Enbrel^® 25 mg/ml powder and solvent for solution for injection for paediatric use.

Each vial contains 25 mg of etanercept. When reconstituted, the solution contains 25 mg/ml of etanercept.

Etanercept is a human tumour necrosis factor receptor p75 Fc fusion protein produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian expression system. Etanercept is a dimer of a chimeric protein genetically engineered by fusing the extracellular ligand binding domain of human tumour necrosis factor receptor-2 (TNFR2/p75) to the Fc domain of human IgG1. This Fc component contains the hinge, CH₂ and CH₃ regions, but not the CH₁ region of IgG1. Etanercept contains 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. The specific activity of etanercept is 1.7 x 10⁶ units/mg.

The solution contains benzyl alcohol 9 mg/ml as a preservative (see section 4.4). For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection (powder for injection).

The powder is white. The solvent is a clear, colourless liquid.

Polyarticular juvenile idiopathic arthritis

Treatment of active polyarticular juvenile idiopathic arthritis in children and adolescents from the age of 2 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 2 years.

Paediatric plaque psoriasis

Treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.

Enbrel treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of juvenile idiopathic arthritis or paediatric plaque psoriasis. Patients treated with Enbrel should be given the Patient Alert Card.

Each vial of Enbrel 25 mg/ml should be used for a maximum of 2 doses administered to the same patient.

Posology

Special populations

Renal and hepatic impairment

No dose adjustment is required.

Paediatric population

Polyarticular juvenile idiopathic arthritis (age 2 years and above)

The recommended dose is 0.4 mg/kg (up to a maximum of 25 mg per dose) after reconstitution of Enbrel in 1 ml of solvent, given twice weekly as a subcutaneous injection with an interval of 3-4 days between doses. Discontinuation of treatment should be considered in patients who show no response after 4 months.

The 10mg vial strength may be more appropriate for administration to children with JIA below the weight of 25 kg.

No formal clinical trials have been conducted in children aged 2 to 3 years. However, limited safety data from a patient registry suggest that the safety profile in children from 2 to 3 years of age is similar to that seen in adults and children aged 4 years and older, when dosed every week with 0.8 mg/kg subcutaneously (see section 5.1).

There is generally no applicable use of Enbrel in children aged below 2 years in the indication polyarticular juvenile idiopathic arthritis.

Paediatric plaque psoriasis (age 6 years and above)

The recommended dose is 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.

There is generally no applicable use of Enbrel in children aged below 6 years in the indication plaque psoriasis.

Method of administration

Enbrel is administered by subcutaneous injection.

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

Hypersensitivity to the active substance or to any of the excipients.

Sepsis or risk of sepsis.

Treatment with Enbrel should not be initiated in patients with active infections, including chronic or localised infections.

Enbrel must not be given to premature babies or neonates as the solvent contains benzyl alcohol.

Infections

Patients should be eva luated for infections before, during, and after treatment with Enbrel, taking into consideration that the mean elimination half-life of etanercept is approximately 70 hours (range 7 to 300 hours).

Serious infections, sepsis, tuberculosis, and 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 eva luating patients for infections, the patient's risk for relevant opportunistic infections (e.g., exposure to endemic mycoses) should be considered.

Patients who develop a new infection while undergoing treatment with Enbrel should be monitored closely. Administration of Enbrel should be discontinued if a patient develops a serious infection. The safety and efficacy of Enbrel in patients with chronic infections have not been eva luated. Physicians should exercise caution when considering the use of Enbrel in patients with a history of recurring or chronic infections or with underlying conditions that may predispose patients to infections, such as advanced or poorly controlled diabetes.

Tuberculosis

Cases of active tuberculosis, including miliary tuberculosis and tuberculosis with extra-pulmonary location, have been reported in patients treated with Enbrel.

Before starting treatment with Enbrel, all patients must be eva luated for both active and inactive ('latent') tuberculosis. This eva luation should include a detailed medical history with personal history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests, i.e., tuberculin skin test and chest X-ray, should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests should be recorded in the patient's alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.

If active tuberculosis is diagnosed, Enbrel therapy must not be initiated. If inactive ('latent') tuberculosis is diagnosed, treatment for latent tuberculosis must be started with anti-tuberculosis therapy before the initiation of Enbrel, and in accordance with local recommendations. In this situation, the benefit/risk balance of Enbrel therapy should be very carefully considered.

All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g., persistent cough, wasting/weight loss, low-grade fever) appear during or after Enbrel treatment.

Hepatitis B virus reactivation

Reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus who are receiving TNF-antagonists, including Enbrel, has been reported. Patients at risk for HBV infection should be eva luated for prior evidence of HBV infection before initiating Enbrel therapy. Caution should be exercised when administering Enbrel to patients identified as carriers of HBV. If Enbrel is used in carriers of HBV, the patients should be monitored for signs and symptoms of active HBV infection, and, if necessary, appropriate treatment should be initiated.

Worsening of hepatitis C

There have been reports of worsening of hepatitis C in patients receiving Enbrel. Enbrel should be used with caution in patients with a history of hepatitis C.

Concurrent treatment with anakinra

Concurrent administration of Enbrel and anakinra has been associated with an increased risk of serious infections and neutropenia compared to Enbrel alone. This combination has not demonstrated increased clinical benefit. Thus, the combined use of Enbrel and anakinra is not recommended (see sections 4.5 and 4.8).

Concurrent treatment with abatacept

In clinical studies, concurrent administration of abatacept and Enbrel resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended (see section 4.5).

Allergic reactions

Allergic reactions associated with Enbrel administration have been reported commonly. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, Enbrel therapy should be discontinued immediately and appropriate therapy initiated.

Immunosuppression

The possibility exists for TNF-antagonists, including Enbrel, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 49 adult 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.

Two juvenile 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 have not been eva luated.

Malignancies and lymphoproliferative disorders

Solid and haematopoietic malignancies (excluding skin cancers)

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have been received in the postmarketing period (see section 4.8).

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 occurrence was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. In the postmarketing setting, cases of leukaemia have been reported in patients treated with TNF-antagonists. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk estimation.

Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded. Caution should be exercised when considering TNF-antagonist therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy.

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiation of therapy 18 years of age), including Enbrel, in the postmarketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies typically associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.

Skin cancers

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF-antagonists, including Enbrel. Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with Enbrel. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Combining the results of controlled clinical trials, more cases of NMSC were observed in patients receiving Enbrel compared with control patients, particularly in patients with psoriasis.

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. In a double-blind, placebo-controlled, randomised clinical study in adult 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 titres in aggregate were moderately lower, and few patients had two-fold rises in titres compared to patients not receiving Enbrel. The clinical significance of this is unknown.

Autoantibody formation

Treatment with Enbrel may result in the formation of autoimmune antibodies (see section 4.8).

Haematologic reactions

Rare cases of pancytopenia and very rare cases of aplastic anaemia, some with fatal outcome, have been reported in patients treated with Enbrel. Caution should be exercised in patients being treated with Enbrel who have a previous history of blood dyscrasias. All patients and parents/caregivers should be advised that if the patient develops signs and symptoms suggestive of blood dyscrasias or infections (e.g., persistent fever, sore throat, bruising, bleeding, paleness) whilst on Enbrel, they should seek immediate medical advice. Such patients should be investigated urgently, including full blood count; if blood dyscrasias are confirmed, Enbrel should be discontinued.

Neurological disorders

There have been rare reports of CNS demyelinating disorders in patients treated with Enbrel (see section 4.8). Additionally, there have been very rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy). Although no clinical trials have been performed eva luating Enbrel therapy in patients with multiple sclerosis, clinical trials of other TNF antagonists in patients with multiple sclerosis have shown increases in disease activity. A careful risk/benefit eva luation, including a neurologic assessment, is recommended when prescribing Enbrel to patients with pre-existing or recent onset of demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.

Combination therapy

In a controlled clinical trial of two years duration in adult 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 (DMARD) has not been established.

The use of Enbrel in combination with other systemic therapies or phototherapy for the treatment of psoriasis has not been studied.

Renal and hepatic impairment

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

Congestive heart failure

Physicians should use caution when using Enbrel in patients who have congestive heart failure (CHF). There have been postmarketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking Enbrel. Two large clinical trials eva luating the use of Enbrel in the treatment of CHF were terminated early due to lack of efficacy. Although not conclusive, data from one of these trials suggest a possible tendency toward worsening CHF in those patients assigned to Enbrel treatment.

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.

Wegener's granulomatosis

A placebo-controlled trial, in which 89 adult patients were treated with Enbrel in addition to standard therapy (including cyclophosphamide or methotrexate, and glucocorticoids) for a median duration of 25 months, has not shown Enbrel to be an effective treatment for Wegener's granulomatosis. The incidence of non-cutaneous malignancies of various types was significantly higher in patients treated with Enbrel than in the control group. Enbrel is not recommended for the treatment of Wegener's granulomatosis.

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.

Special populations

Elderly patients ( 65 years)

In the Phase 3 studies in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, no overall differences in adverse events, serious adverse events, and serious infections in patients age 65 or older who received Enbrel were observed compared with younger patients.

However, caution should be exercised when treating the elderly and particular attention paid with respect to occurrence of infections.

Paediatric population

Vaccinations

It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating Enbrel therapy (see Vaccinations, above).

Inflammatory bowel disease (IBD) in patients with juvenile idiopathic arthritis (JIA)

There have been reports of IBD in JIA patients being treated with Enbrel (see section 4.8).

Benzyl alcohol

Enbrel contains benzyl alcohol as an excipient, which may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old and must not be given to premature babies or neonates.

Concurrent treatment with anakinra

Adult patients treated with Enbrel and anakinra were observed to have a higher rate of serious infection when compared with patients treated with either Enbrel or anakinra alone (historical data).

In addition, in a double-blind, placebo-controlled trial in adult patients receiving background methotrexate, patients treated with Enbrel and anakinra were observed to have a higher rate of serious infections (7%) and neutropenia than patients treated with Enbrel (see sections 4.4 and 4.8). The combination Enbrel and anakinra has not demonstrated increased clinical benefit, and is therefore not recommended.

Concurrent treatment with abatacept

In clinical studies, concurrent administration of abatacept and Enbrel resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended (see section 4.4).

Concurrent treatment with sulfasalazine

In a clinical study of adult patients who were receiving established doses of sulfasalazine, to which Enbrel was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with Enbrel or sulfasalazine alone. The clinical significance of this interaction is unknown. Physicians should use caution when considering combination therapy with sulfasalazine.

Non-interactions

In clinical trials, no interactions have been observed when Enbrel was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, or methotrexate. See section 4.4 for vaccination advice.

No clinically significant pharmacokinetic drug-drug interactions were observed in studies with digoxin or warfarin.

Women of childbearing potential

Women of childbearing potential should be advised to use appropriate contraception to avoid becoming pregnant during Enbrel therapy and for three weeks after discontinuation of therapy.

Pregnancy

Developmental toxicity studies performed in rats and rabbits have revealed no evidence of harm to the foetus or neonatal rat due to etanercept. There are no studies of Enbrel in pregnant women. Thus, Enbrel is not recommended during pregnancy.

Breast-feeding

It is not known whether etanercept is excreted in human milk. Following subcutaneous administration to lactacting rats, etanercept was excreted in the milk and detected in the serum of pups. Because immunoglobulins, in common with many medicinal products, can be excreted in human milk, a decision must be made whether to discontinue breast-feeding or to discontinue Enbrel therapy, taking into account the benefit of breast -feeding for the child and the benefit of therapy for the woman.

Fertility

Preclinical data about peri- and postnatal toxicity of etanercept and of effects of etanercept on fertility and general reproductive performance are not available.

No studies on the effects on the ability to drive and use machines have been performed.

Summary of the safety profile

Paediatric population

Undesirable effects in paediatric patients with polyarticular juvenile idiopathic arthritis

In general, the adverse events in paediatric patients with juvenile idiopathic arthritis were similar in frequency and type to those seen in adult patients (see below, Undesirable effects in adults). 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 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, 43 of 69 (62%) children 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 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).

There were 4 reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials.

There have been reports of inflammatory bowel disease in JIA patients being treated with Enbrel from post-marketing sources, including a very small number of cases indicating a positive rechallenge (see section 4.4).

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.

Adult population

Undesirable effects on adults

The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infections, bronchitis, bladder infections and skin infections), allergic reactions, development of autoantibodies, itching, and fever.

Serious adverse reactions have also been reported for Enbrel. TNF-antagonists, such as Enbrel, affect the immune system and their use may affect the body's defenses against infection and cancer. Serious infections affect fewer than 1 in 100 patients treated with Enbrel. Reports have included fatal and life-threatening infections and sepsis. Various malignancies have also been reported with use of Enbrel, including cancers of the breast, lung, skin and lymph glands (lymphoma).

Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia and very rare reports of aplastic anaemia. Central and peripheral demyelinating events have been seen rarely and very rarely, respectively, with Enbrel use. There have been rare reports of lupus, lupus-related conditions, and vasculitis.

Tabulated list of adverse reactions

The following list of adverse reactions is based on experience from clinical trials in adults and on postmarketing experience.

Within the organ system classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (1/10); common (1/100 to <1/10); uncommon (1/1000 to <1/100); rare (1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data).