Last Updated on eMC 07-12-2017 View medicine  | Pfizer Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

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

Date of revision of text on the SPC:01-12-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



The SPC has been updated as follows:

Section 4.4 - Updated to update the frequency of reporting of peripheral demyelinating polyneuropathies.

Section 4.8 - ADRs have been tabulated and some ADRs frequencies have been updated and 3 additional ADRs (Leukaemia; Lymphoma; and Peripheral demyelinating events) are added. Information on 2 ADRs (Interstitial lung disease and Autoimmune hepatitis) for which there are notable differences observed in the frequencies between the etanercept only and etanercept plus concomitant methotrexate treatment groups is added.

Reasons for adding or updating:

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

Date of revision of text on the SPC:01-06-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Type II Variation update to Section 4.8 ‘Undesirable Effects’ of the SPC in order to change the frequency category of the ADR ‘elevated liver enzymes’ from ‘rare’ to ‘uncommon’ and to add some further details on the frequency of elevated liver enzymes reported with etanercept in double-blind controlled trials with or without concomitant methotrexate use. The Package Leaflet (Section 4) was updated accordingly.

In addition, Pfizer took the opportunity to update Section 4.4 of the SPC to add a statement on traceability of biological medicinal products as requested by the PRAC, to make a small correction in Section 6 of the 50 mg solution for injection in a pre-filled pen Package Leaflet ( EU / 1 / 99 / 126 / 0019-021), and to bring the PI in line with the latest QRD template version 10 (i.e. include the unique identifiers in sections 17 and 18 of Annex IIIA).

Reasons for adding or updating:

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

Date of revision of text on the SPC:01-04-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Update to Section 4.8 ‘Undesirable Effects’ of the SPC in order to change the frequency category of the ADR ‘elevated liver enzymes’ from ‘rare’ to ‘uncommon’ and to add some further details on the frequency of elevated liver enzymes reported with etanercept in double-blind controlled trials with or without concomitant methotrexate use. The Package Leaflet (Section 4) was updated accordingly.

In addition, Pfizer took the opportunity to update Section 4.4 of the SPC to add a statement on traceability of biological medicinal products as requested by the PRAC, to make a small correction in Section 6 of the 50 mg solution for injection in a pre-filled pen Package Leaflet ( EU / 1 / 99 / 126 / 0019-021), and to bring the PI in line with the latest QRD template version 10

Reasons for adding or 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

Date of revision of text on the SPC:01-04-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



The SPC has been updated as follows:

EU EN 043 is an update to Section 5.1 of the SmPC to add efficacy and safety information to reflect the final 2-year data from study B181031 (non-radiographic axial spondyloarthritis study).

EU EN 051 updates to Section 4.4 of the SmPC to include information on new onset congestive heart failure (CHF), including CHF in patients without known pre-existing cardiovascular disease, and Section 4.8 to amend the term ‘worsening of congestive heart failure’ to ‘congestive heart failure’

Reasons for adding or updating:

  • Change to section 4.6 - Fertility, pregnancy and lactation

Date of revision of text on the SPC:01-11-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



The SPC has been updated as follows:

Section 4.6 of the SmPC and Section 2 of the PIL have been updated to include the information on the effects of etanercept on pregnancy to reflect the final report of the OTIS registry.

Reasons for adding or updating:

  • Change to section 6.3 - Shelf life

Date of revision of text on the SPC:01-04-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

The SPC has been updated as follows: Change in the shelf-life from 3 to 4 years for  the diluent of the Enbrel 25 mg powder and solvent for solution

Reasons for adding or updating:

  • Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC:01-03-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



The SPC has been updated as follows: The  10-year efficacy data in rheumatoid arthritis (RA) has been added  in the clinical trials section 5.1 of the Summary of Product Characteristics (SmPC).

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects

Date of revision of text on the SPC:01-09-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Update section 4.8 SmPC to align with CDS to introduce viral infections in the list of opportunistic infections.

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • 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

Date of revision of text on the SPC:01-07-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Updates to sections

4.1, 4.2, 5.1 - Addition of axial spondyloarthritis

4.8 - All presentations have been updated to include the name change of the IMB to HPRA.

10 – date of revision

Reasons for adding or updating:

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

Date of revision of text on the SPC:01-10-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Update to Sections 4.4 & 4.8

Reasons for adding or updating:

  • Change to section 4.6 - Fertility, pregnancy and lactation

Date of revision of text on the SPC:01-07-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Update to section 4.6, Fertility, pregnancy and lactation to add information regarding the placental transfer of etanercept. Enhanced instructions for preparing for an injection using the pre-filled syringe presentations following the introduction of a new packaging design, referred to as a slim-pack design have been added. Minor changes to align with EMA Product Information (PI) QRD templates have also been introduced.

Reasons for adding or updating:

  • Change to section 6.6 - Special precautions for disposal and other handling

Date of revision of text on the SPC:01-05-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Update to the description of the liquid solution in the Enbrel pre-filled syringe (PFS) and pre-filled pen (PFP) presentations.

Reasons for adding or updating:

  • Change to section 4.6 - Fertility, pregnancy and lactation

Date of revision of text on the SPC:01-02-2013

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.6 of the SPC has been updated regarding lactation information

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects

Date of revision of text on the SPC:03-12-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Update to Section 4.8

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:01-10-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Add scleritis as an adverse drug reaction to section 4.8 of the SPC

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:01-08-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Update to sections 4.4 & 4.8  to supplement the infections information in the special warnings and AE sections regarding listeria, legionella, and parasitic infection, including protozoal infections.

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • 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 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-07-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Sections 4.1 - 4.5, 4.8, 5.1, 5.2, 10: Extension the indication for juvenile idiopathic arthritis (JIA) to include three new subtypes of the disease and to include long-term safety information for the JIA population, together with reclassification of the licensed indication of polyarticular JIA into the International League of Associations for Rheumatology (ILAR) classification of polyarthritis (rheumatoid factor positive) and polyarthritis (rheumatoid factor negative). Furthermore, an additional etanercept dosage regimen of 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly is proposed in addition to the current approved JIA dosage of 0.4 mg/kg (up to a maximum of 25 mg per dose) twice weekly for the treatment of JIA

Reasons for adding or updating:

  • Removal of Black Triangle

Date of revision of text on the SPC:24-08-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Enbrel 25mg powder and solvent for solution for injection – Removal of black triangle

Reasons for adding or updating:

  • Change to section 6. 4 - Special Precautions for Storage

Date of revision of text on the SPC:24-08-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Update to section 6.4:  to allow storage outside of a refrigerator for 4 weeks

Reasons for adding or 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 6. 3 - Shelf Life
  • Change to section 6. 4 - Special Precautions for Storage

Date of revision of text on the SPC:24-08-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Section 4.1:    Extension of polyarticular JIA population to include 2 & 3 year olds. Extension of paediatric psoriasis to include 6 & 7 year olds.
Section 4.2:    Update to paediatric population information.
Section 5.1:    Update to Clinical efficacy and safety information. Update to paediatric population information.
Section 6.3:     Update to shelf life information
Section 6.4:     Update to storage information

Reasons for adding or updating:

  • Change to section 7 - Marketing Authorisation Holder

Date of revision of text on the SPC:05-08-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Section 7 Marketing Authorisation Holder now shows Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:29-06-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Section 4.8 has been updated to add systemic vasculitis as a rare side-effect

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:27-05-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Section 4.8 of the SPC: Autoimmune hepatitis has been added as a rare undesirable effect under Hepatobiliary disorders

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:13-05-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Section 4.8 of SPC: Sarcoidosis has been added as a rare undesirable effect under Nervous system disorders.

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:21-02-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

SmPC (Enbrel continues to be a black triangle ▼ product)
Section 4.8 of the SmPC has been updated as follows:
The introduction to the section has been completely revised to bring it more in line with the SPC guideline, highlighting the most common and the most serious AEs, providing the new prescriber with a succinct summary of the AE profile.
The system organ classification (SOC) has been re-ordered, consistent with the SPC guideline
The subsection to the table entitled ‘Serious adverse events reported in clinical trials’ has been deleted. 

Reasons for adding or updating:

  • 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

Date of revision of text on the SPC:21-01-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Section 4.2: Inclusion of "The recommended dose is" under Paediatric populations

Further explanation of dosing in Paediatric populations (in pre-filled syringe and pre-filled pen presentations only)

Section 4.4: Warning of IBD in JIA patients

Section 4.8: Explanation of reports of IBD in JIA patients

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 6. 3 - Shelf Life

Date of revision of text on the SPC:26-11-2010

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

4.4: Updates regarding melanoma, Merkel cell carcinoma & demyelination
Addition of precaution on use in Elderley (65 yrs and older)
4.8: Addition of melanoma, Merkel cell carcinoma
6.3: Increase in shelf life from 2 years to 30 months (PFP & PFS SmPCs only)

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:01-07-2010

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Includes additional warnings in section 4.4 relating to reports of malignancies (including lymphoma) in children and leukaemia.  There is also the addition of leukaemia and lymphoma, as well as worsening of psoriasis as adverse reactions to the table in section 4.8 of the SPC.

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use

Date of revision of text on the SPC:05-05-2010

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Section 4.4 - Additional Text:

Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of Enbrel in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • 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 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties

Date of revision of text on the SPC:26-11-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Section 4.1: Addition text -
psoralen and ultraviolet-A light (PUVA)

Section 4.4: Additional text -
The safety and efficacy of Enbrel in patients with chronic infections have not been evaluated. 

Enbrel should be used with caution in patients with a history of hepatitis C.


Section 4.5: Additional text -

Physicians should use caution when considering combination therapy with sulfasalazine.


Section 4.8:  (Undesirable Effects)

Uveitis and Worsening of congestive heart failure have been added.

Section 5.1: Addition of
Immunosuppressants to the Pharmacotherapeutic group

Secrtion 5.2: Additional text –

Enzyme-Linked Immunosorbent Assay (ELISA)

Reasons for adding or updating:

  • 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 5.1 - Pharmacodynamic Properties

Date of revision of text on the SPC:16-07-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



4.2                        Posology and method of administration
Additional Text:
Continuous therapy beyond 24 weeks may be appropriate for some adult patients (see section 5.1).

Method of administration

Comprehensive instructions for the preparation and administration of the reconstituted Enbrel vial are given in the package leaflet, section 7, "Instructions for preparation and giving an injection of Enbrel."

4.4                   Special warnings and precautions for use

Based on pharmacokinetic data (see section 5.2), no dosage dose adjustment is needed in patients with renal or hepatic impairment; clinical experience in such patients is limited.

4.8                        Undesirable effects

Malignancies and lymphoproliferative disorders

Additional Text:

 

In a group of 2,711 plaque psoriasis patients treated with Enbrel in double-blind and open-label studies of up to 2.5 years, 30 malignancies and 43 nonmelanoma skin cancers were reported.


5.1                   Pharmacodynamic properties

Additional Text:

In long-term (up to 34 months) open-label studies where Enbrel was given without interruption, clinical responses were sustained and safety was comparable to shorter-term studies.

 

An analysis of clinical trial data did not reveal any baseline disease characteristics that would assist clinicians in selecting the most appropriate dosing option (intermittent or continuous). Consequently, the choice of intermittent or continuous therapy should be based upon physician judgment and individual patient needs.

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:29-05-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



SECTION 4.4

 

Non-melanoma skin cancer (NMSC)

 

Non-melanoma skin cancer has been reported in patients treated with TNF-antagonists, including Enbrel. Combining the results of placebo- and active comparator-controlled clinical trials of Enbrel, more cases of NMSC were observed in patients receiving Enbrel compared with control patients, particularly in patients with psoriasis. Periodic skin examination is recommended for all patients who are at increased risk for NMSC (including patients with psoriasis or a history of PUVA therapy).

 

 

Alcoholic hepatitis

 

In a phase II randomised placebo-controlled study of 48 hospitalised patients treated with Enbrel or placebo for moderate to severe alcoholic hepatitis, Enbrel was not efficacious, and the mortality rate in patients treated with Enbrel was significantly higher after 6 months. Consequently, Enbrel should not be used in patients for the treatment of alcoholic hepatitis. Physicians should use caution when using Enbrel in patients who also have moderate to severe alcoholic hepatitis.

 

SECTION 4.8

 

Non-melanoma skin cancers added to Skin and subcutaneous tissue disorders.

 

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:25-03-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



  • In section 4.4 a new sentence on infections has been added –

Serious infections, sepsis, tuberculosis, and other opportunistic infections, including invasive fungal infections, have been reported with the use of Enbrel (see section 4.8). These infections were due to bacteria, mycobacteria, fungi and viruses. In some cases, particular fungal and other opportunistic infections have not been recognised, resulting in delay of appropriate treatment and sometimes death. In evaluating patients for infections, the patient’s risk for relevant opportunistic infections (e.g., exposure to endemic mycoses) should be considered. Some of these infections have been fatal.

  • In section 4.8 a new side-effect and a new paragraph under Serious Infections have been added -

            Infections and infestations:
Very common: Infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections)*
Uncommon: Serious infections (including pneumonia, cellulitis, septic arthritis, sepsis)*
Rare: Tuberculosis, opportunistic infections (including invasive fungal, protozoal, bacterial and atypical mycobacterial infections)*

Serious infections

Opportunistic infections have been reported in association with Enbrel including invasive fungal, protozoal, bacterial (including Listeria and Legionella), and atypical mycobacterial infections. In a pooled data set of clinical trials, the overall incidence of opportunistic infections was 0.09% for the 15,402 subjects who received Enbrel. The exposure‑adjusted rate was 0.06 events per 100 patient‑years. In postmarketing experience, approximately half of all of the case reports of opportunistic infections worldwide were invasive fungal infections. The most commonly reported invasive fungal infections were Pneumocystis and Aspergillus. Invasive fungal infections accounted for more than half of the fatalities amongst patient who developed opportunistic infections. The majority of the reports with a fatal outcome were in patients with Pneumocystis pneumonia, unspecified systemic fungal infections, and aspergillosis (see section 4.4). 

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties

Date of revision of text on the SPC:22-12-2008

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Additional Text as follows:

Section 4.1:

Paediatric plaque psoriasis

 

Treatment of chronic severe plaque psoriasis in children and adolescents from the age of 8 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.


Section 4.2:

Paediatric plaque psoriasis (age 8 years and above)

 

0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly for up to 24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks.

 

If re-treatment with Enbrel is indicated, the above guidance on treatment duration should be followed.  The dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.


Section 4.8:

Undesirable effects in paediatric patients with plaque psoriasis

 

In a 48-week study in 211 children aged 4 to 17 years with paediatric plaque psoriasis, the adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.


Section 5.1:

Paediatric patients with plaque psoriasis

 

The efficacy of Enbrel was assessed in a randomised, double-blind, placebo-controlled study in 211 paediatric patients aged 4 to 17 years with moderate to severe plaque psoriasis (as defined by a sPGA score ≥ 3, involving ≥ 10% of the BSA, and PASI ≥ 12). Eligible patients had a history of receiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy.

 

Patients received Enbrel 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients randomised to Enbrel had positive efficacy responses (e.g., PASI 75) than those randomised to placebo.

 

 Paediatric Plaque Psoriasis Outcomes at 12 Weeks

 

Enbrel

0.8 mg/kg Once Weekly

(N = 106)

Placebo

(N = 105)

PASI 75, n (%)

60 (57%)a

12 (11%)

PASI 50, n (%)

79 (75%)a

24 (23%)

sPGA “clear” or “minimal”, n (%)

56 (53%)a

14 (13%)

Abbreviation:  sPGA-static Physician Global Assessment.

a.   p < 0.0001 compared with placebo.

 

 

After the 12-week double-blind treatment period, all patients received Enbrel 0.8 mg/kg (up to 50 mg) once weekly for additional 24 weeks. Responses observed during the open-label period were similar to those observed in the double-blind period.

 

During a randomised withdrawal period, significantly more patients re-randomised to placebo experienced disease relapse (loss of PASI 75 response) compared with patients re-randomised to Enbrel. With continued therapy, responses were maintained up to 48 weeks.


Section 5.2

Paediatric patients with plaque psoriasis

 

Patients with paediatric plaque psoriasis (aged 4 to 17 years) were administered 0.8 mg/kg (up to a maximum dose of 50 mg per week) of etanercept once weekly for up to 48 weeks.  The mean serum steady state trough concentrations ranged from 1.6 to 2.1 mcg/ml at weeks 12, 24, and 48. These mean concentrations in patients with paediatric plaque psoriasis were similar to the concentrations observed in patients with juvenile idiopathic arthritis (treated with 0.4 mg/kg etanercept twice weekly, up to maximum dose of 50 mg per week). These mean concentrations were similar to those seen in adult patients with plaque psoriasis treated with 25 mg etanercept twice weekly. 


Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:29-08-2008

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Section 4.4: Removal of the word 'adult' under CNS disorders
Section 4.8: Additional information under Immune System Disorders and Skin Disorders
Section 10: Date amended

Reasons for adding or updating:

  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:07-07-2008

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Section 4.2
New dosing information for 'Plaque psoriasis'

Section 4.8
'Undesirable effects in adults' updated to include data from an additional clinical study

Section 5.1
Pharmacological Group and ATC code updated

'Adults with plaque psoriasis' updated to include data from an additional clinical study

Reasons for adding or updating:

  • 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 5.1 - Pharmacodynamic Properties

Date of revision of text on the SPC:01-11-2007

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.4 and Section 4.5

Addition in both sections for statement regarding interaction with abatacept

 

Section 4.8

Addition of Interstitial lung disease as an undesirable effect

 

Section 5.1

Update to the 'Antibodies to Enbrel' section

Reasons for adding or updating:

  • 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 10 date of revision of the text

Date of revision of text on the SPC:01-08-2007

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.2

Addition of wording for a Patient Alert Card

 

Section 4.4

Addition of warnings to the SPC regarding the evaluation of patients for infections before, during and after Enbrel use, screening for TB, what action to take should TB infection be found, the risk of reactivation of hepatitis B virus, and the worsening of hepatitis C 

 

Section 4.5

Update to the interations section of the EU Enbrel SPC to include a statement relating to an absence of interaction between etanercept and either digoxin or warfarin

 

Section 4.8

Amendments to Additional Information section to update wording regarding infections
 

Section 10

Updated website address for EMEA

 

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties

Date of revision of text on the SPC:01-01-2007

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

The following text has changed
 
Section 4.1
 

Psoriatic arthritis

 

Treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug therapy has been inadequate.  Enbrel has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by X‑ray in patients with polyarticular symmetrical subtypes of the disease.

 
Section 4.8
 

Undesirable effects in adults

 

....

Undesirable effects in adults

 

...
Additionally, Enbrel has been studied in 131240  psoriatic arthritis patients who participated in 2 double-blind placebo‑controlled studies and an open-label extension study.
....

 

Infections

 

....

 

In placebo-controlled psoriatic arthritis trials and plaque psoriasis trials, there were no differences in rates of infection among patients treated with Enbrel and those treated with placebo.  In the double-blind and open-label psoriatic arthritis trials, 1 patient reported a serious infection (pneumonia)no serious infections occurred in patients treated with Enbrel.  In the double-blind and open-label plaque psoriasis trials of up to 15 months, serious infections experienced by Enbrel-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis and abscess.
....
 
 Section 5.1
 

Adults with psoriatic arthritis

 

The efficacy of Enbrel was assessed in a randomised, double-blind, placebo-controlled study in 205 patients with psoriatic arthritis. Patients were between 18 and 70 years of age and had active psoriatic arthritis (³ 3 swollen joints and ³ 3 tender joints) in at least one of the following forms:  (1) distal interphalangeal (DIP) involvement; (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); (3) arthritis mutilans; (4) asymmetric psoriatic arthritis; or (5) spondylitis-like ankylosis. Patients also had plaque psoriasis with a qualifying target lesion ³ 2 cm in diameter. Patients had previously been treated with NSAIDs (86%), DMARDs (80%), and corticosteroids (24%). Patients currently on methotrexate therapy (stable for ³ 2 months) could continue at a stable dose of £ 25 mg/week methotrexate. Doses of 25 mg Enbrel (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered SC twice a week for 6 months.  At the end of the double-blind study, patients could enter a long-term open-label extension study for a total duration of up to 2 years.

 

Clinical responsesThe results were expressed as percentages of patients achieving the ACR 20, 50, and 70 response and percentages with improvement in Psoriatic Arthritis Response Criteria (PsARC). Results are summarised in the Table below.

 
[GRAPH APPEARS]
 

Among patients with psoriatic arthritis who received Enbrel, the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. Enbrel was significantly better than placebo in all measures of disease activity (p < 0.001), and responses were similar with and without concomitant methotrexate therapy. Quality of life in psoriatic arthritis patients was assessed at every timepoint using the disability index of the HAQ. The disability index score was significantly improved at all timepoints in psoriatic arthritis patients treated with Enbrel, relative to placebo (p < 0.001).  There is insufficient evidence of the efficacy of Enbrel in patients with ankylosing spondylitis-like psoriatic arthropathy due to the small number of patients studied.

 

Radiographic changes were assessed in the psoriatic arthritis study.  Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24.  The modified TSS at 12 months is presented in the Table below.  In an analysis in which all patients who dropped out of the study for any reason were considered to have progressed, the percentage of patients without progression (TSS change ≤ 0.5) at 12 months was higher in the Enbrel group compared with the placebo group (73% vs. 47%, respectively, p ≤ 0.001).  The effect of Enbrel on radiographic progression was maintained in patients who continued on treatment during the second year.  The slowing of peripheral joint damage was observed in patients with polyarticular symmetrical joint involvement. 
 

Mean (SE) Annualized Change From Baseline in Total Sharp Score

 

Placebo

Etanercept

Time

(n = 104)

(n = 101)

Month 12

1.00 (0.29)

‑0.03 (0.09)a

SE = standard error. 

a. p = 0.0001. 

 

Enbrel treatment resulted in improvement in physical function during the double‑blind period, and this benefit was maintained during the longer‑term exposure of up to 2 years.

 

There is insufficient evidence of the efficacy of Enbrel in patients with ankylosing spondylitis‑like and arthritis mutilans psoriatic arthropathies due to the small number of patients studied.

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:01-11-2006

Legal Category:POM

Black Triangle (CHM): NO

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The following text has changed in section 4.8
 

Undesirable effects in paediatric patients with polyarticular juvenile idiopathic arthritis

 

In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients. Differences from adults and other special considerations are discussed in the following paragraphs.

 

The types of infections seen in clinical trials in juvenile idiopathic arthritis patients aged 2 to 18 years were generally mild to moderate and consistent with those commonly seen in outpatient paediatric populations.  Severe adverse events reported in a trial in 69 juvenile idiopathic arthritis patients aged 4 to 17 years included varicella with signs and symptoms of aseptic meningitis, which resolved without sequelae (see also section 4.4), appendicitis, gastroenteritis, depression/personality disorder, cutaneous ulcer, oesophagitis/gastritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and post-operative wound infection.

 

In one study in children with juvenile idiopathic arthritis aged 4 to 17 years, Forty-three43 of 69 (62%) children with juvenile idiopathic arthritis experienced an infection while receiving Enbrel during 3 months of the study (part 1 open-label), and the frequency and severity of infections was similar in 58 patients completing 12 months of open-label extension therapy. The types of infections reported in juvenile idiopathic arthritis patients were generally mild and consistent with those commonly seen in outpatient paediatric populations. The types and proportion of adverse events in juvenile idiopathic arthritis patients were similar to those seen in trials of Enbrel in adult patients with rheumatoid arthritis, and the majority were mild. Several adverse events were reported more commonly in 69 juvenile idiopathic arthritis patients receiving 3 months of Enbrel compared to the 349 adult rheumatoid arthritis patients. These included headache (19% of patients, 1.7 events per patient year), nausea (9%, 1.0 event per patient year), abdominal pain (19%, 0.74 events per patient year), and vomiting (13%, 0.74 events per patient year).

 

Reasons for adding or updating:

  • Change to section 4.6 - Pregnancy and Lactation

Date of revision of text on the SPC:01-10-2006

Legal Category:POM

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Section 4.6 - the addition of the following statement under subheading 'Lactation': 

"Following subcutaneous administration to lactacting rats, etanercept was excreted in the milk and detected in the serum of pups." 

Reasons for adding or updating:

  • Change to section 3 - Pharmaceutical form
  • 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 4.6 - Pregnancy and Lactation
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 6. 4 - Special Precautions for Storage
  • Change to section 6. 6 - Instructions for use, handling and disposal
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-09-2006

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Section 3
 
Description revised to read 'The powder is white. The solvent is a clear, colourless liquid.'
 
Section 4.2
 
New paragraph:  'Comprehensive instructions for the preparation and administration of the reconstituted Enbrel vial are given in the package leaflet, section 7, "Instructions for preparation and giving an injection of Enbrel."'
 
water for injection has changed to 'solvent'
 
Section 4.6
 
nursing has changed to 'breast-feeding'
 
Section 4.8
 
new heading: 'Undesirable effects in adults'
 
Section 6.4
 
New sentence: 'For storage conditions of the reconstituted medicinal product see section 6.3.'
 
Section 6.6
 
Revised to read:
 
Any unused product or waste material should be disposed of in accordance with local requirements.
 
Instructions for use and handling
Enbrel is reconstituted with 1 ml of water for injections before use, and administered by subcutaneous injection.  Enbrel contains no antibacterial preservative, and therefore, solutions perpared with water for injections should be administered as soon as possible and within 6 hours following reconstitution.  The solution should be clear and cloourless with no lumps, flakes or particles.  Some white foam may remain in the vial--this is normal.  Do not use Enbrel if all the powder in the vial is not dissolved within 10 minutes.  Start again with another vial.
 
Comprehensive instructions for the preparation and administration fo the reconstituted Enbrel vial are given in the package leaflet , section 7, "Instructions for preparation and giving and injection of Enbrel."'
 
Section 10
 
Date revised to 26 September 2006
 
New text added:
 
Detailed information on this product is available on the website of the European medicines Agency (EMEA) http://www.emea.eu.int/.
 
All other sections: Text has been updated in line with recent assessments for new presentations

Reasons for adding or updating:

  • Correction of spelling/typing errors

Reasons for adding or 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
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 10 (date of (partial) revision of the text

Date of revision of text on the SPC:01-05-2006

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Free-text change information supplied by the pharmaceutical company:

The following text has changed. Underline indicates new text; strikethrough indicates deleted text
 
4.1     Therapeutic indications
 
Rheumatoid arthritis

Enbrel in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate.

Enbrel can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

Enbrel is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.

Enbrel, alone or in combination with methotrexate, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function.

Enbrel can be used alone or in combination with methotrexate for the treatment of active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate.

Enbrel is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.

In patients with rheumatoid arthritis, Enbrel used alone or in combination with methotrexate has been shown to slow the progression of disease-associated structural damage as measured by X-ray.

Polyarticular Juvenilejuvenile chronic idiopathic arthritis

Treatment of active polyarticular course juvenile chronic idiopathic arthritis in children aged 4 to 17 years who have had an inadequate response to, or who have proved intolerant of, methotrexate. Enbrel has not been studied in children aged less than 4 years.

Psoriatic arthritis
 
 
Ankylosing spondylitis
 
 
Plaque psoriasis

4.2     Posology and method of administration

 Enbrel is available in strengths of 25 and 50 mg. Each vial of Enbrel 25 mg must be reconstituted with 1 ml of water for injections before use and aministered by subcutaneous injection.

Adults (18-64 years)

 Rheumatoid arthritis

25 mg Enbrel administered twice weekly is the recommended dose., aAlternatively, 50 mg administered once weekly (as two 25 mg injections given at approximately the same time) has been shown to be safe and effective (see section 5.1).

 Psoriatic arthritis and ankylosing spondylitis

The recommended dose is 25 mg Enbrel administered twice weekly, or 50 mg administered once weekly. is the recommended dose. Ddoses other than 25 mg administered twice weekly have not been studied.

 4.4     Special warnings and special precautions for use

 Immunosuppression

The possibility exists for anti-TNF therapies, including Enbrel, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. Reports of various malignancies (including breast and lung carcinoma and lymphoma) have been received in the postmarketing period (see section 4.8). In a study of 49 patients with rheumatoid arthritis treated with Enbrel, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations. Whether treatment with Enbrel might influence the development and course of malignancies and active and/or chronic infections is unknown. The safety and efficacy of Enbrel in patients with immunosuppression or chronic infections have not been evaluated. 

In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurence was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation. With the current knowledge, a possible risk for the development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded.

 Two juvenile chronic idiopathic arthritis patients developed varicella infection and signs and symptoms of aseptic meningitis which resolved without sequelae. Patients with a significant exposure to varicella virus should temporarily discontinue Enbrel therapy and be considered for prophylactic treatment with Varicella Zoster Immune Globulin.

 The safety and efficacy of Enbrel in patients with immunosuppression or chronic infections have not been evaluated.

 Vaccinations

Live vaccines should not be given concurrently with Enbrel. No data are available on the secondary transmission of infection by live vaccines in patients receiving Enbrel. It is recommended that juvenile chronic idiopathic arthritis patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating Enbrel therapy.  In a double blind, placebo controlled, randomised clinical study in patients with psoriatic arthritis 184 patients also received a multivalent pneumococcal polysaccharide vaccine at week 4.  In this study most psoriatic arthritis patients receiving Enbrel were able to mount effective B-cell immune response to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and few patients had two-fold rises in titers compared to patients not receiving Enbrel.  The clinical significance of this is unknown.

 Combination therapy

In a controlled clinical trial of one yeartwo years duration in rheumatoid arthritis patients, the combination of Enbrel and methotrexate did not result in unexpected safety findings, and the safety profile of Enbrel when given in combination with methotrexate was similar to the profiles reported in studies of Enbrel and methotrexate alone.  Long-term studies to assess the safety of the combination are ongoing.  The long-term safety of Enbrel in combination with other disease-modifying antirheumatic drugs has not been established.

 4.8     Undesirable effects

 Enbrel has been studied in 2,680 patients with rheumatoid arthritis in double-blind and open-label trials. This experience includes 2 placebo-controlled studies (349 Enbrel patients and 152 placebo patients) and 2 active-controlled trials, one active-controlled trial comparing Enbrel to methotrexate (415 Enbrel patients and 217 methotrexate patients)and another active-controlled trial comparing Enbrel (223 patients), methotrexate (228 patients) and Enbrel in combination with methotrexate (231 patients). The proportion of patients who discontinued treatment due to adverse events was the same in both the Enbrel and placebo treatment groups; in the first active-controlled trial, the dropout rate was significantly higher for methotrexate (10%) than for Enbrel (5%).  In the second active-controlled trial, the rate of discontinuation for adverse events after 2 years of treatment was similar among all three treatment groups, Enbrel (1116%), methotrexate (1421%) and Enbrel in combination with methotrexate (1017%).  Additionally, Enbrel has been studied in 131 psoriatic arthritis patients who participated in 2 double-blind placebo-controlled studies and an open-label extension study.  Two hundred and three (203) Five hundred and eight (508) ankylosing spondylitis patients were treated with Enbrel in 34 double-blind placebo-controlled studies.  Enbrel has also been studied in 1,084 patients with plaque psoriasis for up to 6 months in 3 double-blind placebo-controlled studies.

 In double-blind clinical trials comparing Enbrel to placebo, injection site reactions were the most frequent adverse events among Enbrel-treated patients. Among patients with rheumatoid arthritis treated in placebo-controlled trials, serious adverse events occurred at a frequency of 4% in 349 patients treated with Enbrel compared with 5% of 152 placebo-treated patients. In the first active-controlled trial, serious adverse events occurred at a frequency of 6% in 415 patients treated with Enbrel compared with 8% of 217 methotrexate-treated patients.  In the second active-controlled trial the rate of serious adverse events after 2 years of treatment was were similar among the three treatment groups (Enbrel 1116%, methotrexate 1215% and Enbrel in combination with methotrexate 817%).  Among patients with plaque psoriasis treated in placebo-controlled trials, the frequency of serious adverse events was about 1% of 933 patients treated with Enbrel compared with 1% of 414 placebo-treated patients.

 Hepatobiliary disorders:

 Rare:                Elevated liver enzymes

 Additional information

 Serious adverse events reported in clinical trials

Among rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis  patients in placebo-controlled, active-controlled, and open-label trials of Enbrel, serious adverse events reported included malignancies (see below), asthma, infections (see below), heart failure, myocardial infarction, myocardial ischaemia, chest pain, syncope, cerebral ischaemia, hypertension, hypotension, cholecystitis, pancreatitis, gastrointestinal haemorrhage, bursitis, confusion, depression, dyspnoea, abnormal healing, renal insufficiency, kidney calculus, deep vein thrombosis, pulmonary embolism, membranous glomerulonephropathy, polymyositis, thrombophlebitis, liver damage, leucopenia, paresis, paresthesia, vertigo, allergic alveolitis, angioedema, scleritis,bone fracture, lymphadenopathy, ulcerative colitis, and intestinal obstruction, eosinophilia, haematuria, and sarcoidosis. 

 Infections

In clinical trials in rheumatic disorders, upper respiratory infections (“colds”) and sinusitis were the most frequently reported infections in patients receiving Enbrel or placebo. In placebo-controlled trials, the incidence of upper respiratory tract infections was 17% in the placebo treatment group and 22% in the group treated with Enbrel. In rheumatoid arthritis patients participating in placebo-controlled trials, there were 0.68 events per patient year in the placebo group and 0.82 events per patient year in the group treated with Enbrel when the longer observation of patients on Enbrel was accounted for. In placebo-controlled trials evaluating Enbrel, no increase in the incidence of serious infections (fatal, life threatening, or requiring hospitalisation or intravenous antibiotics) was observed. Among the 2,680 rheumatoid arthritis patients treated with Enbrel for up to 48 months, including 231 patients treated with Enbrel in combination with methotrexate in the 12-year active-controlled study, 170186 serious infections were observed.  These serious infections included abscess (at various sites), bacteraemia, bronchitis, bursitis, cellulitis, cholecystitis, diarrhoea, diverticulitis, endocarditis (suspected), gastroenteritis, hepatitis B, herpes zoster, leg ulcer, mouth infection, osteomyelitis, otitis, peritonitis, pneumonia, pyelonephritis, sepsis, septic arthritis, sinusitis, skin infection, skin ulcer, urinary tract infection, vasculitis, and wound infection. In the 12-year active-controlled study where patients were treated with either Enbrel alone, methotrexate alone or Enbrel in combination with methotrexate, the rates of serious infections were similar among the treatment groups.  However, it cannot be excluded that the combination of Enbrel with methotrexate could be associated with an increase in the rate of infections. 

 Undesirable effects in paediatric patients with juvenile chronic idiopathic arthritis

In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients. Differences from adults and other special considerations are discussed in the following paragraphs.

 Severe adverse events reported in a trial in 69 juvenile chronic idiopathic arthritis patients aged 4 to 17 included varicella with signs and symptoms of aseptic meningitis which resolved without sequelae (see also 4.4), gastroenteritis, depression/personality disorder, cutaneous ulcer, oesophagitis/gastritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and post-operative wound infection.

 Forty-three of 69 (62%) children with juvenile chronic idiopathic arthritis experienced an infection while receiving Enbrel during 3 months of the study (part 1 open-label), and the frequency and severity of infections was similar in 58 patients completing 12 months of open-label extension therapy. The types of infections reported in juvenile chronic idiopathic arthritis patients were generally mild and consistent with those commonly seen in outpatient paediatric populations. The types and proportion of adverse events in juvenile chronic idiopathic arthritis patients were similar to those seen in trials of Enbrel in adult patients with rheumatoid arthritis, and the majority were mild. Several adverse events were reported more commonly in 69 juvenile chronic idiopathic arthritis patients receiving 3 months of Enbrel compared to the 349 adult rheumatoid arthritis patients. These included headache (19% of patients, 1.7 events per patient year), nausea (9%, 1.0 event per patient year), abdominal pain (19%, 0.74 events per patient year), and vomiting (13%, 0.74 events per patient year).

 5.1    Pharmacodynamic properties

 Pharmacotherapeutic group: Selective immunosuppressantimmunosuppressive agents. 

Clinical trials

This section presents data from four randomised controlled trials in rheumatoid arthritis, 1 study in polyarticular-course juvenile chronic iodiopathic arthritis, 1 study in psoriatic arthritis, 1 study in ankylosing spondylitis and 3 studies in plaque psoriasis.

Patients in the Enbrel in combination with methotrexate therapy group had significantly higher ACR 20, ACR 50, ACR 70 responses and improvement for DAS and HAQ scores at both 24 and 52 weeks than patients in either of the single therapy groups (results shown in table below).  Significant advantages for Enbrel in combination with methotrexate compared with Enbrel monotherapy and methotrexate monotherapy were also observed after 24 months.

 

CLINICAL EFFICACY RESULTS AT 12 MONTHS:  COMPARISON OF ENBREL vs METHOTREXATE vs ENBREL IN COMBINATION WITH METHOTREXATE IN PATIENTS WITH RA OF 6 MONTHS TO 20 YEARS DURATION

 

Endpoint

 

Methotrexate
(n = 228)

Enbrel
(n = 223)

Enbrel +
Methotrexate
(n = 231)

 


ACR  Responsesa at week 52

 

 

 

 

ACR 20

75.058.8%

75.865.5%

84.874.5% †,f

 

ACR 50

42.536.4%

48.443.0%

69.363.2% †,f

 

ACR 70

18.916.7%

24.222.0%

42.939.8% †,f

 

 

 

 

 

 

DAS

 

 

 

 

Baseline scoreab

5.5

5.7

5.5

 

Week 52 scoreab

3.0

3.0

2.3†,f

 

Remissionbc

14%

18%

37%†,f

 

 

 

 

 

 

HAQ

 

 

 

 

Baseline

1.7

1.7

1.8

 

Week 52

1.1

1.0

0.8†,f

 

 

a: Patients who did not complete 12 months in the study were considered to be non-responders.

ab: Values for Disease Activity Score (DAS) are means.

bc: Remission is defined as DAS <1.6

Pairwise comparison p-values: = p < 0.05 for comparisons of Enbrel + methotrexate vs methotrexate and f = p < 0.05 for comparisons of Enbrel + methotrexate vs Enbrel

 

Radiographic progression at 12 monthsweek 52 was significantly less in the Enbrel group than in the methotrexate group, while the combination was significantly better than either monotherapy at slowing radiographic progression (see figure below).

 

RADIOGRAPHIC PROGRESSION: COMPARISON OF ENBREL vs METHOTREXATE vs  ENBREL IN COMBINATION WITH METHOTREXATE IN PATIENTS WITH RA
OF 6 MONTHS TO 20 YEARS DURATION (52-WEEK RESULTS12 MONTH RESULTS)

(graph-no edits)

Significant advantages for Enbrel in combination with methotrexate compared with Enbrel monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for Enbrel monotherapy compared with methotrexate monotherapy were also observed after 24 months.

 In an analysis in which all patients who dropped out of the study for any reason were considered to have progressed, Tthe percentage of patients without progression (TSS change ≤ 0.5) at 24 months was higher in the Enbrel in combination with methotrexate and Enbrel groups compared with methotrexate at week 24 (74%, 68%, and 56%, respectively; p<0.05) and week 52 (80%, 68%, and 57%, respectively; p<0.05). the Enbrel alone and methotrexate alone groups (62%, 50%, and 36%, respectively; p<0.05). The difference between Enbrel alone and methotrexate alone was also significant (p<0.05). Among patients who completed a full 24 months of therapy in the study, the non-progression rates were 78%, 70%, and 61%, respectively.

 Polyarticular-Course Juvenile Chronic Idiopathic Arthritis

The safety and efficacy of Enbrel were assessed in a two-part study in 69 children with polyarticular-course juvenile chronic idiopathic arthritis who had a variety of juvenile chronic idiopathic arthritis onset types. Patients aged 4 to 17 years with moderately to severely active polyarticular-course juvenile chronic idiopathic arthritis refractory to or intolerant of methotrexate were enrolled; patients remained on a stable dose of a single nonsteroidal anti-inflammatory drug and/or prednisone (< 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received 0.4 mg/kg (maximum 25 mg per dose) Enbrel subcutaneously twice weekly. In part 2, patients with a clinical response at day 90 were randomised to remain on Enbrel or receive placebo for four months and assessed for disease flare. Responses were measured using the JRA Definition of Improvement (DOI), defined as ³ 30% improvement in at least three of six and ³ 30% worsening in no more than one of six JRA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and erythrocyte sedimentation rate (ESR). Disease flare was defined as a ³ 30% worsening in three of six JRA core set criteria and ³ 30% improvement in not more than one of the six JRA core set criteria and a minimum of two active joints.

 Studies have not been done in patients with polyarticular-course juvenile chronic idiopathic arthritis to assess the effects of continued Enbrel therapy in patients who do not respond within 3 months of initiating Enbrel therapy or to assess the combination of Enbrel with methotrexate.

 Adults with Psoriatic Arthritis

The efficacy of Enbrel was assessed in a randomised, double-blind, placebo-controlled study in 205 patients with psoriatic arthritis. Patients were between 18 and 70 years of age and had active psoriatic arthritis (³ 3 swollen joints and ³ 3 tender joints) in at least one of the following forms:  (1) distal interphalangeal (DIP) involvement; (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); (3) arthritis mutilans; (4) asymmetric psoriatic arthritis; or (5) spondylitis-like ankylosis. Patients also had plaque psoriasis with a qualifying target lesion ³ 2 cm in diameter. Patients had previously been treated with NSAIDs (86%), DMARDs (80%), and corticosteroids (24%). Patients currently on MTXmethotrexate therapy (stable for ³ 2 months) could continue at a stable dose of £ 25 mg/week MTXmethotexate. Doses of 25 mg Enbrel (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered SC twice a week for 6 months.

 No study has been performed in patients with psoriatic arthitis using the 50mg once weekly dosing regimen.  Evidence of efficacy for the once weekly dosing regimen in this patient population has been base on data from the study in patients with ankylosing spondylitis.

 Adults with Ankylosing Spondylitis

The efficacy of Enbrel in ankylosing spondylitis was assessed in 3 randomised, double-blind, placebo-controlled studies comparing twic weekly administration of 25 mg Enbrel with placebo. A total of in 401 patients with ankylosing spondylitis were enrolled from which 203 were treated with Enbrel. The largest of these trials (n= 277) enrolled patients who were between 18 and 70 years of age and had active ankylosing spondylitis defined as visual analog scale (VAS) scores of ³ 30 for average of duration and intensity of morning stiffness plus VAS scores of ³ 30 for at least 2 of the following 3 parameters: patient global assessment; average of VAS values for nocturnal back pain and total back pain; average of 10 questions on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients receiving DMARDs, NSAIDS, or corticosteroids could continue them on stable doses. Patients with complete ankylosis of the spine were not included in the study.  Doses of 25 mg of Enbrel (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered subcutaneously twice a week for 6 months in 138 patients.

 In a fourth study, the safety and efficacy of 50 mg Enbrel (two 25 mg SC injections) administered once weekly vs 25 mg Enbrel administered twice weekly were evaluated in a double-blind, placebo-controlled study of 356 patients with active ankylosing spondylitis. The safety and efficacy profiles of the 50 mg once weekly and 25 mg twice weekly regimens were similar.

 Antibodies to Enbrel

Antibodies to Enbrel, all non-neutralising, were detected in 4 out of 96 rheumatoid arthritis patients who received Enbrel at a dose of 25 mg twice a week for up to 3 months in a placebo-controlled trial. In the active-controlled trial, 11 (2.8%) of 400 etanercept-treated patients had at least one positive result but none of these patients had a positive neutralising antibody test. Results from JCA patients were similar to those seen in adult RA patients treated with Enbrel. Of 98 patients with psoriatic arthritis who have been tested, no patient has developed antibodies to Enbrel at 24 weeks.  Among 175the 480 ankylosing spondylitis patients treated with Enbrel, 3 5 patients were reported with antibodies to Enbrel, none were neutralising.  In double-blind studies up to 6 months duration in plaque psoriasis, about 1% of the 1,084 patients developed antibodies to Enbrel, none were neutralising.

 5.2     Pharmacokinetic properties

 In a population pharmacokinetics analysis in ankylosing spondylitis patients the etanercept steady state AUCs were 466 ug*hr/mL and 474 ug*h/mL for 50 mg Enbrel once weekly (N= 154) and 25 mg twice weekly (N = 148), respectively.

 Patients with polyarticular-course juvenile chronic idiopathic arthritis

In a polyarticular-course juvenile chronic idiopathic arthritis trial with Enbrel, 69 patients (aged 4 to 17 years) were administered 0.4 mg Enbrel/kg twice weekly for three months. Serum concentration profiles were similar to those seen in adult rheumatoid arthritis patients. The youngest children (4 years of age) had reduced clearance (increased clearance when normalised by weight) compared with older children (12 years of age) and adults. Simulation of dosing suggests that while older children (10-17 years of age) will have serum levels close to those seen in adults, younger children will have appreciably lower levels. 
 
10.     DATE OF REVISION OF THE TEXT

 1 August 2005  31 May 2005

Reasons for adding or updating:

  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.8 - Undesirable Effects

Reasons for adding or 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 4.5 - Interactions with other Medicaments and other forms of Interaction
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 6. 4 - Special Precautions for Storage
  • Change to section 6. 5 - Nature and Contents of Container

Reasons for adding or 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
  • Change to section 5.1 - Pharmacodynamic Properties

Reasons for adding or updating:

  • Change to section 5.2 - Pharmacokinetic Properties

Reasons for adding or updating:

  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Pending awaiting re-submission

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic Indications
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 6. 3 - Shelf Life
  • Change to section 6. 6 - Instruction for Use/Handling

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic Indications
  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties

Reasons for adding or updating:

  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.8 - Undesirable Effects

Reasons for adding or updating:

  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.5 - Interactions with other Medicaments and other forms of Interaction
  • Change to section 4.8 - Undesirable Effects

Reasons for adding or 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
  • Change to section 5.1 - Pharmacodynamic Properties

Reasons for adding or updating:

  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.8 - Undesirable Effects

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic Indications
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties

Reasons for adding or updating:

  • Correction of spelling/typing errors

Reasons for adding or updating:

  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 6. 3 - Shelf Life

Reasons for adding or updating:

  • No reasons supplied

Reasons for adding or updating:

  • No reasons supplied