1. Name Of The Medicinal Product
Enbrel® 10 mg powder and solvent for solution for injection for paediatric use.
2. Qualitative And Quantitative Composition
Each vial contains 10 mg of etanercept. When reconstituted, the solution contains 10 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.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder and solvent for solution for injection (powder for injection).
The powder is white. The solvent is a clear, colourless liquid.
4. Clinical Particulars
4.1 Therapeutic Indications
Polyarticular juvenile idiopathic arthritis
Treatment of active polyarticular juvenile idiopathic arthritis in children and adolescents from the age of 4 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.
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.
4.2 Posology And Method Of Administration
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.
Posology
Special populations
Renal and hepatic impairment
No dose adjustment is required.
Paediatric population
The 10 mg presentation is for paediatric patients prescribed a dose of 10 mg or less. Each vial of Enbrel 10 mg should be used on a single occasion in a single patient, and the remainder of the vial should be discarded.
Polyarticular juvenile idiopathic arthritis (age 4 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.
The safety and efficacy of Enbrel in children with polyarticular juvenile idiopathic arthritis aged 2-3 years have not been established. No data are available. There is generally no applicable use of Enbrel in children aged 0-23 months in the indication polyarticular juvenile idiopathic arthritis.
Paediatric plaque psoriasis (age 8 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.
The safety and efficacy of Enbrel in children with plaque psoriasis aged 6-7 years have not been established. Currently available data are described in section 4.8, 5.1 and 5.2, but no recommendation on a posology can be made. There is generally no applicable use of Enbrel in children aged 0-5 years in the indication plaque psoriasis.
Method of administration
Enbrel is administered by subcutaneous injection.
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".
4.3 Contraindications
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.
4.4 Special Warnings And Precautions For Use
Infections
Patients should be evaluated 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 evaluating 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 evaluated. 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 evaluated for both active and inactive ('latent') tuberculosis. This evaluation 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 evaluated 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 evaluated.
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
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 evaluating 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 evaluation, 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 evaluating 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 (
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).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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.
4.6 Pregnancy And Lactation
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.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable Effects
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 (
Infections and infestations:
|
|
Very common:
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Infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections)*
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Uncommon:
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Serious infections (including pneumonia, cellulitis, septic arthritis, sepsis)*
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Rare:
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Tuberculosis, opportunistic infections (including invasive fungal, protozoal, bacterial and atypical mycobacterial infections)*
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Neoplasms benign, malignant and unspecified (including cysts and polyps):
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|
Uncommon:
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Non-melanoma skin cancers* (see section 4.4)
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Rare:
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Lymphoma, melanoma (see section 4.4)
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Not known:
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Leukaemia, Merkel cell carcinoma (see section 4.4)
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Blood and lymphatic system disorders:
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|
Uncommon:
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Thrombocytopenia
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Rare:
|
Anaemia, leukopenia, neutropenia, pancytopenia*
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Very rare:
|
Aplastic anaemia*
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Immune system disorders:
|
|
Common:
|
Allergic reactions (see Skin and subcutaneous tissue disorders), autoantibody formation*
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Uncommon:
|
Systemic vasculitis (including anti-neutrophilic cytoplasmic antibody positive vasculitis)
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Rare:
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Serious allergic/anaphylactic reactions (including angioedema, bronchospasm)
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Not known:
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Macrophage activation syndrome†
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Nervous system disorders:
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|
Rare:
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Seizures
CNS demyelinating events suggestive of multiple sclerosis or localised demyelinating conditions, such as optic neuritis and transverse myelitis (see section 4.4), sarcoidosis
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Very rare:
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Peripheral demyelinating events, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy (see section 4.4)
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Eye disorders:
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Uncommon:
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Uveitis
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Cardiac disorders:
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Rare:
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Worsening of congestive heart failure (see section 4.4)
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Respiratory, thoracic and mediastinal disorders:
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Uncommon:
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Interstitial lung disease (including pneumonitis and pulmonary fibrosis)*
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Hepatobiliary disorders:
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Rare:
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Elevated liver enzymes, autoimmune hepatitis
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Skin and subcutaneous tissue disorders:
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Common:
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Pruritus
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Uncommon:
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Angioedema, urticaria, rash, psoriasiform rash, psoriasis (including new onset and pustular, primarily palms and soles)
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Rare:
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Cutaneous vasculitis (including leukocytoclastic vasculitis), Stevens-Johnson syndrome, erythema multiforme
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Very rare:
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Toxic epidermal necrolysis
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Musculoskeletal and connective tissue disorders:
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Rare:
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Subacute cutaneous lupus erythematosus, discoid lupus erythematosus, lupus-like syndrome
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General disorders and administration site conditions:
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Very common:
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Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling)*
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Common:
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Fever
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*see Description of selected adverse reactions, below.
† Please see sub-section 'Undesirable effects in paediatric patients with polyarticular juvenile idiopathic arthritis' above.
Description of selected adverse reactions
Malignancies and lymphoproliferative disorders
One hundred and twenty-nine (129) new malignancies of various types were observed in 4,114 rheumatoid arthritis patients treated in clinical trials with Enbrel for up to approximately 6 years, including 231 patients treated with Enbrel in combination with methotrexate in the 2-year active-controlled study. The observed rates and incidences in these clinical trials were similar to those expected for the population studied. A total of 2 malignancies were reported in clinical studies of approximately 2 years duration involving 240 Enbrel-treated psoriatic arthritis patients. In clinical studies conducted for more than 2 years with 351 ankylosing spondylitis patients, 6 malignancies were reported in Enbrel-treated patients. 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.
In a group of 7,416 patients treated with Enbrel in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and psoriasis clinical trials, 18 lymphomas were reported.
Reports of various malignancies (including breast and lung carcinoma and lymphoma) have also been received in the postmarketing period (see section 4.4).
Injection site reactions
Compared to placebo, patients with rheumatic diseases treated with Enbrel had a significantly higher incidence of injection site reactions (36% vs. 9%). Injection site reactions usually occurred in the first month. Mean duration was approximately 3 to 5 days. No treatment was given for the majority of injection site reactions in the Enbrel treatment groups, and the majority of patients who were given treatment received topical preparations, such as corticosteroids, or oral antihistamines. Additionally, some patients developed recall injection site reactions characterised by a skin reaction at the most recent site of injection, along with the simultaneous appearance of injection site reactions at previous injection sites. These reactions were generally transient and did not recur with treatment.
In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with Enbrel developed injection site reactions compared with 3.4% of placebo-treated patients during the first 12 weeks of treatment.
Serious infections
In placebo-controlled trials, no increase in the incidence of serious infections (fatal, life-threatening, or requiring hospitalisation or intravenous antibiotics) was observed. Serious infections occurred in 6.3% of rheumatoid arthritis patients treated with Enbrel for up to 48 months. These 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 2-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.
There were no differences in rates of infection among patients treated with Enbrel and those treated with placebo for plaque psoriasis in placebo-controlled trials of up to 24 weeks duration. Serious infections experienced by Enbrel-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis, gastritis, appendicitis, Streptococcal fasciitis, myositis, septic shock, diverticulitis and abscess. In the double-blind and open-label psoriatic arthritis trials, 1 patient reported a serious infection (pneumonia).
Serious and fatal infections have been reported during use of Enbrel; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred within a few weeks after initiating treatment with Enbrel in patients who have underlying conditions (e.g., diabetes, congestive heart failure, history of active or chronic infections) in addition to their rheumatoid arthritis (see section 4.4). Enbrel treatment may increase mortality in patients with established sepsis.
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 patients 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).
Autoantibodies
Adult patients had serum samples tested for autoantibodies at multiple timepoints. Of the rheumatoid arthritis patients evaluated for antinuclear antibodies (ANA), the percentage of patients who developed new positive ANA (Crithidia luciliae assay (3% of patients treated with Enbrel compared to none of placebo-treated patients). The proportion of patients treated with Enbrel who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The impact of long-term treatment with Enbrel on the development of autoimmune diseases is unknown.
There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a lupus-like syndrome or rashes that are compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy.
Pancytopenia and aplastic anaemia
There have been postmarketing reports of pancytopenia and aplastic anaemia, some of which had fatal outcomes (see section 4.4).
Interstitial lung disease
There have been postmarketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.
Concurrent treatment with anakinra
In studies when adult patients received concurrent treatment with Enbrel plus anakinra, a higher rate of serious infections compared to Enbrel alone was observed, and 2% of patients (3/139) developed neutropenia (absolute neutrophil count < 1000/mm3). While neutropenic, one patient developed cellulitis that resolved after hospitalisation (see sections 4.4 and 4.5).
Paediatric population
See Summary of the safety profile, above.
4.9 Overdose
No dose-limiting toxicities were observed during clinical trials of rheumatoid arthritis patients. The highest dose level evaluated has been an intravenous loading dose of 32 mg/m2 followed by subcutaneous doses of 16 mg/m2 administered twice weekly. One rheumatoid arthritis patient mistakenly self-administered 62 mg Enbrel subcutaneously twice weekly for 3 weeks without experiencing undesirable effects. There is no known antidote to Enbrel.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNF-α) inhibitors, ATC code: L04AB01
Tumour necrosis factor (TNF) is a dominant cytokine in the inflammatory process of rheumatoid arthritis. Elevated levels of TNF are also found in the synovium and psoriatic plaques of patients with psoriatic arthritis and in serum and synovial tissue of patients with ankylosing spondylitis. In plaque psoriasis, infiltration by inflammatory cells, including T-cells, leads to increased TNF levels in psoriatic lesions compared with levels in uninvolved skin. Etanercept is a competitive inhibitor of TNF binding to its cell surface receptors, and thereby inhibits the biological activity of TNF. TNF and lymphotoxin are pro-inflammatory cytokines that bind to two distinct cell surface receptors: the 55-kilodalton (p55) and 75-kilodalton (p75) tumour necrosis factor receptors (TNFRs). Both TNFRs exist naturally in membrane-bound and soluble forms. Soluble TNFRs are thought to regulate TNF biological activity.
TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on cross-linking of cell surface TNFRs. Dimeric soluble receptors, such as etanercept, possess a higher affinity for TNF than monomeric receptors and are considerably more potent competitive inhibitors of TNF binding to its cellular receptors. In addition, use of an immunoglobulin Fc region as a fusion element in the construction of a dimeric receptor imparts a longer serum half-life.
Mechanism of action
Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin pathology in plaque psoriasis is mediated by pro-inflammatory molecules that are linked in a network controlled by TNF. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF binding to cell surface TNFR, preventing TNF-mediated cellular responses by rendering TNF biologically inactive. Etanercept may also modulate biologic responses controlled by additional downstream molecules (e.g., cytokines, adhesion molecules, or proteinases) that are induced or regulated by TNF.
Clinical efficacy and safety
This section presents data from one study in polyarticular juvenile idiopathic arthritis, one study in paediatric patients with plaque psoriasis, four studies in adults with rheumatoid arthritis and four studies in adults with plaque psoriasis.
Paediatric population
The
