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.

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.

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)

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.

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.

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.

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.

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. 

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

Section 4.4 and Section 4.5

Addition in both sections for statement regarding interaction with abatacept

Addition of Interstitial lung disease as an undesirable effect

Section 5.1

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

Undesirable effects in adults

Undesirable effects in adults

Infections

....

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.

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.

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.

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).