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§ decompensated liver disease (see section 4.4)
For both compensated and decompensated liver disease, this indication is based on clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg negative HBV infection. With respect to patients with lamivudine-refractory hepatitis B, see sections 4.4 and 5.1.
Decompensated liver disease
The recommended dose for patients with decompensated liver disease is 1 mg once daily, which must
be taken on an empty stomach (more than 2 hours before or more than 2 hours after a meal) (see
section 5.2). For patients with lamivudine-refractory hepatitis B, see sections 4.4 and 5.1.
In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended.
Patients with decompensated cirrhosisliver disease: a higher rate of serious hepatic adverse events (regardless of causality) has been observed in patients with decompensated cirrhosisliver disease, in particular in those with Child‑Turcotte‑Pugh (CTP) class C disease, compared with rates in patients with compensated liver function. This observation is based on limited experience in 45 Also, patients with Child-Pugh score ³ 7 at the start of entecavir treatment. These patients should be regularly monitored for clinical, virological and serological parameters associated with hepatitis B, liver and renal function and antiviral response during treatment, and if treatment is discontinued, for at least 6 months thereafter. Patients experiencing signs of hepatic insufficiency during or post-treatment should be monitored more frequently as appropriate. Patients with decompensated cirrhosisliver 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).
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.
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%..
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 and , 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. 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.
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 and , 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.
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.
4.6
Pregnancy Fertility, pregnancy and lactation
There
Women of childbearing potential: given that the potential risks to the developing foetus are unknown, women of childbearing potential should use effective contraception.
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.
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.
Given that the potential risks to the developing foetus are unknown, women of child-bearing potential
should use effective contraception.
It
Breastfeeding: it is unknown whether entecavir is excreted in human breast milk. Animal studies
Available toxicological data in animals
have shown excretion of entecavir in breast milk (for details see section 5.3). A risk to the infants cannot be excluded
see section 5.3). A risk to the infants cannot be excluded
. Breastfeeding is not recommendedshould be discontinued
discontinued
during treatment with Baraclude.
Fertility:
toxicology studies in animals administered entecavir have shown no evidence of impaired fertility (see section 5.3). Section 4.8 has been updated: Assessment of adverse reactions is based on four clinical studies in which 1,720 patients with chronic hepatitis B infection received double-blind treatment with entecavir 0.5 mg/day (n = 679), entecavir 1 mg/day (n = 183), or lamivudine (n = 858) for up to 107 weeks. The safety profiles of entecavir and lamivudine, including laboratory test abnormalities, were comparable in these studies. The a. Summary of the safety profile In clinical studies in patients with compensated liver disease, the
fertility (see section 5.3). Section 4.8 has been updated: Assessment of adverse reactions is based on four clinical studies in which 1,720 patients with chronic hepatitis B infection received double-blind treatment with entecavir 0.5 mg/day (n = 679), entecavir 1 mg/day (n = 183), or lamivudine (n = 858) for up to 107 weeks. The safety profiles of entecavir and lamivudine, including laboratory test abnormalities, were comparable in these studies. The
Assessment of adverse reactions is based on four clinical studies in which 1,720 patients with chronic
hepatitis B infection received double-blind treatment with entecavir 0.5 mg/day (n = 679), entecavir
1 mg/day (n = 183), or lamivudine (n = 858) for up to 107 weeks. The safety profiles of entecavir and
lamivudine, including laboratory test abnormalities, were comparable in these studies.
The
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%).
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
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
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
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Version 1.0
02.09.2010
6
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.
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 (
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 (
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.
undesirable effects are presented in order of decreasing seriousness.
Experience in nucleoside naive patients (HBeAg positive and negative): The safety profile is based on treatment exposure to entecavir 0.5 mg once daily for a median of 53 weeks.
Experience in nucleoside naive patients (HBeAg positive and negative):
The safety profile is based on treatment exposure to entecavir 0.5 mg once daily for a median of
53 weeks.
Immune system disorders:
rare: anaphylactoid reaction
Psychiatric disorders:
common: insomnia
Nervous system disorders:
common: headache, dizziness, somnolence
Gastrointestinal disorders:
common: vomiting, diarrhoea, nausea, dyspepsia
General
Hepatobiliary disorders and administration site conditions:
administration site conditions:
common:
fatigue increased transaminases
Psychiatric
Skin and subcutaneous tissue
disorders:
uncommon: rash, alopecia
General disorders and administration site conditions:
General disorders and administration site
conditions:
common: fatigue
Laboratory test abnormalities: 2% of patients had ALT elevations both > 10 times upper limit of the normal range (ULN) and > 2 times baseline, 5% 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. 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/mm
Laboratory test abnormalities: 2% of patients had ALT elevations both > 10 times upper limit of the
normal range (ULN) and > 2 times baseline, 5% 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.
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/mm
3 in < 1%.
Cases of lactic acidosis have been reported, often in association with hepatic decompensation, other serious medical conditions or drug exposures (see section 4.4).
Cases of lactic acidosis have been reported, often in association with hepatic decompensation, other
serious medical conditions or drug exposures (see section 4.4).
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
0.5 mg film‑coated tablets Each tablet contains 0.5 mg or 1 mg entecavir (as monohydrate). Excipients: each 0.5 mg tablet contains 120.5 mg lactose. 1.0 mg film‑coated tablets Each tablet contains 1 mg entecavir (as monohydrate). Excipients: and each 1 mg tablet contains 241 mg lactose. 0.05 mg/ml oral solution Each ml oral solution contains 0.05 mg entecavir (as monohydrate). Excipient: 650380 mg maltitol liquid/ml 21.5 mg methylhydroxybenzoate/ml 0.2818 mg propylhydroxybenzoate/ml 4.2 Posology and method of administration Lamivudine-refractory patients (i.e. with evidence of viraemia while on lamivudine or the presence of lamivudine resistance [LVDr] mutations) (see sections 4.4 and 5.1): the recommended dose is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before or more than 2 hours after a meal) (see sections 4.4, 5.1 and 5.2). 4.4 Special warnings and precautions for use Oral Solution Maltitol: Baraclude oral solution contains maltitol (13 g maltitol liquid per 20 ml dose). Baraclude may have a mild laxative effect. Calorific value 2.3 kcal/g 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). 4.8 Undesirable effects Postmarketing experience: in addition to the adverse drug reactions identified from clinical trials, the following adverse reaction hasreactions have been identified during post-approval use of entecavir. Skin and subcutaneous tissueImmune system disorders: frequency not known: rashanaphylactoid reaction Skin and subcutaneous tissue disorders: frequency not known: rash, alopecia 4.9 Overdose No caseThere is limited experience of entecavir overdose has been 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. 5.1 Pharmacodynamic properties (.) 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 at > 4 times the Cmax of entecavir.or emtricitabine. (....) 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 x ULN. All 57 patients remained positive for HBsAg. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26th26 June 2006 10. DATE OF REVISION OF THE TEXT 10 February04 August 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu//. http://www.emea.europa.eu/.
Each tablet contains 0.5 mg or 1 mg entecavir (as monohydrate).
Excipients: each 0.5 mg tablet contains 120.5 mg lactose.
1.0 mg film‑coated tablets
Each tablet contains 1 mg entecavir (as monohydrate).
Excipients: and each 1 mg tablet contains 241 mg lactose.
0.05 mg/ml oral solution
Each ml oral solution contains 0.05 mg entecavir (as monohydrate).
Excipient: 650380 mg maltitol liquid/ml 21.5 mg methylhydroxybenzoate/ml 0.2818 mg propylhydroxybenzoate/ml
4.2 Posology and method of administration
Lamivudine-refractory patients (i.e. with evidence of viraemia while on lamivudine or the presence of lamivudine resistance [LVDr] mutations) (see sections 4.4 and 5.1): the recommended dose is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before or more than 2 hours after a meal) (see sections 4.4, 5.1 and 5.2).
4.4 Special warnings and precautions for use
Oral Solution
Maltitol: Baraclude oral solution contains maltitol (13 g maltitol liquid per 20 ml dose). Baraclude may have a mild laxative effect. Calorific value 2.3 kcal/g 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).
4.8 Undesirable effects
Postmarketing experience: in addition to the adverse drug reactions identified from clinical trials, the following adverse reaction hasreactions have been identified during post-approval use of entecavir. Skin and subcutaneous tissueImmune system disorders: frequency not known: rashanaphylactoid reaction Skin and subcutaneous tissue disorders: frequency not known: rash, alopecia 4.9 Overdose No caseThere is limited experience of entecavir overdose has been 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. 5.1 Pharmacodynamic properties (.) 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 at > 4 times the Cmax of entecavir.or emtricitabine. (....) 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 x ULN. All 57 patients remained positive for HBsAg. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26th26 June 2006 10. DATE OF REVISION OF THE TEXT 10 February04 August 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu//. http://www.emea.europa.eu/.
Postmarketing experience: in addition to the adverse drug reactions identified from clinical trials, the following adverse reaction hasreactions have been identified during post-approval use of entecavir.
Skin and subcutaneous tissueImmune system disorders:
frequency not known: rashanaphylactoid reaction
Skin and subcutaneous tissue disorders: frequency not known: rash, alopecia 4.9 Overdose No caseThere is limited experience of entecavir overdose has been 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. 5.1 Pharmacodynamic properties (.) 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 at > 4 times the Cmax of entecavir.or emtricitabine. (....) 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 x ULN. All 57 patients remained positive for HBsAg. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26th26 June 2006 10. DATE OF REVISION OF THE TEXT 10 February04 August 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu//. http://www.emea.europa.eu/.
Skin and subcutaneous tissue disorders:
frequency not known: rash, alopecia
4.9 Overdose
No caseThere is limited experience of entecavir overdose has been 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.
5.1 Pharmacodynamic properties (.) 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 at > 4 times the Cmax of entecavir.or emtricitabine. (....) 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 x ULN. All 57 patients remained positive for HBsAg. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26th26 June 2006 10. DATE OF REVISION OF THE TEXT 10 February04 August 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu//. http://www.emea.europa.eu/.
5.1 Pharmacodynamic properties
(.)
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 at > 4 times the Cmax of entecavir.or emtricitabine.
(....) 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 x ULN. All 57 patients remained positive for HBsAg. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26th26 June 2006 10. DATE OF REVISION OF THE TEXT 10 February04 August 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu//. http://www.emea.europa.eu/.
(....)
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 x ULN. All 57 patients remained positive for HBsAg. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26th26 June 2006 10. DATE OF REVISION OF THE TEXT 10 February04 August 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu//. http://www.emea.europa.eu/.
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26th26 June 2006 10. DATE OF REVISION OF THE TEXT 10 February04 August 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu//. http://www.emea.europa.eu/.
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
26th26 June 2006
10. DATE OF REVISION OF THE TEXT
10 February04 August 2009
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu//. http://www.emea.europa.eu/.
http://www.emea.europa.eu/.