Hepavir is indicated for the treatment of chronic hepatitis B virus (HBV) infection (see
section 5.1) in adults with:
• Compensated liver disease and evidence of active viral replication, persistently
elevated serum alanine aminotransferase (ALT) levels and histological
evidence of active inflammation and/or fibrosis.
• Decompensated liver disease (see section 4.4).
For both compensated and decompensated liver disease, this indication is based on
clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg
negative HBV infection. With respect to patients with lamivudine-refractory hepatitis
B, see sections 4.4 and 5.1.
Hepavir is also indicated for the treatment of chronic HBV infection in nucleoside 

naive paediatric patients from 2 to < 18 years of age with compensated liver disease
who have evidence of active viral replication and persistently elevated serum ALT
levels, or histological evidence of moderate to severe inflammation and/or fibrosis.
With respect to the decision to initiate treatment in paediatric patients, see sections 4.2,
4.4, and 5.1.

Renal impairment: dosage adjustment is recommended for patients with renal
impairment (see section 4.2). 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.

Exacerbations of hepatitis: spontaneous exacerbations in chronic hepatitis B are
relatively common and are characterised by transient increases in serum ALT. After
initiating antiviral therapy, serum ALT may increase in some patients as serum HBV
DNA levels decline (see section 4.8). Among entecavir-treated patients on-treatment
exacerbations had a median time of onset of 4-5 weeks. In patients with compensated
liver disease, these increases in serum ALT are generally not accompanied by an
increase in serum bilirubin concentrations or hepatic decompensation. Patients with
advanced liver disease or cirrhosis may be at a higher risk for hepatic decompensation
following hepatitis exacerbation, and therefore should be monitored closely during
therapy.
Acute exacerbation of hepatitis has also been reported in patients who have
discontinued hepatitis B therapy (see section 4.2). Post-treatment exacerbations are
usually associated with rising HBV DNA, and the majority appears to be self-limited.
However, severe exacerbations, including fatalities, have been reported.
Among entecavir-treated nucleoside naive patients, post-treatment exacerbations had a
median time to onset of 23-24 weeks, and most were reported in HBeAg negative
patients (see section 4.8). Hepatic function should be monitored at repeated intervals
with both clinical and laboratory follow-up for at least 6 months after discontinuation
of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be
warranted.
Patients with decompensated liver disease: a higher rate of serious hepatic adverse
events (regardless of causality) has been observed in patients with decompensated liver
disease, in particular in those with Child-Turcotte-Pugh (CTP) class C disease,
compared with rates in patients with compensated liver function. Also, patients with
decompensated liver disease may be at higher risk for lactic acidosis and for specific
renal adverse events such as hepatorenal syndrome. Therefore, clinical and laboratory
parameters should be closely monitored in this patient population (see also sections 4.8
and 5.1). 

Lactic acidosis and severe hepatomegaly with steatosis: occurrences of lactic acidosis
(in the absence of hypoxaemia), sometimes fatal, usually associated with severe
hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside
analogues. As entecavir is a nucleoside analogue, this risk cannot be excluded.
Treatment with nucleoside analogues should be discontinued when rapidly elevating
aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of
unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and
abdominal pain, might be indicative of lactic acidosis development. Severe cases,
sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic
steatosis, renal failure and higher levels of serum lactate. Caution should be exercised
when prescribing nucleoside analogues to any patient (particularly obese women) with
hepatomegaly, hepatitis or other known risk factors for liver disease. These patients

should be followed closely.
To differentiate between elevations in aminotransferases due to response to treatment
and increases potentially related to lactic acidosis, physicians should ensure that
changes in ALT are associated with improvements in other laboratory markers of
chronic hepatitis B.
Resistance and specific precaution for lamivudine-refractory patients: mutations in the
HBV polymerase that encode lamivudine-resistance substitutions may lead to the
subsequent emergence of secondary substitutions, including those associated with
entecavir associated resistance (ETVr). In a small percentage of lamivudine-refractory
patients, ETVr substitutions at residues rtT184, rtS202 or rtM250 were present at
baseline. Patients with lamivudine-resistant HBV are at higher risk of developing
subsequent entecavir resistance than patients without lamivudine resistance. The
cumulative probability of emerging genotypic entecavir resistance after 1, 2, 3, 4 and 5
years treatment in the lamivudine-refractory studies was 6%, 15%, 36%, 47% and
51%, respectively. Virological response should be frequently monitored in the
lamivudine-refractory population and appropriate resistance testing should be
performed. In patients with a suboptimal virological response after 24 weeks of
treatment with entecavir, a modification of treatment should be considered (see
sections 4.5 and 5.1). When starting therapy in patients with a documented history of
lamivudine-resistant HBV, combination use of entecavir plus a second antiviral agent
(which does not share cross-resistance with either lamivudine or entecavir) should be
considered in preference to entecavir monotherapy.

Pre-existing lamivudine-resistant HBV is associated with an increased risk for
subsequent entecavir resistance regardless of the degree of liver disease; in patients
with decompensated liver disease, virologic breakthrough may be associated with
serious clinical complications of the underlying liver disease. Therefore, in patients
with both decompensated liver disease and lamivudine-resistant HBV, combination use
of entecavir plus a second antiviral agent (which does not share cross-resistance with
either lamivudine or entecavir) should be considered in preference to entecavir
monotherapy.
Paediatric population: A lower rate of virologic response (HBV DNA < 50 IU/ml) was
observed in paediatric patients with baseline HBV DNA ≥ 8.0 log10 IU/ml (see section
5.1). Entecavir should be used in these patients only if the potential benefit justifies the
potential risk to the child (e.g. resistance). Since some paediatric patients may require
long-term or even lifetime management of chronic active hepatitis B, consideration
should be given to the impact of entecavir on future treatment options.
Liver transplant recipients: there are limited data on efficacy and safety of entecavir in
liver transplant recipients. Renal function should be carefully evaluated before and
during entecavir therapy in liver transplant recipients receiving cyclosporine or
tacrolimus (see section 5.2).

Co-infection with hepatitis C or D: there are no data on the efficacy of entecavir in
patients co-infected with hepatitis C or D virus.
Human immunodeficiency virus (HIV)/HBV co-infected patients not receiving
concomitant antiretroviral therapy: entecavir has not been evaluated in HIV/HBV coinfected
patients not concurrently receiving effective HIV treatment. Emergence of
HIV resistance has been observed when entecavir was used to treat chronic hepatitis B
infection in patients with HIV infection not receiving highly active antiretroviral
therapy (HAART) (see section 5.1). Therefore, therapy with entecavir should not be
used for HIV/HBV co-infected patients who are not receiving HAART. Entecavir has
not been studied as a treatment for HIV infection and is not recommended for this use.
HIV/HBV co-infected patients receiving concomitant antiretroviral therapy: entecavir
has been studied in 68 adults with HIV/HBV co-infection receiving a lamivudinecontaining
HAART regimen (see section 5.1). No data are available on the efficacy of
entecavir in HBeAg-negative patients co-infected with HIV. There are limited data on
patients co-infected with HIV who have low CD4 cell counts (< 200 cells/mm3).
General: patients should be advised that therapy with entecavir has not been proven to
reduce the risk of transmission of HBV and therefore appropriate precautions should
still be taken.
Tablets
Lactose: this medicinal product contains 241 mg of lactose in each 1 mg daily dose.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.

Since entecavir is predominantly eliminated by the kidney (see section 5.2),
coadministration with medicinal products that reduce renal function or compete for
active tubular secretion may increase serum concentrations of either medicinal product.
Apart from lamivudine, adefovir dipivoxil and tenofovir disoproxil fumarate, the
effects of coadministration of entecavir with medicinal products that are excreted
renally or affect renal function have not been evaluated. Patients should be monitored
closely for adverse reactions when entecavir is coadministered with such medicinal
products.
No pharmacokinetic interactions between entecavir and lamivudine, adefovir or
tenofovir were observed.

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

Women of childbearing potential: given that the potential risks to the developing foetus
are unknown, women of childbearing potential should use effective contraception.
Pregnancy: there are no adequate data from the use of entecavir in pregnant women.
Studies in animals have shown reproductive toxicity at high doses (see section 5.3).
The potential risk for humans is unknown. Hepavir should not be used during
pregnancy unless clearly necessary. There are no data on the effect of entecavir on
transmission of HBV from mother to newborn infant. Therefore, appropriate
interventions should be used to prevent neonatal acquisition of HBV.
Breastfeeding: it is unknown whether entecavir is excreted in human milk. Available
toxicological data in animals have shown excretion of entecavir in milk (for details see
section 5.3). A risk to the infants cannot be excluded. Breastfeeding should be
discontinued during treatment with Hepavir.
Fertility: toxicology studies in animals administered entecavir have shown no evidence
of impaired fertility (see section 5.3).

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

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

Assessment of adverse reactions is based on experience from postmarketing
surveillance and four clinical studies in which 1,720 patients with chronic hepatitis B
infection and compensated liver disease received double-blind treatment with entecavir
(n = 862) or lamivudine (n = 858) for up to 107 weeks (see section 5.1). In these
studies, the safety profiles, including laboratory abnormalities, were comparable for
entecavir 0.5 mg daily (679 nucleoside-naive HBeAg positive or negative patients
treated for a median of 53 weeks), entecavir 1 mg daily (183 lamivudine-refractory
patients treated for a median of 69 weeks), and lamivudine.
Adverse reactions considered at least possibly related to treatment with entecavir are
listed by body system organ class. Frequency is defined as very common (≥ 1/10);
common ( ≥1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare ( ≥1/10,000 to
< 1/1,000). Within each frequency grouping, undesirable effects are presented in order
of decreasing seriousness.

Cases of lactic acidosis have been reported, often in association with hepatic
decompensation, other serious medical conditions or drug exposures (see section 4.4).
Treatment beyond 48 weeks: continued treatment with entecavir for a median duration
of 96 weeks did not reveal any new safety signals.

c. Description of selected adverse reactions
Laboratory test abnormalities: In clinical studies with nucleoside-naive patients, 5%
had ALT elevations > 3 times baseline, and < 1% had ALT elevations > 2 times
baseline together with total bilirubin > 2 times upper limit of normal (ULN) and > 2
times baseline. Albumin levels < 2.5 g/dl occurred in < 1% of patients, amylase levels
> 3 times baseline in 2%, lipase levels > 3 times baseline in 11% and platelets <
50,000/mm3 in < 1%.
In clinical studies with lamivudine-refractory patients, 4% had ALT elevations > 3
times baseline, and < 1% had ALT elevations > 2 times baseline together with total
bilirubin > 2 times ULN and > 2 times baseline. Amylase levels > 3 times baseline
occurred in 2% of patients, lipase levels > 3 times baseline in 18% and platelets <
50,000/mm3 in < 1%.
Exacerbations during treatment: in studies with nucleoside naive patients, on treatment
ALT elevations > 10 times ULN and > 2 times baseline occurred in 2% of entecavir
treated patients vs 4% of lamivudine treated patients. In studies with lamivudinerefractory
patients, on treatment ALT elevations > 10 times ULN and > 2 times
baseline occurred in 2% of entecavir treated patients vs 11% of lamivudine treated
patients. Among entecavir-treated patients, on-treatment ALT elevations had a median
time to onset of 4-5 weeks, generally resolved with continued treatment, and, in a
majority of cases, were associated with a ≥ 2 log10/ml reduction in viral load that
preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function
is recommended during treatment.
Exacerbations after discontinuation of treatment: acute exacerbations of hepatitis have
been 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 lamivudinetreated
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 onstudy
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).

To report any side effect(s):
For Saudi Arabia:
The National Pharmacovigilance Centre (NPC):
SFDA Call Center: 19999.
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa
For UAE:
Pharmacovigilance & Medical Device section
P.O.Box: 1853
Tel: 80011111
Email: pv@mohap.gov.ae
Drug Department
Ministry of Health & Prevention,
Dubai
United Arab Emirates
For OMAN:
Department of Pharmacovigilance & Drug Information
Directorate General of Pharmaceutical Affairs & Drug Control
Ministry of Health, Sultanate of Oman
Phone Nos. 22357687 / 22357686
Fax: 22358489
Email: dg-padc@moh.gov.om
Website: www.moh.gov.om

There is limited experience of entecavir overdose reported in patients. Healthy subjects
who received up to 20 mg/day for up to 14 days, and single doses up to 40 mg had no
unexpected adverse reactions. If overdose occurs, the patient must be monitored for
evidence of toxicity and given standard supportive treatment as necessary.

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.

aNC=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.

Absorption: entecavir is rapidly absorbed with peak plasma concentrations occurring
between 0.5-1.5 hours. The absolute bioavailability has not been determined. Based on
urinary excretion of unchanged drug, the bioavailability has been estimated to be at least
70%. There is a dose-proportionate increase in Cmax and AUC values following multiple
doses ranging from 0.1-1 mg. Steady-state is achieved between 6-10 days after once daily
dosing with ≈ 2 times accumulation. Cmax and Cmin at steady-state are 4.2 and 0.3 ng/ml,
respectively, for a dose of 0.5 mg, and 8.2 and 0.5 ng/ml, respectively, for 1 mg.
Administration of 0.5 mg entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or
a light meal (379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1-1.5 hour fed
vs. 0.75 hour fasted), a decrease in Cmax of 44-46%, and a decrease in AUC of 18-20%.
The lower Cmax and AUC when taken with food is not considered to be of clinical
relevance in nucleoside-naive patients but could affect efficacy in lamivudine-refractory
patients (see section 4.2).
Distribution: the estimated volume of distribution for entecavir is in excess of total body
water. Protein binding to human serum protein in vitro is ≈ 13%.
Biotransformation: entecavir is not a substrate, inhibitor or inducer of the CYP450
enzyme system. Following administration of 14C-entecavir, no oxidative or acetylated
metabolites and minor amounts of the phase II metabolites, glucuronide and sulfate
conjugates, were observed.
Elimination: entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady-state of about 75% of the dose. Renal clearance is independent
of dose and ranges between 360-471 ml/min suggesting that entecavir undergoes both
glomerular filtration and net tubular secretion. After reaching peak levels, entecavir
plasma concentrations decreased in a bi-exponential manner with a terminal elimination
half-life of ≈ 128-149 hours. The observed drug accumulation index is ≈ 2 times with
once daily dosing, suggesting an effective accumulation half-life of about 24 hours.
Hepatic impairment: pharmacokinetic parameters in patients with moderate or severe
hepatic impairment were similar to those in patients with normal hepatic function.
Renal impairment: entecavir clearance decreases with decreasing creatinine clearance. A
4 hour period of haemodialysis removed ≈ 13% of the dose, and 0.3% was removed by
CAPD. The pharmacokinetics of entecavir following a single 1 mg dose in patients
(without chronic hepatitis B infection) are shown in the table below:

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.

In repeat-dose toxicology studies in dogs, reversible perivascular inflammation was
observed in the central nervous system, for which no-effect doses corresponded to
exposures 19 and 10 times those in humans (at 0.5 and 1 mg respectively). This finding
was not observed in repeat-dose studies in other species, including monkeys
administered entecavir daily for 1 year at exposures ≥ 100 times those in humans.
In reproductive toxicology studies in which animals were administered entecavir for up to 4 weeks, no evidence of impaired fertility was seen in male or female rats at high
exposures. Testicular changes (seminiferous tubular degeneration) were evident in
repeat-dose toxicology studies in rodents and dogs at exposures ≥ 26 times those in
humans. No testicular changes were evident in a 1-year study in monkeys.

In pregnant rats and rabbits administered entecavir, no effect levels for embryotoxicity
and maternal toxicity corresponded to exposures ≥ 21 times those in humans. In rats,
maternal toxicity, embryo-foetal toxicity (resorptions), lower foetal body weights, tail
and vertebral malformations, reduced ossification (vertebrae, sternebrae, and
phalanges), and extra lumbar vertebrae and ribs were observed at high exposures. In
rabbits, embryo-foetal toxicity (resorptions), reduced ossification (hyoid), and an
increased incidence of 13th rib were observed at high exposures. In a peri-postnatal
study in rats, no adverse effects on offspring were observed. In a separate study
wherein entecavir was administered to pregnant lactating rats at 10 mg/kg, both foetal
exposure to entecavir and secretion of entecavir into milk were demonstrated. In
juvenile rats administered entecavir from postnatal days 4 to 80, a moderately reduced
acoustic startle response was noted during the recovery period (postnatal days 110 to
114) but not during the dosing period at AUC values ≥ 92 times those in humans at the
0.5 mg dose or paediatric equivalent dose. Given the exposure margin, this finding is
considered of unlikely clinical significance.

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

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

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