Sign Out
In double-blind clinical trials comparing ENBREL to placebo, injection site reactions were the most frequent adverse events among ENBREL-treated patients. Among patients with rheumatoid arthritis treated in placebo-controlled trials, serious adverse events occurred at a frequency of 4% in 349 patients treated with ENBREL compared with 5% of 152 placebo-treated patients. In the first active-controlled trial, serious adverse events occurred at a frequency of 6% in 415 patients treated with ENBREL compared with 8% of 217 methotrexate-treated patients. In the second active-controlled trial the rate of serious adverse events after 2 years treatment was similar among the three treatment groups (ENBREL 16%, methotrexate 15% and ENBREL in combination with methotrexate 17%). Among patients with plaque psoriasis treated in placebo-controlled trials, the frequency of serious adverse events was about 1% of 933 patients treated with ENBREL compared with 1% of 414 placebo-treated patients.
The following list of adverse reactions is based on experience from clinical trials in adults and on post-marketing 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, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (frequency could not be accurately estimated from clinical studies). (See Table 10.)
Click on icon to see table/diagram/imageADDITIONAL INFORMATION: Serious Adverse Events Reported in Clinical Trials: Among rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis patients in placebo-controlled, active-controlled, and open-label trials of ENBREL, serious adverse events reported included malignancies (see as follows), asthma, infections (see as follows), heart failure, myocardial infarction, myocardial ischaemia, chest pain, syncope, cerebral ischaemia, hypertension, hypotension, cholecystitis, pancreatitis, gastrointestinal haemorrhage, bursitis, confusion, depression, dyspnoea, abnormal healing, renal insufficiency, kidney calculus, deep vein thrombosis, pulmonary embolism, membranous glomerulonephropathy, polymyositis, thrombophlebitis, liver damage, leukopenia, paresis, paraesthesia, vertigo, allergic alveolitis, angioedema, scleritis, bone fracture, lymphadenopathy, ulcerative colitis, intestinal obstruction, eosinophilia, haematuria, and sarcoidosis.
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 and subsequently decreased in frequency. In clinical trials, these reactions were generally transient with a mean duration of 4 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 14% of patients treated with ENBREL developed injection site reactions compared with 6% of placebo-treated patients during the first 12 weeks of treatment.
In post-marketing experience, injection site bleeding and bruising have also been observed in conjunction with ENBREL therapy.
Infections: Serious and fatal infections have been reported; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses, and fungi. Opportunistic infections have also been reported including invasive fungal, parasitic (including protozoal), viral (including herpes zoster), bacterial (including Listeria and Legionella), and atypical mycobacterial infections (see Precautions). The most commonly reported invasive fungal infections included Candida, Pneumocystis, Aspergillus, and Histoplasma. 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 Precautions). Data from a sepsis clinical trial not specifically in patients with rheumatoid arthritis suggest that ENBREL treatment may increase mortality in patients with established sepsis.
In clinical trials in rheumatic disorders, upper respiratory infections ("colds") and sinusitis were the most frequently reported non-serious infections in patients receiving ENBREL or placebo. In placebo-controlled trials, the incidence of upper respiratory tract infections was 17% in the placebo treatment group and 22% in the group treated with ENBREL. In controlled trials in patients with rheumatoid arthritis, the rates of reported serious (fatal, life threatening, or required hospitalisation or intravenous antibiotics) and non-serious infection were similar for ENBREL and placebo when adjusted for duration of exposure. In rheumatoid arthritis patients participating in placebo-controlled trials, there were 0.68 events per patient year in the placebo group and 0.82 events per patient year in the group treated with ENBREL when the longer observation of patients on ENBREL was accounted for. In placebo-controlled trials evaluating ENBREL, no increase in the incidence of serious infections (fatal, life threatening, or requiring hospitalisation or intravenous antibiotics) was observed. Among the 2,680 rheumatoid arthritis patients treated with ENBREL for up to 48 months, including 231 patients treated with ENBREL in combination with methotrexate in the 2-year active-controlled study, 186 serious infections were observed. These serious infections included abscess (at various sites), bacteraemia, bronchitis, bursitis, cellulitis, cholecystitis, diarrhoea, diverticulitis, endocarditis (suspected), gastroenteritis, hepatitis B, herpes zoster, leg ulcer, mouth infection, osteomyelitis, otitis, peritonitis, pneumonia, pyelonephritis, sepsis, septic arthritis, sinusitis, skin infection, skin ulcer, urinary tract infection, vasculitis, and wound infection. In the 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.
In placebo-controlled psoriatic arthritis trials and plaque psoriasis trials, there were no differences in rates of infection among patients treated with ENBREL and those treated with placebo. In the psoriatic arthritis trials, no serious infections occurred in patients treated with ENBREL. In the double-blind and open-label plaque psoriasis trials up to 15 months, serious infections experienced by ENBREL-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis and abscess.
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 non-melanoma 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 post-marketing period. There have been reports of malignancies in a clinical trial of patients being treated for Wegener's granulomatosis (see Precautions).
Interstitial Lung Disease: 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 post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.
Elevated Liver Enzymes: 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).
Autoimmune Hepatitis: 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).
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 (≥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.
Pancytopenia and Aplastic Anaemia: There have been post-marketing reports of pancytopenia and aplastic anaemia, some of which had fatal outcomes (see Precautions).
Laboratory Evaluations: Based on the results of clinical studies, normally no special laboratory evaluations are necessary in addition to careful medical management and supervision of patients.
Concurrent ENBREL and Anakinra Treatment: In studies when 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 Precautions and Interactions).
Paediatric Patients: In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.
Undesirable Effects in Paediatric Patients with Juvenile Idiopathic Arthritis: Infection was the most common adverse event reported in paediatric patients taking ENBREL and occurred at an incidence similar to placebo. The types of infections reported in juvenile idiopathic arthritis patients were generally mild and consistent with those commonly seen in outpatient paediatric populations.
In clinical trials, two cases of varicella infection with signs and symptoms suggestive of aseptic meningitis have been reported among juvenile idiopathic arthritis patients treated with ENBREL.
There were 4 reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials.
Undesirable Effects in Paediatric Patients with Plaque Psoriasis: In a 48-week study of 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.
View ADR Monitoring Form
