Etanercept

11 DESCRIPTION Etanercept, a tumor necrosis factor (TNF) blocker, is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the C H 2 domain, the C H 3 domain and hinge region, but not the C H 1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Enbrel (etanercept) Injection in the single-dose prefilled syringe, the single-dose prefilled SureClick autoinjector and the single-dose vial is clear and colorless, sterile, preservative-free solution, and is formulated at pH 6.3 ± 0.2. Enbrel (etanercept) for Injection is supplied in a multiple-dose vial as a sterile, white, preservative-free, lyophilized powder. Reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol) yields a multiple-dose, clear, and colorless solution 1 mL containing 25 mg of Enbrel, with a pH of 7.4 ± 0.3. Enbrel (etanercept) Injection in the Enbrel Mini single-dose prefilled cartridge for use with the AutoTouch reusable autoinjector is clear and colorless, sterile, preservative-free solution, and is formulated at pH 6.3 ± 0.2. Table 5. Contents of Enbrel Presentation Active Ingredient Content Inactive Ingredients Content Enbrel 50 mg prefilled syringe and SureClick autoinjector 50 mg etanercept in 1 mL 25 mM L-arginine hydrochloride 120 mM sodium chloride 1% sucrose Enbrel 25 mg prefilled syringe 25 mg etanercept in 0.5 mL 25 mM L-arginine hydrochloride 120 mM sodium chloride 1% sucrose Enbrel 25 mg single-dose vial 25 mg etanercept in 0.5 mL 25 mM L-arginine hydrochloride 120 mM sodium chloride 1% sucrose Enbrel 25 mg multiple-dose vial After reconstitution, 25 mg etanercept in 1 mL 40 mg mannitol 10 mg sucrose 1.2 mg tromethamine Enbrel 50 mg Enbrel Mini single-dose prefilled cartridge for use with the AutoTouch reusable autoinjector only 50 mg etanercept in 1 mL 25 mM L-arginine hydrochloride 120 mM sodium chloride 1% sucrose

1 INDICATIONS AND USAGE Enbrel is a tumor necrosis factor (TNF) blocker indicated for the treatment of: Adult patients with: Rheumatoid Arthritis (RA) ( 1.1 ) Psoriatic Arthritis (PsA) ( 1.3 ) Ankylosing Spondylitis (AS) ( 1.4 ) Plaque Psoriasis (PsO) ( 1.5 ) Pediatric patients with: Polyarticular Juvenile Idiopathic Arthritis (pJIA), 2 years of age or older ( 1.2 ) Juvenile Psoriatic Arthritis, 2 years of age or older (JPsA) ( 1.6 ) Plaque Psoriasis, 4 years of age or older ( 1.5 ) 1.1 Rheumatoid Arthritis 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. 1.2 Polyarticular Juvenile Idiopathic Arthritis Enbrel is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older. 1.3 Psoriatic Arthritis Enbrel is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in adult patients with psoriatic arthritis (PsA). Enbrel can be used with or without methotrexate. 1.4 Ankylosing Spondylitis Enbrel is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS). 1.5 Plaque Psoriasis 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. 1.6 Juvenile Psoriatic Arthritis Enbrel is indicated for the treatment of active juvenile psoriatic arthritis (JPsA) in pediatric patients 2 years of age and older.

5 WARNINGS AND PRECAUTIONS Do not start Enbrel during an active infection. If an infection develops, monitor carefully and stop Enbrel if infection becomes serious. ( 5.1 ) Consider empiric anti-fungal therapy for patients at risk for invasive fungal infections who develop a severe systemic illness on Enbrel (those who reside or travel to regions where mycoses are endemic). ( 5.1 ) Demyelinating disease, exacerbation or new onset, may occur. ( 5.2 ) Cases of lymphoma have been observed in patients receiving TNF-blocking agents. ( 5.3 ) Congestive heart failure, worsening or new onset, may occur. ( 5.4 ) Advise patients to seek immediate medical attention if symptoms of pancytopenia or aplastic anemia develop, and consider stopping Enbrel. ( 5.5 ) 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. ( 5.6 ) Anaphylaxis or serious allergic reactions may occur. ( 5.7 ) Stop Enbrel if lupus-like syndrome or autoimmune hepatitis develops. ( 5.9 ) 5.1 Serious Infections 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 (6.1) ] . 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. Tuberculosis 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 Bacillus 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. 5.2 Neurologic Reactions 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-Barre 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 Postmarketing Experience (6.3) ] . 5.3 Malignancies Lymphomas 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. Leukemia 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. Other Malignancies 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 versus 0.37 cases per 100 patient-years among 1521 control-treated patients representing 1077 patient-years. Among 1245 adult PsO 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 versus 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. 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 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. Postmarketing Use In global postmarketing adult and pediatric use, lymphoma and other malignancies have been reported. 5.4 New Onset or Worsening of 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 (6.2) ] . 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. 5.5 Hematologic Reactions 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 (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 × 10 9 /L). While neutropenic, one patient developed cellulitis that resolved with antibiotic therapy. 5.6 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 requiring 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. 5.7 Allergic Reactions 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, discontinue administration of Enbrel and initiate appropriate therapy immediately. 5.8 Immunizations Avoid concurrent administration of live vaccines with Enbrel. It is recommended that 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 (7.1) and Use in Specific Populations (8.4) ] . 5.9 Autoimmunity Treatment with Enbrel may result in the formation of autoantibodies [see Adverse Reactions (6.1) ] and, rarely (< 0.1%), in the development of a lupus-like syndrome or autoimmune hepatitis [see Adverse Reactions (6.2) ] , 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, discontinue treatment and evaluate the patient. 5.10 Immunosuppression 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 (6.1) ] . 5.11 Not Recommended for Use in Patients with Granulomatosis with Polyangiitis Receiving Immunosuppressants The use of Enbrel in patients with granulomatosis with polyangiitis receiving immunosuppressive agents is not recommended. In a study of patients with granulomatosis with polyangiitis, 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 (7.3) ] . 5.12 Not Recommended for Use with Anakinra or Abatacept Use of Enbrel with anakinra or abatacept is not recommended [see Drug Interactions (7.2) ] . 5.13 Increased Mortality 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.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infections [see Warnings and Precautions (5.1) ] Neurologic Reactions [see Warnings and Precautions (5.2) ] Malignancies [see Warnings and Precautions (5.3) ] Patients with Heart Failure [see Warnings and Precautions (5.4) ] Hematologic Reactions [see Warnings and Precautions (5.5) ] Hepatitis B Reactivation [see Warnings and Precautions (5.6) ] Allergic Reactions [see Warnings and Precautions (5.7) ] Autoimmunity [see Warnings and Precautions (5.9) ] Immunosuppression [see Warnings and Precautions (5.10) ] Most common adverse reactions (incidence > 5%): infections and injection site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Across clinical studies and postmarketing experience, the most serious adverse reactions with Enbrel were infections, neurologic events, CHF, and hematologic events [see Warnings and Precautions (5) ] . The most common adverse reactions with Enbrel were infections and injection site reactions. Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in clinical practice. Adverse Reactions in Adult Patients with Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, or Plaque Psoriasis The data described below reflect exposure to Enbrel in 2219 adult patients with RA followed for up to 80 months, in 182 patients with PsA for up to 24 months, in 138 patients with AS for up to 6 months, and in 1204 adult patients with PsO for up to 18 months. In controlled trials, the proportion of Enbrel-treated patients who discontinued treatment due to adverse events was approximately 4% in the indications studied. Adverse Reactions in Pediatric Patients In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients [see Warnings and Precautions (5) , Use in Specific Populations (8.4) , and Clinical Studies (14.2 , 14.6) ] . In a 48-week clinical study in 211 children aged 4 to 17 years with pediatric PsO, the adverse reactions reported were similar to those seen in previous studies in adults with PsO. Long-term safety profile for up to 264 additional weeks was assessed in an open-label extension study and no new safety signals were identified. In open-label clinical studies of children with JIA, adverse reactions reported in those ages 2 to 4 years were similar to adverse reactions reported in older children. Infections Infections, including viral, bacterial, and fungal infections, have been observed in adult and pediatric patients. Infections have been noted in all body systems and have been reported in patients receiving Enbrel alone or in combination with other immunosuppressive agents. In controlled portions of trials, the types and severity of infection were similar between Enbrel and the respective control group (placebo or MTX for RA and PsA patients) in RA, PsA, AS and PsO patients. Rates of infections in RA and adult PsO patients are provided in Table 3 and Table 4, respectively. Infections consisted primarily of upper respiratory tract infection, sinusitis and influenza. In controlled portions of trials in RA, PsA, AS and PsO, the rates of serious infection were similar (0.8% in placebo, 3.6% in MTX, and 1.4% in Enbrel/Enbrel + MTX-treated groups). In clinical trials in rheumatologic indications, serious infections experienced by patients have included, but are not limited to, pneumonia, cellulitis, septic arthritis, bronchitis, gastroenteritis, pyelonephritis, sepsis, abscess and osteomyelitis. In clinical trials in adult PsO patients, serious infections experienced by patients have included, but are not limited to, pneumonia, cellulitis, gastroenteritis, abscess and osteomyelitis. The rate of serious infections was not increased in open-label extension trials and was similar to that observed in Enbrel- and placebo-treated patients from controlled trials. In 66 global clinical trials of 17,505 patients (21,015 patient-years of therapy), tuberculosis was observed in approximately 0.02% of patients. In 17,696 patients (27,169 patient-years of therapy) from 38 clinical trials and 4 cohort studies in the U.S. and Canada, tuberculosis was observed in approximately 0.006% of patients. These studies include reports of pulmonary and extrapulmonary tuberculosis [see Warnings and Precautions (5.1) ] . The types of infections reported in pediatric patients with PsO and JIA were generally mild and consistent with those commonly seen in the general pediatric population. Two JIA patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. Injection Site Reactions In placebo-controlled trials in rheumatologic indications, approximately 37% of patients treated with Enbrel developed injection site reactions. In controlled trials in patients with PsO, 15% of adult patients and 7% of pediatric patients treated with Enbrel developed injection site reactions during the first 3 months of treatment. All injection site reactions were described as mild to moderate (erythema, itching, pain, swelling, bleeding, bruising) and generally did not necessitate drug discontinuation. Injection site reactions generally occurred in the first month and subsequently decreased in frequency. The mean duration of injection site reactions was 3 to 5 days. Seven percent of patients experienced redness at a previous injection site when subsequent injections were given. Other Adverse Reactions Table 3 summarizes adverse reactions reported in adult RA patients. The types of adverse reactions seen in patients with PsA or AS were similar to the types of adverse reactions seen in patients with RA. Table 3. Percent of Adult RA Patients Experiencing Adverse Reactions in Controlled Clinical Trials Placebo-Controlled Includes data from the 6-month study in which patients received concurrent MTX therapy in both arms. (Studies I, II, and a Phase 2 Study) Active-Controlled Study duration of 2 years. (Study III) Placebo (N = 152) Enbrel Any dose. (N = 349) MTX (N = 217) Enbrel (N = 415) Adverse Reaction Percent of Patients Percent of Patients Infection Includes bacterial, viral and fungal infections. (total) 39 50 86 81 Upper Respiratory Infections Most frequent Upper Respiratory Infections were upper respiratory tract infection, sinusitis and influenza. 30 38 70 65 Non-upper Respiratory Infections 15 21 59 54 Injection Site Reactions 11 37 18 43 Diarrhea 9 8 16 16 Rash 2 3 19 13 Pruritus 1 2 5 5 Pyrexia – 3 4 2 Urticaria 1 – 4 2 Hypersensitivity – – 1 1 In placebo-controlled adult PsO trials, the percentages of patients reporting adverse reactions in the 50 mg twice a week dose group were similar to those observed in the 25 mg twice a week dose group or placebo group. Table 4 summarizes adverse reactions reported in adult PsO patients from Studies I and II. Table 4. Percent of Adult PsO Patients Experiencing Adverse Reactions in Placebo-Controlled Portions of Clinical Trials (Studies I & II) Placebo (N = 359) Enbrel Includes 25 mg subcutaneous (SC) once weekly (QW), 25 mg SC twice weekly (BIW), 50 mg SC QW, and 50 mg SC BIW doses. (N = 876) Adverse Reaction Percent of Patients Infection Includes bacterial, viral and fungal infections. (total) 28 27 Non-upper Respiratory Infections 14 12 Upper Respiratory Infections Most frequent Upper Respiratory Infections were upper respiratory tract infection, nasopharyngitis and sinusitis. 17 17 Injection Site Reactions 6 15 Diarrhea 2 3 Rash 1 1 Pruritus 2 1 Urticaria – 1 Hypersensitivity – 1 Pyrexia 1 – 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to etanercept in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Immunogenicity Patients with RA, PsA, AS or PsO were tested at multiple time points for antibodies to etanercept. Antibodies to the TNF receptor portion or other protein components of the Enbrel drug product were detected at least once in sera of approximately 6% of adult patients with RA, PsA, AS or PsO. These antibodies were all non-neutralizing. Results from JIA patients were similar to those seen in adult RA patients treated with Enbrel. In adult PsO studies that evaluated the exposure of etanercept for up to 120 weeks, the percentage of patients testing positive at the assessed time points of 24, 48, 72 and 96 weeks ranged from 3.6%-8.7% and were all non-neutralizing. The percentage of patients testing positive increased with an increase in the duration of study; however, the clinical significance of this finding is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. The immunogenicity data of Enbrel beyond 120 weeks of exposure are unknown. In pediatric PsO studies, approximately 10% of subjects developed antibodies to etanercept by Week 48 and approximately 16% of subjects developed antibodies to etanercept by Week 264. All of these antibodies were non-neutralizing. However, because of the limitations of the immunogenicity assays, the incidence of binding and neutralizing antibodies may not have been reliably determined. The data reflect the percentage of patients whose test results were considered positive for antibodies to etanercept in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Autoantibodies Patients with RA had serum samples tested for autoantibodies at multiple time points. In RA Studies I and II, the percentage of patients evaluated for antinuclear antibodies (ANA) who developed new positive ANA (titer ≥ 1:40) was higher in patients treated with Enbrel (11%) than in placebo-treated patients (5%). The percentage of patients who developed new positive anti-double-stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with Enbrel compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with Enbrel compared to none of placebo-treated patients). The proportion of patients treated with Enbrel who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. In RA Study III, no pattern of increased autoantibody development was seen in Enbrel patients compared to MTX patients [see Warnings and Precautions (5.9) ] . 6.3 Postmarketing Experience Adverse reactions have been reported during post approval use of Enbrel in adults and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Enbrel exposure. Adverse reactions are listed by body system below: Blood and lymphatic system disorders: pancytopenia, anemia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, aplastic anemia [see Warnings and Precautions (5.5) ] Cardiac disorders: congestive heart failure [see Warnings and Precautions (5.4) ] Gastrointestinal disorders: inflammatory bowel disease (IBD) General disorders: angioedema, chest pain Hepatobiliary disorders: autoimmune hepatitis, elevated transaminases, hepatitis B reactivation Immune disorders: macrophage activation syndrome, systemic vasculitis, sarcoidosis Musculoskeletal and connective tissue disorders: lupus-like syndrome Neoplasms benign, malignant, and unspecified: melanoma and non-melanoma skin cancers, Merkel cell carcinoma [see Warnings and Precautions (5.3) ] Nervous system disorders: convulsions, multiple sclerosis, demyelination, optic neuritis, transverse myelitis, paresthesias, headache [see Warnings and Precautions (5.2) ] Ocular disorders: uveitis, scleritis Renal and urinary disorders: glomerulonephritis Respiratory, thoracic and mediastinal disorders: interstitial lung disease Skin and subcutaneous tissue disorders: cutaneous lupus erythematosus, cutaneous vasculitis (including leukocytoclastic vasculitis), erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, subcutaneous nodule, new or worsening psoriasis (all sub-types including pustular and palmoplantar) Opportunistic infections, including atypical mycobacterial infection, herpes zoster, aspergillosis and Pneumocystis jiroveci pneumonia, and protozoal infections have also been reported in postmarketing use. Rare (< 0.1%) cases of IBD have been reported in JIA patients receiving Enbrel, which is not effective for the treatment of IBD.

7 DRUG INTERACTIONS Specific drug interaction studies have not been conducted with Enbrel. Live vaccines – Avoid concurrent administration with Enbrel ( 5.8 , 7.1 ) Anakinra – Increased risk of serious infection ( 5.12 , 7.2 ) Abatacept – Increased risk of serious adverse events, including infections ( 5.12 , 7.2 ) Cyclophosphamide – Not recommended for use with Enbrel. ( 7.3 ) 7.1 Vaccines 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. Patients with a significant exposure to varicella virus should temporarily discontinue Enbrel therapy and be considered for prophylactic treatment with varicella zoster immune globulin [see Warnings and Precautions (5.8 , 5.10) ] . 7.2 Immune-Modulating Biologic Products 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 Warnings and Precautions (5.12) ] and did not result in higher ACR response rates compared to Enbrel alone. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure. Two percent of patients treated concurrently with Enbrel and anakinra developed neutropenia (ANC < 1 × 10 9 /L). In clinical studies, concurrent administration of abatacept and Enbrel resulted in increased incidences of serious adverse events, including infections, and did not demonstrate increased clinical benefit [see Warnings and Precautions (5.12) ] . 7.3 Cyclophosphamide The use of Enbrel in patients receiving concurrent cyclophosphamide therapy is not recommended [see Warnings and Precautions (5.11) ] . 7.4 Sulfasalazine Patients in a clinical study who were on established therapy with sulfasalazine, to which Enbrel was added, were noted to develop a mild decrease in mean neutrophil counts in comparison to groups treated with either Enbrel or sulfasalazine alone. The clinical significance of this observation is unknown.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary 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 (e.g., disease severity) may have impacted the occurrence of birth defects (see Data ). Reports of etanercept use during the third trimester of pregnancy demonstrated that placental transfer of etanercept was low in infants at birth (see Data ) . There are risks to the mother and fetus associated with active rheumatoid arthritis. The theoretical risks of administration of live or live-attenuated vaccines to the infants exposed in utero to Enbrel should be weighed against the benefits of vaccinations (see Clinical Considerations ) . In animal reproduction studies with pregnant rats and rabbits, no fetal harm or malformations were observed with subcutaneous administration of etanercept during the period of organogenesis at doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (see Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the United States, about 2-4% of liveborn babies have a major birth defect and about 15-20% of pregnancies end in miscarriage, regardless of drug exposure. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis is correlated with maternal disease activity and that active disease increases the risk of adverse pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) and small for gestational age birth. Fetal/Neonatal Adverse Reactions 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 [see Warnings and Precautions (5.8) and Drug Interactions (7.1) ] . Data Human Data A prospective cohort pregnancy registry conducted by OTIS in the US and Canada between 2000 and 2012 compared the risk of major birth defects in liveborn infants of women with rheumatic diseases or psoriasis exposed to etanercept in the first trimester. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 319) and diseased etanercept unexposed cohorts (N = 144) was 9.4% and 3.5%, respectively. The findings showed no statistically significant increased risk of minor birth defects and no pattern of major or minor birth defects. A Scandinavian study compared the risk of major birth defects in liveborn infants of women with chronic inflammatory disease (CID) exposed to TNF-inhibitors during early pregnancy. Women were identified from the Danish (2004-2012) and Swedish (2006-2012) population-based health registers. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 344) and CID etanercept unexposed cohorts (N = 21,549) was 7.0% and 4.7%, respectively. Overall, while both the OTIS Registry and Scandinavian study show a higher proportion of major birth defects in etanercept-exposed patients compared to diseased etanercept unexposed patients, the lack of pattern of birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects. Reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, varied from undetectable to 32% of the maternal serum level. In a cohort study of 30 pregnant women with RA, 29 were treated with etanercept until 30 weeks of gestation and 1 was treated until 36 weeks of gestation. Etanercept was not detected in the cord blood sample from any infant at delivery. In three published case reports, etanercept was detected in cord blood at levels of 3.3, 3.6, and 7.4% of the maternal concentration, when etanercept was administered at 50 mg every 7-12 days in pregnancy until 4 days prior to delivery, 25 mg twice weekly until 36 weeks of gestation, and 25 mg subcutaneous every week through the third trimester, respectively. There was one post-marketing safety report of a pregnant woman who received etanercept 25 mg once to twice weekly throughout pregnancy, and etanercept was detected in cord blood at 32% of the maternal concentration. Animal Data In embryofetal development studies with etanercept administered during the period of organogenesis to pregnant rats from gestation day (GD) 6 through 20 or pregnant rabbits from GD 6 through 18, there was no evidence of fetal malformations or embryotoxicity in rats or rabbits at respective doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day in rats and 40 mg/kg/day in rabbits). In a peri-and post-natal development study with pregnant rats that received etanercept during organogenesis and the later gestational period from GD 6 through 21, development of pups through post-natal day 4 was unaffected at doses that achieved exposures 48 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day). 8.2 Lactation Risk Summary Data from published literature show that etanercept is present in low levels in human milk but is not detected in the plasma of breastfed infants (see Data ) . There are no data on the effects of etanercept on milk production. There have been no consistent reports of adverse events in breastfed infants over decades of use. The developmental 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. Data In three case reports, etanercept was detected in breast milk at levels ranging from <2 to 7.5 ng/mL after lactating women had received doses of etanercept of 25 mg weekly or twice weekly. Although etanercept was detected in breast milk in these cases, etanercept was not detected in the serum of the breastfed infants. 8.4 Pediatric Use Polyarticular Juvenile Idiopathic Arthritis The safety and effectiveness of Enbrel have been established in pediatric patients 2 years of age and older with pJIA. Enbrel has been studied in 69 children with moderately to severely active polyarticular JIA 2 to 17 years of age. The safety and effectiveness of Enbrel in pediatric patients less than 2 years of age with pJIA have not been established. Juvenile Psoriatic Arthritis The safety and effectiveness of Enbrel have been established in pediatric patients 2 years to 17 years old with JPsA. Use of Enbrel in JPsA is supported by evidence from adequate and well controlled studies of Enbrel in adults with PsA; pharmacokinetic data from adult patients with PsA, RA, and PsO; and pharmacokinetic data from pediatric patients with active JIA and PsO. Safety of Enbrel in JPsA is supported by a clinical study in 69 pediatric patients with moderately to severely active JIA aged 2 to 17 years; a clinical study in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years; and an open-label extension study in 182 pediatric patients with moderate to severe PsO aged 4 to 17 years. The observed pre-dose (trough) concentrations are generally comparable between adults with RA and PsA and pediatric patients with active JIA, as well as adults with PsO and pediatric patients with PsO. The PK exposure is expected to be comparable between adults with PsA and pediatric patients with JPsA [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1 , 14.2 , 14.3 , 14.5 , 14.6) ] . The safety and effectiveness in pediatric patients below the age of 2 years have not been established in JPsA. Plaque Psoriasis The safety and effectiveness of Enbrel for plaque psoriasis have been established in pediatric patients 4 years of age and older. Enbrel has been studied in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years. The safety and effectiveness of Enbrel in pediatric patients below the age of 4 years with PsO have not been established. Malignancies in 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 [see Warnings and Precautions (5.3) ] . 8.5 Geriatric Use 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. 8.6 Use in Patients with Diabetes 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.

8.1 Pregnancy Risk Summary 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 (e.g., disease severity) may have impacted the occurrence of birth defects (see Data ). Reports of etanercept use during the third trimester of pregnancy demonstrated that placental transfer of etanercept was low in infants at birth (see Data ) . There are risks to the mother and fetus associated with active rheumatoid arthritis. The theoretical risks of administration of live or live-attenuated vaccines to the infants exposed in utero to Enbrel should be weighed against the benefits of vaccinations (see Clinical Considerations ) . In animal reproduction studies with pregnant rats and rabbits, no fetal harm or malformations were observed with subcutaneous administration of etanercept during the period of organogenesis at doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (see Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the United States, about 2-4% of liveborn babies have a major birth defect and about 15-20% of pregnancies end in miscarriage, regardless of drug exposure. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis is correlated with maternal disease activity and that active disease increases the risk of adverse pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) and small for gestational age birth. Fetal/Neonatal Adverse Reactions 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 [see Warnings and Precautions (5.8) and Drug Interactions (7.1) ] . Data Human Data A prospective cohort pregnancy registry conducted by OTIS in the US and Canada between 2000 and 2012 compared the risk of major birth defects in liveborn infants of women with rheumatic diseases or psoriasis exposed to etanercept in the first trimester. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 319) and diseased etanercept unexposed cohorts (N = 144) was 9.4% and 3.5%, respectively. The findings showed no statistically significant increased risk of minor birth defects and no pattern of major or minor birth defects. A Scandinavian study compared the risk of major birth defects in liveborn infants of women with chronic inflammatory disease (CID) exposed to TNF-inhibitors during early pregnancy. Women were identified from the Danish (2004-2012) and Swedish (2006-2012) population-based health registers. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 344) and CID etanercept unexposed cohorts (N = 21,549) was 7.0% and 4.7%, respectively. Overall, while both the OTIS Registry and Scandinavian study show a higher proportion of major birth defects in etanercept-exposed patients compared to diseased etanercept unexposed patients, the lack of pattern of birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects. Reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, varied from undetectable to 32% of the maternal serum level. In a cohort study of 30 pregnant women with RA, 29 were treated with etanercept until 30 weeks of gestation and 1 was treated until 36 weeks of gestation. Etanercept was not detected in the cord blood sample from any infant at delivery. In three published case reports, etanercept was detected in cord blood at levels of 3.3, 3.6, and 7.4% of the maternal concentration, when etanercept was administered at 50 mg every 7-12 days in pregnancy until 4 days prior to delivery, 25 mg twice weekly until 36 weeks of gestation, and 25 mg subcutaneous every week through the third trimester, respectively. There was one post-marketing safety report of a pregnant woman who received etanercept 25 mg once to twice weekly throughout pregnancy, and etanercept was detected in cord blood at 32% of the maternal concentration. Animal Data In embryofetal development studies with etanercept administered during the period of organogenesis to pregnant rats from gestation day (GD) 6 through 20 or pregnant rabbits from GD 6 through 18, there was no evidence of fetal malformations or embryotoxicity in rats or rabbits at respective doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day in rats and 40 mg/kg/day in rabbits). In a peri-and post-natal development study with pregnant rats that received etanercept during organogenesis and the later gestational period from GD 6 through 21, development of pups through post-natal day 4 was unaffected at doses that achieved exposures 48 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day).

8.4 Pediatric Use Polyarticular Juvenile Idiopathic Arthritis The safety and effectiveness of Enbrel have been established in pediatric patients 2 years of age and older with pJIA. Enbrel has been studied in 69 children with moderately to severely active polyarticular JIA 2 to 17 years of age. The safety and effectiveness of Enbrel in pediatric patients less than 2 years of age with pJIA have not been established. Juvenile Psoriatic Arthritis The safety and effectiveness of Enbrel have been established in pediatric patients 2 years to 17 years old with JPsA. Use of Enbrel in JPsA is supported by evidence from adequate and well controlled studies of Enbrel in adults with PsA; pharmacokinetic data from adult patients with PsA, RA, and PsO; and pharmacokinetic data from pediatric patients with active JIA and PsO. Safety of Enbrel in JPsA is supported by a clinical study in 69 pediatric patients with moderately to severely active JIA aged 2 to 17 years; a clinical study in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years; and an open-label extension study in 182 pediatric patients with moderate to severe PsO aged 4 to 17 years. The observed pre-dose (trough) concentrations are generally comparable between adults with RA and PsA and pediatric patients with active JIA, as well as adults with PsO and pediatric patients with PsO. The PK exposure is expected to be comparable between adults with PsA and pediatric patients with JPsA [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1 , 14.2 , 14.3 , 14.5 , 14.6) ] . The safety and effectiveness in pediatric patients below the age of 2 years have not been established in JPsA. Plaque Psoriasis The safety and effectiveness of Enbrel for plaque psoriasis have been established in pediatric patients 4 years of age and older. Enbrel has been studied in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years. The safety and effectiveness of Enbrel in pediatric patients below the age of 4 years with PsO have not been established. Malignancies in 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 [see Warnings and Precautions (5.3) ] .