations occurring between 0.5-1.5 hours. The absolute bioavailability has not been determined. Based on urinary excretion ofunchanged drug, the bioavailability has been estimated to be at least 70%. There is a dose-proportionate increase in Cmax and AUC values following multiple doses ranging from 0.1-1 mg.

Steady-state is achieved between 6-10 days after once daily dosing with ≈ 2 times accumulation. Cmaxand Cmin at steady-state are 4.2 and 0.3 ng/ml, respectively, for a dose of 0.5 mg, and 8.2 and0.5 ng/ml, respectively, for 1 mg. The tablet and oral solution were bioequivalent in healthy subjects;therefore, both forms may be used interchangeably.

Administration of 0.5 mg entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal(379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1-1.5 hour fed vs. 0.75 hour fasted), adecrease in Cmax of 44-46%, and a decrease in AUC of 18-20%. The lower Cmax and AUC when takenwith food is not considered to be of clinical relevance in nucleoside-naive patients but could affectefficacy in lamivudine-refractory patients (see section 4.2).

Distribution: the estimated volume of distribution for entecavir is in excess of total body water.

Protein binding to human serum protein in vitro is ≈ 13%.

Biotransformation: entecavir is not a substrate, inhibitor or inducer of the CYP450 enzyme system.

Following administration of 14C-entecavir, no oxidative or acetylated metabolites and minor amountsof the phase II metabolites, glucuronide and sulfate conjugates, were observed.

Elimination: entecavir is predominantly eliminated by the kidney with urinary recovery of unchangeddrug at steady-state of about 75% of the dose. Renal clearance is independent of dose and rangesbetween 360-471 ml/min suggesting that entecavir undergoes both glomerular filtration and nettubular secretion. After reaching peak levels, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of ≈ 128-149 hours. The observed drugaccumulation index is ≈ 2 times with once daily dosing, suggesting an effective accumulation half-lifeof about 24 hours.

Hepatic impairment: pharmacokinetic parameters in patients with moderate or severe hepaticimpairment were similar to those in patients with normal hepatic function.

Renal impairment: entecavir clearance decreases with decreasing creatinine clearance. A 4 hour periodof haemodialysis removed ≈ 13% of the dose, and 0.3% was removed by CAPD. Thepharmacokinetics of entecavir following a single 1 mg dose in patients (without chronic hepatitis Binfection) are shown in the table below:

Baseline Creatinine Clearance (ml/min)

Unimpaired Mild Moderate Severe Severe Severe> 80 > 50; 30-50 20- Managed with Managed≤ 80 < 30 Haemodialysis with CAPD(n = 6) (n = 6) (n = 6) (n = 6) (n = 6) (n = 4)

Cmax (ng/ml) 8.1 10.4 10.5 15.3 15.4 16.6(CV%) (30.7) (37.2) (22.7) (33.8) (56.4) (29.7)

AUC(0-T) 27.9 51.5 69.5 145.7 233.9 221.8(ng·h /ml)(CV) (25.6) (22.8) (22.7) (31.5) (28.4) (11.6)

CLR (ml/min) 383.2 197.9 135.6 40.3 NA NA(SD) (101.8) (78.1) (31.6) (10.1)

CLT/F (ml/min) 588.1 309.2 226.3 100.6 50.6 35.7(SD) (153.7) (62.6) (60.1) (29.1) (16.5) (19.6)

Post-Liver transplant: entecavir exposure in HBV-infected liver transplant recipients on a stable doseof cyclosporine A or tacrolimus (n = 9) was ≈ 2 times the exposure in healthy subjects with normalrenal function. Altered renal function contributed to the increase in entecavir exposure in these patients(see section 4.4).

Gender: AUC was 14% higher in women than in men, due to differences in renal function and weight.

After adjusting for differences in creatinine clearance and body weight there was no difference inexposure between male and female subjects.

Elderly: the effect of age on the pharmacokinetics of entecavir was evaluated comparing elderlysubjects in the age range 65-83 years (mean age females 69 years, males 74 years) with young subjectsin the age range 20-40 years (mean age females 29 years, males 25 years). AUC was 29% higher inelderly than in young subjects, mainly due to differences in renal function and weight. After adjustingfor differences in creatinine clearance and body weight, elderly subjects had a 12.5% higher AUC thanyoung subjects.The population pharmacokinetic analysis covering patients in the age range 16-75 years did not identify age as significantly influencing entecavir pharmacokinetics.

Race: the population pharmacokinetic analysis did not identify race as significantly influencingentecavir pharmacokinetics. However, conclusions can only be drawn for the Caucasian and Asiangroups as there were too few subjects in the other categories.

Paediatric population: the steady-state pharmacokinetics of entecavir were evaluated (study 028) in24 nucleoside naïve HBeAg-positive paediatric subjects from 2 to < 18 years of age with compensatedliver disease. Entecavir exposure among nucleoside naïve subjects receiving once daily doses ofentecavir 0.015 mg/kg up to a maximum dose of 0.5 mg was similar to the exposure achieved in adultsreceiving once daily doses of 0.5 mg. The Cmax, AUC(0-24), and Cmin for these subjects was6.31 ng/ml, 18.33 ng h/ml, and 0.28 ng/ml, respectively.

In repeat-dose toxicology studies in dogs, reversible perivascular inflammation was observed in thecentral nervous system, for which no-effect doses corresponded to exposures 19 and 10 times those inhumans (at 0.5 and 1 mg respectively). This finding was not observed in repeat-dose studies in otherspecies, including monkeys administered entecavir daily for 1 year at exposures ≥ 100 times those inhumans.

In reproductive toxicology studies in which animals were administered entecavir for up to 4 weeks, noevidence of impaired fertility was seen in male or female rats at high exposures. Testicular changes(seminiferous tubular degeneration) were evident in repeat-dose toxicology studies in rodents and dogsat exposures ≥ 26 times those in humans. No testicular changes were evident in a 1-year study inmonkeys.

In pregnant rats and rabbits administered entecavir, no effect levels for embryotoxicity and maternaltoxicity corresponded to exposures ≥ 21 times those in humans. In rats, maternal toxicity, embryo-foetal toxicity (resorptions), lower foetal body weights, tail and vertebral malformations, reducedossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observedat high exposures. In rabbits, embryo-foetal toxicity (resorptions), reduced ossification (hyoid), and anincreased incidence of 13th rib were observed at high exposures. In a peri-postnatal study in rats, noadverse effects on offspring were observed. In a separate study wherein entecavir was administered topregnant lactating rats at 10 mg/kg, both foetal exposure to entecavir and secretion of entecavir intomilk were demonstrated. In juvenile rats administered entecavir from postnatal days 4 to 80, amoderately reduced acoustic startle response was noted during the recovery period (postnatal days110 to 114) but not during the dosing period at AUC values ≥ 92 times those in humans at the 0.5 mgdose or paediatric equivalent dose. Given the exposure margin, this finding is considered of unlikelyclinical significance.

No evidence of genotoxicity was observed in an Ames microbial mutagenicity assay, a mammalian-cell gene mutation assay, and a transformation assay with Syrian hamster embryo cells. Amicronucleus study and a DNA repair study in rats were also negative. Entecavir was clastogenic tohuman lymphocyte cultures at concentrations substantially higher than those achieved clinically.

Two-year carcinogenicity studies: in male mice, increases in the incidences of lung tumours wereobserved at exposures ≥ 4 and ≥ 2 times that in humans at 0.5 mg and 1 mg respectively. Tumourdevelopment was preceded by pneumocyte proliferation in the lung which was not observed in rats,dogs, or monkeys, indicating that a key event in lung tumour development observed in mice likely wasspecies-specific. Increased incidences of other tumours including brain gliomas in male and femalerats, liver carcinomas in male mice, benign vascular tumours in female mice, and liver adenomas andcarcinomas in female rats were seen only at high lifetime exposures. However, the no effect levelscould not be precisely established. The predictivity of the findings for humans is not known. Forclinical data, see section 5.1.

Baraclude 0.5 mg film-coated tablets

Crospovidone

Lactose monohydrate

Magnesium stearate

Cellulose, Microcrystalline

Povidone

Titanium dioxide

Hypromellose

Macrogol 400

Polysorbate 80 (E433)

Baraclude 1 mg film-coated tablets

Crospovidone

Lactose monohydrate

Magnesium stearate

Cellulose, Microcrystalline

Povidone

Titanium dioxide

Hypromellose

Macrogol 400

Iron oxide red

Not applicable.

2 years

Do not store above 30°C. Store in the original carton.

Do not store above 25°C. Keep the bottle tightly closed.

Each carton contains either: 30 x 1 film-coated tablet; 3 blister cards of 10 x 1 film-coated tablet each in Alu/Alu perforatedunit dose blisters, or 90 x 1 film-coated tablet; 9 blister cards of 10 x 1 film-coated tablet each in Alu/Alu perforatedunit dose blisters.

High-density polyethylene (HDPE) bottle with child resistant polypropylene closure containing30 film-coated tablets. Each carton contains one bottle.

Not all pack sizes and container types may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

Baraclude 0.5 mg film-coated tablets

Blister packs: EU/1/06/343/003

EU/1/06/343/006

Bottle packs: EU/1/06/343/001

Baraclude 1 mg film-coated tablets

Blister packs: EU/1/06/343/004

EU/1/06/343/007

Bottle packs: EU/1/06/343/002

Date of first authorisation: 26 June 2006

Date of latest renewal: 26 June 2011

{MM/YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.