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Infections: Serious infections, including sepsis and tuberculosis (TB), have been reported with the use of Enbrel (see Adverse Reactions). Some of these infections have been fatal. These infections were due to bacteria, mycobacteria, fungi, viruses and parasites (including protozoa). Opportunistic infections have also been reported (including listeriosis and legionellosis). 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. Caution should be exercised when considering the use of Enbrel in patients with a history of recurring or chronic infections or with underlying conditions which may predispose patients to infections (see Contraindications and Adverse Reactions).
Patients should be evaluated for infections before, during and after treatment with Enbrel, taking into consideration that the mean elimination half-life of Enbrel is 80 hours (standard deviation of 28 hours; range from 7 to 300 hours).
Opportunistic infections, including invasive fungal infections, have been reported in patients receiving Enbrel. In some cases, fungal and other opportunistic infections are not recognized, and this has resulted in delays in appropriate treatment, sometimes resulting in death. In many of the reports, patients have also received concomitant medicines including immunosuppressants. In evaluating patients for infections, healthcare providers should consider the patient's risk for relevant opportunistic infections (e.g., exposure to endemic mycoses).
Tuberculosis (TB): Tuberculosis (including disseminated or extrapulmonary presentation) has been observed in patients receiving TNF-blocking agents, including Enbrel. Tuberculosis may be due to reactivation of latent TB infection or to new infection.
Before initiation of therapy with Enbrel, any patient at increased risk for TB should be evaluated for active or latent infection. Prophylaxis of latent TB infection should be initiated prior to therapy with Enbrel. Some patients who tested negative for latent TB prior to receiving Enbrel have developed active TB. Physicians should monitor patients receiving Enbrel for signs and symptoms of active TB, including patients who tested negative for latent TB infection. Applicable local guidelines should be consulted. Patients with RA appear to have an increased rate of TB infection.
Hepatitis B reactivation: Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant anti-TNF agents including Enbrel has been reported. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to hepatitis B reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating anti-TNF therapy.
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.
Worsening of hepatitis C: There have been reports of worsening of hepatitis C in patients receiving Enbrel, although a causal relationship with Enbrel has not been established.
Concurrent treatment with anakinra: Concurrent administration of Enbrel and anakinra has been associated with an increased risk of serious infections and neutropenia. This combination has not demonstrated increased clinical benefit; such use is not recommended (see Interactions).
Concurrent treatment with abatacept: In clinical studies, concurrent administration of abatacept and Enbrel therapy resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended (see Interactions).
Wegener's granulomatosis: In a placebo-controlled study of 180 patients with Wegener's granulomatosis, the addition of Enbrel to standard treatment (including cyclophosphamide and high-dose steroids) was no more efficacious than standard treatment alone. The group of patients who received Enbrel experienced more non-cutaneous malignancies of various types than the patient group receiving standard treatment alone. The use of Enbrel for treatment of Wegener's granulomatosis is not recommended.
Alcoholic hepatitis: In a study of 48 hospitalized patients treated with Enbrel or placebo for moderate to severe alcoholic hepatitis [mean Model of End-stage Liver Disease (MELD) score = 25], Enbrel was not efficacious and the mortality rate in patients treated with Enbrel was significantly higher after 6 months. Infections were also higher in the group treated with Enbrel. The use of Enbrel in patients for the treatment of alcoholic hepatitis is not recommended. Physicians should use caution when using Enbrel in patients who also have moderate to severe alcoholic hepatitis.
The needle cover of the pre-filled syringe contain latex (dry natural rubber). Patients or caregivers should contact their doctor before using Enbrel if the needle cover will be handled by or if Enbrel will be given to someone with a known or possible hypersensitivity (allergy) to latex.
Allergic reactions: Allergic reactions associated with Enbrel administration have been reported. If any serious allergic or anaphylactic reaction occurs, discontinue administration of Enbrel immediately (see Adverse Reactions).
Immunosuppression: Anti-TNF therapies, including Enbrel, may affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses.
Malignancies and lymphoproliferative disorders: Solid and hematopoietic malignancies (excluding skin cancers): Reports of malignancies affecting various sites have been received in the post-marketing period. 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 for placebo patients was shorter than for patients receiving TNF-antagonist therapy. Cases of leukemia have been reported in patients treated with TNF-antagonists. There is an increased background risk for lymphoma and leukemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation. Post hoc analyses of rheumatoid arthritis clinical trials with Enbrel have neither confirmed nor excluded an increased risk for malignancies.
Malignancies (particularly Hodgkin's and non-Hodgkin's lymphomas), some fatal, have been reported among children and adolescents who received treatment with TNF-antagonists, including Enbrel. Most of the patients were receiving concomitant immunosuppressants.
Based on current knowledge, a possible risk for the development of lymphomas or other hematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded.
Skin cancers: Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF-antagonists including Enbrel. Post-marketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with Enbrel. Periodic skin examination is recommended for all patients who are at increased risk for skin cancer.
Combining the results of controlled portions of clinical trials of Enbrel, more cases of NMSC were observed in patients receiving Enbrel compared with control patients, particularly in patients with psoriasis.
Hematologic 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 should be advised that if they develop 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 evaluated urgently, including full blood count; if blood dyscrasias are confirmed, Enbrel should be discontinued.
Autoantibody formation: Treatment with Enbrel may be associated with the formation of autoimmune antibodies (see Adverse Reactions).
Vaccinations: In a double-blind, placebo-controlled, randomized clinical study in 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 titers in aggregate were moderately lower and fewer patients had two-fold rises in titers compared to patients not receiving Enbrel. The clinical significance of this is unknown. Live vaccines should not be given concurrently with Enbrel. If possible, bring pediatric patients up to date with immunizations according to current local guidelines before beginning Enbrel therapy.
Neurological disorders: 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. There have been rare reports of central nervous system (CNS) demyelinating disorders in patients treated with Enbrel (see Adverse Reactions). Additionally, there have been rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barre syndrome). A careful risk/benefit evaluation, including a neurological assessment, is recommended when prescribing Enbrel therapy 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.
Congestive heart failure (Cardiac failure congestive): There have been post-marketing reports of worsening of congestive heart failure (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 addition, a clinical trial evaluating the use of infliximab (a monoclonal antibody that binds to TNF-alpha) in the treatment of CHF was terminated early due to an increase in mortality among infliximab treated patients. Physicians should use caution when using Enbrel in patients who also have CHF.
Hypoglycemia in patients treated for diabetes: There have been reports of hypoglycemia following initiation of Enbrel in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.
Inflammatory bowel disease (IBD) in patients with juvenile idiopathic arthritis (JIA): There have been reports of IBD in JIA patients being treated with Enbrel, which is not effective for the treatment of IBD. A causal relationship with Enbrel is unclear because clinical manifestations of bowel inflammation have also been observed in untreated JIA patients.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
