FDA label 6fc34018-1d3c-485d-b5a5-fe31246f75b4

WARNING: SERIOUS INFECTIONS and MALIGNANCIES SERIOUS INFECTIONS Patients treated with Enbrel are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6 )] . Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Enbrel should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before Enbrel use and during therapy. Treatment for latent infection should be initiated prior to Enbrel use. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria. The risks and benefits of treatment with Enbrel should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Enbrel, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MALIGNANCIES Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including Enbrel. WARNING : SERIOUS INFECTIONS and MALIGNANCIES See f ull p rescribing i nformation for complete b oxed w arning. SERIOUS INFECTIONS Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens. ( 5.1 ) Enbrel should be discontinued if a patient develops a serious infection or sepsis during treatment. ( 5.1 ) Perform test for latent TB; if positive, start treatment for TB prior to starting Enbrel. ( 5.1 ) Monitor all patients for active TB during treatment, even if initial latent TB test is negative. ( 5.1 ) MALIGNANCIES Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated wit h TNF blockers, including Enbrel . ( 5.3 )

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 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. 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 Adverse Reactions ( 6.2 )] . 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 - M elanoma S kin C ancer (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 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 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. 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. Post m arketing Use In global postmarketing adult and pediatric use, lymphoma and other malignancies have been reported. 5.4 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 React ion s ( 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 (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 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, 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, the needle cover within the white cap of the SureClick autoinjector, and the needle cover within the purple cap of the Enbrel Mini cartridge. 5.8 Immunizations 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 ( 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, treatment should be discontinued and the patient should be carefully evaluated. 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 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 ( 7.3 ) ] . 5.12 Use with Anakinra or Abatacept Use of Enbrel with anakinra or abatacept is not recommended [see Drug Interactions ( 7.2 )] . 5.13 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.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infections [see Boxed Warning and Warnings and Precautions ( 5.1 )] Neurologic Reactions [ see Warnings and Precautions ( 5.2 )] Malignancies [ see Boxed Warning and 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 w ith R heumatoid A rthritis , 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 and 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 a (Studies I, II, and a Phase 2 S tudy) Active Controlled b (Study III) Placebo (N = 152) E nbrel c (N = 349) MTX (N = 217) E nbrel c (N = 415) Reaction Percent of Patients Percent of Patients Infection d (total) 39 50 86 81 Upper Respiratory Infections e 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 a Includes data from the 6-month study in which patients received concurrent MTX therapy in both arms. b Study duration of 2 years. c Any dose. d Includes bacterial, viral and fungal infections. e Most frequent Upper Respiratory Infections were upper respiratory tract infection, sinusitis and influenza. 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 a (N = 876) Reaction Percent of Patients Infection b (total) 28 27 Non-upper Respiratory Infections 14 12 Upper Respiratory Infections c 17 17 Injection Site Reactions 6 15 Diarrhea 2 3 Rash 1 1 Pruritus 2 1 Urticaria - 1 Hypersensitivity - 1 Pyrexia 1 - a Includes 25 mg subcutaneous (SC) once weekly (QW), 25 mg SC twice weekly (BIW), 50 mg SC QW, and 50 mg SC BIW doses. b Includes bacterial, viral and fungal infections. c Most frequent Upper Respiratory Infections were upper respiratory tract infection, nasopharyngitis and sinusitis. 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 [see Warning s and Precaution s ( 5.2 )] Ocular disorders: uveitis, scleritis 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.

<table> <col width="241"/> <col width="108"/> <col width="108"/> <col width="120"/> <col width="120"/> <tbody> <tr> <td align="center" colspan="5"> <content styleCode="bold">Table 3</content> <content styleCode="bold">.</content> <content styleCode="bold"> Percent of Adult RA Patients Experiencing Adverse Reactions in Controlled Clinical Trials</content> </td> </tr> <tr> <td styleCode="Toprule Lrule Rrule "/> <td align="center" colspan="2" styleCode="Toprule Lrule Rrule "> <content styleCode="bold">Placebo</content> <content styleCode="bold"> </content> <content styleCode="bold">Controlled</content> <content styleCode="bold"> ^a </content> <content styleCode="bold">(Studies I, II, and a Phase 2 </content> <content styleCode="bold">S</content> <content styleCode="bold">tudy)</content> </td> <td align="center" colspan="2" styleCode="Toprule Lrule Rrule "> <content styleCode="bold">Active Controlled</content> <content styleCode="bold"> ^b </content> <content styleCode="bold">(Study III)</content> </td> </tr> <tr> <td styleCode="Lrule Rrule "> <content styleCode="bold"> </content> </td> <td align="center" styleCode="Toprule Lrule Rrule "> <content styleCode="bold">Placebo</content> (N = 152)</td> <td align="center" styleCode="Toprule Rrule "> <content styleCode="bold">E</content> <content styleCode="bold">nbrel</content> <content styleCode="bold"> ^c </content> (N = 349)</td> <td align="center" styleCode="Toprule Lrule "> <content styleCode="bold">MTX </content> (N = 217)</td> <td align="center" styleCode="Toprule Lrule Rrule "> <content styleCode="bold">E</content> <content styleCode="bold">nbrel</content> <content styleCode="bold"> ^c </content> (N = 415)</td> </tr> <tr> <td styleCode="Lrule Rrule "> <content styleCode="bold"> </content> <content styleCode="bold">Reaction</content> </td> <td align="center" colspan="2" styleCode="Toprule Lrule Rrule "> <content styleCode="bold">Percent of Patients</content> </td> <td align="center" colspan="2" styleCode="Toprule Lrule Rrule "> <content styleCode="bold">Percent of Patients</content> </td> </tr> <tr> <td styleCode="Toprule Lrule Rrule "> <content styleCode="bold"> </content> </td> <td align="center" styleCode="Toprule Lrule Rrule "> </td> <td align="center" styleCode="Toprule Rrule "> </td> <td align="center" styleCode="Toprule Lrule Rrule "> </td> <td align="center" styleCode="Toprule Lrule Rrule "> </td> </tr> <tr> <td styleCode="Lrule Rrule "> Infection^d(total)</td> <td align="center" styleCode="Lrule Rrule ">39</td> <td align="center" styleCode="Rrule ">50</td> <td align="center" styleCode="Lrule Rrule ">86</td> <td align="center" styleCode="Lrule Rrule ">81</td> </tr> <tr> <td styleCode="Lrule Rrule "> Upper Respiratory Infections^e </td> <td align="center" styleCode="Lrule Rrule ">30</td> <td align="center" styleCode="Rrule ">38</td> <td align="center" styleCode="Lrule Rrule ">70</td> <td align="center" styleCode="Lrule Rrule ">65</td> </tr> <tr> <td styleCode="Lrule Rrule "> Non-upper Respiratory Infections</td> <td align="center" styleCode="Lrule Rrule ">15</td> <td align="center" styleCode="Rrule ">21</td> <td align="center" styleCode="Lrule Rrule ">59</td> <td align="center" styleCode="Lrule Rrule ">54</td> </tr> <tr> <td styleCode="Lrule Rrule "> Injection Site Reactions</td> <td align="center" styleCode="Lrule Rrule ">11</td> <td align="center" styleCode="Rrule ">37</td> <td align="center" styleCode="Lrule Rrule ">18</td> <td align="center" styleCode="Lrule Rrule ">43</td> </tr> <tr> <td styleCode="Lrule Rrule "> Diarrhea </td> <td align="center" styleCode="Lrule Rrule ">9</td> <td align="center" styleCode="Rrule ">8</td> <td align="center" styleCode="Lrule Rrule ">16</td> <td align="center" styleCode="Lrule Rrule ">16</td> </tr> <tr> <td styleCode="Lrule Rrule "> Rash</td> <td align="center" styleCode="Lrule Rrule ">2</td> <td align="center" styleCode="Rrule ">3</td> <td align="center" styleCode="Lrule Rrule ">19</td> <td align="center" styleCode="Lrule Rrule ">13</td> </tr> <tr> <td styleCode="Lrule Rrule "> Pruritus</td> <td align="center" styleCode="Lrule Rrule ">1</td> <td align="center" styleCode="Rrule ">2</td> <td align="center" styleCode="Lrule Rrule ">5</td> <td align="center" styleCode="Lrule Rrule ">5</td> </tr> <tr> <td styleCode="Lrule Rrule "> Pyrexia </td> <td align="center" styleCode="Lrule Rrule ">-</td> <td align="center" styleCode="Rrule ">3</td> <td align="center" styleCode="Lrule Rrule ">4</td> <td align="center" styleCode="Lrule Rrule ">2</td> </tr> <tr> <td styleCode="Lrule Rrule "> Urticaria </td> <td align="center" styleCode="Lrule Rrule ">1</td> <td align="center" styleCode="Rrule ">-</td> <td align="center" styleCode="Lrule Rrule ">4</td> <td align="center" styleCode="Lrule Rrule ">2</td> </tr> <tr> <td styleCode="Lrule Rrule "> Hypersensitivity</td> <td align="center" styleCode="Lrule Rrule ">-</td> <td align="center" styleCode="Rrule ">-</td> <td align="center" styleCode="Lrule Rrule ">1</td> <td align="center" styleCode="Lrule Rrule ">1</td> </tr> <tr> <td styleCode="Lrule Rrule "> </td> <td align="center" styleCode="Lrule Rrule "> </td> <td align="center" styleCode="Rrule "> </td> <td align="center" styleCode="Lrule Rrule "> </td> <td align="center" styleCode="Lrule Rrule "> </td> </tr> <tr> <td colspan="5" styleCode="Toprule "> ^a Includes data from the 6-month study in which patients received concurrent MTX therapy in both arms. ^b Study duration of 2 years. ^c Any dose. ^d Includes bacterial, viral and fungal infections. ^e Most frequent Upper Respiratory Infections were upper respiratory tract infection, sinusitis and influenza.</td> </tr> </tbody> </table>

<table> <col width="168"/> <col width="144"/> <col width="144"/> <tbody> <tr> <td align="center" colspan="3"> <content styleCode="bold">Table 4</content> <content styleCode="bold">.</content> <content styleCode="bold"> Percent of Adult PsO Patients Experiencing Adverse Reactions </content> <content styleCode="bold">in Placebo-Controlled Portions of Clinical Trials</content> <content styleCode="bold"> (Studies I &amp; II)</content> </td> </tr> <tr> <td styleCode="Toprule Lrule Rrule " valign="bottom"> <content styleCode="bold"> </content> <content styleCode="bold"> </content> <content styleCode="bold"> </content> <content styleCode="bold"> </content> </td> <td align="center" styleCode="Toprule Lrule Rrule "> <content styleCode="bold">Placebo</content> (N = 359)</td> <td align="center" styleCode="Toprule Lrule Rrule "> <content styleCode="bold">Enbrel</content> <content styleCode="bold"> ^a </content> (N = 876)</td> </tr> <tr> <td styleCode="Lrule Rrule "> <content styleCode="bold">Reaction</content> </td> <td align="center" colspan="2" styleCode="Toprule Lrule Rrule "> <content styleCode="bold">Percent of Patients</content> </td> </tr> <tr> <td styleCode="Toprule Lrule Rrule "> <content styleCode="bold"> </content> </td> <td align="center" styleCode="Toprule Lrule Rrule "> </td> <td align="center" styleCode="Toprule Lrule Rrule "> </td> </tr> <tr> <td styleCode="Lrule Rrule ">Infection^b (total)</td> <td align="center" styleCode="Lrule Rrule ">28</td> <td align="center" styleCode="Lrule Rrule ">27</td> </tr> <tr> <td styleCode="Lrule Rrule ">Non-upper Respiratory Infections</td> <td align="center" styleCode="Lrule Rrule ">14</td> <td align="center" styleCode="Lrule Rrule ">12</td> </tr> <tr> <td styleCode="Lrule Rrule ">Upper Respiratory Infections^c </td> <td align="center" styleCode="Lrule Rrule ">17</td> <td align="center" styleCode="Lrule Rrule ">17</td> </tr> <tr> <td styleCode="Lrule Rrule ">Injection Site Reactions</td> <td align="center" styleCode="Lrule Rrule ">6</td> <td align="center" styleCode="Lrule Rrule ">15</td> </tr> <tr> <td styleCode="Lrule Rrule ">Diarrhea </td> <td align="center" styleCode="Lrule Rrule ">2</td> <td align="center" styleCode="Lrule Rrule ">3</td> </tr> <tr> <td styleCode="Lrule Rrule ">Rash</td> <td align="center" styleCode="Lrule Rrule ">1</td> <td align="center" styleCode="Lrule Rrule ">1</td> </tr> <tr> <td styleCode="Lrule Rrule ">Pruritus </td> <td align="center" styleCode="Lrule Rrule ">2</td> <td align="center" styleCode="Lrule Rrule ">1</td> </tr> <tr> <td styleCode="Lrule Rrule ">Urticaria </td> <td align="center" styleCode="Lrule Rrule ">-</td> <td align="center" styleCode="Lrule Rrule ">1</td> </tr> <tr> <td styleCode="Lrule Rrule ">Hypersensitivity</td> <td align="center" styleCode="Lrule Rrule ">-</td> <td align="center" styleCode="Lrule Rrule ">1</td> </tr> <tr> <td styleCode="Lrule Rrule ">Pyrexia</td> <td align="center" styleCode="Lrule Rrule ">1</td> <td align="center" styleCode="Lrule Rrule ">-</td> </tr> <tr> <td styleCode="Lrule Rrule "> </td> <td align="center" styleCode="Lrule Rrule "> </td> <td align="center" styleCode="Lrule Rrule "> </td> </tr> <tr> <td colspan="3" styleCode="Toprule "> ^a Includes 25 mg subcutaneous (SC) once weekly (QW), 25 mg SC twice weekly (BIW), 50 mg SC QW, and 50 mg SC BIW doses. ^b Includes bacterial, viral and fungal infections. ^c Most frequent Upper Respiratory Infections were upper respiratory tract infection, nasopharyngitis and sinusitis.</td> </tr> </tbody> </table>

<table> <col width="276"/> <col width="372"/> <tbody> <tr> <td>Blood and lymphatic system disorders:</td> <td>pancytopenia, anemia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, aplastic anemia <content styleCode="italics">[see Warnings</content> <content styleCode="italics"> and Precautions</content> <content styleCode="italics"> (</content> <content styleCode="italics"> <linkHtml href="#_5_5_Hematologic_Reactions">5.5</linkHtml> </content> <content styleCode="italics">)]</content> </td> </tr> <tr> <td>Cardiac disorders:</td> <td>congestive heart failure <content styleCode="italics">[see </content> <content styleCode="italics">Warnings and Precautions (</content> <content styleCode="italics"> <linkHtml href="#_5_4_Patients_With">5.4</linkHtml> </content> <content styleCode="italics">)]</content> </td> </tr> <tr> <td>Gastrointestinal disorders:</td> <td>inflammatory bowel disease (IBD)</td> </tr> <tr> <td>General disorders:</td> <td>angioedema, chest pain</td> </tr> <tr> <td>Hepatobiliary disorders:</td> <td>autoimmune hepatitis, elevated transaminases, hepatitis B reactivation</td> </tr> <tr> <td>Immune disorders:</td> <td>macrophage activation syndrome, systemic vasculitis, sarcoidosis</td> </tr> <tr> <td>Musculoskeletal and connective tissue disorders:</td> <td>lupus-like syndrome </td> </tr> <tr> <td>Neoplasms benign, malignant, and unspecified:</td> <td>melanoma and non-melanoma skin cancers, Merkel cell carcinoma <content styleCode="italics">[see Warnings and Precautions (</content> <content styleCode="italics"> <linkHtml href="#_5_3_Malignancies">5.3</linkHtml> </content> <content styleCode="italics">)]</content> </td> </tr> <tr> <td>Nervous system disorders:</td> <td>convulsions, multiple sclerosis, demyelination, optic neuritis, transverse myelitis, paresthesias <content styleCode="italics">[see Warning</content> <content styleCode="italics">s</content> <content styleCode="italics"> and Precaution</content> <content styleCode="italics">s (</content> <content styleCode="italics"> <linkHtml href="#_5_2_Neurologic_Reactions">5.2</linkHtml> </content> <content styleCode="italics">)]</content> </td> </tr> <tr> <td>Ocular disorders:</td> <td>uveitis, scleritis </td> </tr> <tr> <td>Respiratory, thoracic and mediastinal disorders:</td> <td>interstitial lung disease</td> </tr> <tr> <td>Skin and subcutaneous tissue disorders:</td> <td>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)</td> </tr> </tbody> </table>