Baraclude 0.5 mg film coated tablets

  • Name:

    Baraclude 0.5 mg film coated tablets

  • Company:
    info
  • Active Ingredients:

    Entecavir monohydrate

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 04/05/20

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XPIL

Summary of Product Characteristics last updated on medicines.ie: 4/5/2020

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Bristol-Myers Squibb Pharma EEIG

Company Products

Medicine NameActive Ingredients
Medicine Name Baraclude 0.05 mg/ml oral solution Active Ingredients Entecavir monohydrate
Medicine Name Baraclude 0.5 mg film coated tablets Active Ingredients Entecavir monohydrate
Medicine Name Baraclude 1.0 mg film coated tablets Active Ingredients Entecavir monohydrate
Medicine Name OPDIVO 10 mg/mL concentrate for solution for infusion Active Ingredients Nivolumab
Medicine Name ORENCIA 125 mg solution for injection in pre-filled pen Active Ingredients Abatacept
Medicine Name ORENCIA 250 mg powder for concentrate for solution for infusion Active Ingredients Abatacept
Medicine Name ORENCIA 50 mg, 87.5 mg and 125 mg solution for injection (pre-filled syringe) Active Ingredients Abatacept
Medicine Name Reyataz 150 mg Hard Capsules Active Ingredients Atazanavir sulfate
Medicine Name Reyataz 200 mg Hard Capsules Active Ingredients Atazanavir sulfate
Medicine Name Reyataz 300 mg Hard Capsules Active Ingredients Atazanavir sulfate
Medicine Name Sprycel 20mg, 50mg, 70mg and 100mg Film-Coated Tablets Active Ingredients dasatinib monohydrate
Medicine Name Sustiva 50 mg , 100 mg , 200 mg Hard Capsules Active Ingredients Efavirenz
Medicine Name Sustiva 600 mg Film-coated Tablets Active Ingredients Efavirenz
Medicine Name Yervoy 5mg per ml concentrate for solution for infusion Active Ingredients ipilimumab
1 - 0 of 14 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 4 May 2020 PIL

Reasons for updating

  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

Free text change information supplied by the pharmaceutical company

  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].

Updated on 4 May 2020

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data

Free text change information supplied by the pharmaceutical company

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

Updated on 3 February 2020

Reasons for updating

  • File format updated to PDF

Updated on 3 February 2020 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Free text change information supplied by the pharmaceutical company

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).

Updated on 3 February 2020

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

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.

Updated on 21 May 2019 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change to other sources of information section

Updated on 25 February 2019 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 22 February 2019

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

The address of the Marketing Authorisation Holder has been changed.

Updated on 20 September 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Correction of spelling/typing errors

Updated on 20 September 2018

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

Updated on 3 July 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 14 April 2016

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 14 April 2016 SPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

  • In section 4.2 new sentence regarding Paediatric population was added (For appropriate dosing in the paediatric population, Baraclude oral solution or Baraclude 0.5 mg film-coated tablets are available.)
  • In section 4.5 lactose content was listed due to both strenghts listed in the SPC (previously both SPCs were split).
  • In section 4.8 in Paediatric Population there was correction of the sentence: These trials provide experience in 173 195 HBeAg-positive nucleoside-treatment-naïve subjects treated with entecavir for a median duration of 60 99 weeks.
  • In section 5.1 in paediatric population section results for the main efficacy endpoints at week 48 and 96 were presented.
  • In section 10 new date of revision is 1st April 2016
  • Updated on 14 April 2016 PIL

    Reasons for updating

    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
    • Change to Section 4.8 – Undesirable effects - how to report a side effect
    • Change to section 5.1 - Pharmacodynamic properties
    • Change to section 10 - Date of revision of the text

    Free text change information supplied by the pharmaceutical company

  • In section 4.2 new sentence regarding Paediatric population was added (For appropriate dosing in the paediatric population, Baraclude oral solution or Baraclude 0.5 mg film-coated tablets are available.)
  • In section 4.5 lactose content was listed due to both strenghts listed in the SPC (previously both SPCs were split).
  • In section 4.8 in Paediatric Population there was correction of the sentence: These trials provide experience in 173 195 HBeAg-positive nucleoside-treatment-naïve subjects treated with entecavir for a median duration of 60 99 weeks.
  • In section 5.1 in paediatric population section results for the main efficacy endpoints at week 48 and 96 were presented.
  • In section 10 new date of revision is 1st April 2016
  • Updated on 4 September 2014 SPC

    Reasons for updating

    • Change to section 4.1 - Therapeutic indications
    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
    • Change to section 4.8 - Undesirable effects
    • Change to Section 4.8 – Undesirable effects - how to report a side effect
    • Change to section 5.1 - Pharmacodynamic properties
    • Change to section 5.2 - Pharmacokinetic properties
    • Change to section 5.3 - Preclinical safety data
    • Change to section 6.5 - Nature and contents of container
    • Change to section 10 - Date of revision of the text

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    SmPC updated with the paediatric indication, paediatric posology and information on the paediatric studies.

    Updated on 4 September 2014 PIL

    Reasons for updating

    • Change to section 4.1 - Therapeutic indications
    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
    • Change to section 4.8 - Undesirable effects
    • Change to Section 4.8 – Undesirable effects - how to report a side effect
    • Change to section 5.1 - Pharmacodynamic properties
    • Change to section 5.2 - Pharmacokinetic properties
    • Change to section 5.3 - Preclinical safety data
    • Change to section 6.5 - Nature and contents of container
    • Change to section 10 - Date of revision of the text

    Free text change information supplied by the pharmaceutical company

    SmPC updated with the paediatric indication, paediatric posology and information on the paediatric studies.

    Updated on 26 February 2014 SPC

    Reasons for updating

    • Change to section 5.1 - Pharmacodynamic properties

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    A typo was noted in the SPC following the update from the safety Ty[pe II varaition (ETV combination treatement in LVD-r patients) in Jan 2014, and therefore has been corrected and updated.

    Updated on 26 February 2014 PIL

    Reasons for updating

    • Change to section 5.1 - Pharmacodynamic properties

    Free text change information supplied by the pharmaceutical company

    A typo was noted in the SPC following the update from the safety Ty[pe II varaition (ETV combination treatement in LVD-r patients) in Jan 2014, and therefore has been corrected and updated.

    Updated on 3 February 2014 PIL

    Reasons for updating

    • Change to section 4.1 - Therapeutic indications
    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 10 - Date of revision of the text

    Free text change information supplied by the pharmaceutical company

    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.

    Updated on 3 February 2014 SPC

    Reasons for updating

    • Change to section 4.1 - Therapeutic indications
    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 10 - Date of revision of the text

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    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.

    Updated on 16 November 2012 SPC

    Reasons for updating

    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 5.1 - Pharmacodynamic properties

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    Update to sections 4.4 and 5.1 to include information on liver transplant recipients with chronic HBV infection.

    Updated on 16 November 2012 PIL

    Reasons for updating

    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 5.1 - Pharmacodynamic properties

    Free text change information supplied by the pharmaceutical company

    Update to sections 4.4 and 5.1 to include information on liver transplant recipients with chronic HBV infection.

    Updated on 23 August 2012 PIL

    Reasons for updating

    • Correction of spelling/typing errors

    Free text change information supplied by the pharmaceutical company

    Spelling errors updated and document has been formatted.

    Updated on 23 August 2012 SPC

    Reasons for updating

    • Correction of spelling/typing errors

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    Spelling errors updated and document has been formatted.

    Updated on 27 May 2011 PIL

    Reasons for updating

    • Change to section 4.2 - Posology and method of administration
    • Change to section 6.6 - Special precautions for disposal and other handling

    Free text change information supplied by the pharmaceutical company

    Very minor changes have been made to the SPC following a renewal.

    Updated on 27 May 2011 SPC

    Reasons for updating

    • Change to section 4.2 - Posology and method of administration
    • Change to section 6.6 - Special precautions for disposal and other handling

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    Very minor changes have been made to the SPC following a renewal.

    Updated on 9 March 2011 SPC

    Reasons for updating

    • Change to section 4.1 - Therapeutic indications
    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 4.8 - Undesirable effects

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    The following changes have been made to the SPC:

    Section 4.1:

    §  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.



    Section 4.2:

    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.



    Section 4.4:

    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.


    Section 4.8:

    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.



     

     

    Updated on 9 March 2011 PIL

    Reasons for updating

    • Change to section 4.1 - Therapeutic indications
    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 4.8 - Undesirable effects

    Free text change information supplied by the pharmaceutical company

    The following changes have been made to the SPC:

    Section 4.1:

    §  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.



    Section 4.2:

    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.



    Section 4.4:

    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.


    Section 4.8:

    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.



     

     

    Updated on 10 September 2010 SPC

    Reasons for updating

    • Change to section 4.6 - Pregnancy and lactation
    • Change to section 4.8 - Undesirable effects

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    Section 4.6 has been updated:

    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.

    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.

    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

     

     

    . Breastfeeding is not recommendedshould be

     

    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

     

     

    most common adverse reactions of

     

    any severity with at least a possible relation to entecavir were headache (9%), fatigue (6%), dizziness

    (4%) and nausea (3%).

     

    Exacerbations of hepatitis during and after discontinuation of entecavir therapy

     

    have also been reported (see section 4.4 and

     

     

    c. Description of selected adverse reactions).

     

     

     

     

     

    b. Tabulated list of adverse reactions

     

     

     

     

    Assessment of adverse reactions is based on experience from postmarketing surveillance and four

    clinical studies in which 1,720 patients with chronic hepatitis B infection and compensated liver

    disease received double-blind treatment with entecavir (n = 862) or lamivudine (n = 858) for up to

    107 weeks (see section 5.1). In these studies, the safety profiles, including laboratory abnormalities,

    were comparable for entecavir 0.5 mg daily (679 nucleoside-naive HBeAg positive or negative

     

     

     

     

    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.

     

     

     

     

    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.

     

     

     

    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:

     

     

     

     

    common:

     

    fatigue increased transaminases

     

     

     

     

     

    Psychiatric

     

     

    Skin and subcutaneous tissue

     

     

     

     

     

    disorders:

     

     

     

    common: insomnia

     

     

    uncommon: rash, alopecia

     

     

     

     

     

    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

     

     

    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).

     

     

     

    Updated on 10 September 2010 PIL

    Reasons for updating

    • Change to section 4.6 - Pregnancy and lactation
    • Change to section 4.8 - Undesirable effects

    Free text change information supplied by the pharmaceutical company

    Section 4.6 has been updated:

    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.

    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.

    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

     

     

    . Breastfeeding is not recommendedshould be

     

    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

     

     

    most common adverse reactions of

     

    any severity with at least a possible relation to entecavir were headache (9%), fatigue (6%), dizziness

    (4%) and nausea (3%).

     

    Exacerbations of hepatitis during and after discontinuation of entecavir therapy

     

    have also been reported (see section 4.4 and

     

     

    c. Description of selected adverse reactions).

     

     

     

     

     

    b. Tabulated list of adverse reactions

     

     

     

     

    Assessment of adverse reactions is based on experience from postmarketing surveillance and four

    clinical studies in which 1,720 patients with chronic hepatitis B infection and compensated liver

    disease received double-blind treatment with entecavir (n = 862) or lamivudine (n = 858) for up to

    107 weeks (see section 5.1). In these studies, the safety profiles, including laboratory abnormalities,

    were comparable for entecavir 0.5 mg daily (679 nucleoside-naive HBeAg positive or negative

     

     

     

     

    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.

     

     

     

     

    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.

     

     

     

    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:

     

     

     

     

    common:

     

    fatigue increased transaminases

     

     

     

     

     

    Psychiatric

     

     

    Skin and subcutaneous tissue

     

     

     

     

     

    disorders:

     

     

     

    common: insomnia

     

     

    uncommon: rash, alopecia

     

     

     

     

     

    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

     

     

    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).

     

     

     

    Updated on 3 September 2009 SPC

    Reasons for updating

    • Change to section 2 - Qualitative and quantitative composition
    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 4.8 - Undesirable effects
    • Change to section 4.9 - Overdose
    • Change to section 5.1 - Pharmacodynamic properties
    • Change to section 9 - Date of renewal of authorisation
    • Change to section 10 - Date of revision of the text

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    

    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/.

     

     

     

     

     

     

     

     

    Updated on 3 September 2009 PIL

    Reasons for updating

    • Change to section 2 - Qualitative and quantitative composition
    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 4.8 - Undesirable effects
    • Change to section 4.9 - Overdose
    • Change to section 5.1 - Pharmacodynamic properties
    • Change to section 9 - Date of renewal of authorisation
    • Change to section 10 - Date of revision of the text

    Free text change information supplied by the pharmaceutical company

    

    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/.

     

     

     

     

     

     

     

     

    Updated on 11 March 2009 SPC

    Reasons for updating

    • Change to section 4.1 - Therapeutic indications
    • Change to section 4.2 - Posology and method of administration
    • Change to section 5.1 - Pharmacodynamic properties
    • Change to section 4.4 - Special warnings and precautions for use

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    In section 4.1-  This indication is based on clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg negative HBV infection, nucleoside naive patients and. With respect to patients with lamivudine-refractory hepatitis B (, see sections 4.4 and 5.1).

    In section 4.2- reference to see sections 4.4 and 5.1 has been added

    In section 4.4-   the section under "Resistance and specific precaution for lamivudine-refractory patient"- has been updated

    Insection 5.1- the table showing clinical resistance has been updated to include 5 year resistance data

    Updated on 11 March 2009 PIL

    Reasons for updating

    • Change to section 4.1 - Therapeutic indications
    • Change to section 4.2 - Posology and method of administration
    • Change to section 5.1 - Pharmacodynamic properties
    • Change to section 4.4 - Special warnings and precautions for use

    Free text change information supplied by the pharmaceutical company

    In section 4.1-  This indication is based on clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg negative HBV infection, nucleoside naive patients and. With respect to patients with lamivudine-refractory hepatitis B (, see sections 4.4 and 5.1).

    In section 4.2- reference to see sections 4.4 and 5.1 has been added

    In section 4.4-   the section under "Resistance and specific precaution for lamivudine-refractory patient"- has been updated

    Insection 5.1- the table showing clinical resistance has been updated to include 5 year resistance data

    Updated on 13 October 2008 SPC

    Reasons for updating

    • Change to section 2 - Qualitative and quantitative composition
    • Change to section 3 - Pharmaceutical form
    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 4.8 - Undesirable effects
    • Change to section 6.5 - Nature and contents of container

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    Change to section 2 - qualitative and quantitative composition,
    Change to section 3 - pharmaceutical form,
    Change to section 4.4 - Special Warnings and Precautions for Use,
    Change to section 4.8 - Undesirable Effects,
    Change to section 6. 5 - Nature and Contents of Container


    Updated on 13 October 2008 PIL

    Reasons for updating

    • Change to section 2 - Qualitative and quantitative composition
    • Change to section 3 - Pharmaceutical form
    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 4.8 - Undesirable effects
    • Change to section 6.5 - Nature and contents of container

    Free text change information supplied by the pharmaceutical company

    Change to section 2 - qualitative and quantitative composition,
    Change to section 3 - pharmaceutical form,
    Change to section 4.4 - Special Warnings and Precautions for Use,
    Change to section 4.8 - Undesirable Effects,
    Change to section 6. 5 - Nature and Contents of Container


    Updated on 5 March 2008 SPC

    Reasons for updating

    • Change to section 10 - Date of revision of the text

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    change to date of text on the SPC

    Updated on 5 March 2008 PIL

    Reasons for updating

    • Change to section 10 - Date of revision of the text

    Free text change information supplied by the pharmaceutical company

    change to date of text on the SPC

    Updated on 9 January 2008 PIL

    Reasons for updating

    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 4.8 - Undesirable effects
    • Change to section 5.1 - Pharmacodynamic properties

    Free text change information supplied by the pharmaceutical company

    Changes to section 4.4, 4.8. 5.1 - revised from previous submission

    Updated on 9 January 2008 SPC

    Reasons for updating

    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 4.8 - Undesirable effects
    • Change to section 5.1 - Pharmacodynamic properties

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    Changes to section 4.4, 4.8. 5.1 - revised from previous submission

    Updated on 13 September 2007 SPC

    Reasons for updating

    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 5.1 - Pharmacodynamic properties

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    Changes to section 4.5 and 5.1

    Updated on 13 September 2007 PIL

    Reasons for updating

    • Change to section 4.4 - Special warnings and precautions for use
    • Change to section 5.1 - Pharmacodynamic properties

    Free text change information supplied by the pharmaceutical company

    Changes to section 4.5 and 5.1

    Updated on 19 June 2007 SPC

    Reasons for updating

    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.4 - Special warnings and precautions for use

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Free text change information supplied by the pharmaceutical company

    Changes to section 4.2 and 4.4

    Updated on 19 June 2007 PIL

    Reasons for updating

    • Change to section 4.2 - Posology and method of administration
    • Change to section 4.4 - Special warnings and precautions for use

    Free text change information supplied by the pharmaceutical company

    Changes to section 4.2 and 4.4

    Updated on 31 July 2006 SPC

    Reasons for updating

    • New SPC for new product

    Legal category: Product subject to medical prescription which may not be renewed (A)

    Updated on 31 July 2006 PIL

    Reasons for updating

    • New SPC for new product