IN POST-MARKETING REPORTS, SERIOUS INFECTIONS AND SEPSIS, INCLUDING FATALITIES, HAVE BEEN REPORTED WITH THE USE OF ENBREL®. MANY OF THE SERIOUS INFECTIONS HAVE OCCURRED IN PATIENTS ON CONCOMITANT IMMUNOSUPPRESSIVE THERAPY THAT, IN ADDITION TO THEIR UNDERLYING DISEASE, COULD PREDISPOSE THEM TO INFECTIONS. RARE CASES OF TUBERCULOSIS (TB) HAVE BEEN OBSERVED IN PATIENTS TREATED WITH TNF ANTAGONISTS, INCLUDING ENBREL®. 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 OR SEPSIS. TREATMENT WITH ENBREL® SHOULD NOT BE INITIATED IN PATIENTS WITH ACTIVE INFECTIONS INCLUDING CHRONIC OR LOCALIZED INFECTIONS. PHYSICIANS SHOULD EXERCISE CAUTION WHEN CONSIDERING THE USE OF ENBREL® IN PATIENTS WITH A HISTORY OF RECURRING INFECTIONS OR WITH UNDERLYING CONDITIONS WHICH MAY PREDISPOSE PATIENTS TO INFECTIONS, SUCH AS ADVANCED OR POORLY CONTROLLED DIABETES (see PRECAUTIONS and ADVERSE REACTIONS: Infections).
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).
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).
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 × 109/L). While neutropenic, one patient developed cellulitis which recovered with antibiotic therapy.
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, 2 lymphomas were observed among 3435 ENBREL®-treated patients versus 0 among 1335 control patients (duration of controlled treatment ranged from 3 to 6 months). In the controlled and open-label portions of clinical trials of ENBREL®, 7 lymphomas were observed in 4650 patients over approximately 9062 patient-years of therapy. This is 2-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
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.
INFORMATION FOR PATIENTS
If a patient or caregiver is to administer ENBREL®, the patient or caregiver should be instructed in injection techniques and how to measure and administer the correct dose (see the ENBREL® (etanercept) "Patient Information" insert). The first injection should be performed under the supervision of a qualified health care professional. The patient's or caregiver's ability to inject subcutaneously should be assessed. Patients and caregivers should be instructed in the technique as well as proper syringe and needle disposal, and be cautioned against reuse of needles and syringes. A puncture-resistant container for disposal of needles and syringes should be used. If the product is intended for multiple use, additional syringes, needles, and alcohol swabs will be required.
PATIENTS WITH HEART FAILURE
Two large clinical trials evaluating the use of ENBREL® in the treatment of heart failure were terminated early due to lack of efficacy. Results of one study suggested higher mortality in patients treated with ENBREL® compared to placebo. Results of the second study did not corroborate these observations. Analyses did not identify specific factors associated with increased risk of adverse outcomes in heart failure patients treated with ENBREL® (see ADVERSE REACTIONS: Patients with Heart Failure). 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 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. Physicians should exercise caution when using ENBREL® in patients who also have heart failure, and monitor patients carefully.
Anti-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 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. 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 (see WARNINGS: Malignancies, ADVERSE REACTIONS: Infections, and Malignancies). The safety and efficacy of ENBREL® in patients with immunosuppression or chronic infections have not been evaluated.
Most psoriatic arthritis 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 two-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® (see PRECAUTIONS: Immunosuppression).
It is recommended that JRA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ENBREL® therapy. Patients with a significant exposure to varicella virus should temporarily discontinue ENBREL® therapy and be considered for prophylactic treatment with Varicella Zoster Immune Globulin.
Treatment with ENBREL® may result in the formation of autoantibodies (see ADVERSE REACTIONS: Autoantibodies) and, rarely, in the development of a lupus-like syndrome (see ADVERSE REACTIONS: Adverse Reaction Information from Spontaneous Reports) which may resolve following withdrawal of ENBREL®. If a patient develops symptoms and findings suggestive of a lupus-like syndrome following treatment with ENBREL®, treatment should be discontinued and the patient should be carefully evaluated.
Specific drug interaction studies have not been conducted with ENBREL®. However, it was observed that the pharmacokinetics of ENBREL® was unaltered by concomitant methotrexate in rheumatoid arthritis patients.
In a study in which patients with active RA were treated for up to 24 weeks with concurrent ENBREL® and anakinra therapy, a 7% rate of serious infections was observed, which was higher than that observed with ENBREL® alone (0%) (see also WARNINGS). Two percent of patients treated concurrently with ENBREL® and anakinra developed neutropenia (ANC < 1 × 109/L).
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
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.
PREGNANCY (CATEGORY B)
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®. There are, however, no studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether ENBREL® is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ENBREL®, a decision should be made whether to discontinue nursing or to discontinue the drug.
A total of 197 RA patients and 89 plaque psoriasis patients ages 65 years or older have been studied in clinical trials. No overall differences in safety or effectiveness were observed between these patients and younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.
ENBREL® is indicated for treatment of polyarticular-course juvenile rheumatoid arthritis in patients who have had an inadequate response to one or more DMARDs. For issues relevant to pediatric patients, in addition to other sections of the label, see also WARNINGS ; PRECAUTIONS: Immunizations ; and ADVERSE REACTIONS: Adverse Reactions in Patients with JRA. ENBREL® has not been studied in children < 4 years of age.
The safety and efficacy of ENBREL® in pediatric patients with plaque psoriasis have not been studied.