ENBREL suppresses the immune system and has been associated with serious and sometimes fatal infections including TB and other opportunistic infections, malignancies, neurologic events, hematologic events, congestive heart failure, hepatitis B reactivation, allergic reactions, lupus-like syndrome and autoimmune hepatitis.1
Anti-tumor necrosis factor (TNF) therapies, including ENBREL, affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 49 RA patients 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. The impact of treatment with ENBREL on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood.1
The risks and benefits of ENBREL should be carefully considered in patients with chronic or recurrent infection or underlying conditions that may predispose them to infection (such as advanced or poorly controlled diabetes) or a history of opportunistic infections, and with those who have been exposed to tuberculosis or areas of endemic tuberculosis or mycoses (such as histoplasmosis, coccidioidomycosis, or blastomycosis).1
In a study of patients with psoriatic arthritis, most patients receiving ENBREL were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccines, but titers in aggregate were moderately lower, and fewer patients had 2-fold rises in titers compared with patients not receiving ENBREL. The clinical significance of this is unknown. Patients receiving ENBREL may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving ENBREL.1
It is recommended that pediatric patients, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines prior to initiating ENBREL therapy.1
Live vaccines are not recommended for patients on ENBREL.1
A total of 480 RA patients ages 65 years or older have been studied in clinical trials. In plaque psoriasis randomized clinical trials, a total of 138 out of 1,965 subjects treated with ENBREL or placebo were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but the number of geriatric psoriasis subjects is too small to determine whether they respond differently from younger subjects. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating elderly patients.1
Patients need to be monitored for the development of any side effects, including potentially serious side effects. For example, patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ENBREL, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. Stop ENBREL if infection becomes serious.1
Physicians should exercise caution when using ENBREL in patients who also have heart failure, and monitor patients carefully.1
Monitor patients previously infected with hepatitis B virus for reactivation during and several months after therapy. If reactivation occurs, consider stopping ENBREL and beginning anti-viral therapy.1
See Prescribing Information for additional warnings and precautions.
Long-term animal studies have not been conducted to evaluate the carcinogenic potential of ENBREL or its effect on fertility. Mutagenesis studies were conducted in vitro and in vivo, and no evidence of mutagenic activity was observed. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Three case reports showed that cord blood levels of etanercept at delivery in infants, born to mothers administered etanercept during pregnancy, were between 3 and 32% of the maternal serum level.1
Available studies with use of etanercept during pregnancy do not reliably support an association between etanercept and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS) ENBREL Pregnancy Registry in women with rheumatic diseases or psoriasis and a Scandinavian study in pregnant women with chronic inflammatory disease. Both the OTIS Registry and the Scandinavian study showed the proportion of liveborn infants with major birth defects was higher for women exposed to etanercept compared to diseased etanercept unexposed women. However, the lack of pattern of major birth defects is reassuring and differences between exposure groups (eg. disease severity) may have impacted the occurrence of birth defects. The risk of fetal/neonatal adverse reactions with in utero exposure to ENBREL is unknown. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to ENBREL in utero.1
Limited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by a breastfed infant. No data are available on the effects of etanercept on the breastfed child or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENBREL and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.1
Yes, the needle covers on the Enbrel Mini® single-dose prefilled cartridge, SureClick® autoinjector, and the single-dose prefilled syringes contain dry natural rubber (derivative of latex), which should not be handled by persons sensitive to the substance.1
*Enbrel Mini® single-dose prefilled cartridge with AutoTouch® reusable autoinjector.
ENBREL should not be administered to patients with sepsis.1
Each single-dose prefilled syringe, SureClick® autoinjector, and Enbrel Mini® cartridge contains 50 mg/mL of etanercept in a single-dose syringe with a 27-gauge, 1/2-inch needle.1
ENBREL single-dose vial is supplied in a carton containing four vials. Each single-dose vial contains 25 mg (0.5mL). Syringes and needles are required and are not supplied with the single-dose vial.
ENBREL multiple-dose vial is supplied in a carton containing four dose trays. Each dose tray contains one 25-mg vial of etanercept, one diluent syringe (1 mL Sterile Bacteriostatic Water for Injection, USP, containing 0.9% benzyl alcohol), one 27-gauge 1/2-inch needle, one vial adapter, and one plunger. Each carton contains four "Mixing Date:" stickers.1
Administration of one 50-mg prefilled syringe or one SureClick® autoinjector provides a dose equivalent to two 25-mg prefilled syringes or two multiple-dose vials of lyophilized ENBREL, when vials are reconstituted and administered as recommended.1
Serious infections, including patients with pneumonia, sinusitis, abscess, and herpes zoster1
ENBREL should be discontinued if a patient develops a serious infection or sepsis. Consider the risks and benefits carefully prior to initiation of therapy in patients with chronic or recurrent infection. Monitor patients closely for infections during and after treatment, including the possible development of tuberculosis (TB) in patients who tested negative for latent TB prior to therapy initiation.
Discontinuation of ENBREL should be considered in patients with confirmed significant hematologic abnormalities.
If an anaphylactic reaction or other serious allergic reaction occurs, administration of ENBREL should be discontinued immediately and appropriate therapy initiated.
Vaccinations, including yellow fever, BCG, rubella, polio, cholera, typhoid, and varicella1
When taking ENBREL, patients may receive concurrent vaccination, except for live vaccines. Patients with significant exposure to varicella virus should temporarily discontinue ENBREL therapy and be considered for prophylactic treatment.
Most PsA patients receiving ENBREL were able to mount effective B-cell immune responses 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. Patients receiving ENBREL may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving ENBREL.
If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with ENBREL, treatment should be discontinued and the patient should be carefully evaluated.
Pregnancy or intent to breast-feed1
ENBREL should be used in pregnancy only if clearly needed. For nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug.
Surgery, including dental surgery or hip replacement1,2
ENBREL can lower the ability of the immune system to fight infections. Patients should consult their physician and be closely monitored for the development of signs and symptoms of infection during and after surgery.
Prescription Enbrel® (etanercept) is administered by injection.
Patients treated with ENBREL are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids or were predisposed to infection because of their underlying disease. ENBREL should not be initiated in the presence of sepsis, active infections, or allergy to ENBREL or its components. ENBREL should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: 1) Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before ENBREL use and periodically during therapy. Treatment for latent infection should be initiated prior to ENBREL use, 2) Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric antifungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness, and 3) Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.
The risks and benefits of treatment with ENBREL should be carefully considered prior to initiating therapy in patients 1) with chronic or recurrent infection, 2) who have been exposed to TB, 3) who have resided or traveled in areas of endemic TB or endemic mycoses, or 4) with underlying conditions that may predispose them to infections such as advanced or poorly controlled diabetes. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ENBREL, including the possible development of TB in patients who tested negative for latent TB prior to initiating therapy.
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including ENBREL.
In adult clinical trials of all TNF blockers, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients. The role of TNF blocker therapy in the development of malignancies is unknown.
Cases of acute and chronic leukemia have been reported in association with postmarketing TNF blocker use in RA and other indications. The risk of leukemia may be higher in patients with RA (approximately 2-fold) than the general population.
Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF blockers, including ENBREL. Periodic skin examinations should be considered for all patients at increased risk for skin cancer.
In patients who initiated therapy at ≤18 years of age, approximately half of the reported malignancies were lymphomas (Hodgkin's and non-Hodgkin's lymphoma). Other cases included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants.
Treatment with TNF-blocking agents, including ENBREL, has been associated with rare (<0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barré syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with ENBREL therapy. Prescribers should exercise caution in considering the use of ENBREL in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.
CONGESTIVE HEART FAILURE
Cases of worsening congestive heart failure (CHF) and, rarely, new-onset cases have been reported in patients taking ENBREL. Caution should be used when using ENBREL in patients with CHF. These patients should be carefully monitored.
Rare cases of pancytopenia, including aplastic anemia, some fatal, have been reported. The causal relationship to ENBREL therapy remains unclear. Exercise caution when considering ENBREL in patients who have a previous history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs or symptoms of blood dyscrasias or infection. Consider discontinuing ENBREL if significant hematologic abnormalities are confirmed.
HEPATITIS B REACTIVATION
Reactivation of hepatitis B has been reported in patients who were previously infected with hepatitis B virus (HBV) and received concomitant TNF-blocking agents, including ENBREL. Most reports occurred in patients also taking immunosuppressive agents, which may contribute to hepatitis B reactivation. Exercise caution when considering ENBREL in these patients.
Allergic reactions associated with administration of ENBREL during clinical trials have been reported in <2% of patients. If an anaphylactic reaction or other serious allergic reaction occurs, administration of ENBREL should be discontinued immediately and appropriate therapy initiated.
Live vaccines should not be administered to patients on ENBREL. Pediatric patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, temporarily discontinue ENBREL and consider prophylactic treatment with Varicella Zoster Immune Globulin.
Autoantibodies may develop with ENBREL, and rarely lupus-like syndrome or autoimmune hepatitis may occur. These may resolve upon withdrawal of ENBREL. Stop ENBREL if lupus-like syndrome or autoimmune hepatitis develops.
WEGENER'S GRANULOMATOSIS PATIENTS
The use of ENBREL in patients with Wegener’s granulomatosis receiving immunosuppressive agents (eg, cyclophosphamide) is not recommended.
MODERATE TO SEVERE ALCOHOLIC HEPATITIS
Based on a study of patients treated for alcoholic hepatitis, exercise caution when using ENBREL in patients with moderate to severe alcoholic hepatitis.
The most commonly reported adverse reactions in RA clinical trials were injection site reaction and infection. In clinical trials of all other adult indications, adverse reactions were similar to those reported in RA clinical trials.
In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients. The types of infections reported in pediatric patients were generally mild and consistent with those commonly seen in the general pediatric population.
The use of ENBREL in patients receiving concurrent cyclophosphamide therapy is not recommended. The risk of serious infection may increase with concomitant use of abatacept therapy. Concurrent therapy with ENBREL and anakinra is not recommended. Hypoglycemia has been reported following initiation of ENBREL therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.
ENBREL is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis (RA). ENBREL can be initiated in combination with methotrexate (MTX) or used alone.
ENBREL is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis (PsA). ENBREL can be used with or without MTX.
ENBREL is indicated for the treatment of patients 4 years or older with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.
ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS).
ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients ages 2 and older.