Enbrel Adverse Reactions

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.
Blood and Lymphatic System Disorders: Uncommon: Thrombocytopenia. Rare: Anemia, leukopenia, neutropenia, pancytopenia*. Very Rare: Aplastic anemia*. (See Precautions.)
Immune System Disorders: Common: Allergic reactions (see Skin and Subcutaneous Disorders as follows), autoantibody formation*. Uncommon: Systemic vasculitis (ANCA positive vasculitis). Rare: Serious allergic/anaphylactic reactions (including angioedema, bronchospasm).
Nervous System Disorders: Rare: Seizures, CNS demyelinating events including multiple sclerosis and localized demyelinating conditions eg, optic neuritis and transverse myelitis (see Precautions).
Skin and Subcutaneous Tissue Disorders: Common: Pruritus. Uncommon: Urticaria, rash, psoriasis and psoriasiform rash. Rare: Cutaneous vasculitis (including leukocytoclastic vasculitis), Stevens-Johnson syndrome, erythema multiforme.
Musculoskeletal, Connective Tissue and Bone Disorders: Rare: Subacute cutaneous lupus erythematosus, discoid lupus erythematosus, lupus-like syndrome.
General Disorders and Administration Site Conditions: Common: Fever.
Cardiac Disorders: Rare: There have been reports of worsening of congestive heart failure (see Precautions).
Hepatobiliary Disorders: Rare: Elevated liver enzymes, autoimmune hepatitis.
*See Additional Information as follows.
Additional Information: Serious Adverse Events Reported in Clinical Trials: Among RA, 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, asthma, infections, heart failure, myocardial infarction, myocardial ischemia, chest pain, syncope, cerebral ischemia, hypertension, hypotension, cholecystitis, pancreatitis, gastrointestinal hemorrhage, bursitis, confusion, depression, dyspnea, abnormal healing, renal insufficiency, kidney calculus, deep vein thrombosis, pulmonary embolism, membranous glomerulonephropathy, polymyositis, thrombophlebitis, liver damage, leucopenia, paresis, paresthesia, vertigo, allergic alveolitis, angioedema, scleritis, bone fracture, lymphadenopathy, ulcerative colitis and intestinal obstruction.
Malignancies: Thirty-eight (38) new malignancies of various types were observed in 2680 RA patients treated in clinical trials with Enbrel for up to 48 months, including 231 patients treated with Enbrel in combination with methotrexate in the 1-year active-controlled study. The observed rates and incidences in these clinical trials were similar to those expected for the population studied. No psoriatic arthritis patients developed malignancies in the double-blind, placebo-controlled studies of up to 6 months duration involving 131 Enbrel-treated patients. Twenty-three (23) malignancies were reported in plaque psoriasis patients treated with Enbrel in double-blind and open-label studies of up to 15 months involving 1261 Enbrel-treated patients.
Reports of malignancies affecting various sites have been received in the post-marketing period (see Precautions).
There have been reports of malignancies in a clinical trial of patients being treated for Wegener's granulomatosis.
Injection Site Reactions: Patients in controlled clinical studies treated with etanercept had a significantly higher incidence of injection site reactions (erythema and/or itching, pain or swelling) compared with placebo-treated patients. The frequency of injection site reactions was greatest in the 1st month and subsequently decreased in frequency. Some patients who experienced injection site reactions also experienced reactions at previous injection sites.
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: In controlled trials in patients with RA, the rates of reported serious (fatal, life-threatening, or required hospitalization or IV antibiotics) and non-serious infection were similar for Enbrel and placebo when adjusted for duration of exposure. Upper respiratory tract infections were the most commonly reported non-serious infections.
In placebo-controlled psoriatic arthritis 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 of up to 15 months, serious infections experienced by Enbrel-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis and abscess.
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 (eg, diabetes, CHF, history of active or chronic infections) in addition to their RA (see Precautions). Data from a sepsis clinical trial, not specifically in patients with RA, suggest that Enbrel treatment may increase mortality in patients with established sepsis.
Autoantibodies: In controlled trials, the percentage of patients who developed new positive antinuclear antibodies (ANA) (≥1:40), new positive anti-double-stranded DNA antibodies, and new anticardiolipin antibodies was increased compared to placebo-treated patients. The impact of long-term treatment with Enbrel on the development of autoimmune diseases is unknown.
Rare reports have been described in patients including those with rheumatoid factor-positive RA, who have developed additional autoantibodies in conjunction with a lupus-like syndrome or rashes compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy.
Pancytopenia and Aplastic Anemia: There have been post-marketing reports of pancytopenia and aplastic anemia, 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, 1 patient developed cellulitis that resolved after hospitalization (see Warnings and Interactions).
Undesirable Effects in Pediatric Patients with Juvenile Chronic Arthritis: In general the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients.
Juvenile chronic arthritis patients treated with Enbrel had a significantly higher incidence of injectionsite reactions (erythema and/or itching, pain or swelling) compared with placebo-treated patients in controlled clinical trials.
Infection was the most common adverse event reported in pediatric patients taking Enbrel and occurred at an incidence similar to placebo. The types of infections reported in juvenile chronic arthritis patients were generally mild and consistent with those commonly seen in outpatient pediatric populations.
In clinical trials, 2 cases of varicella infection with signs and symptoms suggestive of aseptic meningitis have been reported among juvenile chronic arthritis patients treated with Enbrel.
The most frequent non-infectious adverse events seen in each age group were as follows: 4-8 years: Abdominal pain (29%); 9-12 years: vomiting and accidental injury (27% each); and 13-17 years: headache (27%). Five events occurred in >10% of the patients: Abdominal pain, headache, rhinitis, vomiting, rash. The majority of patients (53%) who experienced adverse events had events considered unrelated to drug.