BARACLUDE Product Monograph

PRODUCT MONOGRAPH

BARACLUDE*

(entecavir)

Tablets 0.5 mg

Antiviral

Bristol-Myers Squibb Canada Date of Preparation:

Montreal, Canada June 16, 2006

* TM of Bristol-Myers Squibb Company used under license by

Bristol-Myers Squibb Canada Date of revision:

23 September 2020

Control No. 233293

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ......................................................... 3

SUMMARY PRODUCT INFORMATION................................................................................ 3

INDICATIONS AND CLINICAL USE ..................................................................................... 3

CONTRAINDICATIONS ........................................................................................................... 3

WARNINGS AND PRECAUTIONS ......................................................................................... 3

ADVERSE REACTIONS ........................................................................................................... 6

DRUG INTERACTIONS ......................................................................................................... 10

DOSAGE AND ADMINISTRATION ..................................................................................... 11

OVERDOSAGE ........................................................................................................................ 12

ACTION AND CLINICAL PHARMACOLOGY .................................................................... 12

STORAGE AND STABILITY ................................................................................................. 19

DOSAGE FORMS, COMPOSITION AND PACKAGING..................................................... 19

PART II: SCIENTIFIC INFORMATION ............................................................................... 21

PHARMACEUTICAL INFORMATION ................................................................................. 21

CLINICAL TRIALS ................................................................................................................. 21

DETAILED PHARMACOLOGY ............................................................................................ 30

TOXICOLOGY ......................................................................................................................... 30

PART III: CONSUMER INFORMATION .............................................................................. 40

ABOUT THIS MEDICATION ................................................................................................ 40

WARNINGS AND PRECAUTIONS ....................................................................................... 40

INTERACTIONS WITH THIS MEDICATION ...................................................................... 41

PROPER USE OF THIS MEDICATION ................................................................................. 41

SIDE EFFECTS AND WHAT TO DO ABOUT THEM ......................................................... 42

HOW TO STORE IT ................................................................................................................. 42

BARACLUDE*

(entecavir)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

Clinically Relevant Nonmedicinal Ingredients

Oral

Tablets 0.5 mg

lactose monohydrate

For a complete listing, see Dosage Forms,

Composition and Packaging section

INDICATIONS AND CLINICAL USE

BARACLUDE (entecavir) is indicated for the treatment of chronic hepatitis B virus infection in

adults with evidence of active viral replication and either evidence of persistent elevations in

serum aminotransferases (ALT or AST) or histologically active disease.

This indication is based on efficacy and safety data in nucleoside-treatment-naive and in

lamivudine-refractory adult patients with HBeAg-positive or HBeAg-negative chronic HBV

infection with compensated liver disease and on more limited data in adult patients with

HIV/HBV co-infection who have received prior lamivudine therapy.

CONTRAINDICATIONS

BARACLUDE is contraindicated in patients with previously demonstrated hypersensitivity to

entecavir or any component of the product. (For a complete listing, see Dosage Forms,

Composition and Packaging section).

WARNINGS AND PRECAUTIONS

Severe acute exacerbations of hepatitis B have been reported in patients who have

discontinued anti-hepatitis B therapy, including entecavir. 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, re-initiation of anti-

hepatitis B therapy may be warranted (see ADVERSE REACTIONS: Exacerbations of

Hepatitis After Discontinuation of Treatment).

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been

reported with the use of nucleoside analogues, including BARACLUDE, alone or in

combination with antiretrovirals. Patients with decompensated liver disease may be at

higher risk for lactic acidosis.

Limited clinical experience suggests there is a potential for the development of resistance to

HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if

BARACLUDE is used to treat chronic hepatitis B virus infection in patients with HIV

infection that is not being treated. Therapy with BARACLUDE is not recommended for

HIV/HBV co-infected patients who are not also receiving highly active antiretroviral

therapy (HAART). (see WARNINGS AND PRECAUTIONS: Patients co-infected with

HIV and HBV)

General

BARACLUDE tablets contain lactose and are not recommended for patients with rare hereditary

problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose

malabsorption.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Positive carcinogenic results were found in two-year carcinogenicity studies with entecavir

conducted in mice and rats. In male mice, increases in the incidences of lung adenomas were

observed at exposures ≥ 3 times the exposure in humans at 1 mg and lung carcinomas were

observed in male and female mice at approximately 40 times the exposure in humans at 1 mg.

Tumor development was preceded by pneumocyte proliferation in the lung, which was not

observed in rats, dogs, or monkeys administered entecavir, indicating that a key event in lung

tumor development observed in mice likely was species specific. Drug-related increased

incidences of other types of tumors were seen at the highest entecavir exposures [in mice

approximately 40 times and in rats 35 times (males) and 24 times (females) human exposure at 1

mg], including liver carcinomas in male mice, benign vascular tumors in female mice, brain

microglial tumors in male and female rats, and liver adenomas and carcinomas in female rats.

Skin fibromas were observed in female rats at both the high (0.4 mg/kg/day; equivalent to 4 times

the exposure in humans at 1 mg) and highest (2.6 mg/kg/day; equivalent to 24 times the exposure

in humans at 1 mg) doses. (see TOXICOLOGY, Carcinogenesis, Mutagenesis, Impairment

of Fertility for more detailed information).

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

(see CLINICAL TRIALS, Data from Long-term Observational Study).

Entecavir was clastogenic to human lymphocyte cultures and in mouse lymphoma cells in vitro.

Entecavir was not mutagenic in the Ames bacterial reverse mutation assay, a mammalian-cell

gene mutation assay, and a transformation assay with Syrian hamster embryo cells. Entecavir was

also negative in an oral micronucleus study and an oral DNA repair study in rats. In reproductive

toxicology studies in which rats were administered entecavir at up to 30 mg/kg for up to 4 weeks,

no evidence of impaired fertility was seen in males or females at systemic exposures >90 times

those in humans at 1 mg. In rodent and dog toxicology studies, seminiferous tubular degeneration

was observed at ≥ 35 times the exposure in humans at 1 mg. No testicular changes were evident

in monkeys administered entecavir for 1 year at 167 times the exposure in humans at 1 mg.

Liver Transplant Recipients

The safety and efficacy of BARACLUDE in liver transplant recipients are unknown. The

potential for pharmacokinetic interaction between entecavir and the immunosuppressants

cyclosporine A or tacrolimus was not formally evaluated. If BARACLUDE treatment is

determined to be necessary for a liver transplant recipient who has received or is receiving

cyclosporine or tacrolimus, renal function must be carefully monitored both before and during

treatment with BARACLUDE (see ACTION AND CLINICAL PHARMACOLOGY: Special

Populations and DOSAGE AND ADMINISTRATION: Renal Impairment).

Renal Impairment

BARACLUDE is predominantly eliminated by the kidney. Dosage adjustment of BARACLUDE

is recommended for patients with a creatinine clearance <50 mL/min, including patients on

hemodialysis or CAPD [continuous ambulatory peritoneal dialysis] (see DOSAGE AND

ADMINISTRATION: Renal Impairment).

Special Populations

Patients co-infected with HIV and HBV

BARACLUDE has not been evaluated in patients who are co-infected with HIV and HBV and

are not concurrently receiving effective HIV treatment. Limited clinical experience suggests

there is a potential for the development of resistance to HIV nucleoside reverse transcriptase

inhibitors if BARACLUDE is used to treat chronic hepatitis B virus infection in patients with

HIV infection that is not being treated. Therefore therapy with BARACLUDE is not

recommended for HIV/HBV co-infected patients who are not also receiving highly active

antiretroviral therapy (HAART). BARACLUDE has not been studied as a treatment for HIV

infection and is not recommended for this use. (See ACTION AND CLINICAL

PHARMACOLOGY: Special Populations and Conditions, Patients Co-infected with HIV and

HBV and CLINICAL TRIALS: Special Populations, Patients Co-infected with HIV and HBV).

Before initiating BARACLUDE therapy, HIV antibody testing should be offered to all patients.

Pregnant Women

There are no adequate and well-controlled studies in pregnant women. BARACLUDE should be

used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Entecavir caused effects on embryo-fetal development in rats at doses that also produced

maternal toxicity; at these doses, exposures to entecavir were 180 times those in humans at 1 mg.

In rabbits, embryo-fetal toxicity was observed at exposures to entecavir 883 times those in

humans at 1 mg. There were no adverse effects on growth, development, and reproductive

performance in the progeny of rats administered entecavir at doses associated with exposures to

entecavir > 94 times those in humans at 1 mg. (see TOXICOLOGY, Reproductive Toxicology

for more detailed information).

Pregnancy Registry:

To monitor maternal-fetal outcomes of pregnant women exposed to BARACLUDE a Pregnancy

Registry has been established. To register patients, physicians must obtain prior consent.

Physicians can register patients by calling 1-800-258-4263.

Labor and Delivery

There are no studies in pregnant women and no data on the effect of BARACLUDE on

transmission of HBV from mother to infant. Therefore, appropriate interventions should be used

to prevent neonatal acquisition of HBV.

Nursing Women

Entecavir is excreted in the milk of rats. It is not known whether this drug is excreted in human

milk. Mothers should be instructed not to breast-feed if they are taking BARACLUDE.

Pediatrics (<16 years of age)

Safety and effectiveness of BARACLUDE in pediatric patients below the age of 16 years have

not been established.

Geriatrics (>65 years of age)

Clinical studies of BARACLUDE did not include sufficient numbers of subjects aged 65 years

and over to determine whether they respond differently from younger subjects. Entecavir is

substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in

patients with impaired renal function. Because elderly patients are more likely to have decreased

renal function, care should be taken in dose selection, and it may be useful to monitor renal

function (see DOSAGE AND ADMINISTRATION: Renal Impairment).

Use in Racial/Ethnic Groups

Clinical studies of BARACLUDE did not include sufficient numbers of subjects from some

racial/ethnic minorities (black/African American, Hispanic) to determine whether they respond

differently to treatment with the drug. There are no significant racial differences in entecavir

pharmacokinetics.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Assessment of adverse reactions is based on four pivotal studies (AI463014, AI463022,

AI463026, and AI463027) in which 1720 patients with chronic hepatitis B infection received

double-blind treatment with BARACLUDE 0.5 mg/day (n=679), BARACLUDE 1 mg/day

(n=183), or lamivudine (n=858) for up to two years (Studies AI463022, AI463027 for

nucleoside-naïve patients and studies AI463014, AI463026 for lamivudine-refractory patients).

The safety profiles of BARACLUDE and lamivudine were comparable in these studies.

The safety profile of BARACLUDE 1 mg (n=51) in HIV/HBV co-infected patients enrolled in

Study AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment and

similar to that seen in non-HIV infected patients. (See WARNINGS AND PRECAUTIONS –

Special Populations: Patients Co-infected with HIV and HBV)

The most common (≥ 3%) adverse events of any severity with at least a possible relation to study

drug for BARACLUDE-treated patients were headache, fatigue, dizziness, and nausea. The most

common adverse events among lamivudine-treated patients were headache, fatigue, and

dizziness. One percent of BARACLUDE-treated patients in these four studies compared with 4%

of lamivudine-treated patients discontinued for adverse events or abnormal laboratory test results.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and for approximating

rates.

Clinical adverse reactions occurring in ≥ 3% of BARACLUDE-treated patients during therapy in

four clinical studies in which BARACLUDE was compared with lamivudine, in addition to

selected clinical adverse reactions that occurred in < 3% of patients are presented in Table 1.

Table 1:Clinical Adverse Reactions Reported in ≥ 3% of BARACLUDE-treated Patients,

Plus Selected Clinical Adverse Reactions in Four BARACLUDE Clinical Trials – Through

2 Years of Treatment

Body System/

Adverse Event

Nucleoside-Naive

Lamivudine-Refractory

BARACLUDE

0.5 mg

n = 679

Lamivudine

100 mg

n = 668

BARACLUDE

1 mg

n = 183

Lamivudine

100 mg

n = 190

Gastrointestinal

Nausea

Abdominal pain upper

Dyspepsia

Diarrhea

Vomiting

General

Fatigue

Nervous System

Headache

Dizziness

Somnolence

Psychiatric

Insomnia

a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.

Studies AI463022 and AI463027 Mean duration of therapy was 69 weeks for BARACLUDE-treated and 63

weeks for lamivudine-treated patients.

Includes Study AI463026 and the BARACLUDE 1-mg and lamivudine treatment arms of Study

AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of BARACLUDE (0.1, 0.5, and 1

mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in patients who experienced

recurrent viremia on lamivudine therapy. Mean duration of therapy was 73 weeks for BARACLUDE-treated and 51

weeks for lamivudine-treated patients.

Exacerbations of Hepatitis After Discontinuation of Treatment

In the Phase 3 studies, a subset of patients was allowed to discontinue treatment at or after 52

weeks if they achieved a protocol-defined response to therapy. An exacerbation of hepatitis or

ALT flare was defined as ALT >10 X ULN and >2 X the patient’s reference level (minimum of

the baseline or last measurement at end of dosing). As demonstrated in Table 2, a proportion of

patients experienced post-treatment ALT flares. If BARACLUDE is discontinued without regard

to treatment response, the rate of post-treatment flares could be higher.

Table 2: Exacerbations of Hepatitis During Off-Treatment Follow-up, Patients in Studies

AI463022 , AI463027 and AI463026

Patients with ALT Elevations > 10xULN and >2 x Reference

BARACLUDE

Lamivudine

Total Nucleoside-naïve

HBeAg-positive

HBeAg-negative

28/476 (6%)

4/174 (2%)

24/302 (8%)

43/417 (10%)

13/147 (9%)

30/270 (11%)

Lamivudine-refractory

6/52 (12%)

0/16

Reference is the minimum of the baseline or last measurement at end of dosing. Median time to off-treatment

exacerbation was 23 weeks for BARACLUDE-treated patients and 10 weeks for lamivudine-treated patients.

Abnormal Hematologic and Clinical Chemistry Findings

Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in

four clinical trials of BARACLUDE compared with lamivudine are listed in Table 3.

Table 3: Selected Treatment-Emergent

Laboratory Abnormalities Reported in Four

BARACLUDE Clinical Trials -Through 2 Years

Test

Nucleoside -Naive

Lamivudine-Refractory

BARACLUDE

0.5 mg (n = 679)

Lamivudine

100 mg (n = 668)

BARACLUDE

1 mg (n = 183)

Lamivudine

100 mg (n = 190)

ALT> 10 x ULN and > 2 x baseline

11%

ALT > 5.0 ULN

11%

16%

12%

24%

AST > 5.0 ULN

17%

Albumin < 2.5 g/dL

<1%

Total bilirubin > 2.5 x ULN

Amylase > 2.1 x ULN

Lipase > 2.1 x ULN

Creatinine ≻ 3.0 x ULN

0% 0% 0% 0%

Confirmed creatinine increase ≥

44.2 mmol/L

1% 1% 2% 1%

Hyperglycemia fasting

>13.8 mmol/L

2% 1% 3% 1%

Glycosuria

Hematuria

10%

Platelets < 50,000/mm

<1%

On-treatment value worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin (any on treatment

value <2.5 g/dL), confirmed creatinine increase ≥ 44.2 mmol/L and ALT >10 X ULN and >2 X baseline.

Studies AI463022 and AI463027. . Mean duration of therapy was 69 weeks for BARACLUDE-treated and 63 weeks

for lamivudine-treated patients.

Includes Study AI463026 and the BARACLUDE 1-mg and lamivudine treatment arms of Study AI463014, a Phase 2

multinational, randomized, double-blind study of three doses of BARACLUDE (0.1, 0.5, and 1 mg) once daily versus

continued lamivudine 100 mg once daily for up to 52 weeks in patients who experienced recurrent viremia on

lamivudine therapy. Mean duration of therapy was 73 weeks for BARACLUDE-treated and 51 weeks for lamivudine-

treated patients.

Grade 3=3+, large, ≥ 500 mg/dL; Grade 4=4+, marked, severe

Grade 3=3+, large, Grade 4 =

≥ 4+, marked, severe, many

ULN= upper limit of normal

Among BARACLUDE-treated patients in these studies, on-treatment ALT elevations >10 X

ULN and >2 X baseline generally resolved with continued treatment. A majority of these

exacerbations were associated with a ≥ 2 log

/mL reduction in viral load that preceded or

coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended

during treatment.

Post-Market Adverse Drug Reactions

The following events have been identified during postapproval use of BARACLUDE. Because

reports are voluntary from a population of unknown size, an estimate of frequency cannot be

made, as well, the existence of underlying medical conditions confounds the assessment of

causality.

Gastrointestinal disorders: upper abdominal pain, pancreatitis

Metabolism and nutrition disorders: lactose intolerance. Lactic acidosis has been reported, often

in association with hepatic decompensation, other serious medical conditions, or drug exposures.

Patients with decompensated liver disease may be at higher risk for lactic acidosis.

Hepatobiliary disorders: increased transaminases

Skin and subcutaneous tissue disorders: alopecia, rash

Blood and lymphatic system disorders: leukopenia, neutropenia, platelet count decreased

Immune System Disorders: hypersensitivity and drug hypersensitivity including anaphylactoid

reaction

DRUG INTERACTIONS

Overview

Since entecavir is primarily eliminated by the kidneys (see ACTION AND CLINICAL

PHARMACOLOGY: Metabolism and Elimination), coadministration of BARACLUDE with

drugs that reduce renal function or compete for active tubular secretion may increase serum

concentrations of either entecavir or the coadministered drug. In clinical trials, coadministration

of BARACLUDE with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not

result in significant drug interactions. The effects of coadministration of BARACLUDE with

other drugs that are renally eliminated or are known to affect renal function have not been

evaluated, and patients should be monitored closely for adverse events when BARACLUDE is

coadministered with such drugs.

The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a

substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At

concentrations up to approximately 10,000-fold higher than those obtained in humans, entecavir

inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1.

At concentrations up to approximately 340-fold higher than those observed in humans, entecavir

did not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. (See

ACTION AND CLINICAL PHARMACOLOGY: Metabolism and Elimination.) The

pharmacokinetics of entecavir are unlikely to be affected by coadministration with agents that are

either metabolized by, inhibit, or induce the CYP450 system. Likewise, the pharmacokinetics of

known CYP substrates are unlikely to be affected by coadministration of BARACLUDE.

Drug-Drug Interactions

In clinical studies, the steady-state pharmacokinetics of BARACLUDE and coadministered drug

were not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and

tenofovir disoproxil fumarate.

Drug-Food Interactions

Oral administration of 0.5 mg of BARACLUDE 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 (1.0-1.5 hour

fed vs. 0.75 hours fasted), a decrease in C

max

of 44%-46%, and a decrease in AUC of 18%-20%.

Therefore, BARACLUDE should be administered on an empty stomach (at least 2 hours after a

meal and at least 2 hours before the next meal).

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

The usual recommended dose of BARACLUDE for chronic hepatitis B virus infection in adults

and adolescents 16 years of age or older is 0.5 mg once daily.

For adults and adolescents 16 years of age or older with a history of hepatitis B viremia while

receiving lamivudine or with known lamivudine resistance mutations, the recommended dose of

BARACLUDE is 1 mg (two 0.5 mg tablets) once daily.

BARACLUDE should be administered on an empty stomach (at least 2 hours after a meal and at

least 2 hours before the next meal).

Renal Impairment

In patients with renal impairment, the apparent oral clearance of entecavir decreased as creatinine

clearance decreased. Dosage adjustment is recommended for patients with creatinine clearance

<50 mL/min, including patients on hemodialysis or CAPD (continuous ambulatory peritoneal

dialysis), as shown in Table 4.

Table 4: Recommended Dosage of BARACLUDE in Patients with Renal Impairment

Creatinine Clearance (mL/min)

Usual Dose (0.5 mg)

Lamivudine Refractory (1 mg)

≥ 50

0.5 mg once daily

1 mg once daily

30 to <50 0.5 mg every 48 hours

0.5 mg once daily

1 mg every 48 hours

10 to <30

0.5 mg every 72 hours

1 mg every 72 hours

<10

Hemodialysis

or CAPD

0.5 mg every 7 days 01 mg every 7 days

On hemodialysis days, administer after hemodialysis.

Hepatic Impairment

No dosage adjustment is necessary for patients with hepatic impairment.

Duration of Therapy

The optimal duration of treatment with BARACLUDE for patients with chronic hepatitis B

infection and the relationship between treatment and long-term outcomes such as cirrhosis and

hepatocellular carcinoma are unknown.

OVERDOSAGE

For management of a suspected drug overdose, please contact your regional Poison Control

Centre.

Activated charcoal may be administered to aid in the removal of unabsorbed drug. General

supportive measures are recommended. Healthy subjects who received single entecavir doses up

to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in, or unexpected,

adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and

standard supportive treatment applied as necessary.

Following a single 1-mg dose of entecavir, a 4-hour hemodialysis session removed approximately

13% of the entecavir dose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Entecavir is a guanosine nucleoside analogue that is efficiently phosphorylated to the active

triphosphate form and exhibits selective activity against HBV polymerase, competes with the

natural substrate deoxyguanosine triphosphate, and inhibits all three functional activities of the

HBV polymerase (reverse transcriptase, rt): (1) base priming, (2) reverse transcription of the

negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of

HBV DNA. Entecavir triphosphate has an inhibition constant (Ki) for HBV DNA polymerase of

0.0012 μM and is a weak inhibitor of cellular DNA polymerases α, ß, and δ and mitochondrial

DNA polymerase γ with Ki values ranging from 18 to >160 μM.

Antiviral Activity

Entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentration of 0.004 μM

in human HepG2 cells transfected with wild-type HBV. The median EC50 value for entecavir

against lamivudine resistant HBV (rtL180M, rtM204V) was 0.026 μM (range 0.010-0.059 μM).

A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and

clinical HIV-1 isolates 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 in HIV

reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high

entecavir concentrations. HIV variants containing the M184I substitution showed loss of

susceptibility to entecavir.

The coadministration of HIV nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with

BARACLUDE is unlikely to reduce the antiviral efficacy of BARACLUDE against HBV or of

any of these agents against HIV. In HBV combination assays in vitro, abacavir, didanosine,

lamivudine, stavudine, tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of

entecavir over a wide range of concentrations. In HIV antiviral assays, entecavir was not

antagonistic to the in vitro anti-HIV activity of these six NRTIs or emtricitabine at concentrations

greater than 100 times the Cmax of entecavir using the 1-mg dose.

Drug Resistance

Clinical Studies

In nucleoside-naive studies (AI463022, AI463027, and rollover study AI463901) and in studies

of lamivudine-refractory HBV (AI463026, AI463014, AI463015, and rollover study AI463901),

patients initially treated with entecavir 0.5 mg (nucleoside-naïve) or 1.0 mg (lamivudine

refractory) and with an on-therapy PCR HBV DNA measurement at or after Week 24 were

monitored for resistance. Virologic breakthroughs due to resistance to entecavir are observed in

viruses which harbour primary lamivudine resistance substitutions (M204I/V ± L180M) along

with additional substitutions at residues T184, S202 or M250 of the viral polymerase.

Nucleoside-naïve patients:

Through Year 5, genotypic evidence of entecavir resistance (ETVr) substitutions at residues

T184, S202 or M250 was observed in 3 patients (<1%), 2 of whom experienced virologic

breakthrough (see Table 5). The results reflect use of a 1 mg dose of entecavir in 147 patients in

Year 3 and all patients in Years 4 and 5 and of entecavir-lamivudine combination therapy

(followed by long-term entecavir monotherapy) for a median of 20 weeks for 130 patients in

Year 3 and for 1 week for one patient in Year 4 in a rollover study.

Table 5: Genotypic Entecavir Resistance and Virologic Breakthrough with Resistance

Through Year 5, Nucleoside-Naïve Studies

Year 1

Year 2

Year 3

Year 4

Year 5

Subjects treated and monitored for

resistance

663

278

149

121

108

Emerging Genotypic ETV

c,d

Genotypic ETVr

c,d

withVirologic

breakthrough

Cumulative probability of emerging

genotypic ETVr

c,d

0.2%

0.5%

1.2%

Cumulative probability of genotypic

ETVr

c,d

with virologic

breakthrough

0.2%

0.8%

Results reflect the use of a 1-mg dose of entecavir for 147 subjects in Year 3 and all subjects in Years 4 and 5 and of

combination entecavir-lamivudine therapy (followed by long-term entecavir therapy) for a median of 20 weeks for 130 subjects

in Year 3 and for 1 week for 1 subject in Year 4 in rollover study.

Includes subjects 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 through week 204 (Year 4),

or after week 204 through week 252 (Year 5).

ETVr = entecavir resistance substitutions at residues T184, S202 or M250.

Subjects also had lamivudine resistance substitutions (rtM204V and rtL180M).

≥1 log

increase above nadir in HBV DNA by PCR, confirmed with successive measurements or at the end of the windowed

point.

Emerging amino acid substitutions at M204I/V ± L180M, L80I, or V173L, which conferred

decreased phenotypic susceptibility to entecavir in the absence of S202, T184, or M250 changes,

were detected in the HBV of 3 patients (3/663 = <1%) who experienced virologic breakthrough

by the end of Year 5.

Lamivudine-refractory patients:

Through Year 5, genotypic evidence of entecavir resistance (ETVr) substitutions at residues

T184, S202 or M250 was observed in 47 patients, 39 of whom experienced virologic

breakthrough (see Table 6) The results reflect the use of entecavir-lamivudine combination

therapy (followed by long-term entecavir monotherapy) for a median of 13 weeks for 48 patients

in Year 3, for a median of 38 weeks for 10 patients in Year 4 and for 16 weeks for 1 patient in

Year 5 in a rollover study.

Table 6: Genotypic Entecavir Resistance and Virologic Breakthrough with Resistance

Through Year 5, Lamivudine-Refractory Studies

Year 1

Year 2

Year 3

Year 4

Year 5

Subjects treated and monitored for

resistance

187

146

Emerging Genotypic ETV

c,d

Genotypic ETVr

c,d

with Virologic

breakthrough

Cumulative probability of emerging

genotypic ETVr

c,d

15%

36%

47%

51%

Cumulative probability of

genotypic ETVr

c,d

with virologic

breakthrough

11%

27%

41%

44%

Results reflect the use of combination entecavir-lamivudine therapy (followed by long-term entecavir therapy) for a median of 13

weeks for 48 subjects in Year 3, for a median of 38 weeks for 10 subjects in Year 4, and for 16 weeks for 1 patient in Year 5 in a

rollover study.

Includes subjects 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 through week 204 (Year 4),

or after week 204 through week 252 (Year 5).

ETVr = entecavir resistance substitutions at residues T184, S202 or M250.

Subjects also had lamivudine resistance substitutions (rtM204V/I± rtL180M).

≥1 log

increase above nadir in HBV DNA by PCR, confirmed with successive measurements or at the end of the windowed

point.

ETVr occurring in any year, virologic breakthrough in a specified year.

The presence of ETVr substitutions at baseline in isolates from 10 (5%) of 187 lamivudine-

refractory patients indicates that prior lamivudine treatment can select these resistance

substitutions and they can exist at a low frequency before entecavir treatment. Through Year 5, 3

of the 10 patients experienced virologic breakthrough. Isolates from patients who experienced

virologic breakthrough with the emergence of S202, T184 and/or M250 substitutions (n=39), had

a median 285 fold-change in entecavir susceptibility as compared to wild type HBV. Three

additional subjects experienced virologic breakthrough with the emergence of M204I/V ±

L180M, L80V or V173L/M alone.

Integrated Analysis of Phase 2 and 3 Clinical Studies

In a post-approval integrated analysis of entecavir 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 with entecavir. This substitution was detected only in the presence

of lamivudine resistance-associated substitutions rtL180M plus rtM204V.

Cross-resistance

Cross-resistance has been observed among HBV nucleoside analogues. In cell-based assays,

HBV containing lamivudine resistance substitutions M204V/I +/- L180M was 8-fold less

susceptible to entecavir than wild type virus. Further reductions (>70 fold) in entecavir

phenotypic susceptibility required the presence of primary lamivudine resistance amino acid

substitutions (M204V/I +/- L180M ) along with additional substitutions at residues rtT184,

rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution

in the HBV polymerase.

Recombinant HBV genomes encoding adefovir resistance-associated substitutions at either

rtN236T or rtA181V remained susceptible to entecavir. HBV isolates from lamivudine-refractory

patients failing BARACLUDE therapy were susceptible in vitro to adefovir but retained

resistance to lamivudine.

Lamivudine-resistant strains harboring rtL180M plus rtM204V in combination with amino acid

substitution rtA181C conferred 16- to 122-fold reductions in entecavir phenotypic susceptibility.

Pharmacokinetics

The single- and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects

and patients with chronic hepatitis B infection (including liver transplant recipients). Steady-state

Pharmacokinetics of entecavir are summarized in Table 7.

Table 7 - Summary of Entecavir Pharmacokinetic Parameters in Healthy Subjects

Cmax

(ng/mL)

1/2

(h)

AUC(TAU)

(ng.h/mL)

Clearance

(CLT/F)

(mL/min)

CLR

(mL/min)

Steady-state

mean (0.5 mg)

4.2

130

14.8

572

360

Steady-state

mean (1.0 mg)

8.2

149

26.4

636

471

Geometric mean

Absorption

Following oral administration in healthy subjects, entecavir was rapidly absorbed with peak

plasma concentrations occurring between 0.5 and 1.5 hours. Following multiple daily doses

ranging from 0.1 to 1.0 mg, C

max

and area under the concentration-time curve (AUC) at steady

state increased in proportion to dose. Steady state was achieved after 6-10 days of once-daily

administration with approximately 2 fold accumulation. For a 0.5-mg oral dose, C

max

at steady

state was 4.2 ng/mL and trough plasma concentration (C

trough

) was 0.3 ng/mL. For a 1 mg oral

dose, C

max

was 8.2 ng/mL and C

trough

was 0.5 ng/mL.

Effects of food on oral absorption: Oral administration of 0.5 mg of 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 delay in

absorption (1.0-1.5 hours fed vs. 0.75 hours fasted), a decrease in C

max

of 44%-46%, and a

decrease in AUC of 18%-20%. Therefore, BARACLUDE should be administered on an empty

stomach (at least 2 hours after a meal and at least 2 hours before the next meal).

Distribution

Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent

volume of distribution is in excess of total body water, suggesting that entecavir is extensively

distributed into tissues. Protein binding to human serum protein in vitro was approximately 13%.

Metabolism

The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a

substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At

concentrations approximately 10,000 fold higher than those obtained in humans, entecavir

inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1.

At concentrations approximately 340 fold higher than those observed in humans, entecavir did

not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. Following

administration of

C-entecavir in humans and rats, no oxidative or acetylated metabolites were

observed. Minor amounts of the phase II metabolites glucuronide and sulfate conjugate were

observed.

Excretion

After reaching peak concentration, entecavir plasma concentrations decreased in a bi- exponential

manner with a terminal elimination half-life of approximately 128-149 hours.

The observed drug accumulation index is approximately 2 fold with once-daily dosing, indicating

an effective accumulation half-life of approximately 24 hours.

Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at

steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent

of dose and ranges from 360 to 471 mL/min suggesting that entecavir undergoes both glomerular

filtration and net tubular secretion (see DRUG INTERACTIONS).

Special Populations and Conditions

Patients Co-Infected with HIV and HBV

Study AI463038 was a randomized, double-blind, placebo-controlled study of BARACLUDE

versus placebo in 68 patients co-infected with HIV and HBV, who experienced recurrence of

HBV viremia while receiving a lamivudine-containing highly active antiretroviral (HAART)

regimen. Patients continued their lamivudine-containing HAART regimen (lamivudine dose 300

mg/day) and were assigned to add either BARACLUDE 1 mg once daily (51 patients) or placebo

(17 patients) for 24 weeks followed by an open-label phase for an additional 24 weeks where all

patients received BARACLUDE. At baseline, patients had a mean serum HBV DNA level by

PCR of 9.13 log 10 copies /mL. Ninety-nine percent of patients were HBeAg-positive at

baseline, with a mean baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable

at approximately 2 log10 copies/mL through 24 weeks of blinded therapy. Virologic and

biochemical endpoints at Week 24 are shown in Table8. There are no data in patients with

HIV/HBV co-infection who have not received prior lamivudine therapy. BARACLUDE has not

been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving

effective HIV treatment. (See WARNINGS AND PRECAUTIONS – Special Populations:

Patients Co-Infected with HIV and HBV)

Table 8: Virologic and Biochemical Endpoints at Week 24, Study AI463038

BARACLUDE 1 mg

N=51

Placebo

N=17

HBV DNA

Proportion undetectable (<300 copies/mL)

Mean change from baseline (log

copies/mL)

(-3.65*)

(+0.11)

ALT normalization (≤ 1 x ULN)

(34%)

(8%)

All patients also received a lamivudine-containing HAART regimen

Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL)

Percentage of patients with abnormal ALT (> 1 x ULN) at baseline who achieved ALT normalization (n=35

for BARACLUDE and n=12 for placebo)

* p < 0.0001

For patients originally assigned to BARACLUDE, at the end of the open-label phase (Week 48),

8% of patients had HBV DNA < 300 copies/mL by PCR, the mean change from baseline HBV

DNA by PCR was -4.20 log

copies/mL, and 37% of patients with abnormal ALT at baseline had

ALT normalization (≤ 1 X ULN).

Pediatrics

Pharmacokinetic studies have not been conducted in children.

Geriatrics

The effect of age on the pharmacokinetics of entecavir was evaluated following administration of

a single 1mg oral dose in healthy young (20–40 years old) and elderly (65-83 years old)

volunteers. Entecavir AUC was 29.3% greater in elderly subjects compared to young subjects.

The disparity in exposure between elderly and young subjects was most likely attributable to

differences in renal function. Dosage adjustment of BARACLUDE should be based on the renal

function of the patient, rather than age (see DOSAGE AND ADMINISTRATION: Renal

Impairment).

Gender / race

There are no significant gender/racial differences in entecavir pharmacokinetics.

Hepatic Impairment

No dosage adjustment of BARACLUDE is recommended for patients with hepatic impairment.

The pharmacokinetics of entecavir following a single 1 mg dose were studied in patients (without

chronic hepatitis B infection) with moderate and severe hepatic impairment. The

pharmacokinetics of entecavir were similar between hepatically impaired patients and healthy

control subjects.

Post-liver transplant

The safety and efficacy of BARACLUDE in liver transplant recipients are unknown. However, in

a small pilot study of entecavir use in HBV-infected liver transplant recipients on a stable dose of

cyclosporine A (n=5) or tacrolimus (n=4), entecavir exposure was approximately 2 fold the

exposure in healthy subjects with normal renal function. Altered renal function contributed to the

increase in entecavir exposure in these patients. The potential for pharmacokinetic interactions

between entecavir and cyclosporine A or tacrolimus was not formally evaluated. Renal function

must be carefully monitored both before and during treatment with BARACLUDE in liver

transplant recipients who have received or are receiving an immunosuppressant that may affect

renal function, such as cyclosporine or tacrolimus (see DOSAGE AND ADMINISTRATION:

Renal Impairment).

Renal Insufficiency

The pharmacokinetics of entecavir following a single 1 mg dose were studied in patients (without

chronic hepatitis B infection) with selected degrees of renal impairment, including patients whose

renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis

(CAPD). Results are shown in Table 9.

Table 9: Pharmacokinetic Parameters in Subjects with Selected Degrees of Renal

Function

Baseline Creatinine Clearance (mL/min)

Severe

Managed with

Hemodialysis

(n = 6)

Severe

Managed

with CAPD

(n = 4)

Unimpaired

> 80

(n = 6)

Mild

> 50≤ 80

(n = 6)

Moderate

30-50

(n = 6)

Severe

< 30

(n = 6)

max

(ng/mL)

(CV%)

8.1

(30.7)

10.4

(37.2)

10.5

(22.7)

15.3

(33.8)

15.4

(56.4)

16.6

(29.7)

AUC

(0-T)

(ng·h/mL)

(CV)

27.9

(25.6)

51.5

(22.8)

69.5

(22.7)

145.7

(31.5)

233.9

(28.4)

221.8

(11.6)

CLR (mL/min)

(SD)

383.2

(101.8)

197.9

(78.1)

135.6

(31.6)

40.3

(10.1)

NA NA

CLT/F (mL/min)

(SD)

588.1

(153.7)

309.2

(62.6)

226.3

(60.1)

100.6

(29.1)

50.6

(16.5)

35.7

(19.6)

Dosed immediately following hemodialysis

CLR=renal clearance; CLT/F=apparent oral clearance.

Dosage adjustment is recommended for patients with a creatinine clearance <50 mL/min,

including patients on hemodialysis or CAPD. (See DOSAGE AND ADMINISTRATION:

Renal Impairment).

Following a single 1 mg dose of BARACLUDE, hemodialysis removed approximately 13% of

the BARACLUDE dose over 4 hours and CAPD removed approximately 0.3% of the dose over 7

days. BARACLUDE should be administered after hemodialysis.

STORAGE AND STABILITY

BARACLUDE Tablets should be stored in a tightly closed container at 25° C; excursions

permitted between 15-30° C. Keep bottle in the outer carton to protect from light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

BARACLUDE (entecavir) film-coated tablets contains entecavir as the active ingredient.

BARACLUDE film-coated tablets contain the following inactive ingredients: lactose

monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The

tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80.

BARACLUDE Tablets are available in the following strength and configuration of plastic bottles

with child-resistant closures:

Product Strength and

Dosage Form

Description Quantity

0.5 mg film-coated tablet

White to off-white, triangular-shaped tablet, debossed

with “BMS” on one side and “1611" on the other side

30 tablets

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Entecavir

Chemical name: 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-

2- methylenecyclopentyl]- 6H-purin-6-one, monohydrate.

Molecular formula and molecular mass: C

•H

O 295.3

Structural formula:

Physicochemical properties: White to off-white powder. It is slightly soluble in water

(2.4 mg/mL), and the pH of the saturated solution in water

is 7.9 at 25° ± 0.5° C.

CLINICAL TRIALS

The safety and efficacy of BARACLUDE were evaluated in three pivotal active-controlled trials

on five continents. These studies included 1633 patients 16 years of age or older with chronic

hepatitis B infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of

viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR

assay). Subjects had persistently elevated ALT levels ≥ 1.3 times the upper limit of normal

(ULN) and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral

hepatitis. The safety and efficacy of BARACLUDE were also evaluated in a study of 68 patients

co-infected with HBV and HIV.

Nucleoside-Naive Patients With Compensated Liver Disease, Outcomes at 48 Weeks

HBeAg-positive

Study AI463022 was a multinational, randomized, double-blind study of BARACLUDE 0.5 mg

once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 709 (of 715

randomized) nucleoside-naive patients with chronic hepatitis B infection and detectable HBeAg.

The mean age of patients was 35 years, 75% were male, 57% were Asian, 40% were Caucasian,

and 13% had previously received interferon-α. At baseline, patients had a mean Knodell

Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS

Amplicor® PCR assay was 9.66 log

copies/mL, and mean serum ALT was 143 U/L. Paired,

adequate liver biopsy samples were available for 89% of patients.

HBeAg-negative (anti-HBe positive/HBV DNA positive)

Study AI463027 was a multinational, randomized, double-blind study of BARACLUDE 0.5 mg

once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 638 (of 648

randomized) nucleoside-naive patients with HBeAg-negative (HBeAb-positive) chronic hepatitis

B infection. The mean age of patients was 44 years, 76% were male, 39% were Asian, 58% were

Caucasian, and 13% had previously received interferon-α. At baseline, patients had a mean

Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche

COBAS Amplicor PCR assay was 7.58 log

copies/mL, and mean serum ALT level was 142

U/L. Paired, adequate liver biopsy samples were available for 88% of patients.

In Studies AI463022 and AI463027, BARACLUDE was superior to lamivudine on the primary

efficacy endpoint of Histologic Improvement, defined as ≥ 2-point reduction in Knodell

Necroinflammatory Score with no worsening in Knodell Fibrosis Score at Week 48, and on the

secondary efficacy measures of reduction in viral load and ALT normalization. Histologic

Improvement and change in Ishak Fibrosis Score are shown in Table 10. Biochemical, virologic,

and serologic outcome measures are shown in Table 11.

Table 10: Histologic Improvement and Change in Ishak Fibrosis Score at Week 48,

Nucleoside-Naive Patients in Studies AI463022 and AI463027

Study AI463022 (HBeAg-Positive)

Study AI463027 (HBeAg-Negative)

BARACLUDE

0.5 mg

n = 314

Lamivudine

100 mg

n = 314

Difference

BARACLUDE

Lamivudine

(95% CI)

BARACLUDE

0.5 mg

n = 296

Lamivudine

100 mg

n = 287

Difference

BARACLUDE

Lamivudine

(95% CI)

Histologic Improvement (Knodell Scores)

Improvement

72% 62%

9.9%

(2.6%, 17.2%)

p < 0.01

70% 61%

9.6%

(2.0%, 17.3%)

p < 0.05

No improvement

21% 24% 19% 26%

Ishak Fibrosis Score

Improvement

39% 35%

3.2%

(-4.4%, 10.7%)

p= NS

36% 38%

-1.8%

(-9.7%, 6.0%)

p= NS

No change

46% 40% 41% 34%

Worsening

8% 10% 12% 15%

Missing Week

48 biopsy

7% 14% 10% 13%

Patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2).

In these analyses, missing or inadequate biopsies at Week 48 were classified “no improvement.”

≥ 2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the

Knodell Fibrosis Score.

For Ishak Fibrosis Score, improvement = ≥ 1-point decrease from baseline and worsening = ≥ 1-

point increase from baseline.

NS = Not significant.

Table 11: Selected Virologic, Biochemical, and Serologic Endpoints at Week 48,

Nucleoside-Naive Patients in Studies AI463022 and AI463027

Study AI463022 (HBeAg-Positive)

Study AI463027 (HBeAg-Negative)

BARACLUDE

0.5 mg

n = 354

Lamivudine

100 mg

n = 355

Difference

BARACLUDE

Lamivudine

(95% CI)

BARACLUDE

0.5 mg

n = 325

Lamivudine

100 mg

n = 313

Difference

BARACLUDE

Lamivudine

(95% CI)

ALT normalization

(

≤ 1.0X ULN)

68 % 60 %

8.4 %

1.3%, 15.4%

p = 0.0202

78 % 71%

6.9 %

0.2, 13.7

p = 0.0451

HBV DNA

Mean change from

baseline by

PCR

(log

copies/mL)

-6.86 -5.39

-1.5

(-1.8 -1.3)

p < 0.0001

-5.04 -4.53

-0.4

(-0.6 -0.3)

p < 0.0001

Proportion

undetectable

(< 300 copies/mL)

by PCR

a, b

67% 36%

30.3%

(23.3%-37.3%)

p < 0.0001

90% 72%

18.3%

(12.3%, 24.2%)

p < 0.0001

<0.7 MEq/mL by

bDNA

91% 65%

25.6%

(19.8%, 31.4%)

p < 0.0001

95% 89%

5.9%

(1.8%, 10.1%)

p < 0.01

Loss of HBeAg

22% 20% N/A N/A

HBeAg

seroconversion

21% 18% N/A N/A

Roche COBAS Amplicor PCR assay.

At Week 24, HBV DNA <300 copies/mL by PCR was observed in 42% of BARACLUDE-treated

patients and 25% of lamivudine-treated patients (p<0.0001) in Study AI463022 and 74% of

BARACLUDE -treated patients and 62% of lamivudine-treated patients (p = 0.0013) in Study AI463027.

Quantiplex bDNA assay.

Histologic improvement was independent of baseline levels of HBV DNA or ALT.

Lamivudine-Refractory Patients, Outcomes at 48 Weeks

Study AI463026 was a multinational, randomized, double-blind study of BARACLUDE in 286

(of 293 randomized) HBeAg-positive patients with lamivudine-refractory chronic hepatitis B

infection. Patients receiving lamivudine at study entry either switched to BARACLUDE 1 mg

once daily (with neither a washout nor an overlap period) or continued on lamivudine 100 mg for

a minimum of 52 weeks. The mean age of patients was 39 years, 76% were male, 37% were

Asian, 62% were Caucasian, and 52% had previously received interferon-α. The mean duration

of prior lamivudine therapy was 2.7 years, and 85% had lamivudine resistance mutations at

baseline by an investigational line probe assay. At baseline, patients had a mean Knodell

Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS

Amplicor PCR assay was 9.36 log

copies/mL, and mean serum ALT level was 128 U/L. Paired,

adequate liver biopsy samples were available for 87% of patients.

BARACLUDE was superior to lamivudine on a primary endpoint of Histologic Improvement

(using the Knodell Score at Week 48). These results and change in Ishak Fibrosis Score are

shown in Table 12. Table 13 shows selected virologic, biochemical, and serologic endpoints.

Table12: Histologic Improvement and Change in Ishak Fibrosis Score, and Composite

Endpoint at Week 48, Lamivudine-Refractory Patients in Study AI463026

Study AI463026 (HBeAg-Negative)

BARACLUDE

1 mg

n = 124

Lamivudine

100 mg

n = 116

Difference BARACLUDE

Lamivudine

(97.5% CI)

Histologic Improvement (Knodell Scores)

Improvement

55%

28%

27.3%

(13.6%, 40.9%)

p < 0.0001

No improvement

34%

57%

Ishak Fibrosis Score

Improvement

34%

16%

17.5%

(6.8%, 28.2%)

p < 0.01

No change

44%

42%

Worsening

11%

26%

Inadequate Week 48

biopsy

Missing Week 48 biopsy

10%

15%

Patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2).

≥ 2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell

Fibrosis Score.

In this analysis, missing or inadequate biopsies at Week 48 were classified “no improvement.”

For Ishak Fibrosis Score, improvement = ≥1-point decrease from baseline and worsening = ≥ 1-point

increase from baseline.

95% confidence interval.

Table 13: Selected Virologic, Biochemical, and Serologic Endpoints at Week 48,

Lamivudine-Refractory Patients in Study AI463026

Study AI463026

BARACLUDE

1 mg

n = 141

Lamivudine

100 mg

n = 145

Difference BARACLUDE

Lamivudine

(95% CI)

ALT normalization (

≤ 1.0 X

ULN)

61% 15 %

45.8 %

(35.9 %, 55.8 %)

p < 0.0001

HBV DNA

Mean change from baseline

by PCR

(log

copies/mL)

-5.1 -0.48

-4.4

(-4.8, -4.0)

Proportion undetectable

(< 300 copies/mL by PCR

)

19% 1%

17.8%

(11.0, 24.5)

p < 0.0001

<0.7 MEq/mL by bDNA

66% 6%

60.4%

(51.8%, 69.1%)

p < 0.0001

Loss of HBeAg

10%

HBeAg

seroconversion

8% 3%

Roche COBAS Amplicor PCR assay.

At Week 24, HBV DNA <300copies/mL by PCR was observed in 7% of BARACLUDE-treated patients and no

lamivudine-treated patients (p=0.0011) in Study AI463026

Quantiplex bDNA assay.

Histologic improvement was independent of baseline levels of HBV DNA or ALT.

Outcomes Beyond 48 Weeks

The optimal duration of therapy with BARACLUDE is unknown. According to protocol-

mandated criteria in the Phase 3 clinical trials, patients discontinued BARACLUDE or

lamivudine treatment after 52 weeks according to a definition of response based on HBV

virologic suppression (<0.7 MEq/mL by bDNA assay) and loss of HBeAg (in HBeAg-positive

patients) or ALT <1.25 X ULN (in HBeAg-negative patients) at Week 48. Patients who achieved

virologic suppression but did not have a serologic response (HBeAg-positive) or did not achieve

ALT <1.25 X ULN (HBeAg-negative) continued blinded dosing through 96 weeks or until

response was achieved. These protocol-specified patient management guidelines are not intended

as guidance for clinical practice.

Nucleoside-naive, outcomes beyond 48 weeks: Cumulative confirmed outcomes through Week 96

for all treated patients in studies of nucleoside-naive patients are shown in Table 14.

Table 14: Outcomes Through 96 Weeks, Nucleoside-Naïve Patients in Studies AI463022

and AI463027 (All Treated)

Study AI463022

(HBeAg-Positive)

Study AI463027

(HBeAg-Negative)

BARACLUDE

0.5 mg

n=354

Lamivudine

100 mg

n=355

BARACLUDE

0.5 mg

N=325

Lamivudine

100 mg

n=313

HBV DNA

Proportion undetectable

(< 300 copies/mL)

80%*

39%

94%*

77%

ALT normalization

(≤ 1xULN)

87%*

79%

89%

84%

HBeAg seroconversion

31%

26%

HBeAg loss

<1%

a Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).

b through the last observation on or off treatment.

* p<0.01

Among nucleoside-naive HBeAg-positive patients, 243 BARACLUDE-treated and 164

lamivudine-treated patients continued blinded treatment into year 2 (median duration of therapy

was 96 weeks). The proportion of patients with HBV DNA <300 copies/mL by PCR increased

from 64% at Week 48 to 81% at Week 96/EOD [End of Dosing (last observation carried forward)

for patients who discontinued between Weeks 48 and 96] for BARACLUDE-treated patients and

remained stable for lamivudine-treated patients (40% at Week 48 and 39% at Week 96/EOD).

For BARACLUDE-treated patients, ALT normalization (≤1 X ULN) occurred in 66% at Week

48 and 79% at Week 96/EOD. The percentage of lamivudine-treated patients with ALT

normalization was 71% at Week 48 and 68% at Week 96/EOD.

Among nucleoside-naive HBeAg-negative patients, 26 patients continued BARACLUDE

treatment and 28 patients continued lamivudine treatment into year 2 (median duration of therapy

was 96 weeks). The proportion of patients with HBV DNA <300 copies/mL remained stable in

both treatment groups (BARACLUDE 100% at Week 48 and 96% at Week 96/EOD; lamivudine

64% at both Week 48 and Week 96/EOD). No patient in either treatment group had ALT

normalization at Week 48, while 27% of BARACLUDE-treated patients and 21% of lamivudine-

treated patients achieved ALT normalization at Week 96/EOD.

Liver biopsy results: Of the 679 BARACLUDE-treated patients in the two nucleoside-naïve

studies, 293 (43%) eligible patients enrolled in a long-term rollover study and continued

BARACLUDE therapy. Patients in the rollover study received BARACLUDE 1 mg once daily.

Sixty-nine of the 293 patients elected to have a repeat liver biopsy after a total treatment duration

of more than 144 weeks (3 years). Fifty-seven patients had both an evaluable baseline and long-

term biopsy, with a median duration of BARACLUDE therapy of 280 weeks (approximately 6

years). Ninety-six percent of these patients had Histologic Improvement as previously defined

(see Table 10, footnote c) and 88% had a ≥ 1-point decrease in Ishak fibrosis score. Of the 43

patients with a baseline Ishak fibrosis score of ≥ 2, 58% had a ≥ 2-point decrease. At the time of

the long-term biopsy, 57 (100%) of patients had HBV DNA < 300 copies/mL and 49 (86%) had

serum ALT ≤ 1 X ULN.

Lamivudine-refractory, outcomes beyond 48 weeks: Cumulative confirmed outcomes through

Week 96 for all treated lamivudine-refractory patients are shown in Table 15.

Table 15: Outcomes Through 96 Weeks, Lamivudine Refractory Patients in Study

AI463026 (All Treated)

BARACLUDE

1 mg

n= 141

LAMIVUDINE

100 mg

n=145

HBV DNA

Proportion undetectable (<300 copies/mL)

30%*

<1%

ALT normalization (≤ 1 x ULN)

85%*

29%

HBeAg seroconversion

17%*

a Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).

b through the last observation on or off treatment.

*p<0.01

Among lamivudine-refractory patients in Study AI463026, 77 BARACLUDE-treated patients

continued dosing into year 2 (median duration of therapy was 96 weeks). The proportion of

patients with HBV DNA <300 copies/mL increased from 21% at Week 48 to 40% at Week

96/EOD. The proportion of patients with ALT normalization increased from 65% at Week 48 to

81% at Week 96/EOD.

Post-Treatment Follow-up

For the 31% of nucleoside-naive, HBeAg-positive BARACLUDE-treated patients who met

response criteria (virologic suppression by bDNA assay and loss of HBeAg) and discontinued

therapy, response was sustained throughout the 24-week post-treatment follow-up period in 75%.

For the 88% of nucleoside-naive, HBeAg-negative BARACLUDE-treated patients who met

response criteria (virologic suppression by bDNA assay and ALT <1.25 X ULN), response was

sustained throughout the 24-week post-treatment follow-up period in 46%. Of the 22 (16%)

lamivudine-refractory patients who met response criteria (virologic response on bDNA assay and

loss of HBeAg) while receiving BARACLUDE, response was sustained throughout the 24-week

post-treatment follow-up period in 11 (50%).

Data from Long-term Observational Study

Study AI463080 was a randomized, global, observational, open-label Phase 4 study to assess

long-term risks and benefits of BARACLUDE (0.5 mg/day or 1 mg/day) treatment as compared

to other standard of care hepatitis B virus nucleos(t)ide analogues in subjects with chronic HBV

(CHB) infection.

A total of 12,378 patients were treated with Baraclude (n=6,216) or other HBV nucleos(t)ide

(non-entecavir (ETV) (n=6,162). The patients were evaluated at baseline and subsequently every

6 months for up to 10 years. The principal clinical outcome events assessed during the study were

overall malignant neoplasms, liver-related HBV disease progression, non-HCC malignant

neoplasms, HCC, and deaths. The study showed that Baraclude was not significantly associated

with an increased risk of malignant neoplasms compared to other standard of care HBV

nucleos(t)ides, as assessed by either the composite endpoint of overall malignant neoplasms or

the individual endpoint of non-HCC malignant neoplasm. The most commonly reported

malignancy was HCC followed by gastrointestinal malignancies in both the Baraclude and non-

ETV groups. The data also showed that long-term Baraclude use was not associated with a lower

occurrence of HBV disease progression or a lower rate of death overall compared to other HBV

nucleo(t)ides. The principal clinical outcome event assessments are shown in Table 16:

Table 16: Principal Analyses of Time to Adjudicated Events - Randomized Treated

Subjects

Number of Subjects with

Events

Endpoint

ETV

N=6,216

Non-ETV

N=6,162

Hazard Ratio

[ETV:Non-ETV] (CI)

P-value

Primary Endpoints

Overall malignant neoplasm 331 337 0.93 (0.800, 1.084) 0.3553

Liver-related HBV disease progression

350

375

0.89 (0.769, 1.030)

0.1182

Death

238

264

0.85 (0.713, 1.012)

0.0676

Secondary Endpoints

Non-HCC malignant neoplasm

1.10 (0.817, 1.478)

HCC

240

263 0.87 (0.727, 1.032)

Overall malignant neoplasm is a composite event of HCC or non-HCC malignant neoplasm. Liver-related HBV

disease progression is a composite event of liver-related death, HCC, or non-HCC HBV disease progression.

95.03% CI for overall malignant neoplasm, death, and liver-related HBV disease progression; 95% CI for non-

HCC malignant neoplasm, HCC, liver-related death, and non-HCC HBV disease progression.

P-values are provided to the COEs that are primary endpoints per protocol specification

One subject had a pre-treatment HCC event and was excluded from the analysis.

CI = confidence interval; N = total number of subjects.

Limitations of the study included population changes over the long-term follow-up period and

more frequent post-randomization treatment changes in the non-ETV group. In addition, the

study was underpowered to demonstrate a difference in the non-HCC malignancy rate because of

the lower than expected background rate.

Special Populations

Patients Co-Infected with HIV and HBV

Study AI463038 was a randomized, double-blind, placebo-controlled study of BARACLUDE

versus placebo in 68 patients co-infected with HIV and HBV who experienced recurrence of

HBV viremia while receiving a lamivudine-containing highly active antiretroviral (HAART)

regimen. Patients continued their lamivudine-containing HAART regimen (lamivudine dose 300

mg/day) and were assigned to add either BARACLUDE 1 mg once daily (51 patients) or placebo

(17 patients) for 24 weeks followed by an open-label phase for an additional 24 weeks where all

patients received BARACLUDE. At baseline, patients had a mean serum HBV DNA level by

PCR of 9.13 log

copies/mL. Ninety-nine percent of patients were HBeAg-positive at

baseline, with a mean baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable at

approximately 2 log

copies/mL through 24 weeks of blinded therapy. Virologic and

biochemical endpoints at Week 24 are shown in Table16. There are no data in patients with

HIV/HBV co-infection who have not received prior lamivudine therapy. BARACLUDE has not

been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving

effective HIV treatment. (See WARNINGS AND PRECAUTIONS – Special Populations:

Patients Co-infected with HIV and HBV).

Table 17: Virologic and Biochemical Endpoints at Week 24, Study AI463038

BARACLUDE 1 mg

n = 51

Placebo

n = 17

HBV DNA

Proportion undetectable (< 300 copies/mL)

Mean change from baseline (log

copies/mL)

(-3.65*)

(+0.11)

ALT normalization (≤ 1 x ULN)

(34%)

(8%)

All patients also received a lamivudine-containing HAART regimen

Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL)

Percentage of patients with abnormal ALT (> 1 x ULN) at baseline who achieved ALT normalization (n=35 for

BARACLUDE and n=12 for placebo)

* p < 0.0001

For patients originally assigned to BARACLUDE, at the end of the open-label phase (Week 48),

8% of patients had HBV DNA < 300 copies/mL by PCR, the mean change from baseline HBV

DNA by PCR was -4.20 log10 copies/mL, and 37% of patients with abnormal ALT at baseline

had ALT normalization (≤ 1% ULN).

DETAILED PHARMACOLOGY

Mechanism of Action

Entecavir is a guanosine nucleoside analogue that is efficiently phosphorylated to the active

triphosphate form and exhibits selective activity against HBV polymerase. Entecavir triphosphate

competes with the natural substrate deoxyguanosine triphosphate, and inhibits all three functional

activities of the HBV polymerase (reverse transcriptase, rt): (1) base priming, (2) reverse

transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of

the positive strand of HBV DNA. Entecavir triphosphate has an inhibition constant (Ki) for HBV

DNA polymerase of 0.0012 μM and is a weak inhibitor of cellular DNA polymerases α, ß, and δ

and mitochondrial DNA polymerase γ with Ki values ranging from 18 to >160 μM.

Antiviral Activity

Entecavir inhibited HBV DNA synthesis (50% reduction, EC

) at a concentration of 0.004 µM

in human HepG2 cells transfected with wild-type HBV. The median EC

value for entecavir

against lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 µM (range 0.010-0.059 µM).

A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and

clinical HIV-1 isolates using a variety of cells and assay conditions yielded EC

values ranging

from 0.026 to >10 µM: the lower EC

values were observed when decreased levels of virus were

used in the assay. In cell culture, entecavir selected for an M184I substitution in HIV reverse

transcriptase at micromolar concentrations, confirming inhibitory pressure at high entecavir

concentrations. HIV variants containing the M184I substitution showed loss of susceptibility to

entecavir.

Daily or weekly entecavir treatment significantly reduced viral DNA levels (4 to 8 log10) in two

relevant animal models, woodchucks chronically infected with woodchuck hepatitis virus (WHV)

and ducks infected with duck HBV. Long-term studies in woodchucks demonstrated that oral

weekly dosing of 0.5 mg/kg entecavir (similar exposure to the 1 mg human dose) maintained

viral DNA levels at undetectable levels (<200 copies/mL by PCR) for up to 3 years in 3 of 5

woodchucks. No entecavir resistance changes were detected in the HBV polymerase in any of the

treated animals for up to 3 years of treatment.

TOXICOLOGY

Acute Toxicity (Table 1)

Single-dose oral toxicity studies with entecavir were conducted in mice and rats at doses ranging

from 40 to 5000 mg/kg. In mice, no drug-related changes were noted at 40 mg/kg. Body-weight

losses were noted at ≥ 200 mg/kg. At ≥1000 mg/kg, signs of overt toxicity and deaths were

observed. In rats, no drug-related changes were observed at doses of 40 or 200 mg/kg. Deaths

occurred at ≥ 1000 mg/kg.

Repeat-Dose Toxicity (Table 2)

Repeat-dose studies utilizing once daily oral dosing were conducted in mice, rats, dogs, and

monkeys. Pivotal studies included two 6-month oral studies each in mice and rats to assess

chronic toxicity and to aid in the selection of doses for oral carcinogenicity studies; two 3-month

studies in dogs to assess toxicity and reversibility of drug-related changes, and a 1-year toxicity

study in monkeys that included a 3-month interim evaluation.

In dogs, species-specific, reversible CNS inflammation was observed at doses that achieved ≥ 51

times the exposure to entecavir in humans at 1 mg. The species-specificity, reversibility, and

high exposure multiples at which the CNS inflammation was observed suggest that this finding is

not relevant to human safety. Other target organs in repeat-dose studies in animals were the

kidneys, liver, lungs, skeletal muscle and testis; the changes in these organs were considered

unlikely to be relevant to human safety because they were either species-specific, associated with

high exposure multiples relative to humans, and/or, in clinical trials with entecavir, they were not

target tissues. With regard to target-organ toxicity in general, the results of a 1-year study in

monkeys were most compelling because no target organ toxicity was evident at ≥ 136 times the

exposure to entecavir in humans at 1 mg.

Reproductive Toxicology (Table 3)

Reproductive toxicology studies were conducted with entecavir to assess potential effects on

embryonic and fetal development in rats and rabbits and on growth, development, and

reproductive performance of progeny in rats.

In rats and rabbits, no embryotoxicity or maternal toxicity was observed at 28 and 212 times,

respectively, the exposure to entecavir at 1 mg in humans. In rats, maternal toxicity, embryo-fetal

toxicity (resorptions), and associated decreases in live-litter size occurred at 180 times the

exposure in humans at 1 mg. Additional findings in rat fetuses at 3100 times the exposure in

humans at 1 mg included lower body weights, tail and vertebral malformations, reduced

ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs. In

rabbits, embryo-fetal toxicity (resorptions), reduced ossification (hyoid), and an increased

incidence of 13th rib were observed at 883 times the exposure in humans at 1 mg. In a peri-

postnatal study in rats, no adverse effects on offspring were seen at > 94 times the exposure in

humans at 1 mg.

Carcinogenesis, Mutagenesis, Impairment of Fertility (Tables 4 & 5)

Long-term oral carcinogenicity studies of entecavir in mice and rats were carried out at exposures

up to approximately 42 times (mice) and 35 times (rats) those observed in humans at 1 mg.

MICE: Lung adenomas were increased in males and females at exposures 3 and 40 times those

in humans at 1 mg, respectively. Lung carcinomas in both male and female mice were increased

at exposures approximately 40 times those in humans at 1 mg. Lung tumor development was

preceded by pneumocyte proliferation in the lung, which was not observed in rats, dogs, or

monkeys administered entecavir, indicating that a key event in lung tumor development observed

in mice likely was species specific. At the highest dose level tested (equivalent to approximately

40 times the exposure in humans at 1 mg) hepatocellular carcinomas and the combined incidence

of adenomas and carcinomas in male mice and vascular tumors (hemangiomas of ovaries and

uterus and hemangiomas/hemangiosarcomas of spleen) in female mice were significantly

increased.

The NOEL for neoplasia was 0.004 mg/kg/day for males (equivalent to 1-times the exposure in

humans at 1 mg), based on pulmonary adenomas; for all other tumors in male and female mice

the NOEL was 0.4 mg/kg (equivalent to 14 and 11 times the exposure in humans at 1 mg for

male and female mice, respectively). At tumorigenic doses, systemic exposures were 3-times

(pulmonary tumors in male mice) and approximately 40-times (all other tumors) that in humans

at 1 mg daily.

RATS: In female rats, hepatocellular adenomas and the combined incidence of adenomas and

carcinomas were significantly increased at the highest dose level, equivalent to 24-times the

exposure in humans at 1 mg. Brain microglial tumors were significantly increased in both male

and female rats at the highest dose, equivalent to 35 and 24 times exposure in humans at 1 mg

respectively. Skin fibromas in female rats were significantly increased at the 0.4 (high) and 2.6

mg/kg/day (highest) doses, equivalent to 4 and 24 times exposure in humans at 1 mg respectively.

The NOEL for neoplasia was 0.2 mg/kg/day for males (equivalent to 5 times the exposure in

humans at 1 mg) and for females 0.06 mg/kg/day based on skin fibromas (equivalent to < 1 times

the exposure in humans at 1 mg) or 0.4 mg/kg/day (all other tumors, equivalent to 4 times the

exposure in humans at 1 mg). At tumorigenic doses, systemic exposures were 35 and 4/24 times

that in humans at 1 mg in male and female rats, respectively.