Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Sepsis or risk of sepsis.
Treatment with Enbrel should not be initiated in patients with active infections, including chronic or localised infections.
In order to improve the traceability of biological medicinal products, the trademark and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
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, listeriosis and legionellosis, have been reported with the use of Enbrel (see section 4.8). These infections were due to bacteria, mycobacteria, fungi, viruses and parasites (including protozoa). 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.
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 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.
Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant TNF-antagonists, including Enbrel, has been reported. This includes reports of reactivation of hepatitis B in patients who were anti-HBc positive but HBsAg negative. Patients should be tested for HBV infection before initiating treatment with Enbrel. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when administering Enbrel in patients previously infected with HBV. These patients should be monitored for signs and symptoms of active HBV infection throughout therapy and for several weeks following termination of therapy. Adequate data from treating patients infected with HBV with anti-viral therapy in conjunction with TNF-antagonist therapy are not available. In patients who develop HBV infection, Enbrel should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
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 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).
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 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.
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.
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.
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.
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.
Treatment with Enbrel may result in the formation of autoimmune antibodies (see section 4.8).
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.
There have been rare reports of CNS demyelinating disorders in patients treated with Enbrel (see section 4.8). Additionally, there have been 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.
In a controlled clinical trial of two 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 (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.
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.
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. There have also been rare (<0.1%) reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. 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.
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.
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.
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.
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.
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).
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.
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).
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.
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 methotrexate, digoxin or warfarin.
Women of childbearing potential should consider the use of appropriate contraception to avoid becoming pregnant during Enbrel therapy and for three weeks after discontinuation of therapy.
Developmental toxicity studies performed in rats and rabbits have revealed no evidence of harm to the foetus or neonatal rat due to etanercept. The effects of etanercept on pregnancy outcomes have been investigated in two observational cohort studies. A higher rate of major birth defects was observed in one observational study comparing pregnancies exposed to etanercept (n=370) during the first trimester with pregnancies not exposed to etanercept or other TNF-antagonists (n=164) (adjusted odds ratio 2.4, 95% CI: 1.0-5.5). The types of major birth defects were consistent with those most commonly reported in the general population and no particular pattern of abnormalities was identified. No change in the rate of spontaneous abortion, stillbirth, or minor malformations was observed. In another observational multi-country registry study comparing the risk of adverse pregnancy outcomes in women exposed to etanercept during the first 90 days of pregnancy (n=425) to those exposed to non-biologic drugs (n=3497), there was no observed increased risk of major birth defects (crude odds ratio [OR] = 1.22, 95% CI: 0.79-1.90; adjusted OR = 0.96, 95% CI: 0.58-1.60 after adjusting for country, maternal disease, parity, maternal age and smoking in early pregnancy). This study also showed no increased risks of minor birth defects, preterm birth, stillbirth, or infections in the first year of life for infants born to women exposed to etanercept during pregnancy. Enbrel should only be used during pregnancy if clearly needed.
Etanercept crosses the placenta and has been detected in the serum of infants born to female patients treated with Enbrel during pregnancy. The clinical impact of this is unknown, however, infants may be at increased risk of infection. Administration of live vaccines to infants for 16 weeks after the mother’s last dose of Enbrel is generally not recommended.
In lactating rats following subcutaneous administration, etanercept was excreted in the milk and detected in the serum of pups. Limited information from the published literature indicates etanercept has been detected at low levels in human milk. Etanercept could be considered for use during breast-feeding taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
While systemic exposure in a breastfed infant is expected to be low because etanercept is largely degraded in the gastrointestinal tract, limited data regarding systemic exposure in the breastfed infant are available. Therefore, the administration of live vaccines (e.g., BCG) to a breastfed infant when the mother is receiving etanercept could be considered 16 weeks after stopping breast-feeding (or at an earlier timepoint if the infant etanercept serum levels are undetectable).
Preclinical data about peri- and postnatal toxicity of etanercept and of effects of etanercept on fertility and general reproductive performance are not available.
Enbrel has no or negligible influence on the ability to drive and use machines.
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), headache, 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.
The following list of adverse reactions is based on experience from clinical trials 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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
| System Organ Class | Very Common ≥1/10 | Common ≥1/100 to <1/10 | Uncommon ≥1/1,000 to <1/100 | Rare ≥1/10,000 to <1/1,000 | Very Rare <1/10,000 | Not Known (Cannot be Estimated from Available Data) |
|---|---|---|---|---|---|---|
| Infections and infestations | Infection (including upper respiratory tract infection, bronchitis, cystitis, skin infection)* | Serious infections (including pneumonia, cellulitis, arthritis bacterial, sepsis and parasitic infection)* | Tuberculosis, opportunistic infection (including invasive fungal, protozoal, bacterial, atypical mycobacterial, viral infections, and Legionella)* | Hepatitis B reactivation, listeria | ||
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Non-melanoma skin cancers* (see section 4.4) | Malignant melanoma (see section 4.4), lymphoma, leukaemia | Merkel cell carcinoma (see section 4.4), Kaposi’s sarcoma | |||
| Blood and lymphatic system disorders | Thrombocytopenia, anaemia, leukopenia, neutropenia | Pancytopenia* | Aplastic anaemia* | Histiocytosis haematophagic (macrophage activation syndrome)* | ||
| Immune system disorders | Allergic reactions (see Skin and subcutaneous tissue disorders), autoantibody formation* | Vasculitis (including antineutrophilic cytoplasmic antibody positive vasculitis) | Serious allergic/anaphylactic reactions (including angioedema, bronchospasm), sarcoidosis | Worsening of symptoms of dermatomyositis | ||
| Nervous system disorders | Headache | CNS demyelinating events suggestive of multiple sclerosis or localised demyelinating conditions, such as optic neuritis and transverse myelitis (see section 4.4), peripheral demyelinating events, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy (see section 4.4), seizure | ||||
| Eye disorders | Uveitis, scleritis | |||||
| Cardiac disorders | Worsening of cardiac failure congestive (see section 4.4) | New onset cardiac failure congestive (see section 4.4) | ||||
| Respiratory, thoracic, and mediastinal disorders | Interstitial lung disease (including pneumonitis and pulmonary fibrosis)* | |||||
| Gastrointestinal disorders | Inflammatory bowel disease | |||||
| Hepatobiliary disorders | Elevated liver enzymes* | Autoimmune hepatitis* | ||||
| Skin and subcutaneous tissue disorders | Pruritus, rash | Angioedema, psoriasis (including new onset or worsening and pustular, primarily palms and soles), urticaria, psoriasiform rash | Stevens-Johnson syndrome, cutaneous vasculitis (including hypersensitivity vasculitis), erythema multiforme, lichenoid reactions | Toxic epidermal necrolysis | ||
| Musculoskeletal and connective tissue disorders | Cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, lupus-like syndrome | |||||
| General disorders and administration site conditions | Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling)* | Pyrexia |
* see Description of selected adverse reactions, below.
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).
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.
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, parasitic (including protozoal), viral (including herpes zoster), 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 included Candida, Pneumocystis, Aspergillus, and Histoplasma. 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).
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 (1:40) was higher in patients treated with Enbrel (11%) than in placebo-treated patients (5%). The percentage of patients who developed new positive anti-double-stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with Enbrel compared to 4% of placebo-treated patients) and by 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.
There have been postmarketing reports of pancytopenia and aplastic anaemia, some of which had fatal outcomes (see section 4.4).
In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of interstitial lung disease in patients receiving etanercept without concomitant methotrexate was 0.06% (frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of interstitial lung disease was 0.47% (frequency uncommon). There have been postmarketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.
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).
In the double-blind periods of controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of adverse events of elevated liver enzymes in patients receiving etanercept without concomitant methotrexate was 0.54% (frequency uncommon). In the double-blind periods of controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of adverse events of elevated liver enzymes was 4.18% (frequency common).
In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of autoimmune hepatitis in patients receiving etanercept without concomitant methotrexate was 0.02% (frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of autoimmune hepatitis was 0.24% (frequency uncommon).
In general, the adverse events in paediatric patients with juvenile idiopathic arthritis 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 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.
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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