Drug Information for ENBREL (etanercept) For Subcutaneous Injection (Immunex Corp): WARNINGS

  • Risk of Serious Infections(see also Boxed Warning)

    Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving TNF-blocking agents. Among opportunistic infections, tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most commonly reported. Patients have frequently presented with disseminated rather than localized disease, and are often taking concomitant immunosuppressants such as methotrexate or corticosteroids with ENBREL®.

    Treatment with ENBREL® should not be initiated in patients with an active infection, including clinically important localized infections. 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;
    • 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 PRECAUTIONS and ADVERSE REACTIONS: Infections).

    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, post-marketing cases of tuberculosis reactivation have been reported for TNF blockers, including ENBREL®. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating ENBREL® and periodically during therapy.

    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 5mm 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.

    Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ENBREL®, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may be falsely negative while on therapy 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.

    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®. Nonetheless, post marketing 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 antifungal 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 antifungal 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 antifungal therapy.

    In a 24-week study of concurrent ENBREL® and anakinra therapy, the rate of serious infections in the combination arm (7%) was higher than with ENBREL® alone (0%). The combination of ENBREL® and anakinra did not result in higher ACR response rates compared to ENBREL® alone (see CLINICAL STUDIES: Clinical Response and ADVERSE REACTIONS: Infections). Concurrent therapy with ENBREL® and anakinra is not recommended.

  • Neurologic Events

  • Treatment with ENBREL® and other agents that inhibit TNF have been associated with rare cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability. Cases of transverse myelitis, optic neuritis, multiple sclerosis, and new onset or exacerbation of seizure disorders have been observed in association with ENBREL® therapy. The causal relationship to ENBREL® therapy remains unclear. While no clinical trials have been performed evaluating ENBREL® therapy in patients with multiple sclerosis, other TNF antagonists administered to patients with multiple sclerosis have been associated with increases in disease activity.7, 8 Prescribers should exercise caution in considering the use of ENBREL® in patients with preexisting or recent-onset central nervous system demyelinating disorders (see ADVERSE REACTIONS).

  • Hematologic Events

  • Rare reports of pancytopenia including 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 (e.g., 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 which recovered with antibiotic therapy.

  • Malignancies

  • In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving the TNF blocker compared to control patients. During the controlled portions of ENBREL® trials, 3 lymphomas were observed among 4509 ENBREL®-treated patients versus 0 among 2040 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 5723 patients over approximately 11,201 patient-years of therapy. This is 3-fold higher than that expected in the general population. While patients with rheumatoid arthritis or psoriasis, particularly those with highly active disease, may be at a higher risk (up to several fold) for the development of lymphoma, the potential role of TNF-blocking therapy in the development of malignancies is not known (see ADVERSE REACTIONS: Malignancies).11, 12

    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.

  • Pediatric Patients

  • 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 post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.

    In clinical trials of 696 patients, representing 1282 patient-years of therapy, no malignancies, including lymphoma or NMSC, have been reported.

  • Wegener’s Granulomatosis Patients

  • In a randomized, placebo-controlled study of 180 patients with Wegener's granulomatosis where ENBREL® was added to standard treatment (including cyclophosphamide, methotrexate, and corticosteroids), patients receiving ENBREL® experienced more non-cutaneous solid malignancies than patients receiving placebo (see ADVERSE REACTIONS: Malignancies). The addition of ENBREL® to standard treatment was not associated with improved clinical outcomes when compared with standard therapy alone. The use of ENBREL® in patients with Wegener’s granulomatosis receiving immunosuppressive agents is not recommended. The use of ENBREL® in patients receiving concurrent cyclophosphamide therapy is not recommended.

  • Hepatitis B Virus Reactivation

  • Use of TNF blockers, including ENBREL®, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV 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 HBV 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 for patients identified as carriers of 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 who are carriers of 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.

  • 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 one month but significantly higher after six months. Physicians should use caution when using ENBREL® in patients with moderate to severe alcoholic hepatitis.

  • Drug Information Provided by National Library of Medicine (NLM).