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Infections: Sepsis and serious infections (fatal, life-threatening, or requiring hospitalization or IV antibiotics) have been reported with the use of Enbrel (see Adverse Reactions). Many of these serious events have occurred in patients with underlying diseases that in addition to their RA could predispose them to infections. 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. Physicians should exercise caution 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 eg, advanced or poorly controlled diabetes.
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 80 hrs (standard deviation of 28 hrs; range from 7-300 hrs).
Concurrent Enbrel and Anakinra Treatment: 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 Interactions and Adverse Reactions).
In placebo-controlled study of 180 patients with Wegener's granulomatosis, the addition of etanercept to standard treatment (including cyclophosphamide and high-dose steroids) was no more efficacious than standard treatment alone. The group of patients who received etanercept experienced more non-cutaneous malignancies of various types than the patient group receiving standard treatment alone. The use of etanercept for treatment of Wegener's granulomatosis is not recommended.
Allergic Reactions: The needle cover of the pre-filled syringe contains latex (dry natural rubber) that may cause hypersensitivity reactions when handled by or when Enbrel is administered to persons with known or possible latex sensitivity.
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.
Immunosuppression: The possibility exists for anti-TNF therapies, including Enbrel, to affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. Reports of various malignancies (including breast and lung carcinoma and lymphoma) have been received in the post-marketing period (see Adverse Reactions). In a study of 49 patients with RA 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. Whether treatment with Enbrel might influence the development and course of malignancies and active and/or chronic infections is unknown. The safety and efficacy of Enbrel in patients with immunosuppression or chronic infections have not been evaluated.
Two juvenile chronic 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.
Vaccinations: Most psoriatic arthritis patients receiving Enbrel were able to mount effective β-cell immune response to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and fewer patients had 2-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. No data are available on the secondary transmission of infection by live vaccines in patients receiving Enbrel. It is recommended that juvenile chronic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Enbrel therapy.
Autoantibody Formation: Treatment with Enbrel may be associated with the formation of autoimmune antibodies (see Adverse Reactions).
Hematologic Reactions: Rare cases of pancytopenia and very rare cases of aplastic anemia, 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 (eg, 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.
CNS 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 CNS demyelinating disorders in patients treated with Enbrel (see Adverse Reactions); the causal relationship to Enbrel therapy remains unclear. A careful risk/benefit evaluation including a neurological assessment, is recommended when prescribing Enbrel to patients with preexisting or recent onset of CNS demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.
Congestive Heart Failure (CHF): Physicians should use caution when using Enbrel in patients who also have CHF. There have been post-marketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking Enbrel. 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 TNFα) in the treatment of CHF was terminated early due to an increase in mortality among infliximab-treated patients.
Tuberculosis (TB): 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 Enbrel therapy. Applicable local guidelines should be consulted. Patients with RA appear to have an increased rate of TB infection. It is not known whether Enbrel therapy increases this risk.
Hepatitis B Virus (HBV) Reactivation: Reactivation of HBV in patients who are chronic carriers of this virus receiving anti-TNF agents including etanercept 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 HBV reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating anti-TNF therapy.
Although a causal relationship has not been established for etanercept, caution should be exercised when administering etanercept in patients identified as carriers of HBV. If etanercept is used in carriers of HBV, the 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 etanercept, although a causal relationship with etanercept has not been established.
Combination Therapy: In a controlled clinical trial of 1-year duration in RA 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 DMARDs 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.
Renal and Hepatic Impairment: Based on pharmacokinetic data (see Pharmacokinetics under Actions), no dosage adjustment is needed in patients with renal or hepatic impairment; clinical experience in such patients is limited.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
Use in pregnancy: The safe use of etanercept during pregnancy has not been established. Use etanercept during pregnancy only if clearly needed.
Developmental toxicity studies have been performed in rats and rabbits at doses resulting in AUC-based systemic exposure levels of etanercept that were at least 21- to 25-fold higher than in humans at the recommended therapeutic dose of 50 mg weekly, and are approximately 10- to 13-fold higher than in humans at the maximum recommended human dose of 50 mg twice weekly (for psoriasis) have revealed no evidence of harm to the fetus or neonatal rat due to etanercept. Preclinical data about peri- and postnatal toxicity of etanercept and of effects of etanercept on fertility and general reproductive performance are not available.
Use in lactation: The safe use of etanercept during lactation has not been established.
It is not known whether etanercept is excreted in human milk. Because immunoglobulins and many medicinal products can be excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue Enbrel while nursing.
