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

Posology

Compensated liver disease
Nucleoside naïve patients: the recommended dose 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 of lamivudine resistance [LVDr] mutations) (see sections 4.4 and 5.1): the
recommended dose is 1 mg once daily, which must be taken on an empty stomach
(more than 2 hours before or more than 2 hours after a meal) (see section 5.2).
Decompensated liver disease
The recommended dose for patients with decompensated liver disease is 1 mg once
daily, which must be taken on an empty stomach (more than 2 hours before or 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 as follows:
• In HBeAg positive patients, treatment should be administered at least until HBe
seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection on two
consecutive serum samples at least 3-6 months apart) or until HBs seroconversion or
there is loss of efficacy (see section 4.4).
• In HBeAg negative patients, treatment should be administered at least until HBs
seroconversion or there is evidence of loss of efficacy. With prolonged treatment for
more than 2 years, regular reassessment is recommended to confirm that continuing the
selected therapy remains appropriate for the patient.
In patients with decompensated liver disease or cirrhosis, treatment cessation is not
recommended.

Paediatric population
For appropriate dosing in the paediatric population, Hepavir oral solution or Hepavir
0.5 mg film-coated tablets are available.
The decision to treat paediatric patients should be based on careful consideration of
individual patient needs and with reference to current paediatric treatment guidelines

including the value of baseline histological information. The benefits of long-term
virologic suppression with continued therapy must be weighed against the risk of
prolonged treatment, including the emergence of resistant hepatitis B virus.
Serum ALT should be persistently elevated for at least 6 months prior to treatment of
paediatric patients with compensated liver disease due to HBeAg positive chronic
hepatitis B; and for at least 12 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 one 0.5 mg tablet or 10 ml (0.5 mg) of the oral solution, with or without food.
The oral solution should be used 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
practice guidelines, treatment discontinuation may be considered as follows:
▪ In HBeAg positive paediatric patients, treatment should be administered for at least 12
months after achieving undetectable HBV DNA and HBeAg seroconversion (HBeAg
loss and anti-HBe detection on two consecutive serum samples at least 3-6 months
apart) or until HBs seroconversion or there is loss of efficacy. Serum ALT and HBV
DNA levels should be followed regularly after treatment discontinuation (see section
4.4).
▪ In HBeAg negative paediatric patients, treatment should be administered until HBs
seroconversion 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 the patient'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 (see section 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 reduction of the daily dose using entecavir
oral solution, as detailed in the table, is recommended. As an alternative, in case the oral
solution is not available, the dose can be adjusted by increasing the dosage interval, also
shown in the table. The proposed dose modifications are based on extrapolation of
limited data, and their safety and effectiveness have not been clinically evaluated.
Therefore, virological response should be closely monitored.

* for doses < 0.5 mg Hepavir oral solution is recommended.
** on haemodialysis days, administer entecavir after haemodialysis.
Hepatic impairment: no dose adjustment is required in patients with hepatic
impairment.
Paediatric population: the safety and efficacy of Hepavir in children below 18 years of
age have not yet been established. No data are available.
Method of administration
Hepavir should be taken orally.

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 conditions:

common: fatigue

.Exacerbations after discontinuation of treatment: acute exacerbations of hepatitis have
been reported in patients who have discontinued anti-hepatitis B virus therapy,
including therapy with entecavir (see section 4.4). In studies in nucleoside-naive
patients, 6% of entecavir-treated patients and 10% of lamivudine-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. Among
entecavir-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 in lamivudine-refractory patients, with only limited numbers of
patients being followed up, 11% of entecavir-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 flares could be higher.
d. Paediatric Population
The safety of entecavir in paediatric patients from 2 to < 18 years of age is based on two
clinical trials in 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 adverse reactions observed in paediatric subjects who
received treatment with entecavir were consistent with those observed in clinical trials
of entecavir in adults (see a. Summary of the safety profile and section 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 patients with decompensated liver disease was assessed in a randomized open-label
comparative study in which 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 adverse reactions, one additional adverse
reaction [decrease in blood bicarbonate (2%)] was observed in entecavir-treated patients
through week 48. The on-study cumulative death rate was 23% (23/102), and causes of
death were generally liver-related, as expected in this population. The on-study
cumulative rate of hepatocellular carcinoma (HCC) was 12% (12/102). Serious adverse
events were generally liver-related, with an on-study cumulative frequency of 69%.
Patients with high baseline CTP score were at higher risk of developing serious adverse
events (see section 4.4).
Laboratory test abnormalities: through week 48 among entecavir-treated patients with
decompensated liver disease, none had ALT elevations both > 10 times ULN and > 2
times baseline, and 1% of patients had ALT elevations > 2 times baseline together with
total bilirubin > 2 times ULN and > 2 times baseline. Albumin levels < 2.5 g/dl
occurred in 30% of patients, lipase levels > 3 times baseline in 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 antiretroviral therapy) 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 authorization of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via:

.

Pharmacotherapeutic group: antivirals for systemic use, nucleoside and nucleotide reverse
transcriptase inhibitors
ATC code: J05AF10
Mechanism of action: entecavir, a guanosine nucleoside analogue with activity against
HBV polymerase, is efficiently phosphorylated to the active triphosphate (TP) form,
which has an intracellular 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 HBV polymerase, (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 DNA polymerase is 0.0012 μM. Entecavir-TP
is a weak inhibitor of cellular DNA polymerases α, β, and δ with Ki values of 18 to 40 μM.
In addition, high exposures of entecavir had no relevant adverse effects on γ polymerase
or mitochondrial DNA synthesis in HepG2 cells (Ki > 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 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 remained fully susceptible to entecavir.
An 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
at micromolar concentrations, confirming inhibitory pressure at high entecavir
concentrations. HIV variants containing the M184V substitution showed loss of
susceptibility to entecavir (see section 4.4).
In HBV combination assays in cell culture, 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 at micromolar concentrations was not antagonistic to the 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
and rtL180M substitutions within the reverse transcriptase exhibit 8-fold decreased
susceptibility to entecavir. Incorporation of additional ETVr amino acid changes rtT184,
rtS202 or rtM250 decreases entecavir 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- to 741-fold relative to wild-type virus.
The ETVr substitutions at residues rtT184, rtS202 and rtM250 alone have only a modest
effect on entecavir susceptibility, and have not been observed in the absence of LVDr
substitutions in more than 1000 patient samples sequenced. Resistance is mediated by
reduced inhibitor binding to the altered HBV reverse transcriptase, and resistant HBV
exhibits reduced replication 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 adults with chronic hepatitis B infection, evidence of viral
replication and compensated liver disease. The safety 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 Knodell fibrosis score. Responses for patients with baseline Knodell
Fibrosis Scores of 4 (cirrhosis) were comparable to overall responses on all efficacy
outcome measures (all patients had compensated liver disease). High baseline Knodell
necroinflammatory scores (> 10) were associated with greater histological improvement in
nucleoside-naive patients. Baseline ALT levels ≥ 2 times ULN and baseline 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
of baseline characteristics, the majority of patients showed histological and virological
responses to treatment.

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.

Experience in lamivudine-refractory patients with compensated liver disease:
In a randomised, double-blind study in HBeAg positive lamivudine-refractory patients
(026), with 85% of patients presenting LVDr mutations at baseline, patients receiving
lamivudine at study entry either 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 the table.

Results beyond 48 weeks of treatment:
Treatment was discontinued when prespecified response criteria were met either at 48
weeks or during the 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 continued blinded 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 in cumulative response rates of 80% for HBV DNA < 300 copies/ml by PCR,
87% for ALT normalisation, 31% for HBeAg seroconversion and 2% for HBsAg
seroconversion (5% for HBsAg loss). For lamivudine (n = 355), cumulative response rates
were 39% for HBV DNA < 300 copies/ml by PCR, 79% for ALT normalisation, 26% for
HBeAg seroconversion, and 2% for HBsAg seroconversion (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 cumulative response rates of 94% for HBV DNA < 300 copies/ml by PCR and 89% for
ALT normalisation versus 77% for HBV DNA < 300 copies/ml by PCR and 84% for ALT
normalisation for lamivudine-treated patients (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 lamivudinetreated
patients had HBV DNA < 300 copies/ml by PCR at end of dosing. ALT
normalisation ( 1 times ULN) occurred in 27% of entecavir-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) for lamivudine responders in study 022 and 46% (131/286) of entecavir
responders vs 31% (79/253) for lamivudine responders in study 027. By 48 weeks of posttreatment
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) and 027 (HBeAg negative) who enrolled in a long-term rollover study were
evaluated for long-term liver histology outcomes. The entecavir dosage was 0.5 mg daily
in the pivotal studies (mean exposure 85 weeks) and 1 mg daily in the rollover study
(mean exposure 177 weeks), and 51 patients in the rollover 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 (Ishak fibrosis score of 4, 5 or 6) had a 1 point decrease (median decrease from
baseline was 1.5 points). At the time of the long-term biopsy, all patients had HBV DNA
< 300 copies/ml and 49/57 (86%) had serum 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 in cumulative response rates of 30% for HBV DNA < 300 copies/ml by PCR,
85% for ALT normalisation and 17% for HBeAg seroconversion.
For the 77 patients who continued entecavir treatment beyond 52 weeks (median 96
weeks), 40% of patients had HBV DNA < 300 copies/ml by PCR and 81% had ALT
normalisation (≤ 1 times ULN) at end of dosing.
Age/gender:

There was no apparent difference in efficacy for entecavir based on gender (≈ 25%
women in the clinical 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 of entecavir 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 principal clinical 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-HCC malignant neoplasms, HCC, and deaths,
including liver related deaths. In this study, ETV was not associated with an increased risk
of malignant neoplasms compared to use of non-ETV, as assessed by either 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 malignancy in both ETV and non-ETV groups was HCC followed by
gastrointestinal malignancies.

Special populations
Patients with decompensated liver disease: in study 048, 191 patients with HBeAg
positive or negative chronic HBV infection and evidence of hepatic decompensation,
defined as a CTP score of 7 or higher, received entecavir 1 mg once daily or adefovir
dipivoxil 10 mg once daily. Patients were either 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% of patients were
CTP class C. The mean baseline Model for End Stage Liver Disease (MELD) score was
16.23. 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 from baseline in serum HBV DNA by PCR at week 24.
Results for selected study endpoints at weeks 24 and 48 are shown in the table.

The time to onset of HCC or death (whichever occurred first) was comparable in the two
treatment groups; on-study cumulative death rates were 23% (23/102) and 33% (29/89)
for patients treated with entecavir 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 and 17% for adefovir at week 48.
HIV/HBV co-infected patients receiving concomitant HAART: study 038 included 67
HBeAg positive and 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 baseline entecavir-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). Patients continued 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 received
entecavir. At 24 weeks the reduction in HBV viral load was significantly greater with
entecavir (-3.65 vs an increase of 0.11 log10 copies/ml). For patients originally assigned to
entecavir treatment, the reduction in HBV DNA at 48 weeks was -4.20 log10 copies/ml,
ALT normalisation had occurred in 37% 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 implications for the selection of HAART 

regimens that the patient may take in the future. Therefore, entecavir should not be used in
this setting due to the potential for development of HIV resistance (see section 4.4).
Liver transplant recipients: the safety and efficacy of entecavir 1 mg once daily were
assessed in a single-arm study in 65 patients who received a liver transplant for
complications of chronic HBV infection 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 HBeAgnegative
disease at the time of transplant. Of the 61 patients who were evaluable for
efficacy (received entecavir for at least 1 month), 60 also received hepatitis B immune
globulin (HBIg) as part of the post-transplant prophylaxis regimen. Of these 60 patients,
49 received more than 6 months of HBIg therapy. At Week 72 post-transplant, none of 55
observed cases had virologic recurrence of HBV [defined as HBV DNA ≥50 IU/ml
(approximately 300 copies/ml)], and there was no reported virologic recurrence at time of
censoring for the remaining 6 patients. All 61 patients had HBsAg loss posttransplantation,
and 2 of these later became HBsAg positive despite maintaining
undetectable HBV DNA (<6 IU/ml). The frequency and nature of adverse events in this
study were consistent with those expected in patients who have received a liver transplant
and the known safety profile of entecavir.

Paediatric population: Study 189 is a study of the efficacy and safety of entecavir among
180 nucleoside-treatment-naïve children and adolescents from 2 to < 18 years of age with
HBeAg-positive chronic 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 2 treatment
arms and across age cohorts. At study entry, the mean HBV DNA was 8.1 log10 IU/ml and
mean ALT was 103 U/l across the study population. Results for the main efficacy
endpoints at Week 48 and Week 96 are presented in the table below.

a NC=F (noncompleter=failure)
* Patients randomized to placebo who did not have HBe- seroconversion by Week 48
rolled over to open-label entecavir for the 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
paediatric patients with HBeAg-positive chronic HBV infection in two clinical trials (028
and 189). The two trials provide resistance data in 183 patients treated and monitored in
Year 1 and 180 patients treated and monitored in Year 2. Genotypic evaluations were
performed for all patients with available samples who 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 of resistance
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 DNA measurement 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 virologic breakthrough (see table). These substitutions were observed only in
the presence of LVDr substitutions (rtM204V and rtL180M).

ETVr substitutions (in addition to LVDr substitutions rtM204V/I ± rtL180M) were
observed at baseline in isolates from 10/187 (5%) lamivudine-refractory patients treated
with entecavir and monitored for resistance, indicating that prior lamivudine treatment can
select these resistance substitutions 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). Emerging entecavir resistance in
lamivudine-refractory studies through Week 240 is summarized in the table.

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 genotypic entecavir resistance (cumulative probability 18.8% through 5
years of follow-up) than the overall study population (see table). Also, lamivudinerefractory
patients who achieved HBV DNA < 104 log10 copies/ml by PCR at Week 24
had a lower rate of resistance than those who did not (5-year cumulative probability
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 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.

Post-Liver transplant: entecavir exposure in HBV-infected liver transplant recipients on a
stable dose of cyclosporine A or tacrolimus (n = 9) was ≈ 2 times the exposure in healthy
subjects with normal renal 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 in exposure between male and female subjects.
Elderly: the effect of age on the pharmacokinetics of entecavir was evaluated comparing elderly subjects in the age range 65-83 years (mean age females 69 years, males 74 years)
with young subjects in the age range 20-40 years (mean age females 29 years, males 25
years). AUC was 29% higher in elderly than in young subjects, mainly due to differences
in renal function and weight. After adjusting for differences in creatinine clearance and
body weight, elderly subjects had a 12.5% higher AUC than young 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
influencing entecavir pharmacokinetics. However, conclusions can only be drawn for the
Caucasian and Asian groups as there were too few subjects in the other categories.
Paediatric population: the steady-state pharmacokinetics of entecavir were evaluated
(study 028) in 24 nucleoside naïve HBeAg-positive paediatric subjects from 2 to < 18
years of age with compensated liver disease. Entecavir exposure among nucleoside naïve
subjects receiving once daily doses of entecavir 0.015 mg/kg up to a maximum dose of 0.5
mg was similar to the exposure achieved in adults receiving once daily doses of 0.5 mg.
The Cmax, AUC(0-24), and Cmin for these subjects was 6.31 ng/ml, 18.33 ng h/ml, and
0.28 ng/ml, respectively.

Not applicable.

No Special Disposal.