Baraclude 0.5 mg film coated tablets

1. to add Swords Laboratories T/A Bristol-Myers Squibb Pharmaceutical Operations, External Manufacturing [Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland] as an alternative site responsible for batch release
2. to change the name and amend the address of the site responsible for batch release from Bristol-Myers Squibb S.r.l. [Contrada Fontana del Ceraso, 03012 Anagni (FR), Italy] to CATALENT ANAGNI S.R.L. [Loc. Fontana del Ceraso snc, Strada Provinciale 12 Casilina, 41 03012 Anagni (FR), Italy].

Approved Product Information (PI) changes:

• to briefly reflect data in the final clinical study reports for Study AI463-080
• to remove information on the PK of ETV in lamivudine-experienced paediatric patients currently presented in section 5.2 (as requested by CHMP)
• to remove the word “ongoing” from the descriptions of studies AI463-028 and AI463-189

4.       Possible side effects

Patients treated with Baraclude have reported the following side effects:

Adults

• common (at least 1 in 100 patients): headache, insomnia (inability to sleep), fatigue (extreme tiredness), dizziness, somnolence (sleepiness), vomiting, diarrhoea, nausea, dyspepsia (indigestion), and increased blood levels of liver enzymes.
• uncommon (at least 1 in 1,000 patients): rash, hair loss.
• rare (at least 1 in 10,000 patients): severe allergic reaction.

Children and adolescents

The side effects experienced in children and adolescents are similar to those experienced in adults as described above with the following difference:

Very common (at least 1 in 10 patients): low levels of neutrophils (one type of white blood cells, which are important in fighting infection).

4.8     Undesirable effects

d. 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 a. Summary of the safety profile and section 5.1) with the following exception in the paediatric patients:

• very common adverse reactions: neutropenia.

The address of the Marketing Authorisation Holder has been changed.

This type II variation has been submitted further to the CHMP request following the study report submitted for study AI463-111, where BMS was requested to update the SmPC with regard to the fact that ETV monotherapy is not optimal in patients with LVD-r.  

As a result of this variation,  

·         Sections 4.2 and 4.4 of the SmPC were updated to initiate combination therapy with entecavir plus a second antiviral agent, instead of entecavir monotherapy, in patients with lamivudine-resistant hepatitis B virus infection.

·         Section 4.1 of the SmPC was updated to include a cross reference to section 4.2 with respect to patients with lamivudine-refractory hepatitis B.

·         We also took the opportunity to update the list of local representatives in the Package Leaflet.

·         and brought the PI in line with the latest QRD template version 9.

This type II variation has been submitted further to the CHMP request following the study report submitted for study AI463-111, where BMS was requested to update the SmPC with regard to the fact that ETV monotherapy is not optimal in patients with LVD-r.  

As a result of this variation,  

·         Sections 4.2 and 4.4 of the SmPC were updated to initiate combination therapy with entecavir plus a second antiviral agent, instead of entecavir monotherapy, in patients with lamivudine-resistant hepatitis B virus infection.

·         Section 4.1 of the SmPC was updated to include a cross reference to section 4.2 with respect to patients with lamivudine-refractory hepatitis B.

·         We also took the opportunity to update the list of local representatives in the Package Leaflet.

·         and brought the PI in line with the latest QRD template version 9.

§  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.

§  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.

Women of childbearing potential: given that the potential risks to the developing foetus are

unknown, women of childbearing potential should use effective contraception.

Breastfeeding: it is unknown whether entecavir is excreted in human breast milk. Animal studies

have shown excretion of entecavir in breast milk (for details

see section 5.3). A risk to the infants cannot be excluded

. Breastfeeding is not recommendedshould be

discontinued

during treatment with Baraclude.

Women of childbearing potential: given that the potential risks to the developing foetus are

unknown, women of childbearing potential should use effective contraception.

Breastfeeding: it is unknown whether entecavir is excreted in human breast milk. Animal studies

have shown excretion of entecavir in breast milk (for details

see section 5.3). A risk to the infants cannot be excluded

. Breastfeeding is not recommendedshould be

discontinued

during treatment with Baraclude.

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.

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/.

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.

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/.