arthritis (see section 4.4). Etanercept treatment may increase mortality in patients with established sepsis. Opportunistic infections have been reported in association with etanercept, 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 etanercept. The exposure-adjusted rate was 0.06 events per 100 patient-years.
In post-marketing 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). 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 etanercept (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 etanercept compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with etanercept compared to none of placebo-treated patients).
The proportion of patients treated with etanercept who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The impact of long-term treatment with etanercept 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 section 4.4). 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. Concurrent treatment with anakinra In studies when adult patients received concurrent treatment with etanercept plus anakinra, a higher rate of serious infections compared to etanercept alone was observed and 2% of patients (3/139) developed neutropenia (absolute neutrophil count ˂ 1,000/mm 3 ). While neutropenic, one patient developed cellulitis that resolved after hospitalisation (see sections 4.4 and 4.5).
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). 15