Enbrel Special Precautions

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 etanercept 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 etanercept 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 recognised, 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. A causal relationship has not been established for ENBREL. In some instances, HBV reactivation occurring in conjunction with anti-TNF therapy has been fatal. 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. Prescribers should exercise caution in prescribing anti-TNF agents in patients previously infected with HBV. These patients should be monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with anti-TNF therapy to prevent HBV reactivation. If HBV reactivation should develop in patients who are receiving ENBREL, treatment should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
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 benefits; 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.
Allergic Reactions: Parenteral administration of any biological product should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Allergic reactions associated with ENBREL administration have been reported. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, discontinue administration of ENBREL immediately (see Adverse Reactions).
Powder and Solvent for Solution for Injection: The rubber closure of the solvent syringe contains latex (dry natural rubber). Patients or caregivers should contact their doctor before using ENBREL if the rubber closure of the solvent syringe will be handled by or if ENBREL will be given to someone with a known or possible hypersensitivity (allergy) to latex.
Solution for Injection in Pre-filled Syringe: The needle cover of the pre-filled syringe contains 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.
Immunosuppression and Malignancy: TNF modulates immune responses and has a protective effect against the development of some tumours. The impact of treatment with ENBREL, on the course of development of malignancies, including those caused by immunosuppressive agents, is not understood and has not been studied. The possibility exists for TNF therapies, including ENBREL, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. The impact of treatment with ENBREL on the development and course of malignancies and active and/or chronic infections is not fully understood (see Adverse Reactions). Reports of malignancies affecting various sites have been received in the post-marketing period including breast and lung carcinoma and lymphoma.
In a study of 49 patients with rheumatoid arthritis 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. Reports of malignancies affecting various sites have been received in the post-marketing period. Based on current knowledge, a possible risk for the development of lymphomas or other haematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded. Whether treatment with ENBREL might influence the development and course of 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.
Solid and Haematopoietic 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 leukaemia have been reported in patients treated with TNF antagonists. There is an increased background risk for lymphoma and leukaemia 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. During the controlled portions of ENBREL trials, 3 lymphomas were observed among 4,509 ENBREL-treated patients vs. 0 among 2,040 control patients (duration of controlled treatment ranged from 3 to 24 months). In the controlled and open-label portions of clinical trials of ENBREL, 9 lymphomas were observed in 5,723 patients over approximately 11,201 patient-years of therapy. This is 3-fold higher than that expected in the general population.
Based on current knowledge, a possible risk for the development of lymphomas or other haematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded.
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.
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.
Haematologic 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 and parents/caregivers should be advised that if the patient develops 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 investigated 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, randomised 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 titres in aggregate were moderately lower and fewer patients had two-fold rises in titres 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. If possible, bring paediatric patients up to date with immunisations 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-Barré 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.
Hypoglycaemia in Patients Treated with Diabetes: There have been reports of hypoglycaemia following initiation of ENBREL in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.
Combination Therapy: In a controlled clinical trial of two years duration in rheumatoid arthritis 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 disease-modifying antirheumatic drugs (DMARD) 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 Pharmacology: Pharmacokinetics under Actions), no dosage adjustment is needed in patients with renal or hepatic impairment; clinical experience in such patients is limited.
Alcoholic Hepatitis: In a study of 48 hospitalised 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.
Use in Psoriasis: The safety and efficacy of ENBREL in combination with other immunosuppressive agents used in psoriasis or with phototherapy have not been studied. ENBREL should not be used in combination with such agents because of the possibility of excessive immunosuppression.
Monitoring: Based on the results of clinical studies in rheumatoid arthritis, normally no special laboratory evaluations are necessary in addition to careful medical management and supervision of patients.
Genotoxicity and Effects on Fertility: Genotoxicity studies showed no evidence of gene mutations or chromosomal damage. Long-term animal studies have not been conducted to evaluate the carcinogenic potential of ENBREL or its effects on fertility.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.