Baraclude

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Baraclude 0.5 mg film-coated tablets 
Baraclude 1 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Baraclude 0.5 mg film-coated tablets 
Each tablet contains 0.5 mg entecavir (as monohydrate). 
 
Baraclude 1 mg film-coated tablets 
Each tablet contains 1 mg entecavir (as monohydrate). 
 
Excipients with known effect 
Each 0.5 mg film-coated tablet contains 120.5 mg lactose. 
Each 1 mg film-coated tablet contains 241 mg lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet) 
 
Baraclude 0.5 mg film-coated tablets 
White to off-white and triangular-shaped tablet with “BMS” debossed on one side and “1611” on the 
other. 
 
Baraclude 1 mg film-coated tablets 
Pink and triangular-shaped tablet with “BMS” debossed on one side and “1612” on the other. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Baraclude is indicated for the treatment of chronic hepatitis B virus (HBV) infection (see section 5.1) 
in adults with:  
 compensated liver disease and evidence of active viral replication, persistently elevated 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 4.2, 4.4 and 5.1. 
 
Baraclude 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. 
 



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4.2 Posology and method of administration 
 
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 in adults is 0.5 mg once daily, with or without food. 
 
Lamivudine-refractory patients (i.e. with evidence of viraemia while on lamivudine or the presence of 
lamivudine resistance [LVDr] mutations) (see sections 4.4 and 5.1): the recommended dose in adults is 
1 mg once daily, which must be taken on an empty stomach (more than 2 hours before and more than 
2 hours after a meal) (see section 5.2). In the presence of LVDr mutations, 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 (see section 4.4.). 
 
Decompensated liver disease 
 
The recommended dose for adult patients with decompensated liver disease is 1 mg once daily, which 
must be taken on an empty stomach (more than 2 hours before and more than 2 hours after a meal) 
(see section 5.2). For patients with lamivudine-refractory hepatitis B, see sections 4.4 and 5.1. 
 
Duration of therapy 
The optimal duration of treatment is unknown. Treatment discontinuation may be considered as 
follows: 
 In HBeAg positive adult patients, treatment should be administered at least until 12 months after 

achieving 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 adult 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, Baraclude oral solution or Baraclude 0.5 mg film-
coated tablets are available.  
 
The decision to treat paediatric patients should be based on careful consideration of individual 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. 
 



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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 Baraclude 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.  
 

 Baraclude dosage* 

Creatinine clearance 
(ml/min) 

 

Nucleoside naïve patients 
 
 

Lamivudine-refractory or 
decompensated liver disease 

 
≥ 50 0.5 mg once daily 1 mg once daily 

30 - 49 0.25 mg once daily* 
OR 

0.5 mg every 48 hours 

0.5 mg once daily 
 

10 - 29 0.15 mg once daily* 
OR 

0.5 mg every 72 hours 

0.3 mg once daily* 
OR 

0.5 mg every 48 hours 
< 10 

Haemodialysis or 
CAPD** 

0.05 mg once daily* 
OR 

0.5 mg every 5-7 days 

0.1 mg once daily* 
OR 

0.5 mg every 72 hours 
* for doses < 0.5 mg Baraclude oral solution is recommended. 
** on haemodialysis days, administer entecavir after haemodialysis. 
 
Hepatic impairment: no dose adjustment is required in patients with hepatic impairment. 
 
Method of administration 
 
Baraclude should be taken orally. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 



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4.4 Special warnings and precautions for use 
 
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 



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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: 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 co-infected 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 lamivudine-containing 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. 
 
Lactose: this medicinal product contains 120.5 mg of lactose in each 0.5 mg daily dose or 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. A lactose-free Baraclude oral solution is 
available for these individuals. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 



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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. 
 
Paediatric population 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
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. Baraclude 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. 
 
Breast-feeding: 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. Breast-feeding should be discontinued during treatment with Baraclude. 
 
Fertility: toxicology studies in animals administered entecavir have shown no evidence of impaired 
fertility (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
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. 



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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 

 
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 lamivudine-refractory 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 lamivudine-treated patients developed ALT elevations during post-
treatment follow-up. 
 



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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 authorisation 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 the 
national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 



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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
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. Lamivudine-resistant strains harboring rtL180M plus rtM204V in 
combination with amino acid substitution rtA181C conferred 16- to 122-fold reductions in entecavir 
phenotypic susceptibility. 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. 
 



 11 

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. 
 
 Nucleoside Naive 

HBeAg Positive 
(study 022) 

HBeAg Negative 
(study 027) 

ETV 
0.5 mg 

once daily 

LVD 
100 mg 

once daily 

ETV 
0.5 mg 

once daily 

LVD 
100 mg 

once daily 
n 314a 314a 296a 287a 
Histological improvementb 72%* 62% 70%* 61% 
Ishak fibrosis score improvement 39% 35% 36% 38% 
Ishak fibrosis score worsening 8% 10% 12% 15% 
n 354 355 325 313 
Viral load reduction (log10 copies/ml)c -6.86* -5.39 -5.04* -4.53 
HBV DNA undetectable 
(< 300 copies/ml by PCR)c 

67%* 36% 90%* 72% 

ALT normalisation (≤ 1 times ULN) 68%* 60% 78%* 71% 
     
HBeAg Seroconversion 21% 18%   
*p value vs lamivudine < 0.05 
a patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2) 
b a primary endpoint 
c Roche Cobas Amplicor PCR assay (LLOQ = 300 copies/ml) 

 
Experience in lamivudine-refractory patients with compensated liver disease: 
In a randomised, double-blind study in HBeAg positive lamivudine-refractory patients (026), 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. 
 



 12 

 Lamivudine-refractory 
HBeAg positive (study 026) 

ETV 1.0 mg once daily LVD 100 mg once daily 
n 124a 116a 
Histological improvementb 55%* 28% 
Ishak fibrosis score improvement 34%* 16% 
Ishak fibrosis score worsening 11% 26% 
n 141 145 
Viral load reduction (log10 copies/ml)c -5.11* -0.48 
HBV DNA undetectable (< 300 copies/ml 
by PCR)c 

19%* 1% 

ALT normalisation (≤ 1 times ULN) 61%* 15% 
   
HBeAg Seroconversion 8% 3% 
*p value vs lamivudine < 0.05 
a patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2) 
b a primary endpoint. 
c Roche Cobas Amplicor PCR assay (LLOQ = 300 copies/ml) 

 
Results beyond 48 weeks of treatment: 
Treatment was discontinued when prespecified response criteria were met either at 48 weeks or 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 lamivudine-treated 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 post-treatment follow-up, a substantial number of 
HBeAg negative patients lost response. 
 
Liver biopsy results: 57 patients from the pivotal nucleoside-naive studies 022 (HBeAg positive) and 
027 (HBeAg negative) who enrolled in a long-term rollover study were evaluated for long-term liver 



 13 

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. 
 



 14 

  Week 24 Week 48 

  

ETV 
1 mg 

once daily 

Adefovir 
Dipivoxil 

10 mg  
once daily 

ETV  
1 mg 

once daily 

Adefovir 
Dipivoxil 

10 mg 
once daily 

n 100 91 100 91 

HBV DNAa 

Proportion undetectable (<300 copies/ml)b 49%* 16% 57%* 20% 
Mean change from baseline 
(log10 copies/ml)c 

-4.48* -3.40 -4.66 -3.90 

Stable or improved CTP scoreb,d 66% 71% 61% 67% 
MELD score 
Mean change from baselinec,e 

 
-2.0 

 
-0.9 

 
-2.6 

 
-1.7 

HBsAg lossb 1% 0 5% 0 

Normalization of:f 

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

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

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

 Prothrombin time (≤1 X ULN)b 9/95 (9%) 6/82 (7%) 8/95 (8%) 7/82 (9%) 
a Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/ml). 
b NC=F (noncompleter=failure), meaning treatment discontinuations before the analysis week, including reasons such as 

death, lack of efficacy, adverse event, noncompliance/loss-to-follow-up, are counted as failures (e.g., HBV 
DNA ≥ 300 copies/ml) 

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

*p<0.05 
ULN=upper limit of normal, LLN=lower limit of normal. 
 
The time to onset of HCC or death (whichever occurred first) was comparable in the two 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.  



 15 

 
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 HBeAg-negative 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 post-transplantation, 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.  
 
                Entecavir Placebo* 
 Week 48 Week 96 Week 48 
n 120 120 60 
HBV DNA < 50 IU/mL and 
HBeAg seroconversiona  

24.2% 35.8% 3.3% 

HBV DNA < 50 IU/mLa 49.2% 64.2% 3.3.% 
HBeAg seroconversiona 24.2% 36.7% 10.0% 
ALT normalizationa 67.5% 81.7% 23.3% 

HBV DNA < 50 IU/mLa  
 

  

      Baseline HBV   
      DNA < 8 log10 IU/ml 

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

     Baseline HBV DNA   
      ≥ 8 log10 IU/ml 

    28.4% (21/74)  52.7%  (39/74) 0% (0/29) 

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 . 



 16 

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

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

Patients treated and monitored for 
resistanceb 

663 278 149 121 108 

Patients in specific year with:      
 - emerging genotypic ETVrc  1  1  1  0 0 

 - genotypic ETVrc with virologic 
breakthroughd 

1  0 1 0 0 

Cumulative probability of:      

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

 - genotypic ETVrc with virologic 
breakthroughd  

0.2% 0.2% 0.8% 0.8% 0.8% 

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

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

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

windowed time point. 
 
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. 
 



 17 

Genotypic Entecavir Resistance Through Year 5, Lamivudine-Refractory Studies 

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

Patients treated and monitored for 
resistanceb 

187 146 80 52 33 

Patients in specific year with:      

 - emerging genotypic ETVrc 11  12  16  6  2 

 - genotypic ETVrc with virologic 
breakthroughd 

2e 14e 13e 9e 1e 

Cumulative probability of:      

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

 - genotypic ETVrc with virologic 
breakthroughd 

1.1%e 10.7% e 27% e 41.3% e 43.6% e 

a Results reflect use of combination entecavir-lamivudine therapy (followed by long-term entecavir therapy) for a 
median of 13 weeks for 48 of 80 patients in Year 3, a median of 38 weeks for 10 of 52 patients in Year 4, and for 16 
weeks for 1 of 33 patients in Year 5 in a rollover study. 

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

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

windowed time point. 
e ETVr occurring in any year; virologic breakthrough in specified year. 

 
Among lamivudine-refractory patients with baseline HBV DNA < 107 log10 copies/ml, 64% (9/14) 
achieved HBV DNA < 300 copies/ml at Week 48. These 14 patients had a lower rate of genotypic 
entecavir resistance (cumulative probability 18.8% through 5 years of follow-up) than the overall 
study population (see table). Also, lamivudine-refractory 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. 
 
5.2 Pharmacokinetic properties 
 
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. The tablet and oral solution were bioequivalent in healthy subjects; 
therefore, both forms may be used interchangeably. 
 
Administration of 0.5 mg entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal 
(379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1-1.5 hour fed vs. 0.75 hour fasted), 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). 
 



 18 

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: 
 
 Baseline Creatinine Clearance (ml/min)   

Unimpaired 
> 80 

 
 

(n = 6) 

Mild 
> 50; 
≤ 80 

 
(n = 6) 

Moderate 
30-50 

 
 

(n = 6) 

Severe 
20-
< 30 

 
(n = 6) 

Severe 
Managed with 
Haemodialysis 

 
(n = 6) 

Severe 
Managed 

with CAPD 
 

(n = 4) 
Cmax (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) 

 
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 



 19 

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.  
 
5.3 Preclinical safety data 
 
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. 
 



 20 

 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Baraclude 0.5 mg film-coated tablets 
Tablet core: 
Crospovidone 
Lactose monohydrate 
Magnesium stearate 
Cellulose, Microcrystalline 
Povidone 
 
Tablet coating: 
Titanium dioxide 
Hypromellose 
Macrogol 400 
Polysorbate 80 (E433) 
 
Baraclude 1 mg film-coated tablets 
Tablet core: 
Crospovidone 
Lactose monohydrate 
Magnesium stearate 
Cellulose, Microcrystalline 
Povidone 
 
Tablet coating: 
Titanium dioxide 
Hypromellose 
Macrogol 400 
Iron oxide red 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
Blisters: 
Do not store above 30°C. Store in the original carton. 
 
Bottles: 
Do not store above 25°C. Keep the bottle tightly closed. 
 
6.5 Nature and contents of container 
 
Each carton contains either: 
 30 x 1 film-coated tablet; 3 blister cards of 10 x 1 film-coated tablet each in Alu/Alu perforated 

unit dose blisters, or 
 90 x 1 film-coated tablet; 9 blister cards of 10 x 1 film-coated tablet each in Alu/Alu perforated 

unit dose blisters. 
 



 21 

High-density polyethylene (HDPE) bottle with child resistant polypropylene closure containing 
30 film-coated tablets. Each carton contains one bottle. 
 
Not all pack sizes and container types may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG  
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
Baraclude 0.5 mg film-coated tablets 
Blister packs: EU/1/06/343/003 

EU/1/06/343/006 
Bottle packs: EU/1/06/343/001 
 
Baraclude 1 mg film-coated tablets 
Blister packs: EU/1/06/343/004 

EU/1/06/343/007 
Bottle packs: EU/1/06/343/002 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 June 2006 
Date of latest renewal: 26 June 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{MM/YYYY} 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 



 22 

1. NAME OF THE MEDICINAL PRODUCT 
 
Baraclude 0.05 mg/ml oral solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml oral solution contains 0.05 mg entecavir (as monohydrate). 
 
Excipients with known effect 
380 mg maltitol/ml 
1.5 mg methylhydroxybenzoate/ml 
0.18 mg propylhydroxybenzoate/ml 
0.3 mg sodium/ml 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Oral solution 
 
Clear, colourless to pale yellow solution 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Baraclude is indicated for the treatment of chronic hepatitis B virus (HBV) infection (see section 5.1) 
in adults with: 
 compensated liver disease and evidence of active viral replication, persistently elevated 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 4.2, 4.4 and 5.1. 
 
Baraclude 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.  
 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the management of chronic hepatitis B 
infection. 
 
It is recommended that the dosing spoon be rinsed with water after each daily dose. 
 
Posology 
 
Compensated liver disease 
 



 23 

Nucleoside naïve patients: the recommended dose in adults is 0.5 mg once daily, with or without food. 
 
Lamivudine-refractory patients (i.e. with evidence of viraemia while on lamivudine or the presence of 
lamivudine resistance [LVDr] mutations) (see sections 4.4 and 5.1): the recommended dose in adults is 
1 mg once daily, which must be taken on an empty stomach (more than 2 hours before and more than 
2 hours after a meal) (see section 5.2). In the presence of LVDr mutations, 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 (see section 4.4.). 
 
Decompensated liver disease 
The recommended dose for adult patients with decompensated liver disease is 1 mg once daily, which 
must be taken on an empty stomach (more than 2 hours before and more than 2 hours after a meal) 
(see section 5.2). For patients with lamivudine-refractory hepatitis B, see sections 4.4 and 5.1. 
 
Duration of therapy 
The optimal duration of treatment is unknown. Treatment discontinuation may be considered as 
follows: 
 In HBeAg positive adult patients, treatment should be administered at least until 12 months after 

achieving 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 adult 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 
 
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.  
 
The recommended once-daily dose in paediatric patients weighing at least 10 kg, is presented in the 
table below. Patients may be dosed with or without food. The oral solution should be used for patients 
with body weight less than 32.6 kg. Paediatric patients with body weight at least 32.6 kg, should be 
administered 10 ml (0.5 mg) of the oral solution or one 0.5 mg tablet once daily. 
 
Dosing for nucleoside naive paediatric patients aged 2 to < 18 years 

Body Weighta 
Recommended Once Daily Dose of Oral 

Solutionb 

10.0 - 14.1 kg 4.0 ml 

14.2 - 15.8 kg 4.5 ml 

15.9 - 17.4 kg 5.0 ml 

17.5 - 19.1 kg 5.5 ml 

19.2 - 20.8 kg 6.0 ml 

20.9 - 22.5 kg 6.5 ml 



 24 

Dosing for nucleoside naive paediatric patients aged 2 to < 18 years 

Body Weighta 
Recommended Once Daily Dose of Oral 

Solutionb 

22.6 - 24.1 kg 7.0 ml 

24.2 - 25.8 kg 7.5 ml 

25.9 - 27.5 kg 8.0 ml 

27.6 - 29.1 kg 8.5 ml 

29.2 - 30.8 kg 9.0 ml 

30.9 - 32.5 kg 9.5 ml 

At least 32.6 kgb 10.0 ml 
a Body weight should be rounded to the nearest 0.1 kg. 

b Children with body weight at least 32.6 kg should receive 10.0 ml (0.5 mg) of oral solution or one 0.5 mg tablet once daily. 

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 Baraclude 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. 
 

 Baraclude dosage 

Creatinine clearance 
(ml/min) 

 

Nucleoside naïve patients 
 

Lamivudine-refractory or 
decompensated liver disease 

 
≥ 50  0.5 mg once daily 1 mg once daily 

30 - 49 0.25 mg once daily 
OR 

0.5 mg every 48 hours 

0.5 mg once daily 
 

10 - 29 0.15 mg once daily 
OR 

0.5 mg every 72 hours 

0.3 mg once daily 
OR 

0.5 mg every 48 hours 



 25 

 Baraclude dosage 

Creatinine clearance 
(ml/min) 

 

Nucleoside naïve patients 
 

Lamivudine-refractory or 
decompensated liver disease 

 
< 10 

Haemodialysis or 
CAPD** 

0.05 mg once daily 
 OR 

0.5 mg every 5-7 days 

0.1 mg once daily 
OR 

0.5 mg every 72 hours 
**on haemodialysis days, administer entecavir after haemodialysis. 
 
Hepatic impairment: no dose adjustment is required in patients with hepatic impairment. 
 
Method of administration 
 
Baraclude should be taken orally. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
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 



 26 

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: 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 co-infected 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. 
 



 27 

HIV/HBV co-infected patients receiving concomitant antiretroviral therapy: entecavir has been studied 
in 68 adults with HIV/HBV co-infection receiving a lamivudine-containing 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. 
 
Maltitol: Baraclude oral solution contains maltitol. Patients with rare hereditary problems of fructose 
intolerance should not take this medicine. Baraclude tablets do not contain maltitol and can be taken 
by patients with fructose intolerance. 
 
Parahydroxybenzoates: Baraclude oral solution contains the preservatives methylhydroxybenzoate 
and propylhydroxybenzoate, that may cause allergic reactions (possibly delayed). 
 
Sodium: Each ml of this medicinal product contains 0.015 mmol (or 0.3 mg) sodium. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 
 
Paediatric population 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
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. Baraclude 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. 
 
Breast-feeding: 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. Breast-feeding should be discontinued during treatment with Baraclude. 
 
Fertility: toxicology studies in animals administered entecavir have shown no evidence of impaired 
fertility (see section 5.3).  
 



 28 

4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
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. 
 
 
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 

 
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%. 



 29 

 
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 lamivudine-refractory 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 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 



 30 

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 authorisation 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 the 
national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
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 



 31 

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. Lamivudine-resistant strains harboring rtL180M plus rtM204V in 
combination with amino acid substitution rtA181C conferred 16- to 122-fold reductions in entecavir 
phenotypic susceptibility. 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. 
 



 32 

Experience in nucleoside-naive patients with compensated liver disease: 
Results at 48 weeks of randomised, double blind studies comparing entecavir (ETV) to lamivudine 
(LVD) in HBeAg positive (022) and HBeAg negative (027) patients are presented in the table. 
 
 Nucleoside Naive 

HBeAg Positive 
(study 022) 

HBeAg Negative 
(study 027) 

ETV 
0.5 mg 

once daily 

LVD 
100 mg 

once daily 

ETV 
0.5 mg 

once daily 

LVD 100 mg 
once daily 

n 314a 314a 296a 287a 
Histological improvementb 72%* 62% 70%* 61% 
Ishak fibrosis score improvement 39% 35% 36% 38% 
Ishak fibrosis score worsening 8% 10% 12% 15% 
n 354 355 325 313 
Viral load reduction (log10 copies/ml)c -6.86* -5.39 -5.04* -4.53 
HBV DNA undetectable 
(< 300 copies/ml by PCR)c 

67%* 36% 90%* 72% 

ALT normalisation (≤ 1 times ULN) 68%* 60% 78%* 71% 
     
HBeAg Seroconversion 21% 18%   
*p value vs lamivudine < 0.05 
a patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2) 
b a primary endpoint 
c Roche Cobas Amplicor PCR assay (LLOQ = 300 copies/ml) 

 
Experience in lamivudine-refractory patients with compensated liver disease: 
In a randomised, double-blind study in HBeAg positive lamivudine-refractory patients (026), 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. 
 
 Lamivudine-refractory 

HBeAg positive (study 026) 
ETV 1.0 mg once daily LVD 100 mg once daily 

n 124a 116a 
Histological improvementb 55%* 28% 
Ishak fibrosis score improvement 34%* 16% 
Ishak fibrosis score worsening 11% 26% 
n 141 145 
Viral load reduction (log10 copies/ml)c -5.11* -0.48 
HBV DNA undetectable (< 300 copies/ml 
by PCR)c 

19%* 1% 

ALT normalisation (≤ 1 times ULN) 61%* 15% 
   
HBeAg Seroconversion 8% 3% 
*p value vs lamivudine < 0.05 
a patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2) 
b a primary endpoint. 
c Roche Cobas Amplicor PCR assay (LLOQ = 300 copies/ml) 

 
Results beyond 48 weeks of treatment: 
Treatment was discontinued when prespecified response criteria were met either at 48 weeks or 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 



 33 

(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 lamivudine-treated 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 post-treatment follow-up, a substantial number of 
HBeAg negative patients lost response. 
 
Liver biopsy results: 57 patients from the pivotal nucleoside-naive studies 022 (HBeAg positive) 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). 
 



 34 

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. 
 



 35 

  Week 24 Week 48 

  

ETV 
1 mg 

once daily 

Adefovir 
Dipivoxil 

10 mg  
once daily 

ETV  
1 mg 

once daily 

Adefovir 
Dipivoxil 

10 mg 
once daily 

n 100 91 100 91 

HBV DNAa 

Proportion undetectable (<300 copies/ml)b 49%* 16% 57%* 20% 
Mean change from baseline 
(log10 copies/ml)c 

-4.48* -3.40 -4.66 -3.90 

Stable or improved CTP scoreb,d 66% 71% 61% 67% 
MELD score 
Mean change from baselinec,e 

 
-2.0 

 
-0.9 

 
-2.6 

 
-1.7 

HBsAg lossb 1% 0 5% 0 

Normalization of:f 

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

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

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

 Prothrombin time (≤1 X ULN)b 9/95 (9%) 6/82 (7%) 8/95 (8%) 7/82 (9%) 
a Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/ml). 
b NC=F (noncompleter=failure), meaning treatment discontinuations before the analysis week, including reasons such as 

death, lack of efficacy, adverse event, noncompliance/loss-to-follow-up, are counted as failures (e.g., HBV 
DNA ≥ 300 copies/ml) 

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

*p<0.05 
ULN=upper limit of normal, LLN=lower limit of normal. 
 
The time to onset of HCC or death (whichever occurred first) was comparable in the two 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. 
 



 36 

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 HBeAg-negative 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 post-transplantation, 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. 
 
                Entecavir Placebo* 
 Week 48 Week 96 Week 48 
n 120 120 60 
HBV DNA < 50 IU/mL and 
HBeAg seroconversiona  

24.2% 35.8% 3.3% 

HBV DNA < 50 IU/mLa 49.2% 64.2% 3.3.% 
HBeAg seroconversiona 24.2% 36.7% 10.0% 
ALT normalizationa 67.5% 81.7% 23.3% 

HBV DNA < 50 IU/mLa  
 

  

      Baseline HBV   
      DNA < 8 log10 IU/ml 

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

     Baseline HBV DNA   
      ≥ 8 log10 IU/ml 

    28.4% (21/74)  52.7%  (39/74) 0% (0/29) 

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 . 



 37 

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 (rtM204Vand rtL180M). 
 
Emerging Genotypic Entecavir Resistance Through Year 5, Nucleoside-Naive Studies 

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

Patients treated and monitored for 
resistanceb 

663 278 149 121 108 

Patients in specific year with:      
 - emerging genotypic ETVrc  1 1 1 0 0 

 - genotypic ETVrc with virologic 
breakthroughd 

1 0 1 0 0 

Cumulative probability of:      

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

 - genotypic ETVrc with virologic 
breakthroughd  

0.2% 0.2% 0.8% 0.8% 0.8% 

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

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

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

windowed time point. 
 
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. 

Genotypic Entecavir Resistance Through Year 5, Lamivudine-Refractory Studies 

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

Patients treated and monitored for 
resistanceb 

187 146 80 52 33 

Patients in specific year with:      

 - emerging genotypic ETVrc  11  12  16  6  2 

 - genotypic ETVrc with virologic 
breakthroughd 

2e 14e 13e 9e 1e 

Cumulative probability of:      



 38 

 
 
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, lamivudine-refractory 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. 
 
5.2 Pharmacokinetic properties 
 
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. The tablet and oral solution were bioequivalent in healthy subjects; 
therefore, both forms may be used interchangeably. 
 
Administration of 0.5 mg entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal 
(379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1-1.5 hour fed vs. 0.75 hour fasted), 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 

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

 - genotypic ETVrc with virologic 
breakthroughd  

1.1%e 10.7% e 27% e 41.3% e 43.6% e 

a Results reflect use of combination entecavir-lamivudine therapy (followed by long-term entecavir therapy) for a 
median of 13 weeks for 48 of 80 patients in Year 3, a median of 38 weeks for 10 of 52 patients in Year 4, and for 16 
weeks for 1 of 33 patients in Year 5 in a rollover study. 

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

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

windowed time point. 
e ETVr occurring in any year; virologic breakthrough in specified year. 



 39 

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: 
 
 Baseline Creatinine Clearance (ml/min)   

Unimpaired 
> 80 

 
 

(n = 6) 

Mild 
> 50; 
≤ 80 

 
(n = 6) 

Moderate 
30-50 

 
 

(n = 6) 

Severe 
20-
< 30 

 
(n = 6) 

Severe 
Managed with 
Haemodialysis 

 
(n = 6) 

Severe 
Managed 

with CAPD 
 

(n = 4) 
Cmax (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) 

 
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. 



 40 

 
5.3 Preclinical safety data 
 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Maltitol (E965) 
Sodium citrate 
Citric acid, anhydrous 
Methylhydroxybenzoate (E218) 
Propylhydroxybenzoate (E216) 
Orange flavour (acacia and natural flavours) 
Sodium hydroxide to adjust pH to approximately 6 
Hydrochloric acid to adjust pH to approximately 6 



 41 

Purified water 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with water, other solvents or other medicinal products. 
 
6.3 Shelf life 
 
2 years 
After opening, the solution can be used up to the expiry date on the bottle. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. Keep the bottle in the outer carton in order to protect from light. 
 
6.5 Nature and contents of container 
 
210 ml oral solution in a HDPE bottles with child-resistant closures (polypropylene). Each carton 
includes a measuring spoon (polypropylene) with markings from 0.5 ml up to 10 ml 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG  
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/343/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 June 2006 
Date of latest renewal: 26 June 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{MM/YYYY} 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 
 



 42 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



 43 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
CATALENT ANAGNI S.R.L., Loc. Fontana del Ceraso snc, Strada Provinciale 12 Casilina, 41, 
03012 Anagni (FR), Italy 
 
Swords Laboratories T/A Bristol-Myers Squibb Pharmaceutical Operations, External Manufacturing, 
Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
 Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



 44 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



 45 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 46 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON TEXT (BOTTLE AND BLISTER PRESENTATIONS) AND BOTTLE 
LABEL TEXT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Baraclude 0.5 mg film-coated tablets 
entecavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 0.5 mg of entecavir. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose monohydrate. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Blister pack: 30 x 1 film-coated tablet 

90 x 1 film-coated tablet 
Bottle pack: 30 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Blister pack: 
Do not store above 30°C. 
Store in the original carton. 



 47 

 
Bottle pack: 
Do not store above 25°C. 
Keep the bottle tightly closed. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG  
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
Blister pack : EU/1/06/343/003  30 x 1 film-coated tablet 

EU/1/06/343/006  90 x 1 film-coated tablet 
Bottle pack: EU/1/06/343/001  30 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Outer carton: Baraclude 0.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
<NN> 



 48 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Baraclude 0.5 mg tablets 
entecavir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



 49 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON TEXT (BOTTLE AND BLISTER PRESENTATIONS) AND BOTTLE 
LABEL TEXT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Baraclude 1 mg film-coated tablets 
entecavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 1 mg of entecavir. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose monohydrate. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Blister pack: 30 x 1 film-coated tablet 

90 x 1 film-coated tablet 
Bottle pack: 30 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Blister pack: 
Do not store above 30°C. 
Store in the original carton. 



 50 

 
Bottle pack: 
Do not store above 25°C. 
Keep the bottle tightly closed. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG  
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
Blister pack : EU/1/06/343/004  30 x 1 film-coated tablet 

EU/1/06/343/007  90 x 1 film-coated tablet 
Bottle pack: EU/1/06/343/002  30 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Outer carton: Baraclude 1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
<NN> 



 51 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Baraclude 1 mg tablets 
entecavir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



 52 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND BOTTLE LABEL TEXT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Baraclude 0.05 mg/ml oral solution 
entecavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml contains 0.05 mg entecavir. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: maltitol, preservatives E216, E218. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
210 ml oral solution with a measuring spoon. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Keep the bottle in the outer carton in order to protect from light. 
 
 



 53 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG  
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/343/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Outer carton: Baraclude 0.05 mg/ml 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
<NN> 



 54 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 55 

Package leaflet: Information for the user 
 

Baraclude 0.5 mg film-coated tablets 
Entecavir 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Baraclude is and what it is used for 
2. What you need to know before you take Baraclude 
3. How to take Baraclude 
4. Possible side effects 
5. How to store Baraclude 
6. Contents of the pack and other information 
 
 
1. What BARACLUDE is and what it is used for 
 
Baraclude tablets are anti-viral medicines, used to treat chronic (long term) hepatitis B virus 
(HBV) infection in adults. Baraclude can be used in people whose liver is damaged but still functions 
properly (compensated liver disease) and in people whose liver is damaged and does not function 
properly (decompensated liver disease). 
 
Baraclude tablets are also used to treat chronic (long term) HBV infection in children and 
adolescents aged 2 years to less than 18 years. Baraclude can be used in children whose liver is 
damaged but still functions properly (compensated liver disease). 
 
Infection by the hepatitis B virus can lead to damage to the liver. Baraclude reduces the amount of 
virus in your body, and improves the condition of the liver. 
 
 
2. What you need to know before you take BARACLUDE 
 
Do not take Baraclude 
 if you are allergic (hypersensitive) to entecavir or any of the other ingredients of this medicine 

(listed in section 6). 
 
Warning and precautions 
Talk to your doctor or pharmacist before taking Baraclude 
 if you have ever had problems with your kidneys, tell your doctor. This is important because 

Baraclude is eliminated from your body through the kidneys and your dose or dosing schedule 
may need to be adjusted. 

 
 do not stop taking Baraclude without your doctor’s advice since your hepatitis may worsen 

after stopping treatment. When your treatment with Baraclude is stopped, your doctor will 
continue to monitor you and take blood tests for several months. 

 
 discuss with your doctor whether your liver functions properly and, if not, what the possible 

effects on your Baraclude treatment may be. 
 



 56 

 if you are also infected with HIV (human immunodeficiency virus) be sure to tell your doctor. 
You should not take Baraclude to treat your hepatitis B infection unless you are taking 
medicines for HIV at the same time, as the effectiveness of future HIV treatment may be 
reduced. Baraclude will not control your HIV infection. 

 
 taking Baraclude will not stop you from infecting other people with hepatitis B virus 

(HBV) through sexual contact or body fluids (including blood contamination). So, it is 
important to take appropriate precautions to prevent others from becoming infected with HBV. 
A vaccine is available to protect those at risk from becoming infected with HBV. 

 
 Baraclude belongs to a class of medicines that can cause lactic acidosis (excess of lactic acid 

in your blood) and enlargement of the liver. Symptoms such as nausea, vomiting and stomach 
pain might indicate the development of lactic acidosis. This rare but serious side effect has 
occasionally been fatal. Lactic acidosis occurs more often in women, particularly if they are 
very overweight. Your doctor will monitor you regularly while you are receiving Baraclude. 

 
 if you have previously received treatment for chronic hepatitis B, please inform your doctor. 
 
Children and adolescents 
Baraclude should not be used for children below 2 years of age or weighing less than 10 kg. 
 
Other medicines and Baraclude 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Baraclude with food and drink 
In most cases you may take Baraclude with or without food. However, if you have had a previous 
treatment with a medicine containing the active substance lamivudine you should consider the 
following. If you were switched over to Baraclude because the treatment with lamivudine was not 
successful, you should take Baraclude on an empty stomach once daily. If your liver disease is very 
advanced, your doctor will also instruct you to take Baraclude on an empty stomach. Empty stomach 
means at least 2 hours after a meal and at least 2 hours before your next meal. 
Children and adolescents (from 2 to less than 18 years of age) can take Baraclude with or without 
food. 
Pregnancy, breast-feeding and fertility 
Tell your doctor if you are pregnant or planning to become pregnant. It has not been demonstrated that 
Baraclude is safe to use during pregnancy. Baraclude must not be used during pregnancy unless 
specifically directed by your doctor. It is important that women of childbearing age receiving 
treatment with Baraclude use an effective method of contraception to avoid becoming pregnant. 
 
You should not breast-feed during treatment with Baraclude. Tell your doctor if you are breast-
feeding. It is not known whether entecavir, the active ingredient in Baraclude, is excreted in human 
breast milk. 
 
Driving and using machines 
Dizziness, tiredness (fatigue) and sleepiness (somnolence) are common side effects which may impair 
your ability to drive and use machines. If you have any concerns consult your doctor. 
 
Baraclude contains lactose 
This medicinal product contains lactose. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
 
3. How to take BARACLUDE 
 
Not all patients need to take the same dose of Baraclude. 
 



 57 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.  
 
For adults the recommended dose is either 0.5 mg or 1 mg once daily orally (by mouth). 
 
Your dose will depend on: 
 whether you have been treated for HBV infection before, and what medicine you received. 
 whether you have kidney problems. Your doctor may prescribe a lower dose for you or instruct 

you to take it less often than once a day. 
 the condition of your liver. 
 
For children and adolescents (from 2 to less than 18 years of age), your child's doctor will decide the 
right dose based on your child's weight. The Baraclude oral solution is recommended for patients 
weighing from 10 kg to 32.5 kg.Children weighing at least 32.6 kg may take the oral solution or the 
0.5 mg tablet. All dosing will be taken once daily orally (by mouth). There are no recommendations 
for Baraclude in children less than 2 years of age or weighing less than 10 kg. 
 
Your doctor will advise you on the dose that is right for you. Always take the dose recommended by 
your doctor to ensure that your medicine is fully effective and to reduce the development of resistance 
to treatment. Take Baraclude as long as your doctor has told you. Your doctor will tell you if and when 
you should stop the treatment. 
 
Some patients must take Baraclude on an empty stomach (see Baraclude with food and drink in 
Section 2). If your doctor instructs you to take Baraclude on an empty stomach, empty stomach means 
at least 2 hours after a meal and at least 2 hours before your next meal. 
 
If you take more Baraclude than you should 
Contact your doctor at once. 
 
If you forget to take Baraclude 
It is important that you do not miss any doses. If you miss a dose of Baraclude, take it as soon as 
possible, and then take your next scheduled dose at its regular time. If it is almost time for your next 
dose, do not take the missed dose. Wait and take the next dose at the regular time. Do not take a 
double dose to make up for a forgotten dose. 
 
Do not stop Baraclude without your doctor’s advice 
Some people get very serious hepatitis symptoms when they stop taking Baraclude. Tell your doctor 
immediately about any changes in symptoms that you notice after stopping treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Patients treated with Baraclude have reported the following side effects: 
 
Adults 
 common (at least 1 in 100 patients): headache, insomnia (inability to sleep), fatigue (extreme 

tiredness), dizziness, somnolence (sleepiness), vomiting, diarrhoea, nausea, dyspepsia 
(indigestion), and increased blood levels of liver enzymes. 

 uncommon (at least 1 in 1,000 patients): rash, hair loss. 
 rare (at least 1 in 10,000 patients): severe allergic reaction. 
 



 58 

Children and adolescents 
The side effects experienced in children and adolescents are similar to those experienced in adults as 
described above with the following difference: 
Very common (at least 1 in 10 patients): low levels of neutrophils (one type of white blood cells, 
which are important in fighting infection). 
 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist or. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store BARACLUDE 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle, blister or carton after EXP. 
That expiry date refers to the last day of that month. 
 
Blister packs: do not store above 30°C. Store in the original carton. 
Bottle packs: do not store above 25°C. Keep the bottle tightly closed. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Baraclude contains 
 The active substance is entecavir. Each film-coated tablet contains 0.5 mg entecavir. 
 The other ingredients are: 

Tablet core: crospovidone, lactose monohydrate, magnesium stearate, cellulose microcrystalline 
and povidone. 
Tablet coating: hypromellose, macrogol 400, titanium dioxide (E171), and polysorbate 80 
(E433). 

 
What Baraclude looks like and contents of the pack 
The film-coated tablets (tablets) are white to off-white and triangular-shaped. They are marked with 
“BMS” on one side and “1611” on the other. Baraclude 0.5 mg film-coated tablets are supplied in 
cartons containing 30 x 1 or 90 x 1 film-coated tablet (in unit-dose blisters) and in bottles containing 
30 film-coated tablets. 
 
Not all pack sizes may be marketed in your country. 
 
Marketing Authorisation Holder and Manufacturer 
Marketing Authorisation Holder: 
Bristol-Myers Squibb Pharma EEIG  
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 



 59 

Manufacturer: 
CATALENT ANAGNI S.R.L. 
Loc. Fontana del Ceraso snc 
Strada Provinciale 12 Casilina, 41 
03012 Anagni (FR) 
Italy 
 
Swords Laboratories T/A Bristol-Myers Squibb Pharmaceutical Operations, External Manufacturing 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
Belgique/België/Belgien 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Lietuva 
Bristol-Myers Squibb Kft. 
Tel: + 370 52 369140 
 

България 
Bristol-Myers Squibb Kft. 
Teл.: + 359 2 4942 480  
 

Luxembourg/Luxemburg 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Česká republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 420 221 016 111 
 

Magyarország 
Bristol-Myers Squibb Kft. 
Tel.: + 36 1 9206 550 
 

Danmark 
Bristol-Myers Squibb 
Tlf: + 45 45 93 05 06 
 

Malta 
Bristol-Myers Squibb S.r.l. 
Tel: + 356 23976333 
 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: 0800 0752002 (+49 (0)89 121 42-350) 

Nederland 
Bristol-Myers Squibb B.V. 
Tel: + 31 (0)30 300 2222 
 

Eesti 
Bristol-Myers Squibb Kft. 
Tel: + 372 640 1030 
 

Norge 
Bristol-Myers Squibb Norway Ltd 
Tlf: + 47 67 55 53 50 
 

Ελλάδα 
Bristol-Myers Squibb A.E. 
Τηλ: + 30 210 6074300 
 

Österreich 
Bristol-Myers Squibb GesmbH 
Tel: + 43 1 60 14 30 
 

España 
Bristol-Myers Squibb, S.A. 
Tel: + 34 91 456 53 00 
 

Polska 
Bristol-Myers Squibb Polska Sp. z o.o. 
Tel.: + 48 22 2606400 
 
 

France 
Bristol-Myers Squibb SARL 
Tél: + 33 (0)1 58 83 84 96 
 

Portugal 
Bristol-Myers Squibb Farmacêutica Portuguesa, 
S.A. 
Tel: + 351 21 440 70 00 
 



 60 

Hrvatska 
Bristol-Myers Squibb spol. s r.o. 
TEL: + 385 1 2078 508 
 

România 
Bristol-Myers Squibb Kft. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: + 353 (0)1 483 3625 
 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 386 1 2355 100 
 

Ísland 
Bristol-Myers Squibb AB hjá Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 20833 600 
 

Italia 
Bristol-Myers Squibb S.r.l. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
Oy Bristol-Myers Squibb (Finland) Ab 
Puh/Tel: + 358 9 251 21 230 
 

Κύπρος 
Bristol-Myers Squibb A.E. 
Τηλ: + 357 800 92666 
 

Sverige 
Bristol-Myers Squibb AB 
Tel: + 46 8 704 71 00 
 

Latvija 
Bristol-Myers Squibb Kft. 
Tel: + 371 66164750 
 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 44 (0800) 731 1736 
 

 
 
This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 



 61 

Package leaflet: Information for the user 
 

Baraclude 1 mg film-coated tablets 
Entecavir 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Baraclude is and what it is used for 
2. What you need to know before you take Baraclude 
3. How to take Baraclude 
4. Possible side effects 
5. How to store Baraclude 
6. Contents of the pack and other information 
 
 
1. What BARACLUDE is and what it is used for 
 
Baraclude tablets are anti-viral medicines, used to treat chronic (long term) hepatitis B virus 
(HBV) infection in adults. Baraclude can be used in people whose liver is damaged but still functions 
properly (compensated liver disease) and in people whose liver is damaged and does not function 
properly (decompensated liver disease). 
 
Baraclude tablets are also used to treat chronic (long term) HBV infection in children and 
adolescents aged 2 years to less than 18 years. Baraclude can be used in children whose liver is 
damaged but still functions properly (compensated liver disease). 
 
Infection by the hepatitis B virus can lead to damage to the liver. Baraclude reduces the amount of 
virus in your body, and improves the condition of the liver. 
 
 
2. What you need to know before you take BARACLUDE 
 
Do not take Baraclude 
 if you are allergic (hypersensitive) to entecavir or any of the other ingredients of this medicine 

(listed in section 6). 
 
Warning and precautions 
Talk to your doctor or pharmacist before taking Baraclude 
 if you have ever had problems with your kidneys, tell your doctor. This is important because 

Baraclude is eliminated from your body through the kidneys and your dose or dosing schedule 
may need to be adjusted. 

 
 do not stop taking Baraclude without your doctor’s advice since your hepatitis may worsen 

after stopping treatment. When your treatment with Baraclude is stopped, your doctor will 
continue to monitor you and take blood tests for several months. 

 
 discuss with your doctor whether your liver functions properly and, if not, what the possible 

effects on your Baraclude treatment may be. 
 



 62 

 if you are also infected with HIV (human immunodeficiency virus) be sure to tell your doctor. 
You should not take Baraclude to treat your hepatitis B infection unless you are taking 
medicines for HIV at the same time, as the effectiveness of future HIV treatment may be 
reduced. Baraclude will not control your HIV infection. 

 
 taking Baraclude will not stop you from infecting other people with hepatitis B virus 

(HBV) through sexual contact or body fluids (including blood contamination). So, it is 
important to take appropriate precautions to prevent others from becoming infected with HBV. 
A vaccine is available to protect those at risk from becoming infected with HBV. 

 
 Baraclude belongs to a class of medicines that can cause lactic acidosis (excess of lactic acid 

in your blood) and enlargement of the liver. Symptoms such as nausea, vomiting and stomach 
pain might indicate the development of lactic acidosis. This rare but serious side effect has 
occasionally been fatal. Lactic acidosis occurs more often in women, particularly if they are 
very overweight. Your doctor will monitor you regularly while you are receiving Baraclude. 

 
 if you have previously received treatment for chronic hepatitis B, please inform your doctor. 
 
Children and adolescents 
Baraclude should not be used for children below 2 years of age or weighing less than 10 kg. 
 
Other medicines and Baraclude 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Baraclude with food and drink 
In most cases you may take Baraclude with or without food. However, if you have had a previous 
treatment with a medicine containing the active substance lamivudine you should consider the 
following. If you were switched over to Baraclude because the treatment with lamivudine was not 
successful, you should take Baraclude on an empty stomach once daily. If your liver disease is very 
advanced, your doctor will also instruct you to take Baraclude on an empty stomach. Empty stomach 
means at least 2 hours after a meal and at least 2 hours before your next meal. 
 
Pregnancy, breast-feeding and fertility 
Tell your doctor if you are pregnant or planning to become pregnant. It has not been demonstrated that 
Baraclude is safe to use during pregnancy. Baraclude must not be used during pregnancy unless 
specifically directed by your doctor. It is important that women of childbearing age receiving 
treatment with Baraclude use an effective method of contraception to avoid becoming pregnant. 
 
You should not breast-feed during treatment with Baraclude. Tell your doctor if you are breast-
feeding. It is not known whether entecavir, the active ingredient in Baraclude, is excreted in human 
breast milk. 
 
Driving and using machines 
Dizziness, tiredness (fatigue) and sleepiness (somnolence) are common side effects which may impair 
your ability to drive and use machines. If you have any concerns consult your doctor. 
 
Baraclude contains lactose 
This medicinal product contains lactose. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
 
3. How to take BARACLUDE 
 
Not all patients need to take the same dose of Baraclude. 
 



 63 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.  
 
For adults the recommended dose is either 0.5 mg or 1 mg once daily orally (by mouth). 
 
Your dose will depend on: 
 whether you have been treated for HBV infection before, and what medicine you received. 
 whether you have kidney problems. Your doctor may prescribe a lower dose for you or instruct 

you to take it less often than once a day. 
 the condition of your liver. 
 
For children and adolescents (from 2 to less than 18 years of age), Baraclude oral solution or 
Baraclude 0.5 mg tablets are available 
 
Your doctor will advise you on the dose that is right for you. Always take the dose recommended by 
your doctor to ensure that your medicine is fully effective and to reduce the development of resistance 
to treatment. Take Baraclude as long as your doctor has told you. Your doctor will tell you if and when 
you should stop the treatment. 
 
Some patients must take Baraclude on an empty stomach (see Baraclude with food and drink in 
Section 2). If your doctor instructs you to take Baraclude on an empty stomach, empty stomach means 
at least 2 hours after a meal and at least 2 hours before your next meal. 
 
If you take more Baraclude than you should 
Contact your doctor at once. 
 
If you forget to take Baraclude 
It is important that you do not miss any doses. If you miss a dose of Baraclude, take it as soon as 
possible, and then take your next scheduled dose at its regular time. If it is almost time for your next 
dose, do not take the missed dose. Wait and take the next dose at the regular time. Do not take a 
double dose to make up for a forgotten dose. 
 
Do not stop Baraclude without your doctor’s advice 
Some people get very serious hepatitis symptoms when they stop taking Baraclude. Tell your doctor 
immediately about any changes in symptoms that you notice after stopping treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Patients treated with Baraclude have reported the following side effects: 
 
Adults 
 common (at least 1 in 100 patients): headache, insomnia (inability to sleep), fatigue (extreme 

tiredness), dizziness, somnolence (sleepiness), vomiting, diarrhoea, nausea, dyspepsia 
(indigestion), and increased blood levels of liver enzymes. 

 uncommon (at least 1 in 1,000 patients): rash, hair loss. 
 rare (at least 1 in 10,000 patients): severe allergic reaction. 
 
Children and adolescents 
The side effects experienced in children and adolescents are similar to those experienced in adults as 
described above with the following difference: 
Very common (at least 1 in 10 patients): low levels of neutrophils (one type of white blood cells, 
which are important in fighting infection). 



 64 

 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist or. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store BARACLUDE 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle, blister or carton after EXP. 
That expiry date refers to the last day of that month. 
 
Blister packs: do not store above 30°C. Store in the original carton. 
Bottle packs: do not store above 25°C. Keep the bottle tightly closed. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Baraclude contains 
 The active substance is entecavir. Each film-coated tablet contains 1 mg entecavir. 
 The other ingredients are: 

Tablet core: crospovidone, lactose monohydrate, magnesium stearate, cellulose microcrystalline 
and povidone. 
Tablet coating: hypromellose, macrogol 400, titanium dioxide (E171), and iron oxide red. 

 
What Baraclude looks like and contents of the pack 
The film-coated tablets (tablets) are pink and triangular-shaped. They are marked with “BMS” on one 
side and “1612” on the other. Baraclude 1 mg film-coated tablets are supplied in cartons containing 
30 x 1 or 90 x 1 film-coated tablet (in unit-dose blisters) and in bottles containing 30 film-coated 
tablets. 
 
Not all pack sizes may be marketed in your country. 
 
Marketing Authorisation Holder and Manufacturer 
Marketing Authorisation Holder: 
Bristol-Myers Squibb Pharma EEIG  
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
Manufacturer: 
CATALENT ANAGNI S.R.L. 
Loc. Fontana del Ceraso snc  
Strada Provinciale 12 Casilina, 41 
03012 Anagni (FR) 
Italy 
 



 65 

Swords Laboratories T/A Bristol-Myers Squibb Pharmaceutical Operations, External Manufacturing 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
Belgique/België/Belgien 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Lietuva 
Bristol-Myers Squibb Kft. 
Tel: + 370 52 369140 
 

България 
Bristol-Myers Squibb Kft. 
Teл.: + 359 2 4942 480  
 

Luxembourg/Luxemburg 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Česká republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 420 221 016 111 
 

Magyarország 
Bristol-Myers Squibb Kft. 
Tel.: + 36 1 9206 550 
 

Danmark 
Bristol-Myers Squibb 
Tlf: + 45 45 93 05 06 
 

Malta 
Bristol-Myers Squibb S.r.l. 
Tel: + 356 23976333 
 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: 0800 0752002 (+49 (0)89 121 42-350) 

Nederland 
Bristol-Myers Squibb B.V. 
Tel: + 31 (0)30 300 2222 
 

Eesti 
Bristol-Myers Squibb Kft. 
Tel: + 372 640 1030 
 

Norge 
Bristol-Myers Squibb Norway Ltd 
Tlf: + 47 67 55 53 50 
 

Ελλάδα 
Bristol-Myers Squibb A.E. 
Τηλ: + 30 210 6074300 
 

Österreich 
Bristol-Myers Squibb GesmbH 
Tel: + 43 1 60 14 30 
 

España 
Bristol-Myers Squibb, S.A. 
Tel: + 34 91 456 53 00 
 

Polska 
Bristol-Myers Squibb Polska Sp. z o.o. 
Tel.: + 48 22 2606400 
 
 

France 
Bristol-Myers Squibb SARL 
Tél: + 33 (0)1 58 83 84 96 
 

Portugal 
Bristol-Myers Squibb Farmacêutica Portuguesa, 
S.A. 
Tel: + 351 21 440 70 00 
 

Hrvatska 
Bristol-Myers Squibb spol. s r.o. 
TEL: + 385 1 2078 508 
 

România 
Bristol-Myers Squibb Kft. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: + 353 (0)1 483 3625 
 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 386 1 2355 100 
 



 66 

Ísland 
Bristol-Myers Squibb AB hjá Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 20833 600 
 

Italia 
Bristol-Myers Squibb S.r.l. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
Oy Bristol-Myers Squibb (Finland) Ab 
Puh/Tel: + 358 9 251 21 230 
 

Κύπρος 
Bristol-Myers Squibb A.E. 
Τηλ: + 357 800 92666 
 

Sverige 
Bristol-Myers Squibb AB 
Tel: + 46 8 704 71 00 
 

Latvija 
Bristol-Myers Squibb Kft. 
Tel: + 371 66164750 
 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 44 (0800) 731 1736 
 

 
 
This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 



 67 

Package leaflet: Information for the user 
 

Baraclude 0.05 mg/ml oral solution 
Entecavir 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Baraclude is and what it is used for 
2. What you need to know before you take Baraclude 
3. How to take Baraclude 
4. Possible side effects 
5. How to store Baraclude 
6. Contents of the pack and other information 
 
 
1. What BARACLUDE is and what it is used for 
 
Baraclude oral solution is an anti-viral medicine, used to treat chronic (long term) hepatitis B 
virus (HBV) infection in adults. Baraclude can be used in people whose liver is damaged but still 
functions properly (compensated liver disease) and in people whose liver is damaged and does not 
function properly (decompensated liver disease). 
 
Baraclude oral solution is also used to treat chronic (long term) HBV infection in children and 
adolescents aged 2 years to less than 18 years. Baraclude can be used in children whose liver is 
damaged but still functions properly (compensated liver disease). 
 
Infection by the hepatitis B virus can lead to damage to the liver. Baraclude reduces the amount of 
virus in your body, and improves the condition of the liver. 
 
 
2. What you need to know before you take BARACLUDE 
 
Do not take Baraclude 
 if you are allergic (hypersensitive) to entecavir or any of the other ingredients of this medicine 

(listed in section 6). 
 
Warning and precautions 
Talk to your doctor or pharmacist before taking Baraclude 
 if you have ever had problems with your kidneys, tell your doctor. This is important because 

Baraclude is eliminated from your body through the kidneys and your dose or dosing schedule 
may need to be adjusted. 

 
 do not stop taking Baraclude without your doctor’s advice since your hepatitis may worsen 

after stopping treatment. When your treatment with Baraclude is stopped, your doctor will 
continue to monitor you and take blood tests for several months. 

 
 discuss with your doctor whether your liver functions properly and, if not, what the possible 

effects on your Baraclude treatment may be. 
 



 68 

 if you are also infected with HIV (human immunodeficiency virus) be sure to tell your doctor. 
You should not take Baraclude to treat your hepatitis B infection unless you are taking 
medicines for HIV at the same time, as the effectiveness of future HIV treatment may be 
reduced. Baraclude will not control your HIV infection. 

 
 taking Baraclude will not stop you from infecting other people with hepatitis B virus 

(HBV) through sexual contact or body fluids (including blood contamination). So, it is 
important to take appropriate precautions to prevent others from becoming infected with HBV. 
A vaccine is available to protect those at risk from becoming infected with HBV. 

 
 Baraclude belongs to a class of medicines that can cause lactic acidosis (excess of lactic acid 

in your blood) and enlargement of the liver. Symptoms such as nausea, vomiting and stomach 
pain might indicate the development of lactic acidosis. This rare but serious side effect has 
occasionally been fatal. Lactic acidosis occurs more often in women, particularly if they are 
very overweight. Your doctor will monitor you regularly while you are receiving Baraclude. 

 
 if you have previously received treatment for chronic hepatits B, please inform your doctor. 
 
Children and adolescents 
Baraclude should not be used for children below 2 years of age or weighing less than 10 kg. 
 
Other medicines and Baraclude 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Baraclude with food and drink 
In most cases you may take Baraclude with or without food. However, if you have had a previous 
treatment with a medicine containing the active substance lamivudine you should consider the 
following. If you were switched over to Baraclude because the treatment with lamivudine was not 
successful, you should take Baraclude on an empty stomach once daily. If your liver disease is very 
advanced, your doctor will also instruct you to take Baraclude on an empty stomach.Empty stomach 
means at least 2 hours after a meal and at least 2 hours before your next meal. 
 
Children and adolescents (from 2 to less than 18 years of age) can take Baraclude with or without 
food. 
 
Pregnancy, breast-feeding and fertility 
Tell your doctor if you are pregnant or planning to become pregnant. It has not been demonstrated that 
Baraclude is safe to use during pregnancy. Baraclude must not be used during pregnancy unless 
specifically directed by your doctor. It is important that women of childbearing age receiving 
treatment with Baraclude use an effective method of contraception to avoid becoming pregnant. 
 
You should not breast-feed during treatment with Baraclude. Tell your doctor if you are breast-
feeding. It is not known whether entecavir, the active ingredient in Baraclude, is excreted in human 
breast milk. 
 
Driving and using machines 
Dizziness, tiredness (fatigue) and sleepiness (somnolence) are common side effects which may impair 
your ability to drive and use machines. If you have any concerns consult your doctor. 
 
Baraclude contains maltitol, methylhydroxybenzoate (E218), propylhydroxybenzoate (E216) 
and sodium 
This medicinal product contains maltitol. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
This product contains methylhydroxybenzoate (E218) and propylhydroxybenzoate (E216) that may 
cause allergic reactions (possibly delayed). 



 69 

This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-
free’. 
 
 
3. How to take BARACLUDE 
 
Not all patients need to take the same dose of Baraclude. 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.  
 
For adults the recommended dose is either 0.5 mg (10 ml) or 1 mg (20 ml) once daily orally (by 
mouth). 
 
Your dose will depend on: 
 whether you have been treated for HBV infection before, and what medicine you received. 
 whether you have kidney problems. Your doctor may prescribe a lower dose for you or instruct 

you to take it less often than once a day. 
 the condition of your liver.  
 
For children and adolescents (from 2 to less than 18 years of age), your child's doctor will decide the 
right dose based on your child's weight. The correct dose of Baraclude oral solution for children and 
adolescents is calculated by body weight and is taken once daily orally (by mouth) as shown below: 

Body Weight Recommended Once Daily Dose of Oral Solution 
10.0 - 14.1 kg 4.0 ml 
14.2 - 15.8 kg 4.5 ml 
15.9 - 17.4 kg 5.0 ml 
17.5 - 19.1 kg 5.5 ml 
19.2 - 20.8 kg 6.0 ml 
20.9 - 22.5 kg 6.5 ml 
22.6 - 24.1 kg 7.0 ml 
24.2 - 25.8 kg 7.5 ml 
25.9 - 27.5 kg 8.0 ml 
27.6 - 29.1 kg 8.5 ml 
29.2 - 30.8 kg 9.0 ml 
30.9 - 32.5 kg 9.5 ml 

At least 32.6 kg 10.0 ml 
There are no dosing recommendations for Baraclude in children less than 2 years of age or weighing 
less than 10 kg. 
 
Your doctor will advise you on the dose that is right for you. Always take the dose recommended by 
your doctor to ensure that your medicine is fully effective and to reduce the development of resistance 
to treatment. Take Baraclude as long as your doctor has told you. Your doctor will tell you if and when 
you should stop the treatment. 
 
Baraclude oral solution is designed as a ready-to-use product. Do not dilute or mix this solution with 
water or anything else. 
 
Baraclude oral solution comes with a measuring spoon with markings from 0.5 up to 10 milliliters. 
Use the spoon as follows: 
 



 70 

1. Hold the spoon in a vertical (upright) position and fill it 
gradually to the mark corresponding to the prescribed 
dose. Holding the spoon with the volume marks facing 
you, check that it has been filled to the proper mark. 

 
2. Swallow the medicine directly from the measuring spoon. 
 
3. After each use, rinse the spoon with water and allow it to 

air dry. 
 

 
 
Some patients must take Baraclude on an empty stomach (see Baraclude with food and drink in 
Section 2). If your doctor instructs you to take Baraclude on an empty stomach, empty stomach means 
at least 2 hours after a meal and at least 2 hours before your next meal. 
 
If you take more Baraclude than you should 
Contact your doctor at once. 
 
If you forget to take Baraclude 
It is important that you do not miss any doses. If you miss a dose of Baraclude, take it as soon as 
possible, and then take your next scheduled dose at its regular time. If it is almost time for your next 
dose, do not take the missed dose. Wait and take the next dose at the regular time. Do not take a 
double dose to make up for a forgotten dose. 
 
Do not stop Baraclude without your doctor’s advice 
Some people get very serious hepatitis symptoms when they stop taking Baraclude. Tell your doctor 
immediately about any changes in symptoms that you notice after stopping treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Patients treated with Baraclude have reported the following side effects: 
 
Adults 
 common (at least 1 in 100 patients): headache, insomnia (inability to sleep), fatigue (extreme 

tiredness), dizziness, somnolence (sleepiness), vomiting, diarrhoea, nausea, dyspepsia 
(indigestion), and increased blood levels of liver enzymes. 

 uncommon (at least 1 in 1,000 patients): rash, hair loss. 
 rare (at least 1 in 10,000 patients): severe allergic reaction. 
 
Children and adolescents 
The side effects experienced in children and adolescents are similar to those experienced in adults as 
described above with the following difference: 
Very common (at least 1 in 10 patients): low levels of neutrophils (one type of white blood cells, 
which are important in fighting infection). 
 



 71 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist or. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store BARACLUDE 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on bottle or carton after EXP. That 
expiry date refers to the last day of that month. 
 
Do not store above 30°C. Keep the bottle in the outer carton in order to protect from light. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Baraclude contains 
 The active substance is entecavir. Each ml of oral solution contains 0.05 mg entecavir. 
 The other ingredients are: citric acid anhydrous, maltitol (E965), methylhydroxybenzoate 

(E218), propylhydroxybenzoate (E216), orange flavour (acacia and natural flavours), sodium 
citrate, sodium hydroxide, hydrochloric acid and purified water. 

 
What Baraclude looks like and contents of the pack 
The oral solution is a clear, colorless to pale yellow solution. Baraclude 0.05 mg/ml oral solution is 
supplied in a bottle containing 210 ml oral solution. Each carton includes a measuring spoon 
(polypropylene) with markings from 0.5 ml up to 10 ml 
 
Marketing Authorisation Holder and Manufacturer 
Marketing Authorisation Holder: 
Bristol-Myers Squibb Pharma EEIG  
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
Manufacturer: 
CATALENT ANAGNI S.R.L.  
Loc. Fontana del Ceraso snc  
Strada Provinciale 12 Casilina, 41 
03012 Anagni (FR) 
Italy 
 
Swords Laboratories T/A Bristol-Myers Squibb Pharmaceutical Operations, External Manufacturing 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 



 72 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
Belgique/België/Belgien 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Lietuva 
Bristol-Myers Squibb Kft. 
Tel: + 370 52 369140 
 

България 
Bristol-Myers Squibb Kft. 
Teл.: + 359 2 4942 480  
 

Luxembourg/Luxemburg 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Česká republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 420 221 016 111 
 

Magyarország 
Bristol-Myers Squibb Kft. 
Tel.: + 36 1 9206 550 
 

Danmark 
Bristol-Myers Squibb 
Tlf: + 45 45 93 05 06 
 

Malta 
Bristol-Myers Squibb S.r.l. 
Tel: + 356 23976333 
 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: 0800 0752002 (+49 (0)89 121 42-350) 

Nederland 
Bristol-Myers Squibb B.V. 
Tel: + 31 (0)30 300 2222 
 

Eesti 
Bristol-Myers Squibb Kft. 
Tel: + 372 640 1030 
 

Norge 
Bristol-Myers Squibb Norway Ltd 
Tlf: + 47 67 55 53 50 
 

Ελλάδα 
Bristol-Myers Squibb A.E. 
Τηλ: + 30 210 6074300 
 

Österreich 
Bristol-Myers Squibb GesmbH 
Tel: + 43 1 60 14 30 
 

España 
Bristol-Myers Squibb, S.A. 
Tel: + 34 91 456 53 00 
 

Polska 
Bristol-Myers Squibb Polska Sp. z o.o. 
Tel.: + 48 22 2606400 
 

France 
Bristol-Myers Squibb SARL 
Tél: + 33 (0)1 58 83 84 96 
 

Portugal 
Bristol-Myers Squibb Farmacêutica Portuguesa, 
S.A. 
Tel: + 351 21 440 70 00 
 

Hrvatska 
Bristol-Myers Squibb spol. s r.o. 
TEL: + 385 1 2078 508 
 

România 
Bristol-Myers Squibb Kft. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: + 353 (0)1 483 3625 
 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 386 1 2355 100 
 

Ísland 
Bristol-Myers Squibb AB hjá Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 20833 600 
 

Italia 
Bristol-Myers Squibb S.r.l. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
Oy Bristol-Myers Squibb (Finland) Ab 
Puh/Tel: + 358 9 251 21 230 
 



 73 

Κύπρος 
Bristol-Myers Squibb A.E. 
Τηλ: + 357 800 92666 
 

Sverige 
Bristol-Myers Squibb AB 
Tel: + 46 8 704 71 00 
 

Latvija 
Bristol-Myers Squibb Kft. 
Tel: + 371 66164750 
 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 44 (0800) 731 1736 
 

 
 
The measuring spoon is manufactured by: Comar Plastics Division, One Comar Place, Buena, NJ 
08310, USA. 
 
Authorised Representative in the EEA for Comar Plastics: MDSS GmbH, Schiffgraben 41, 30175 
Hannover, Germany 
 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 
 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET