Entecavir Mylan

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 0.5 mg film-coated tablets  
Entecavir Mylan 1 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains entecavir monohydrate equivalent to 0.5 mg entecavir. 
Each film-coated tablet contains entecavir monohydrate equivalent to 1 mg entecavir. 
 
Excipient with known effect:  
Each film-coated tablet contains 62.5 mg lactose monohydrate.  
Each film-coated tablet contains 125 mg lactose monohydrate. 
 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet).  
 
0.5 mg: white, film-coated, round, biconvex, beveled edge tablet debossed with “M” on one side and 
“EA” on the other side. Diameter: approximately 6.8 mm. 
 
1 mg: white, film-coated, round, biconvex, beveled edge tablet debossed with “M” on one side and 
“EB” on the other side. Diameter: approximately 8.8 mm. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Entecavir Mylan 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.  
  
Entecavir Mylan 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.  
 



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Entecavir Mylan is only available as 0.5 and 1 mg film-coated tablets. For patients who are not able to 
swallow tablets, or for whom a dose reduction is recommended, other entecavir-containing products 
with more suitable formulations may be available. 
 
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 Entecavir Mylan 0.5 mg Film-coated Tablets are 
available and for doses below 0.5 mg an oral solution may be 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 with or without food. An 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 an oral solution is recommended. As an alternative, in case the oral solution is 
not available, the dose can be adjusted by increasing the dosage interval, as detailed 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.   
  

 
Creatinine clearance 

(ml/min) 
 

Entecavir dosage* 

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 entecavir 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  
  
Entecavir Mylan 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 



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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.  
  
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).  
  



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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 lactose. Patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
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. 
Entecavir Mylan 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 Entecavir Mylan.  
  
Fertility 
 
Toxicology studies in animals administered entecavir have shown no evidence of impaired fertility 
(see section 5.3). 
 



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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 
 
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 Description of selected adverse reactions).  
  
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.  
  
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 



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(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.  
  
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.  
  
Paediatric Population  
  
The safety of entecavir in paediatric patients from 2 to <18 years of age is based on two ongoing 
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 Summary of the safety profile and 
section 5.1).  
  
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 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).  
  



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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. 
 
 
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.  
  



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An analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical HIV-1 
isolates using a variety of cells and assay conditions yielded EC50 values ranging from 0.026 to 
>10 µM; the lower EC50 values were observed when decreased levels of virus were used in the assay. 
In cell culture, entecavir selected for an M184I substitution at micromolar concentrations, confirming 
inhibitory pressure at high entecavir concentrations. HIV variants containing the M184V substitution 
showed loss of susceptibility to entecavir (see section 4.4).  
  
In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir or 
zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of 
concentrations. In HIV antiviral assays, entecavir at micromolar concentrations was not antagonistic to 
the anti-HIV activity in cell culture of these six NRTIs or emtricitabine.   
  
Resistance in cell culture 
 
Relative to wild-type HBV, LVDr viruses containing rtM204V and rtL180M substitutions within the 
reverse transcriptase exhibit 8-fold decreased susceptibility to entecavir. Incorporation of additional 
ETVr amino acid changes rtT184, rtS202 or rtM250 decreases entecavir susceptibility in cell culture. 
Substitutions observed in clinical isolates (rtT184A, C, F, G, I, L, M or S; rtS202 C, G or I; and/or 
rtM250I, L or V) further decreased entecavir susceptibility 16- to 741-fold relative to wild-type virus. 
The ETVr substitutions at residues rtT184, rtS202 and rtM250 alone have only a modest effect on 
entecavir susceptibility, and have not been observed in the absence of LVDr substitutions in more than 
1000 patient samples sequenced. Resistance is mediated by reduced inhibitor binding to the altered 
HBV reverse transcriptase, and resistant HBV exhibits reduced replication capacity in cell culture.  
  
Clinical experience 
 
The demonstration of benefit is based on histological, virological, biochemical, and serological 
responses after 48 weeks of treatment in active-controlled clinical trials of 1,633 adults with chronic 
hepatitis B infection, evidence of viral replication and compensated liver disease. The safety and 
efficacy of entecavir were also evaluated in an active-controlled clinical trial of 191 HBV-infected 
patients with decompensated liver disease and in a clinical trial of 68 patients co-infected with HBV 
and HIV.  
  
In studies in patients with compensated liver disease, histological improvement was defined as a ≥2-
point decrease in Knodell necro-inflammatory score from baseline with no worsening of the Knodell 
fibrosis score. Responses for patients with baseline Knodell Fibrosis Scores of 4 (cirrhosis) were 
comparable to overall responses on all efficacy outcome measures (all patients had compensated liver 
disease). High baseline Knodell necroinflammatory scores (>10) were associated with greater 
histological improvement in nucleoside-naive patients. Baseline ALT levels ≥2 times ULN and 
baseline HBV DNA ≤9.0 log10 copies/ml were both associated with higher rates of virologic response 
(Week 48 HBV DNA <400 copies/ml) in nucleoside-naive HBeAg-positive patients. Regardless of 
baseline characteristics, the majority of patients showed histological and virological responses to 
treatment.  
  
Experience in nucleoside-naive patients with compensated liver disease 
Results at 48 weeks of randomised, double blind studies comparing entecavir (ETV) to lamivudine 
(LVD) in HBeAg positive (022) and HBeAg negative (027) patients are presented in the table.  
  

  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% 



12 

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 
(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 



13 

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).  
  
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 



14 

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.  
  
   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) 
d Defined 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 



15 

lamivudine-containing HAART regimen. HAART regimens did not include emtricitabine or tenofovir 
disoproxil fumarate. At baseline entecavir-treated patients had a median duration of prior lamivudine 
therapy of 4.8 years and median CD4 count of 494 cells/mm3 (with only 5 subjects having CD4 count 
<200 cells/mm3). Patients continued their lamivudine-regimen and were assigned to add either 
entecavir 1 mg once daily (n = 51) or placebo (n = 17) for 24 weeks followed by an additional 
24 weeks where all received entecavir. At 24 weeks the reduction in HBV viral load was significantly 
greater with entecavir (-3.65 vs an increase of 0.11 log10 copies/ml). For patients originally assigned to 
entecavir treatment, the reduction in HBV DNA at 48 weeks was -4.20 log10 copies/ml, ALT 
normalisation had occurred in 37% of patients with abnormal baseline ALT and none achieved 
HBeAg seroconversion.   
  
HIV/HBV co-infected patients not receiving concomitant HAART 
Entecavir has not been evaluated in HIV/HBV co-infected patients not concurrently receiving 
effective HIV treatment. Reductions in HIV RNA have been reported in HIV/HBV co-infected 
patients receiving entecavir monotherapy without HAART. In some cases, selection of HIV variant 
M184V has been observed, which has implications for the selection of HAART regimens that the 
patient may take in the future. Therefore, entecavir should not be used in this setting due to the 
potential for development of HIV resistance (see section 4.4).  
  
Liver transplant recipients 
The safety and efficacy of entecavir 1 mg once daily were assessed in a single-arm study in 65 patients 
who received a liver transplant for complications of chronic HBV infection and had HBV DNA 
<172 IU/ml (approximately 1000 copies/ml) at the time of transplant. The study population was 82% 
male, 39% Caucasian, and 37% Asian, with a mean age of 49 years; 89% of patients had 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 an ongoing 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 normalisationa 67.5% 81.7% 23.3% 
HBV DNA <50 IU/mLa 
 
Baseline HBV 

 
 

82.6% (38/46)

 
 

82.6% (38/46)

 
 

6.5% (2/31)



16 

DNA <8 log10 IU/mL 
Baseline HBV DNA 
≥8 log10 IU/mL 

 
28.4% (21/74) 

 
52.7% (39/74) 

 
0% (0/29) 

a NC=F (noncompleter = failure) 
* Patients randomised to placebo who did not have HBe serconversion by Week 48 rolled over to open-label entecavir for 

the second year of the study; therefore randomised 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 ongoing clinical trials (028 and 189). The 
two trials provide resistance data in 183 patients treated and monitored in Year 1 and 180 patients 
treated and monitored in Year 2. Genotypic evaluations were performed for all patients with available 
samples who had virologic breakthrough through Week 96 or HBV DNA ≥50 IU/ml at Week 48 or 
Week 96. During Year 2, genotypic resistance to ETV was detected in 2 patients (1.1% cumulative 
probability of resistance through Year 2). 
 
Clinical resistance in adults 
 
Patients in clinical trials initially treated with entecavir 0.5 mg (nucleoside-naive) or 1.0 mg 
(lamivudine-refractory) and with an on-therapy PCR HBV DNA measurement at or after Week 24 
were monitored for resistance.  
 
Through Week 240 in nucleoside-naive studies, genotypic evidence of ETVr substitutions at rtT184, 
rtS202, or rtM250 was identified in 3 patients treated with entecavir, 2 of whom experienced virologic 
breakthrough (see table). These substitutions were observed only in the presence of LVDr 
substitutions (rtM204V and rtL180M).  
  

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

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

Patients treated and monitored for 
resistance b  

663 278 149 121 108 

Patients in specific year with:   
- emerging genotypic ETVr c  1 1 1 0 0 

- genotypic ETVr c with virologic   
breakthrough d 

1 0 1 0 0 

Cumulative probability of:       

- emerging genotypic ETVr c 0.2% 0.5% 1.2% 1.2% 1.2% 

- genotypic ETVr c with virologic 
breakthrough d  

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 
resistance b 

187 146 80 52 33 

Patients in specific year with:       

- emerging genotypic ETVr c 11 12 16 6 2 

- genotypic ETVr with virologic 
breakthrough d 

2 e 14 e 13 e 9 e 1 e 

Cumulative probability of:       

- emerging genotypic ETVr c 6.2% 15% 36.3% 46.6% 51.45% 

- genotypic ETVr c with virologic 
breakthrough d 

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). 
 
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%.  



18 

  
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 



19 

 
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 and 19 lamivudine-experienced 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.  
 
Entecavir exposure among lamivudine-experienced subjects receiving once daily doses of entecavir 
0.030 mg/kg up to a maximum dose of 1.0 mg was similar to the exposure achieved in adults receiving 
once daily doses of 1.0 mg. The Cmax, AUC(0-24), and Cmin for these subjects was 14.48 ng/ml, 
38.58 ng·h/ml, and 0.47 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 



20 

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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Microcrystalline cellulose 
Crospovidone 
Lactose monohydrate 
Magnesium stearate 
 
Tablet coating:  
Titanium dioxide (E171) 
Hypromellose 
Macrogol 400 
Polysorbate 80  
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions.  
 
6.5 Nature and contents of container  
 
OPA/Aluminium/PVC-Aluminium foil blister packs containing 30 film-coated tablets.  
 
OPA/Aluminium/PVC-Aluminium perforated unit-dose foil blister packs containing 30 x 1 or 90 x 1 
film-coated tablets.  
 



21 

High density polyethylene (HDPE) bottle with child-resistant polypropylene closure containing 30 or 
90 film-coated tablets.  
 
Not all pack sizes 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 
 
Mylan S.A.S. 
117 Allée des Parcs 
69800 Saint Priest 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1227/001 
EU/1/17/1227/002 
EU/1/17/1227/003 
EU/1/17/1227/004 
EU/1/17/1227/005 
EU/1/17/1227/006 
EU/1/17/1227/007 
EU/1/17/1227/008 
EU/1/17/1227/009 
EU/1/17/1227/010 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
<Date of first authorisation: {DD month YYYY}> 
<Date of latest renewal: {DD month YYYY}> 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 
  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) 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 

 
 



23 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
McDermott Laboratories Limited trading as Gerard Laboratories 
Unit 35/36 Baldoyle Industrial Estate, 
Grange Road, Dublin 13 
Ireland 
 
Mylan Hungary Kft. 
Mylan utca 1, 
Komárom - 2900 
Hungary 
 
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. 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports 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 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. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 

 
  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



26 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 0.5 mg film-coated tablets 
entecavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains entecavir monohydrate equivalent to 0.5 mg entecavir 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose. See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
30 film-coated tablets  
30 x 1 film-coated tablets 
90 x 1 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 
 
 
 



27 

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 
 
Mylan S.A.S. 
117 Allée des Parcs 
69800 Saint Priest 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1227/002 
EU/1/17/1227/003 
EU/1/17/1227/005 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Entecavir Mylan 0.5 mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
  



28 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 0.5 mg film-coated tablets 
entecavir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan S.A.S. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



29 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 0.5 mg tablets 
entecavir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan S.A.S. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



30 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 0.5 mg film-coated tablets 
entecavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains entecavir monohydrate equivalent to 0.5 mg entecavir 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose. See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Tablet 
 
30 tablets 
90 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 
 
 
 



31 

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 
 
Mylan S.A.S. 
117 Allée des Parcs 
69800 Saint Priest 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1227/001 
EU/1/17/1227/004 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Entecavir Mylan 0.5 mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



32 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 0.5 mg film-coated tablets 
entecavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains entecavir monohydrate equivalent to 0.5 mg entecavir 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose. See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Tablet 
 
30 tablets 
90 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 
 
 
 



33 

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 
 
Mylan S.A.S. 
117 Allée des Parcs 
69800 Saint Priest 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1227/001 
EU/1/17/1227/004 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
 



34 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 1 mg film-coated tablets 
entecavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains entecavir monohydrate equivalent to 1 mg entecavir 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose. See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
30 film-coated tablets  
30 x 1 film-coated tablets 
90 x 1 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 
 
 
 



35 

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 
 
Mylan S.A.S. 
117 Allée des Parcs 
69800 Saint Priest 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1227/007 
EU/1/17/1227/008 
EU/1/17/1227/010 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Entecavir Mylan 1 mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 
  



36 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 1 mg film-coated tablets 
entecavir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan S.A.S. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



37 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 1 mg tablets 
entecavir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan S.A.S. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



38 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 1 mg film-coated tablets 
entecavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains entecavir monohydrate equivalent to 1 mg entecavir 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose. See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Tablet 
 
30 tablets 
90 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 
 
 
 



39 

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 
 
Mylan S.A.S. 
117 Allée des Parcs 
69800 Saint Priest 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1227/006 
EU/1/17/1227/009 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Entecavir Mylan 1 mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



40 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Entecavir Mylan 1 mg film-coated tablets 
entecavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains entecavir monohydrate equivalent to 1 mg entecavir 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose. See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Tablet 
 
30 tablets 
90 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 
 
 
 



41 

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 
 
Mylan S.A.S. 
117 Allée des Parcs 
69800 Saint Priest 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1227/006 
EU/1/17/1227/009 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
 
 



42 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



43 

Package leaflet: Information for the user 
 

Entecavir Mylan 0.5 mg film-coated tablets 
Entecavir Mylan 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 Entecavir Mylan is and what it is used for 
2. What you need to know before you take Entecavir Mylan 
3. How to take Entecavir Mylan 
4. Possible side effects 
5. How to store Entecavir Mylan 
6. Contents of the pack and other information 
 
 
1. What Entecavir Mylan is and what it is used for 
 
Entecavir Mylan tablets are anti-viral medicines, used to treat chronic (long term) hepatitis B 
virus (HBV) infection in adults. Entecavir Mylan 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).  
  
Entecavir Mylan tablets are also used to treat chronic (long term) HBV infection in children and 
adolescents aged 2 years to less than 18 years. Entecavir Mylan 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. Entecavir Mylan reduces the amount 
of virus in your body, and improves the condition of the liver.  
 
 
2. What you need to know before you take Entecavir Mylan  
 
Do not take Entecavir Mylan 
 if you are allergic (hypersensitive) to entecavir or any of the other ingredients of this medicine 

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

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

  
 do not stop taking Entecavir Mylan without your doctor’s advice since your hepatitis may 

worsen after stopping treatment. When your treatment with Entecavir Mylan 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 Entecavir Mylan treatment may be.  



44 

  
 if you are also infected with HIV (human immunodeficiency virus) be sure to tell your doctor. 

You should not take Entecavir Mylan 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. Entecavir Mylan will not control your HIV infection.  

  
 taking Entecavir Mylan 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.  

  
 Entecavir Mylan 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 Entecavir 
Mylan.  

  
 if you have previously received treatment for chronic hepatitis B, please inform your doctor.  
  
Children and adolescents  
Entecavir Mylan should not be used for children below 2 years of age or weighing less than 10 kg.  
  
Other medicines and Entecavir Mylan  
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  
  
Entecavir Mylan with food and drink  
In most cases you may take Entecavir Mylan 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 Entecavir Mylan because the treatment with lamivudine 
was not successful, you should take Entecavir Mylan on an empty stomach once daily. If your liver 
disease is very advanced, your doctor will also instruct you to take Entecavir Mylan 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 Entecavir Mylan 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 
entecavir is safe to use during pregnancy. Entecavir Mylan must not be used during pregnancy unless 
specifically directed by your doctor. It is important that women of childbearing age receiving 
treatment with Entecavir Mylan use an effective method of contraception to avoid becoming pregnant.  
  
You should not breast-feed during treatment with Entecavir Mylan. Tell your doctor if you are 
breastfeeding. It is not known whether entecavir, the active ingredient in Entecavir Mylan, 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.  
  
Entecavir Mylan 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. 
 



45 

 
3. How to take Entecavir Mylan 
 
Not all patients need to take the same dose of Entecavir Mylan.  
  
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. Children weighing at least 32.6 kg may take the 0.5 mg tablet 
or an entecavir oral solution may be available. For patients weighing from 10 kg to 32.5 kg, an 
entecavir oral solution is recommended. All doses should be taken once daily orally (by mouth). There 
are no recommendations for entecavir in children less than 2 years of age or weighing less than 10 kg.  
 
For children and adolescents (from 2 to less than 18 years of age), Entecavir Mylan 0.5 mg Film-
coated Tablets are available or an oral solution may be available. Your child’s doctor will decide the 
right dose based on your child’s weight. 
  
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 Entecavir Mylan 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 Entecavir Mylan on an empty stomach (see Entecavir Mylan with food and 
drink in Section 2). If your doctor instructs you to take Entecavir Mylan 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 Entecavir Mylan than you should  
Contact your doctor at once.  
  
If you forget to take Entecavir Mylan  
It is important that you do not miss any doses. If you miss a dose of Entecavir Mylan, 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 Entecavir Mylan without your doctor’s advice  
Some people get very serious hepatitis symptoms when they stop taking entecavir. 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 entecavir have reported the following side effects:  



46 

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.  
 
Reporting of side effects  
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via [to be completed nationally]. By 
reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Entecavir Mylan 
 
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. 
The expiry date refers to the last day of that month. 
 
This medicinal product does not require any special storage conditions.  
 
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 Entecavir Mylan contains  
 
The active substance is entecavir. Each film-coated tablet contains entecavir monohydrate equivalent 
to 0.5 mg entecavir.  
The active substance is entecavir. Each film-coated tablet contains entecavir monohydrate equivalent 
to 1 mg entecavir.  
 
The other ingredients are: 
Tablet core: microcrystalline cellulose, crospovidone, lactose monohydrate (see section 2, “Entacavir 
Mylan contains lactose”), magnesium stearate 
Tablet coating: titanium dioxide (E171), hypromellose, macrogol 400, polysorbate 80.  
 
What Entecavir Mylan looks like and contents of the pack 
 
0.5 mg: the film-coated tablets (tablets) are white, film-coated, round, biconvex, beveled edge tablet 
debossed with “M” on one side and “EA” on the other side. 
 
1 mg: the film-coated tablets (tablets) are white, film-coated, round, biconvex, beveled edge tablet 
debossed with “M” on one side and “EB” on the other side. 
 
Entecavir Mylan 0.5 mg film-coated tablets Entecavir Mylan 1 mg film-coated tablets are supplied in 
blisters packs containing 30 tablets, perforated blister packs containing 30 x 1 or 90 x 1 tablets, and in 
bottles containing 30 or 90 tablets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder  
Mylan S.A.S. 
117 Allée des Parcs 
69800 Saint Priest 



47 

France 
 
Manufacturer 
McDermott Laboratories Limited t/a Gerard Laboratories 
Unit 35/36 Baldoyle Industrial Estate, 
Grange Road, Dublin 13 
Ireland 
 
Mylan Hungary Kft. 
Mylan utca 1, 
Komárom - 2900 
Hungary 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Mylan bvba/sprl 
Tél/Tel: + 32 (0)2 658 61 00 
 

Lietuva 
BGP Products UAB 
Tel: +370 5 205 1288 
 
 

България 
Майлан ЕООД 
Teл.: +359 2 44 55 400 
 

Luxembourg/Luxemburg 
Mylan bvba/sprl 
Tel: + 32 (0)2 658 61 00 
(Belgique/Belgien) 
 

Česká republika 
Mylan Pharmaceuticals.s.r.o. 
Tel: +420 222 004 400 
 

Magyarország 
Mylan EPD Kft 
Tel: + 36 1 465 2100  

Danmark 
Mylan AB 
Tlf: + 46 855 522 750  
(Sverige) 
 

Malta 
V.J. Salomone Pharma Ltd 
Tel: +  356 21 22 01 74 
 

Deutschland 
Mylan dura GmbH  
Tel: + 49-(0) 6172 888 01 
 

Nederland 
Mylan BV 
Tel: + 31 (0)20 426 3300 

Eesti 
BGP Products Switzerland GmbH Eesti filiaal  
Tel: + 372 6363 052 
 
 

Norge 
Mylan AB 
Tel: + 46 855 522 750 
(Sverige) 
 

Ελλάδα  
Generics Pharma Hellas ΕΠΕ  
Τηλ:  +30 210 993 6410  
 

Österreich 
Arcana Arzneimittel GmbH 
Tel: +43 1 416 2418 
 

España 
Mylan Pharmaceuticals, S.L 
Tel: + 34 900 102 712 
 

Polska 
Mylan Healthcare Sp. z.o.o. 
Tel: + 48 22 546 64 00 
 



48 

France 
Mylan S.A.S 
Tel: +33 4 37 25 75 00 
 

Portugal 
Mylan, Lda. 
Tel: + 351 21 412 72 56 
 

Hrvatska 
Mylan Hrvatska d.o.o.  
Tel: +385 1 23 50 599 
  

România 
BGP Products SRL 
Tel: + 40 372 579 000 
 

Ireland 
Mylan Ireland 
Tel: +353 (0) 87 1694982  

Slovenija 
GSP Proizvodi d.o.o. 
Tel: + 386 1 236 31 85 
 

Ísland 
Mylan AB 
Tel: + 46 855 522 750 
(Svíþjóð) 
 

Slovenská republika 
Mylan s.r.o. 
Tel: +421 2 32 199 100 

Italia 
Mylan S.p.A 
Tel: + 39 02 612 46921 
 

Suomi/Finland 
Mylan OY 
Puh/Tel: + 358 20 720 9555 
 

Κύπρος 
Pharmaceutical Trading Co. Ltd. 
Τηλ: + 357 99403969 
 

Sverige 
Mylan AB  
Tel: + 46 855 522 750 
 

Latvija 
BGP Products SIA  
Tel: +371 676 055 80 
 
 

United Kingdom 
Generics [UK] Ltd 
Tel: +44 1707 853000 

 
 
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. MANUFACTURER(S) 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