WARNINGS AND PRECAUTIONS
Patients treated with Enbrel are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.
Treatment with Enbrel should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:
- With chronic or recurrent infection;
- Who have been exposed to tuberculosis;
- With a history of an opportunistic infection;
- Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
- With underlying conditions that may predispose them to infection, such as advanced or poorly controlled diabetes [see Adverse Reactions ].
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Enbrel.
Enbrel should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with Enbrel should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.
Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving Enbrel, including patients who have previously received treatment for latent or active tuberculosis. Data from clinical trials and preclinical studies suggest that the risk of reactivation of latent tuberculosis infection is lower with Enbrel than with TNF-blocking monoclonal antibodies. Nonetheless, postmarketing cases of tuberculosis reactivation have been reported for TNF blockers, including Enbrel. Tuberculosis has developed in patients who tested negative for latent tuberculosis prior to initiation of therapy. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating Enbrel and periodically during therapy. Tests for latent tuberculosis infection may be falsely negative while on therapy with Enbrel.
Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating Enbrel, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
Anti-tuberculosis therapy should also be considered prior to initiation of Enbrel in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Tuberculosis should be strongly considered in patients who develop a new infection during Enbrel treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
Invasive Fungal Infections
Cases of serious and sometimes fatal fungal infections, including histoplasmosis, have been reported with TNF blockers, including Enbrel. For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric anti-fungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric anti-fungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of anti-fungal therapy. In 38 Enbrel clinical trials and 4 cohort studies in all approved indications representing 27,169 patient-years of exposure (17,696 patients) from the United States and Canada, no histoplasmosis infections were reported among patients treated with Enbrel.
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 [see Adverse Reactions].
In the controlled portions of clinical trials of TNF‑blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared to control patients. During the controlled portions of Enbrel trials in adult patients with RA, AS, and PsA, 2 lymphomas were observed among 3306 Enbrel‑treated patients versus 0 among 1521 control patients (duration of controlled treatment ranged from 3 to 36 months).
Among 6543 adult rheumatology (RA, PsA, AS) patients treated with Enbrel in controlled and uncontrolled portions of clinical trials, representing approximately 12,845 patient‑years of therapy, the observed rate of lymphoma was 0.10 cases per 100 patient‑years. This was 3‑fold higher than the rate of lymphoma expected in the general U.S. population based on the Surveillance, Epidemiology, and End Results (SEER) Database. An increased rate of lymphoma up to several-fold has been reported in the RA patient population, and may be further increased in patients with more severe disease activity.
Among 4410 adult PsO patients treated with Enbrel in clinical trials up to 36 months, representing approximately 4278 patient‑years of therapy, the observed rate of lymphoma was 0.05 cases per 100 patient‑years, which is comparable to the rate in the general population. No cases were observed in Enbrel- or placebo-treated patients during the controlled portions of these trials.
Cases of acute and chronic leukemia have been reported in association with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF-blocker therapy, patients with rheumatoid arthritis may be at higher risk (approximately 2-fold) than the general population for the development of leukemia.
During the controlled portions of Enbrel trials, 2 cases of leukemia were observed among 5445 (0.06 cases per 100 patient-years) Enbrel-treated patients versus 0 among 2890 (0%) control patients (duration of controlled treatment ranged from 3 to 48 months).
Among 15,401 patients treated with Enbrel in controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of leukemia was 0.03 cases per 100 patient-years.
Information is available from 10,953 adult patients with 17,123 patient-years and 696 pediatric patients with 1282 patient-years of experience across 45 Enbrel clinical studies.
For malignancies other than lymphoma and non-melanoma skin cancer, there was no difference in exposure-adjusted rates between the Enbrel and control arms in the controlled portions of clinical studies for all indications. Analysis of the malignancy rate in combined controlled and uncontrolled portions of studies has demonstrated that types and rates are similar to what is expected in the general U.S. population based on the SEER database and suggests no increase in rates over time. Whether treatment with Enbrel might influence the development and course of malignancies in adults is unknown.
Melanoma and Non-melanoma skin cancer (NMSC)
Melanoma and non-melanoma skin cancer has been reported in patients treated with TNF antagonists including etanercept.
Among 15,401 patients treated with Enbrel in controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of melanoma was 0.043 cases per 100 patient-years.
Among 3306 adult rheumatology (RA, PsA, AS) patients treated with Enbrel in controlled clinical trials representing approximately 2669 patient‑years of therapy, the observed rate of NMSC was 0.41 cases per 100 patient‑years vs 0.37 cases per 100 patient-years among 1521 control-treated patients representing 1077 patient-years. Among 1245 adult psoriasis patients treated with Enbrel in controlled clinical trials, representing approximately 283 patient‑years of therapy, the observed rate of NMSC was 3.54 cases per 100 patient-years vs 1.28 cases per 100 patient-years among 720 control-treated patients representing 156 patient-years.
Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with Enbrel.
Periodic skin examinations should be considered for all patients at increased risk for skin cancer.
Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy at ≤ 18 years of age), including Enbrel. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.
In clinical trials of 1140 pediatric patients representing 1927.2 patient-years of therapy, no malignancies, including lymphoma or NMSC, have been reported.
In global postmarketing adult and pediatric use, lymphoma and other malignancies have been reported.
Patients With Heart Failure
Two clinical trials evaluating the use of Enbrel in the treatment of heart failure were terminated early due to lack of efficacy. One of these studies suggested higher mortality in Enbrel-treated patients compared to placebo [see Adverse Reactions ]. There have been postmarketing 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 preexisting cardiovascular disease. Some of these patients have been under 50 years of age. Physicians should exercise caution when using Enbrel in patients who also have heart failure, and monitor patients carefully.
Rare (< 0.1%) reports of pancytopenia, including very rare (< 0.01%) reports of aplastic anemia, some with a fatal outcome, have been reported in patients treated with Enbrel. The causal relationship to Enbrel therapy remains unclear. Although no high-risk group has been identified, caution should be exercised in patients being treated with Enbrel who have a previous history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (eg, persistent fever, bruising, bleeding, pallor) while on Enbrel. Discontinuation of Enbrel therapy should be considered in patients with confirmed significant hematologic abnormalities.
Two percent of patients treated concurrently with Enbrel and anakinra developed neutropenia (ANC < 1 x 109/L). While neutropenic, one patient developed cellulitis that resolved with antibiotic therapy.
Hepatitis B Reactivation
Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant TNF-blocking agents, including very rare cases (< 0.01%) with Enbrel, has been reported. In some instances, hepatitis B reactivation occurring in conjunction with TNF-blocker 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 TNF-blocker therapy. Prescribers should exercise caution in prescribing TNF blockers in patients previously infected with HBV. 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 TNF-blocker therapy to prevent HBV reactivation. Patients previously infected with HBV and require treatment with Enbrel should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, consideration should be given to stopping Enbrel and initiating anti-viral therapy with appropriate supportive treatment. The safety of resuming Enbrel therapy after HBV reactivation is controlled is not known. Therefore, prescribers should weigh the risks and benefits when considering resumption of therapy in this situation.
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.
Caution: The following components contain dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex: the needle cover of the prefilled syringe and the needle cover within the needle cap of the SureClick autoinjector.
Live vaccines should not be given concurrently with Enbrel. 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 [see Drug Interactions].
Treatment with Enbrel may result in the formation of autoantibodies [see Adverse Reactions (
and, rarely (< 0.1%), in the development of a lupus-like syndrome or autoimmune hepatitis [see Adverse Reactions (
, which may resolve following withdrawal of 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.
TNF mediates inflammation and modulates cellular immune responses. TNF-blocking agents, including Enbrel, affect host defenses against infections. The effect of TNF inhibition on the development and course of malignancies is not fully understood. 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 [see Warnings and Precautions (5.1, 5.3) and Adverse Reactions ].
Use in Wegener’s Granulomatosis Patients
The use of Enbrel in patients with Wegener’s granulomatosis receiving immunosuppressive agents is not recommended. In a study of patients with Wegener’s granulomatosis, the addition of Enbrel to standard therapy (including cyclophosphamide) was associated with a higher incidence of non-cutaneous solid malignancies and was not associated with improved clinical outcomes when compared with standard therapy alone [see Drug Interactions].
Use with Anakinra or Abatacept
Use of Enbrel with anakinra or abatacept is not recommended [see Drug Interactions ].
Use in Patients with Moderate to Severe Alcoholic Hepatitis
In a study of 48 hospitalized patients treated with Enbrel or placebo for moderate to severe alcoholic hepatitis, the mortality rate in patients treated with Enbrel was similar to patients treated with placebo at 1 month but significantly higher after 6 months. Physicians should use caution when using Enbrel in patients with moderate to severe alcoholic hepatitis.
USE IN SPECIFIC POPULATIONS
Pregnancy Category B
Pregnancy Surveillance Program
There is a Pregnancy Surveillance Program that monitors outcomes in women exposed to Enbrel during pregnancy. Women who become pregnant during Enbrel treatment are encouraged to enroll. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
There are no adequate and well controlled studies in pregnant women. Based on limited data, etanercept concentration in cord blood at the time of delivery showed that etanercept crossed the placenta in small amounts.
Developmental toxicity studies have been performed in rats and rabbits at doses ranging from 60‑ to 100‑fold higher than the human dose and have revealed no evidence of harm to the fetus due to Enbrel. 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.
Limited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by a breastfed infant. Caution should be exercised when Enbrel is administered to a nursing woman. 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.
Women who choose to continue Enbrel treatment while nursing are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
Enbrel has not been studied in children < 2 years of age with JIA. The safety and efficacy of Enbrel in pediatric patients with PsO have not been studied.
Rare (< 0.1%) cases of IBD have been reported in JIA patients receiving Enbrel, which is not effective for the treatment of IBD [see Adverse Reactions].
The clinical significance of infant exposure to Enbrel in utero is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to exposed infants.
A total of 480 RA patients ages 65 years or older have been studied in clinical trials. In PsO randomized clinical trials, a total of 138 out of 1965 patients 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 PsO patients is too small to determine whether they respond differently from younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.
Use in Diabetics
There have been reports of hypoglycemia following initiation of Enbrel therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.