CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Adult Rheumatoid Arthritis. The safety and efficacy of Enbrel were assessed in four randomized, double-blind, controlled studies. The results of all four trials were expressed in percentage of patients with improvement in RA using ACR response criteria.Study evaluated 234 patients with active RA who were >= 18 years old, had failed therapy with at least one but no more than four disease-modifying antirheumatic drugs (DMARDs) (e.g. hydroxychloroquine, oral or injectable gold, MTX, azathioprine, D-penicillamine, sulfasalazine), and had >= 12 tender joints, >= 10 swollen joints, and either erythrocyte sedimentation rate (ESR) >= 28 mm/hr, C-reactive protein (CRP) 2.0 mg/dL, or morning stiffness for >= 45 minutes. Doses of 10 mg or 25 mg Enbrel or placebo were administered SC twice week for consecutive months. Study II evaluated 89 patients and had similar inclusion criteria to Study except that patients in Study II had additionally received MTX for at least months with stable dose (12.5 to 25 mg/week) for at least weeks and they had at least tender or painful joints. Patients in Study II received dose of 25 mg Enbrel or placebo SC twice week for months in addition to their stable MTX dose.Study III compared the efficacy of Enbrel to MTX in patients with active RA. This study evaluated 632 patients who were >= 18 years old with early (<= years disease duration) active RA, had never received treatment with MTX, and had >= 12 tender joints, >= 10 swollen joints, and either ESR >= 28 mm/hr, CRP 2.0 mg/dL, or morning stiffness for >= 45 minutes. Doses of 10 mg or 25 mg Enbrel were administered SC twice week for 12 consecutive months. The study was unblinded after all patients had completed at least 12 months (and median of 17.3 months) of therapy. The majority of patients remained in the study on the treatment to which they were randomized through years, after which they entered an extension study and received open-label 25 mg Enbrel. MTX tablets (escalated from 7.5 mg/week to maximum of 20 mg/week over the first weeks of the trial) or placebo tablets were given once week on the same day as the injection of placebo or Enbrel doses, respectively.Study IV evaluated 682 adult patients with active RA of months to 20 years duration (mean of years) who had an inadequate response to at least one DMARD other than MTX. Forty-three percent of patients had previously received MTX for mean of years prior to the trial at mean dose of 12.9 mg. Patients were excluded from this study if MTX had been discontinued for lack of efficacy or for safety considerations. The patient baseline characteristics were similar to those of patients in Study I. Patients were randomized to MTX alone (7.5 to 20 mg weekly, dose escalated as described for Study III; median dose 20 mg), Enbrel alone (25 mg twice weekly), or the combination of Enbrel and MTX initiated concurrently (at the same doses as above). The study evaluated ACR response, Sharp radiographic score, and safety.. Clinical ResponseA higher percentage of patients treated with Enbrel and Enbrel in combination with MTX achieved ACR 20, ACR 50, and ACR 70 responses and Major Clinical Responses than in the comparison groups. The results of Studies I, II, and III are summarized in Table 6. The results of Study IV are summarized in Table 7.Table 6. ACR Responses in Placebo- and Active-Controlled Trials (Percent of Patients)Placebo-ControlledActive-ControlledStudy IStudy IIStudy IIIPlaceboEnbrel25 mg Enbrel SC twice weekly. MTX/PlaceboMTX/Enbrel MTXEnbrel ResponseN 80N 78N 30N 59N 217N 207ACR 20Month 323%62%p 0.01, Enbrel versus placebo. 33%66% 56%62%Month 611%59% 27%71% 58%65%Month 12NANANANA65%72%ACR 50Month 38%41% 0%42% 24%29%Month 65%40% 3%39% 32%40%Month 12NANANANA43%49%ACR 70Month 34%15% 0%15% 7%13%p 0.05, Enbrel versus MTX. Month 61%15% 0%15% 14%21% Month 12NANANANA22%25%Table 7. Study IV Clinical Efficacy Results: Comparison of MTX versus Enbrel versus Enbrel in Combination with MTX in Patients with Rheumatoid Arthritis of Months to 20 Years Duration (Percent of Patients)EndpointMTX(N 228)Enbrel(N 223)Enbrel/MTX(N 231)ACR NValues are medians., ACR is the percent improvement based on the same core variables used in defining ACR 20, ACR 50, and ACR 70.Month 1240%47%63%p 0.05 for comparisons of Enbrel/MTX versus Enbrel alone or MTX alone. ACR 20Month 1259%66%75% ACR 50Month 1236%43%63% ACR 70Month 1217%22%40% Major Clinical ResponseMajor clinical response is achieving an ACR 70 response for continuous 6-month period.6%10%24% The time course for ACR 20 response rates for patients receiving placebo or 25 mg Enbrel in Studies and II is summarized in Figure 1. The time course of responses to Enbrel in Study III was similar.Among patients receiving Enbrel, the clinical responses generally appeared within to weeks after initiation of therapy and nearly always occurred by months. dose response was seen in Studies and III: 25 mg Enbrel was more effective than 10 mg (10 mg was not evaluated in Study II). Enbrel was significantly better than placebo in all components of the ACR criteria as well as other measures of RA disease activity not included in the ACR response criteria, such as morning stiffness.In Study III, ACR response rates and improvement in all the individual ACR response criteria were maintained through 24 months of Enbrel therapy. Over the 2-year study, 23% of Enbrel patients achieved major clinical response, defined as maintenance of an ACR 70 response over 6-month period.The results of the components of the ACR response criteria for Study are shown in Table 8. Similar results were observed for Enbrel-treated patients in Studies II and III.Table 8. Components of ACR Response in Study IPlaceboN 80Enbrel25 mg Enbrel SC twice weekly. = 78Parameter (median)Baseline3 MonthsBaseline3 MonthsResults at months showed similar improvement. Number of tender joints Scale 0-71. 34.029.531.210.0p 0.01, Enbrel versus placebo, based on mean percent change from baseline. Number of swollen joints Scale 0-68. 24.022.023.512.6 Physician global assessment Visual analog scale: = best; 10 worst. 7.06.57.03.0 Patient global assessment 7.07.07.03.0 Pain 6.96.66.92.4 Disability index Health Assessment Questionnaire: = best; = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. 1.71.81.61.0 ESR (mm/hr)31.032.028.015.5 CRP (mg/dL)2.83.93.50.9 After discontinuation of Enbrel, symptoms of arthritis generally returned within month. Reintroduction of treatment with Enbrel after discontinuations of up to 18 months resulted in the same magnitudes of response as in patients who received Enbrel without interruption of therapy, based on results of open-label studies.Continued durable responses were seen for over 60 months in open-label extension treatment trials when patients received Enbrel without interruption. substantial number of patients who initially received concomitant MTX or corticosteroids were able to reduce their doses or discontinue these concomitant therapies while maintaining their clinical responses.. Figure 1. Physical Function ResponseIn Studies I, II, and III, physical function and disability were assessed using the Health Assessment Questionnaire (HAQ). Additionally, in Study III, patients were administered the SF-36 Health Survey. In Studies and II, patients treated with 25 mg Enbrel twice weekly showed greater improvement from baseline in the HAQ score beginning in month through month in comparison to placebo (p 0.001) for the HAQ disability domain (where = none and = severe). In Study I, the mean improvement in the HAQ score from baseline to month was 0.6 (from 1.6 to 1.0) for the 25 mg Enbrel group and (from 1.7 to 1.7) for the placebo group. In Study II, the mean improvement from baseline to month was 0.6 (from 1.5 to 0.9) for the Enbrel/MTX group and 0.2 (from 1.3 to 1.2) for the placebo/MTX group. In Study III, the mean improvement in the HAQ score from baseline to month was 0.7 (from 1.5 to 0.7) for 25 mg Enbrel twice weekly. All subdomains of the HAQ in Studies and III were improved in patients treated with Enbrel.In Study III, patients treated with 25 mg Enbrel twice weekly showed greater improvement from baseline in SF-36 physical component summary score compared to Enbrel 10 mg twice weekly and no worsening in the SF-36 mental component summary score. In open-label Enbrel studies, improvements in physical function and disability measures have been maintained for up to years.In Study IV, median HAQ scores improved from baseline levels of 1.8, 1.8, and 1.8 to 1.1, 1.0, and 0.6 at 12 months in the MTX, Enbrel, and Enbrel/MTX combination treatment groups, respectively (combination versus both MTX and Enbrel, < 0.01). Twenty-nine percent of patients in the MTX alone treatment group had an improvement of HAQ of at least unit versus 40% and 51% in the Enbrel alone and the Enbrel/MTX combination treatment groups, respectively. Radiographic ResponseIn Study III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score. Radiographs of hands/wrists and forefeet were obtained at baseline, months, 12 months, and 24 months and scored by readers who were unaware of treatment group. The results are shown in Table 9. significant difference for change in erosion score was observed at months and maintained at 12 months.Table 9. Mean Radiographic Change Over and 12 Months in Study IIIMTX25 mg EnbrelMTX/Enbrel(95% Confidence Interval95% confidence intervals for the differences in change scores between MTX and Enbrel.)P Value12 MonthsTotal Sharp Score1.591.000.59 (-0.12, 1.30)0.1Erosion Score1.030.470.56 (0.11, 1.00)0.002JSN Score0.560.520.04 (-0.39, 0.46)0.56 MonthsTotal Sharp Score1.060.570.49 (0.06, 0.91)0.001Erosion Score0.680.300.38 (0.09, 0.66)0.001JSN Score0.380.270.11 (-0.14, 0.35)0.6Patients continued on the therapy to which they were randomized for the second year of Study III. Seventy-two percent of patients had x-rays obtained at 24 months. Compared to the patients in the MTX group, greater inhibition of progression in TSS and erosion score was seen in the 25 mg Enbrel group, and, in addition, less progression was noted in the JSN score.In the open-label extension of Study III, 48% of the original patients treated with 25 mg Enbrel have been evaluated radiographically at years. Patients had continued inhibition of structural damage, as measured by the TSS, and 55% of them had no progression of structural damage. Patients originally treated with MTX had further reduction in radiographic progression once they began treatment with Enbrel.In Study IV, less radiographic progression (TSS) was observed with Enbrel in combination with MTX compared with Enbrel alone or MTX alone at month 12 (Table 10). In the MTX treatment group, 55% of patients experienced no radiographic progression (TSS change <= 0.0) at 12 months compared to 63% and 76% in the Enbrel alone and the Enbrel/MTX combination treatment groups, respectively. Table 10. Mean Radiographic Change in Study IV at 12 Months (95% Confidence Interval)MTX(N 212)Analyzed radiographic ITT population. Enbrel(N 212) Enbrel/MTX(N 218) Total Sharp Score (TSS)2.80(1.08, 4.51)0.52p 0.05 for comparison of Enbrel versus MTX. (-0.10, 1.15)-0.54p 0.05 for comparison of Enbrel/MTX versus MTX. p 0.05 for comparison of Enbrel/MTX versus Enbrel. (-1.00, -0.07)Erosion Score (ES)1.68(0.61, 2.74)0.21 (-0.20, 0.61)-0.30 (-0.65, 0.04)Joint Space Narrowing (JSN) Score1.12(0.34, 1.90)0.32(0.00, 0.63)-0.23 (-0.45, -0.02). Once Weekly DosingThe safety and efficacy of 50 mg Enbrel (two 25 mg SC injections) administered once weekly were evaluated in double-blind, placebo-controlled study of 420 patients with active RA. Fifty-three patients received placebo, 214 patients received 50 mg Enbrel once weekly, and 153 patients received 25 mg Enbrel twice weekly. The safety and efficacy profiles of the two Enbrel treatment groups were similar.. 14.2Polyarticular Juvenile Idiopathic Arthritis (JIA). The safety and efficacy of Enbrel were assessed in 2-part study in 69 children with polyarticular JIA who had variety of JIA onset types. Patients ages to 17 years with moderately to severely active polyarticular JIA refractory to or intolerant of MTX were enrolled; patients remained on stable dose of single nonsteroidal anti-inflammatory drug and/or prednisone (<= 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received 0.4 mg/kg (maximum 25 mg per dose) Enbrel SC twice weekly. In part 2, patients with clinical response at day 90 were randomized to remain on Enbrel or receive placebo for months and assessed for disease flare. Responses were measured using the JIA Definition of Improvement (DOI), defined as >= 30% improvement in at least three of six and >= 30% worsening in no more than one of the six JIA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and ESR. Disease flare was defined as >= 30% worsening in three of the six JIA core set criteria and >= 30% improvement in not more than one of the six JIA core set criteria and minimum of two active joints.In part of the study, 51 of 69 (74%) patients demonstrated clinical response and entered part 2. In part 2, of 25 (24%) patients remaining on Enbrel experienced disease flare compared to 20 of 26 (77%) patients receiving placebo (p 0.007). From the start of part 2, the median time to flare was >= 116 days for patients who received Enbrel and 28 days for patients who received placebo. Each component of the JIA core set criteria worsened in the arm that received placebo and remained stable or improved in the arm that continued on Enbrel. The data suggested the possibility of higher flare rate among those patients with higher baseline ESR. Of patients who demonstrated clinical response at 90 days and entered part of the study, some of the patients remaining on Enbrel continued to improve from month through month 7, while those who received placebo did not improve. The majority of JIA patients who developed disease flare in part and reintroduced Enbrel treatment up to months after discontinuation re-responded to Enbrel therapy in open-label studies. Most of the responding patients who continued Enbrel therapy without interruption have maintained responses for up to 48 months.Studies have not been done in patients with polyarticular JIA to assess the effects of continued Enbrel therapy in patients who do not respond within months of initiating Enbrel therapy, or to assess the combination of Enbrel with MTX. 14.3Psoriatic Arthritis. The safety and efficacy of Enbrel were assessed in randomized, double-blind, placebo-controlled study in 205 patients with PsA. Patients were between 18 and 70 years of age and had active PsA (>= swollen joints and >= tender joints) in one or more of the following forms: (1) distal interphalangeal (DIP) involvement (N 104); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis; = 173); (3) arthritis mutilans (N 3); (4) asymmetric psoriatic arthritis (N 81); or (5) ankylosing spondylitis-like (N 7). Patients also had plaque psoriasis with qualifying target lesion >= cm in diameter. Patients on MTX therapy at enrollment (stable for >= months) could continue at stable dose of <= 25 mg/week MTX. Doses of 25 mg Enbrel or placebo were administered SC twice week during the initial 6-month double-blind period of the study. Patients continued to receive blinded therapy in an up to 6-month maintenance period until all patients had completed the controlled period. Following this, patients received open-label 25 mg Enbrel twice week in 12-month extension period. Compared to placebo, treatment with Enbrel resulted in significant improvements in measures of disease activity (Table 11).Table 11. Components of Disease Activity in Psoriatic ArthritisPlaceboN 104Enbrelp 0.001 for all comparisons between Enbrel and placebo at months. = 101Parameter (median)Baseline6 MonthsBaseline6 MonthsNumber of tender jointsScale 0-78. 17.013.018.05.0Number of swollen jointsScale 0-76. 12.59.513.05.0Physician global assessmentLikert scale: = best; = worst. 3.03.03.01.0Patient global assessment 3.03.03.01.0Morning stiffness (minutes)60606015Pain 3.03.03.01.0Disability indexHealth Assessment Questionnaire: = best; = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. 1.00.91.10.3CRP (mg/dL)Normal range: 0-0.79 mg/dL. 1.11.11.60.2Among patients with PsA who received Enbrel, the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through months of therapy. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. At months, the ACR 20/50/70 responses were achieved by 50%, 37%, and 9%, respectively, of patients receiving Enbrel, compared to 13%, 4%, and 1%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of PsA, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. The results of this study were similar to those seen in an earlier single-center, randomized, placebo-controlled study of 60 patients with PsA.The skin lesions of psoriasis were also improved with Enbrel, relative to placebo, as measured by percentages of patients achieving improvements in the Psoriasis Area and Severity Index (PASI). Responses increased over time, and at months, the proportions of patients achieving 50% or 75% improvement in the PASI were 47% and 23%, respectively, in the Enbrel group (N 66), compared to 18% and 3%, respectively, in the placebo group (N 62). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. Radiographic ResponseRadiographic changes were also assessed in the PsA study. Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24. modified Total Sharp Score (TSS), which included distal interphalangeal joints (i.e., not identical to the modified TSS used for RA) was used by readers blinded to treatment group to assess the radiographs. Some radiographic features specific to PsA (e.g. pencil-and-cup deformity, joint space widening, gross osteolysis, and ankylosis) were included in the scoring system, but others (e.g. phalangeal tuft resorption, juxta-articular and shaft periostitis) were not.Most patients showed little or no change in the modified TSS during this 24-month study (median change of in both patients who initially received Enbrel or placebo). More placebo-treated patients experienced larger magnitudes of radiographic worsening (increased TSS) compared to Enbrel treatment during the controlled period of the study. At 12 months, in an exploratory analysis, 12% (12 of 104) of placebo patients compared to none of the 101 Enbrel-treated patients had increases of points or more in TSS. Inhibition of radiographic progression was maintained in patients who continued on Enbrel during the second year. Of the patients with 1-year and 2-year x-rays, 3% (2 of 71) had increases of points or more in TSS at and years. Physical Function ResponseIn the PsA study, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 25 mg Enbrel twice weekly showed greater improvement from baseline in the HAQ-DI score (mean decreases of 54% at both months and 6) in comparison to placebo (mean decreases of 6% at both months and 6) (p 0.001). At months and 6, patients treated with Enbrel showed greater improvement from baseline in the SF-36 physical component summary score compared to patients treated with placebo, and no worsening in the SF-36 mental component summary score. Improvements in physical function and disability measures were maintained for up to years through the open-label portion of the study.. 14.4Ankylosing Spondylitis. The safety and efficacy of Enbrel were assessed in randomized, double-blind, placebo-controlled study in 277 patients with active AS. Patients were between 18 and 70 years of age and had AS as defined by the modified New York Criteria for Ankylosing Spondylitis. Patients were to have evidence of active disease based on values of >= 30 on 0-100 unit Visual Analog Scale (VAS) for the average of morning stiffness duration and intensity, and two of the following three other parameters: a) patient global assessment, b) average of nocturnal and total back pain, and c) the average score on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients with complete ankylosis of the spine were excluded from study participation. Patients taking hydroxychloroquine, sulfasalazine, methotrexate, or prednisone (<= 10 mg/day) could continue these drugs at stable doses for the duration of the study. Doses of 25 mg Enbrel or placebo were administered SC twice week for months.The primary measure of efficacy was 20% improvement in the Assessment in Ankylosing Spondylitis (ASAS) response criteria. Compared to placebo, treatment with Enbrel resulted in improvements in the ASAS and other measures of disease activity (Figure and Table 12). Figure 2. ASAS 20 Responses in Ankylosing SpondylitisAt 12 weeks, the ASAS 20/50/70 responses were achieved by 60%, 45%, and 29%, respectively, of patients receiving Enbrel, compared to 27%, 13%, and 7%, respectively, of patients receiving placebo (p <= 0.0001, Enbrel versus placebo). Similar responses were seen at Week 24. Responses were similar between those patients receiving concomitant therapies at baseline and those who were not. The results of this study were similar to those seen in single-center, randomized, placebo-controlled study of 40 patients and multicenter, randomized, placebo-controlled study of 84 patients with AS.Table 12. Components of Ankylosing Spondylitis Disease ActivityPlaceboN 139Enbrelp 0.0015 for all comparisons between Enbrel and placebo at months. values for continuous endpoints were based on percent change from baseline. = 138Median values at time pointsBaseline6 MonthsBaseline6 MonthsASAS response criteria Patient global assessment Measured on Visual Analog Scale (VAS) with = none and 100 severe. 63566336 Back pain Average of total nocturnal and back pain scores, measured on VAS with = no pain and 100 most severe pain. 62566034 BASFI Bath Ankylosing Spondylitis Functional Index (BASFI), average of 10 questions. 56555236 Inflammation Inflammation represented by the average of the last questions on the 6-question Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 64576133Acute phase reactants CRP (mg/dL) C-reactive protein (CRP) normal range: 0-1.0 mg/dL. 2.01.91.90.6Spinal mobility (cm): Modified Schobers test3.02.93.13.3 Chest expansion3.23.03.33.9 Occiput-to-wall measurement5.36.05.64.5. Figure 2. 14.5Adult Plaque Psoriasis. The safety and efficacy of Enbrel were assessed in two randomized, double-blind, placebo-controlled studies in adults with chronic stable PsO involving >= 10% of the body surface area, minimum Psoriasis Area and Severity Index (PASI) score of 10 and who had received or were candidates for systemic antipsoriatic therapy or phototherapy. Patients with guttate, erythrodermic, or pustular psoriasis and patients with severe infections within weeks of screening were excluded from study. No concomitant major antipsoriatic therapies were allowed during the study.Study evaluated 672 subjects who received placebo or Enbrel SC at doses of 25 mg once week, 25 mg twice week, or 50 mg twice week for months. After months, subjects continued on blinded treatments for an additional months during which time subjects originally randomized to placebo began treatment with blinded Enbrel at 25 mg twice weekly (designated as placebo/Enbrel in Table 13); subjects originally randomized to Enbrel continued on the originally randomized dose (designated as Enbrel/Enbrel groups in Table 13).Study II evaluated 611 subjects who received placebo or Enbrel SC at doses of 25 mg or 50 mg twice week for months. After months of randomized, blinded treatment, subjects in all three arms began receiving open-label Enbrel at 25 mg twice weekly for additional months.Response to treatment in both studies was assessed after months of therapy and was defined as the proportion of subjects who achieved reduction in PASI score of at least 75% from baseline. The PASI is composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of psoriatic changes within the affected regions (induration, erythema and scaling).Other evaluated outcomes included the proportion of subjects who achieved score of clear or minimal by the Static Physician Global Assessment (sPGA) and the proportion of subjects with reduction of PASI of at least 50% from baseline. The sPGA is 6-category scale ranging from 5 severe to 0 none indicating the physicians overall assessment of the PsO severity focusing on induration, erythema and scaling. Treatment success of clear or minimal consisted of none or minimal elevation in plaque, up to faint red coloration in erythema and none or minimal fine scale over 5% of the plaque.Subjects in all treatment groups and in both studies had median baseline PASI score ranging from 15 to 17, and the percentage of subjects with baseline sPGA classifications ranged from 54% to 66% for moderate, 17% to 26% for marked and 1% to 5% for severe. Across all treatment groups, the percentage of subjects who previously received systemic therapy for PsO ranged from 61% to 65% in Study and 71% to 75% in Study II, and those who previously received phototherapy ranged from 44% to 50% in Study and 72% to 73% in Study II. More subjects randomized to Enbrel than placebo achieved at least 75% reduction from baseline PASI score (PASI 75) with dose response relationship across doses of 25 mg once week, 25 mg twice week and 50 mg twice week (Tables 13 and 14). The individual components of the PASI (induration, erythema and scaling) contributed comparably to the overall treatment-associated improvement in PASI.Table 13. Study Outcomes at and MonthsPlacebo/EnbrelEnbrel/Enbrel25 mg BIW25 mg QW25 mg BIW50 mg BIW(N 168)(N 169)(N 167)(N 168)3 MonthsPASI 75 (%)6 (4%)23 (14%)p 0.001 compared with placebo. 53 (32%)p 0.0001 compared with placebo. 79 (47%) Difference (95% CI)10% (4, 16)28% (21, 36)43% (35, 52)sPGA, clear or minimal (%)8 (5%)36 (21%) 53 (32%) 79 (47%) Difference (95% CI)17% (10, 24)27% (19, 35)42% (34, 50)PASI 50 (%)24 (14%)62 (37%) 90 (54%) 119 (71%) Difference (95% CI)22% (13, 31)40% (30, 49)57% (48, 65)6 Months PASI 75 (%)55 (33%)36 (21%)68 (41%)90 (54%)Table 14. Study II Outcomes at MonthsPlaceboEnbrel25 mg BIW50 mg BIW(N 204)(N 204)(N 203)PASI 75 (%)6 (3%)66 (32%)p 0.0001 compared with placebo. 94 (46%) Difference (95% CI)29% (23, 36)43% (36, 51)sPGA, clear or minimal (%)7 (3%)75 (37%) 109 (54%) Difference (95% CI)34% (26, 41)50% (43, 58)PASI 50 (%)18 (9%)124 (61%) 147 (72%) Difference (95% CI)52% (44, 60)64% (56, 71)Among PASI 75 achievers in both studies, the median time to PASI 50 and PASI 75 was approximately month and approximately months, respectively, after the start of therapy with either 25 or 50 mg twice week.In Study I, subjects who achieved PASI 75 at month were entered into study drug withdrawal and retreatment period. Following withdrawal of study drug, these subjects had median duration of PASI 75 of between and months. In Study I, among subjects who were PASI 75 responders at months, retreatment with their original blinded Enbrel dose after discontinuation of up to months resulted in similar proportion of responders as in the initial double-blind portion of the study.In Study II, most subjects initially randomized to 50 mg twice week continued in the study after month and had their Enbrel dose decreased to 25 mg twice week. Of the 91 subjects who were PASI 75 responders at month 3, 70 (77%) maintained their PASI 75 response at month 6.. 14.6Pediatric Plaque Psoriasis. 48-week, randomized, double-blind, placebo-controlled study enrolled 211 pediatric subjects to 17 years of age, with moderate to severe plaque psoriasis (PsO) (as defined by sPGA score >= [moderate, marked, or severe], involving >= 10% of the body surface area, and PASI score >= 12) who were candidates for phototherapy or systemic therapy, or were inadequately controlled on topical therapy. Subjects in all treatment groups had median baseline PASI score of 16.4, and the percentage of subjects with baseline sPGA classifications was 65% for moderate, 31% for marked, and 3% for severe. Across all treatment groups, the percentage of subjects who previously received systemic or phototherapy for PsO was 57%. Subjects received Enbrel 0.8 mg/kg (up to maximum of 50 mg per dose) or placebo once weekly for the first 12 weeks. After 12 weeks, subjects entered 24-week open-label treatment period, in which all subjects received Enbrel at the same dose. This was followed by 12-week withdrawal-retreatment period. Response to treatment was assessed after 12 weeks of therapy and was defined as the proportion of subjects who achieved reduction in PASI score of at least 75% from baseline. The PASI is composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of psoriatic changes within the affected regions (induration, erythema and scaling).Other evaluated outcomes included the proportion of subjects who achieved score of clear or almost clear by the sPGA and the proportion of subjects with reduction in PASI score of at least 90% from baseline. The sPGA is 6-category scale ranging from 5 severe to 0 none indicating the physicians overall assessment of the PsO severity focusing on induration, erythema and scaling. Treatment success of clear or almost clear consisted of none or minimal elevation in plaque, up to faint red coloration in erythema and none or minimal fine scale over 5% of the plaque.Efficacy results are summarized in Table 15.Table 15. Pediatric Plaque Psoriasis Outcomes at 12 WeeksPlacebo(N 105)Enbrel0.8 mg/kg Once Weekly(N 106)PASI 75, (%)12 (11%)60 (57%)PASI 90, (%)7 (7%)29 (27%)sPGA clear or almost clear (%)14 (13%)55 (52%). Maintenance of ResponseTo evaluate maintenance of response, subjects who achieved PASI 75 response at Week 36 were re-randomized to either Enbrel or placebo during 12-week randomized withdrawal period. The maintenance of PASI 75 response was evaluated at Week 48. The proportion of subjects who maintained PASI 75 response at Week 48 was higher for subjects treated with Enbrel (65%) compared to those treated with placebo (49%).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Etanercept can modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (e.g. E-selectin, and to lesser extent, intercellular adhesion molecule-1 [ICAM-1]), serum levels of cytokines (e.g. IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3 or stromelysin). Etanercept has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis.

ADVERSE REACTIONS SECTION.

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 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)] 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 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 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 PsoriasisThe 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 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 PatientsIn 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 48-week clinical study in 211 children aged 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 to years were similar to adverse reactions reported in older children.. InfectionsInfections, 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 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 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 ReactionsIn 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 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 to days. Seven percent of patients experienced redness at previous injection site when subsequent injections were given.. Other Adverse ReactionsTable 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 TrialsPlacebo-ControlledIncludes data from the 6-month study in which patients received concurrent MTX therapy in both arms. (Studies I, II, and Phase Study)Active-ControlledStudy duration of years. (Study III)Placebo(N 152)EnbrelAny dose. (N 349)MTX (N 217)Enbrel (N 415) ReactionPercent of PatientsPercent of PatientsInfectionIncludes bacterial, viral and fungal infections. (total)39508681Upper Respiratory InfectionsMost frequent Upper Respiratory Infections were upper respiratory tract infection, sinusitis and influenza. 30387065Non-upper Respiratory Infections15215954Injection Site Reactions11371843Diarrhea981616Rash231913Pruritus1255Pyrexia-342Urticaria1-42Hypersensitivity--11In placebo-controlled adult PsO trials, the percentages of patients reporting adverse reactions in the 50 mg twice week dose group were similar to those observed in the 25 mg twice week dose group or placebo group. Table summarizes adverse reactions reported in adult PsO patients from Studies and II.Table 4. Percent of Adult PsO Patients Experiencing Adverse Reactions in Placebo-Controlled Portions of Clinical Trials (Studies & II)Placebo(N 359)EnbrelIncludes 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)ReactionPercent of PatientsInfectionIncludes bacterial, viral and fungal infections. (total)2827Non-upper Respiratory Infections1412Upper Respiratory InfectionsMost frequent Upper Respiratory Infections were upper respiratory tract infection, nasopharyngitis and sinusitis. 1717Injection Site Reactions615Diarrhea23Rash11Pruritus21Urticaria-1Hypersensitivity-1Pyrexia1-. 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.. ImmunogenicityPatients 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. AutoantibodiesPatients with RA had serum samples tested for autoantibodies at multiple time points. In RA Studies 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 painHepatobiliary disorders:autoimmune hepatitis, elevated transaminases, hepatitis reactivationImmune disorders:macrophage activation syndrome, systemic vasculitis, sarcoidosisMusculoskeletal and connective tissue disorders:lupus-like syndromeNeoplasms 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, scleritisRespiratory, thoracic and mediastinal disorders:interstitial lung diseaseSkin 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Product: 50090-3531NDC: 50090-3531-0 mL in KIT.

BOXED WARNING SECTION.

WARNING: SERIOUS INFECTIONS and MALIGNANCIES. WARNING: SERIOUS INFECTIONS and MALIGNANCIESSee full prescribing information for complete boxed warning.SERIOUS INFECTIONSIncreased 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 patient develops 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)MALIGNANCIESLymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF-blockers, including Enbrel. (5.3). 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 patient develops 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). Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF-blockers, including Enbrel. (5.3). SERIOUS INFECTIONSPatients 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 patient develops 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.. 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.. MALIGNANCIESLymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF-blockers, including Enbrel.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been conducted to evaluate the carcinogenic potential of etanercept or its effect on fertility.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. TNF is naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of RA, polyarticular JIA, PsA, and AS and the resulting joint pathology. In addition, TNF plays role in the inflammatory process of PsO. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, JIA, PsA, AS, and PsO.Two distinct receptors for TNF (TNFRs), 55 kilodalton protein (p55) and 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR.Etanercept is dimeric soluble form of the p75 TNF receptor that can bind TNF molecules. Etanercept inhibits binding of TNF- and TNF- (lymphotoxin alpha [LT-]) to cell surface TNFRs, rendering TNF biologically inactive. In in vitro studies, large complexes of etanercept with TNF- were not detected and cells expressing transmembrane TNF (that binds Enbrel) are not lysed in the presence or absence of complement.. 12.2 Pharmacodynamics. Etanercept can modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (e.g. E-selectin, and to lesser extent, intercellular adhesion molecule-1 [ICAM-1]), serum levels of cytokines (e.g. IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3 or stromelysin). Etanercept has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis.. 12.3 Pharmacokinetics. After administration of 25 mg of Enbrel by single SC injection to 25 patients with RA, mean +- standard deviation half-life of 102 +- 30 hours was observed with clearance of 160 +- 80 mL/hr. maximum serum concentration (Cmax) of 1.1 +- 0.6 mcg/mL and time to Cmax of 69 +- 34 hours was observed in these patients following single 25 mg dose. After months of twice weekly 25 mg doses in these same RA patients, the mean Cmax was 2.4 +- 1.0 mcg/mL (N 23). Patients exhibited 2- to 7-fold increase in peak serum concentrations and approximately 4-fold increase in AUC0-72 hr (range 1- to 17-fold) with repeated dosing. Serum concentrations in patients with RA have not been measured for periods of dosing that exceed months. In another study, serum concentration profiles at steady-state were comparable among patients with RA treated with 50 mg Enbrel once weekly and those treated with 25 mg Enbrel twice weekly. The mean (+- standard deviation) Cmax, Cmin, and partial AUC were 2.4 +- 1.5 mcg/mL, 1.2 +- 0.7 mcg/mL, and 297 +- 166 mcgoh/mL, respectively, for patients treated with 50 mg Enbrel once weekly (N 21); and 2.6 +- 1.2 mcg/mL, 1.4 +- 0.7 mcg/mL, and 316 +- 135 mcgoh/mL for patients treated with 25 mg Enbrel twice weekly (N 16).Patients with JIA (ages to 17 years) were administered 0.4 mg/kg of Enbrel twice weekly (up to maximum dose of 50 mg per week) for up to 18 weeks. The mean serum concentration after repeated SC dosing was 2.1 mcg/mL, with range of 0.7 to 4.3 mcg/mL. Limited data suggest that the clearance of etanercept is reduced slightly in children ages to years. Population pharmacokinetic analyses predict that the pharmacokinetic differences between the regimens of 0.4 mg/kg twice weekly and 0.8 mg/kg once weekly in JIA patients are of the same magnitude as the differences observed between twice weekly and weekly regimens in adult RA patients. The mean (+- SD) serum steady-state trough concentrations for the 50 mg QW dosing in adult PsO subjects were 1.5 +- 0.7 mcg/mL. Pediatric PsO patients (age to 17 years) were administered 0.8 mg/kg of Enbrel once weekly (up to maximum dose of 50 mg per week) for up to 48 weeks. The mean (+- SD) serum steady-state trough concentrations ranged from 1.6 +- 0.8 to 2.1 +- 1.3 mcg/mL at weeks 12, 24, and 48.In clinical studies with Enbrel, pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. The pharmacokinetics of etanercept were unaltered by concomitant MTX in RA patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on etanercept disposition.

CLINICAL TRIALS EXPERIENCE SECTION.

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 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 PsoriasisThe 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 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 PatientsIn 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 48-week clinical study in 211 children aged 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 to years were similar to adverse reactions reported in older children.. InfectionsInfections, 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 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 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 ReactionsIn 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 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 to days. Seven percent of patients experienced redness at previous injection site when subsequent injections were given.. Other Adverse ReactionsTable 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 TrialsPlacebo-ControlledIncludes data from the 6-month study in which patients received concurrent MTX therapy in both arms. (Studies I, II, and Phase Study)Active-ControlledStudy duration of years. (Study III)Placebo(N 152)EnbrelAny dose. (N 349)MTX (N 217)Enbrel (N 415) ReactionPercent of PatientsPercent of PatientsInfectionIncludes bacterial, viral and fungal infections. (total)39508681Upper Respiratory InfectionsMost frequent Upper Respiratory Infections were upper respiratory tract infection, sinusitis and influenza. 30387065Non-upper Respiratory Infections15215954Injection Site Reactions11371843Diarrhea981616Rash231913Pruritus1255Pyrexia-342Urticaria1-42Hypersensitivity--11In placebo-controlled adult PsO trials, the percentages of patients reporting adverse reactions in the 50 mg twice week dose group were similar to those observed in the 25 mg twice week dose group or placebo group. Table summarizes adverse reactions reported in adult PsO patients from Studies and II.Table 4. Percent of Adult PsO Patients Experiencing Adverse Reactions in Placebo-Controlled Portions of Clinical Trials (Studies & II)Placebo(N 359)EnbrelIncludes 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)ReactionPercent of PatientsInfectionIncludes bacterial, viral and fungal infections. (total)2827Non-upper Respiratory Infections1412Upper Respiratory InfectionsMost frequent Upper Respiratory Infections were upper respiratory tract infection, nasopharyngitis and sinusitis. 1717Injection Site Reactions615Diarrhea23Rash11Pruritus21Urticaria-1Hypersensitivity-1Pyrexia1-.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Enbrel should not be administered to patients with sepsis.. Sepsis (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Etanercept, tumor necrosis factor (TNF) blocker, is 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 CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1. Etanercept is produced by recombinant DNA technology in 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 multiple-dose vial as sterile, white, preservative-free, lyophilized powder. Reconstitution with mL of the supplied Sterile Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol) yields multiple-dose, clear, and colorless solution mL containing 25 mg of Enbrel, with 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 EnbrelPresentationActive Ingredient ContentInactive Ingredients ContentEnbrel 50 mg prefilled syringe and SureClick autoinjector50 mg etanercept in mL25 mM L-arginine hydrochloride120 mM sodium chloride1% sucroseEnbrel 25 mg prefilled syringe25 mg etanercept in 0.5 mL25 mM L-arginine hydrochloride120 mM sodium chloride1% sucroseEnbrel 25 mg single-dose vial25 mg etanercept in 0.5 mL25 mM L-arginine hydrochloride120 mM sodium chloride1% sucroseEnbrel 25 mg multiple-dose vialAfter reconstitution, 25 mg etanercept in mL40 mg mannitol10 mg sucrose1.2 mg tromethamineEnbrel 50 mg Enbrel Mini single-dose prefilled cartridge for use with the AutoTouch reusable autoinjector only50 mg etanercept in mL25 mM L-arginine hydrochloride120 mM sodium chloride1% sucrose.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administration of one 50 mg Enbrel single-dose prefilled syringe, one single-dose prefilled Enbrel SureClick autoinjector, or one Enbrel Mini single-dose prefilled cartridge (for use with the AutoTouch reusable autoinjector only), provides dose equivalent to two 25 mg Enbrel single-dose prefilled syringes, two 25 mg single-dose vials, or two multiple-dose vials of lyophilized Enbrel, when multiple-dose vials are reconstituted and administered as recommended.. Enbrel is administered by subcutaneous injection.Patient PopulationRecommended Dose and FrequencyAdult RA and PsA (2.1)50 mg once weekly with or without methotrexate (MTX)AS (2.1)50 mg once weeklyAdult PsO (2.1)50 mg twice weekly for months, followed by 50 mg once weeklyPediatric PsO or JIA (2.2) 0.8 mg/kg weekly, with maximum of 50 mg per week. 2.1Adult Patients. Enbrel is administered by subcutaneous injection.Table 1. Dosing and Administration for Adult PatientsPatient PopulationRecommended Dosage Strength and FrequencyAdult RA, AS, and PsA50 mg weeklyAdult PsOStarting Dose: 50 mg twice weekly for monthsMaintenance Dose: 50 mg once weeklySee the Enbrel (etanercept) Instructions for Use insert for detailed information on injection site selection and dose administration [see Dosage and Administration (2.3) and Patient Counseling Information (17)].. Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis PatientsMethotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be continued during treatment with Enbrel.Based on study of 50 mg Enbrel twice weekly in patients with RA that suggested higher incidence of adverse reactions but similar American College of Rheumatology (ACR) response rates, doses higher than 50 mg per week are not recommended. Adult Plaque Psoriasis PatientsIn addition to the 50 mg twice weekly recommended starting dose, starting doses of 25 mg or 50 mg per week were shown to be efficacious. The proportion of responders was related to Enbrel dosage [see Clinical Studies (14.5)].. 2.2Pediatric Patients. Enbrel is administered by subcutaneous injection.Table 2. Dosing and Administration for Pediatric Patients (PsO or JIA)Pediatric Patients WeightRecommended Dose63 kg (138 pounds) or more50 mg weeklyLess than 63 kg (138 pounds)0.8 mg/kg weeklyTo achieve pediatric doses other than 25 mg or 50 mg, use Enbrel solution in single-dose vial or reconstituted lyophilized powder in multiple-dose vial.Doses of Enbrel higher than those described in Table have not been studied in pediatric patients.In JIA patients, glucocorticoids, NSAIDs, or analgesics may be continued during treatment with Enbrel.. 2.3Preparation of Enbrel. Enbrel is intended for use under the guidance and supervision of physician. Patients may self-inject when deemed appropriate and if they receive medical follow-up, as necessary. Patients should not self-administer until they receive proper training in how to prepare and administer the correct dose. Administer injections subcutaneously in the thigh, abdomen or outer area of the upper arm.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 [see Warnings and Precautions (5.7)].The Enbrel (etanercept) Instructions for Use insert for each presentation contains more detailed instructions on injection site selection and the preparation of Enbrel.. Preparation of Enbrel Single-dose Prefilled Syringe For more comfortable injection, leave Enbrel prefilled syringes at room temperature for about 15 to 30 minutes before injecting. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature.Inspect visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present.When using the Enbrel single-dose prefilled syringe, check to see if the amount of liquid in the prefilled syringe falls between the two purple fill level indicator lines on the syringe. If the syringe does not have the right amount of liquid, DO NOT USE THAT SYRINGE.. Preparation of Enbrel Single-dose Prefilled SureClick AutoinjectorLeave the autoinjector at room temperature for at least 30 minutes before injecting. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature.Inspect visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present.. Preparation of Enbrel Single-dose VialFor more comfortable injection, leave Enbrel vial(s) at room temperature for at least 30 minutes before injecting. DO NOT remove the vial cap while allowing the vial to reach room temperature.Inspect visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present.When using the Enbrel single-dose vial, administer the correct dose of solution using the following recommended materials:A mL Luer-Lock syringe.A withdrawal needle with Luer-Lock connection, sterile, 22-gauge, length 1/2 inch.An injection needle with Luer-Lock connection, sterile, 27-gauge, length 1/2 inch. Two vials may be required to administer the total prescribed dose. Use the same syringe for each vial. The vial does not contain preservatives; therefore discard unused portions.. 1 mL Luer-Lock syringe.. withdrawal needle with Luer-Lock connection, sterile, 22-gauge, length 1/2 inch.. An injection needle with Luer-Lock connection, sterile, 27-gauge, length 1/2 inch. Preparation of Enbrel Lyophilized Powder in Multiple-dose VialEnbrel lyophilized powder should be reconstituted aseptically with mL of the supplied Sterile Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol), giving solution of mL containing 25 mg of Enbrel.A vial adapter is supplied for use when reconstituting the lyophilized powder. However, the vial adapter should not be used if multiple doses are going to be withdrawn from the vial. If the vial will be used for multiple doses, 25-gauge needle should be used for reconstituting and withdrawing Enbrel, and the supplied Mixing Date: sticker should be attached to the vial and the date of reconstitution entered. Reconstituted solution must be refrigerated at 36F to 46F (2C to 8C) and used within 14 days. Discard reconstituted solution after 14 days because product stability and sterility cannot be assured after 14 days. DO NOT store reconstituted Enbrel solution at room temperature.For more comfortable injection, leave the Enbrel dose tray at room temperature for about 15 to 30 minutes before injecting. If using the vial adapter, twist the vial adapter onto the diluent syringe. Then, place the vial adapter over the Enbrel vial and insert the vial adapter into the vial stopper. Push down on the plunger to inject the diluent into the Enbrel vial. If using 25-gauge needle to reconstitute and withdraw Enbrel, the diluent should be injected very slowly into the Enbrel vial. It is normal for some foaming to occur. Keeping the diluent syringe in place, gently swirl the contents of the Enbrel vial during dissolution. To avoid excessive foaming, do not shake or vigorously agitate.Generally, dissolution of Enbrel takes less than 10 minutes. Do not use the solution if discolored or cloudy, or if particulate matter remains.Withdraw the correct dose of reconstituted solution into the syringe. Some foam or bubbles may remain in the vial. Remove the syringe from the vial adapter or remove the 25-gauge needle from the syringe. Attach 27-gauge needle to inject Enbrel.The contents of one vial of Enbrel solution should not be mixed with, or transferred into, the contents of another vial of Enbrel. No other medications should be added to solutions containing Enbrel, and do not reconstitute Enbrel with other diluents. Do not filter reconstituted solution during preparation or administration.. Preparation of Enbrel Mini(R) single-dose prefilled cartridge using the AutoTouch(R) reusable autoinjector Leave Enbrel Mini single-dose prefilled cartridge at room temperature for at least 30 minutes before injecting. DO NOT remove the purple cap while allowing the cartridge to reach room temperature.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present.To use AutoTouch reusable autoinjector, open the door by pushing the door button and inserting Enbrel Mini single-dose prefilled cartridge into AutoTouch. When inserted correctly, Enbrel Mini single-dose prefilled cartridge will slide freely and completely into the door. Close the door and AutoTouch reusable autoinjector is ready for injection.. 2.4Monitoring to Assess Safety. Prior to initiating Enbrel and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection [see Warnings and Precautions (5.1)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 25 mg/0.5 mL and 50 mg/mL clear, colorless solution in single-dose prefilled syringe Injection: 50 mg/mL clear, colorless solution in single-dose prefilled SureClick autoinjector Injection: 25 mg/0.5 mL clear, colorless solution in single-dose vial For Injection: 25 mg lyophilized powder in multiple-dose vial for reconstitution Injection: 50 mg/mL clear, colorless solution in Enbrel Mini single-dose prefilled cartridge for use with the AutoTouch reusable autoinjector only. Injection: 25 mg/0.5 mL and 50 mg/mL clear, colorless solution in single-dose prefilled syringe. Injection: 50 mg/mL clear, colorless solution in single-dose prefilled SureClick autoinjector. Injection: 25 mg/0.5 mL clear, colorless solution in single-dose vial. For Injection: 25 mg lyophilized powder in multiple-dose vial for reconstitution. Injection: 50 mg/mL clear, colorless solution in Enbrel Mini single-dose prefilled cartridge for use with the AutoTouch reusable autoinjector only. Injection: 25 mg/0.5 mL and 50 mg/mL solution in single-dose prefilled syringe (3) Injection: 50 mg/mL solution in single-dose prefilled SureClick(R) Autoinjector (3) Injection: 25 mg/0.5 mL solution in single-dose vial (3) For Injection: 25 mg lyophilized powder in multiple-dose vial for reconstitution (3) Injection: 50 mg/mL solution in Enbrel Mini(R) single-dose prefilled cartridge for use with the AutoTouch(R) reusable autoinjector only (3). Injection: 25 mg/0.5 mL and 50 mg/mL solution in single-dose prefilled syringe (3). Injection: 50 mg/mL solution in single-dose prefilled SureClick(R) Autoinjector (3). Injection: 25 mg/0.5 mL solution in single-dose vial (3). For Injection: 25 mg lyophilized powder in multiple-dose vial for reconstitution (3). Injection: 50 mg/mL solution in Enbrel Mini(R) single-dose prefilled cartridge for use with the AutoTouch(R) reusable autoinjector only (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Specific drug interaction studies have not been conducted with Enbrel.. Live vaccines should not be given 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 use with Enbrel is not recommended (7.3). Live vaccines should not be given 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 use with Enbrel is not recommended (7.3). 7.1Vaccines. 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 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)].. 7.2Immune-Modulating Biologic Products In study in which patients with active RA were treated for up to 24 weeks with concurrent Enbrel and anakinra therapy, 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 1 109/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)].. 7.3Cyclophosphamide. The use of Enbrel in patients receiving concurrent cyclophosphamide therapy is not recommended [see Warnings and Precautions (5.11)].. 7.4Sulfasalazine. Patients in clinical study who were on established therapy with sulfasalazine, to which Enbrel was added, were noted to develop 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use. total of 480 RA patients ages 65 years or older have been studied in clinical trials. In PsO randomized clinical trials, 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 higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.

IMMUNOGENICITY.

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.. ImmunogenicityPatients 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. AutoantibodiesPatients with RA had serum samples tested for autoantibodies at multiple time points. In RA Studies 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)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Enbrel is tumor necrosis factor (TNF) blocker indicated for the treatment of: Rheumatoid Arthritis (RA) (1.1) Polyarticular Juvenile Idiopathic Arthritis (JIA) in patients aged years or older (1.2) Psoriatic Arthritis (PsA) (1.3) Ankylosing Spondylitis (AS) (1.4) Plaque Psoriasis (PsO) in patients years or older (1.5). Rheumatoid Arthritis (RA) (1.1). Polyarticular Juvenile Idiopathic Arthritis (JIA) in patients aged years or older (1.2). Psoriatic Arthritis (PsA) (1.3). Ankylosing Spondylitis (AS) (1.4). Plaque Psoriasis (PsO) in patients years or older (1.5). 1.1Rheumatoid 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.. 1.2Polyarticular Juvenile Idiopathic Arthritis. Enbrel is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients ages and older.. 1.3Psoriatic Arthritis. Enbrel is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis (PsA). Enbrel can be used with or without methotrexate.. 1.4Ankylosing Spondylitis Enbrel is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS).. 1.5Plaque Psoriasis. Enbrel is indicated for the treatment of patients years or older with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using Enbrel, and each time the prescription is renewed, as there may be new information they need to know.Patients or their caregivers should be provided the Enbrel Medication Guide and provided an opportunity to read it and ask questions prior to initiation of therapy. The healthcare provider should ask the patient questions to determine any risk factors for treatment. Patients developing signs and symptoms of infection should seek medical evaluation immediately.. Patient Counseling Patients should be advised of the potential benefits and risks of Enbrel. Physicians should instruct their patients to read the Medication Guide before starting Enbrel therapy and to reread each time the prescription is renewed. Infections Inform patients that Enbrel may lower the ability of their immune system to fight infections. Advise patients of the importance of contacting their doctor if they develop any symptoms of infection, tuberculosis or reactivation of hepatitis virus infections.. Other Medical ConditionsAdvise patients to report any signs of new or worsening medical conditions, such as central nervous system demyelinating disorders, heart failure or autoimmune disorders, such as lupus-like syndrome or autoimmune hepatitis. Counsel about the risk of lymphoma and other malignancies while receiving Enbrel. Advise patients to report any symptoms suggestive of pancytopenia, such as bruising, bleeding, persistent fever or pallor.. Allergic ReactionsAdvise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the following components contain dry natural rubber (a derivative of latex) that 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 within the purple cap of the Enbrel Mini cartridge.. Administration of EnbrelIf patient or caregiver is to administer Enbrel, the patient or caregiver should be instructed in injection techniques and how to measure and administer the correct dose [see the Enbrel (etanercept) Instructions for Use insert]. For weight-based dosing, instruct caregivers and patients on the proper techniques for preparing, storing, measuring, and administering Enbrel solution in single-dose vial or reconstituted lyophilized powder in multiple-dose vial.The first injection should be performed under the supervision of qualified healthcare professional. The patients or caregivers ability to inject subcutaneously should be assessed. Patients and caregivers should be instructed in the technique, as well as proper syringe and needle disposal, and be cautioned against reuse of needles and syringes.When using the SureClick autoinjector to administer Enbrel, the patient or caregiver should be informed that the window turns yellow when the injection is complete. After removing the autoinjector, if the window has not turned yellow, or if it looks like the medicine is still injecting, this means the patient has not received full dose. The patient or caregiver should be advised to call their healthcare provider immediately.When using the AutoTouch reusable autoinjector to administer Enbrel, the patient or caregiver should be informed that the status button turns green upon contact with the skin, flashes green after starting the injection, and turns off at completion of the injection. After removing the AutoTouch reusable autoinjector from the skin, if the status button has turned red, the patient or caregiver should be advised to call 1-888-4Enbrel (1-888-436-2735) immediately. If it looks like the medicine is still injecting or there is still fluid in Enbrel Mini, this means the patient has not received full dose. The patient or caregiver should be advised to call their healthcare provider immediately.A puncture-resistant container for disposal of needles, syringes, SureClick autoinjectors, single-dose vials, and Enbrel Mini cartridges should be used. If the product is intended for multiple use, additional syringes, needles and alcohol swabs will be required.Patients can be advised to call 1-888-4ENBREL (1-888-436-2735) or visit www.enbrel.com for more information about Enbrel.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use. WelcomeThe Enbrel SureClick autoinjector is single-dose prefilled autoinjector. It contains one 50 mg dose of Enbrel.Your healthcare provider has prescribed Enbrel SureClick autoinjector for your injections. If your healthcare provider decides that you or caregiver may be able to give your injections of Enbrel at home, you should receive training on the right way to prepare and inject Enbrel. Do not try to inject yourself until you have been shown the right way to give the injections by your healthcare provider.Please read all of the instructions before using Enbrel SureClick autoinjector. Call your healthcare provider if you or your caregiver has any questions about the right way to inject Enbrel.Instructions for Use Enbrel(R) (en-brel) (etanercept)injection, for subcutaneous useSingle-dose Prefilled SureClick(R) AutoinjectorGuide to partsBefore useAfter useImportant: Needle is inside the green safety guardImportantBefore you use an Enbrel SureClick autoinjector, read this important information:Storing your Enbrel SureClick autoinjectorsStore the Enbrel SureClick autoinjector in the refrigerator at 36F to 46F (2C to 8C).Store the Enbrel SureClick autoinjector in the original carton to protect from light or physical damage. If needed, you may store the Enbrel SureClick autoinjector at room temperature at 68F to 77F (20C to 25C) for up to 14 days. Once Enbrel has reached room temperature, do not put it back in the refrigerator. Throw away any Enbrel SureClick autoinjector that has been stored at room temperature after 14 days.Do not store the Enbrel SureClick autoinjector in extreme heat or cold. For example, avoid storing the Enbrel SureClick autoinjector in your vehicles glove box or trunk.Do not freeze.Do not shake.Keep the Enbrel SureClick autoinjector and all medicines out of the reach of children. If you have any questions about storage, contact your healthcare provider or call 1-888-4ENBREL (1-888-436-2735) for further instructions.Using your Enbrel SureClick autoinjectorIt is important that you do not try to give the injection unless you or your caregiver has received training from your healthcare provider.Do not use an Enbrel SureClick autoinjector after the expiration date on the label.Do not shake the Enbrel SureClick autoinjector.Do not remove the white cap from the Enbrel SureClick autoinjector until you are ready to inject.Do not use an Enbrel SureClick autoinjector if it has been dropped on hard surface. Part of the Enbrel SureClick autoinjector may be broken even if you cannot see the break. Use new Enbrel SureClick autoinjector, and call 1-888-4ENBREL (1-888-436-2735). The white needle cap on the Enbrel SureClick autoinjector contains dry natural rubber, which is made from latex. Tell your healthcare provider if you are allergic to latex.Children must weigh at least 138 pounds to use the Enbrel SureClick autoinjector. Children who weigh less than 138 pounds should use different form of Enbrel.If you have any questions about usage, contact your healthcare provider, visit www.enbrel.com or call 1-888-4ENBREL (1-888-436-2735).Step 1: PrepareA Remove one Enbrel SureClick autoinjector from the package.Carefully lift the autoinjector straight up out of the box. Put the original package with any unused autoinjectors back in the refrigerator.Leave the autoinjector at room temperature for at least 30 minutes before injecting.Do not put the autoinjector back in the refrigerator once it has reached room temperature.Do not try to warm the autoinjector by using heat source such as hot water or microwave.Do not shake the autoinjector.Do not remove the white cap from the autoinjector yet.B Inspect the Enbrel SureClick autoinjector.Make sure the medicine in the window is clear and colorless.It is okay if you see small white particles in the medicine.Do not use the autoinjector if:The medicine is cloudy or discolored or contains large lumps, flakes, or colored particles.Any part appears cracked or broken.The white cap is missing or not securely attached.The expiration date printed on the label has passed. In all cases, use new autoinjector, and call 1-888-4ENBREL (1-888-436-2735).C Gather all materials needed for your injection.Wash your hands thoroughly with soap and water. On clean, well-lit work surface, place the:New autoinjector Alcohol wipesCotton ball or gauze padAdhesive bandageSharps disposal container. See Step 4: Finish Prepare and clean your injection site.Only use these injection sites:Your thighStomach area (abdomen), except for 2 inch area right around your navel (belly button)Outer area of upper arm (only if someone else is giving you the injection)Clean your injection site with an alcohol wipe. Let your skin dry.Do not touch this area again before injecting.Choose different site each time you give yourself an injection. If you need to use the same injection site, just make sure it is not the same spot on that site you used last time.Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. If you have psoriasis, you should avoid injecting directly into raised, thick, red, or scaly skin patch or lesion.Step 2: Get readyE Pull white cap straight off, only when you are ready to inject. Do not leave the white cap off for more than minutes. This can dry out the medicine. White capIt is normal to see drop of liquid at the end of the needle or green safety guard.Do not twist or bend the white cap.Do not put the white cap back onto the autoinjector.Do not put fingers into the green safety guard.Do not remove the white cap from the autoinjector until you are ready to inject.F Create firm surface at the selected injection site (thigh, stomach, or outer areas of the upper arm), by using either the Stretch method or the Pinch method. Stretch methodStretch skin firmly by moving your thumb and fingers in opposite directions, creating an area about inches wide.Pinch methodPinch skin firmly between your thumb and fingers, creating an area about inches wide.Important: Keep the skin stretched or pinched while injecting.Step 3: InjectG Keep holding the stretched or pinched skin. With the white cap off, put the green safety guard on your skin at 90 degrees. The needle is inside the green safety guard. Do not touch the purple start button yet.H Firmly push the autoinjector down onto skin until it stops moving.Important: You must push all the way down but do not touch purple start button until you are ready to inject.I When you are ready to inject, press the purple start button.J Keep pushing down on your skin. Then lift your thumb while still holding the autoinjector on your skin. Your injection could take about 15 seconds.Window turns from clear to yellow when the injection is done. You may hear second click.Note: After you remove the autoinjector from your skin, the needle will be automatically covered.Important: When you remove the autoinjector, if the window has not turned yellow, or if it looks like the medicine is still injecting, this means you have not received full dose. Call your healthcare provider immediately.Step 4: FinishK Discard the used autoinjector and the white cap. Put the used SureClick autoinjector in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the SureClick autoinjector in your household trash.If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposalDo not reuse the autoinjector.Do not recycle the autoinjector or sharps disposal container or throw them into household trash.Important: Always keep the sharps disposal container out of the reach of children.L Examine the injection site. If there is blood, press cotton ball or gauze pad on your injection site. Do not rub the injection site. Apply an adhesive bandage if needed.Please see the Medication Guide for Enbrel and accompanying Prescribing Information.Commonly asked questionsWhat will happen if press the purple start button before am ready to do the injection on my skinEven when you press the purple start button, the injection will only happen when the green safety guard is also pushed into the autoinjector. Can move the autoinjector around on my skin while am choosing an injection siteIt is okay to move the autoinjector around on the injection site as long as you do not press the purple start button. However, if you press the purple start button and the green safety guard is pushed into the autoinjector, the injection will begin.Can release the purple start button after start my injectionYou can release the purple start button, but continue to hold the autoinjector firmly against your skin during the injection.Will the purple start button pop up after release my thumbThe purple start button may not pop up after you release your thumb if you held your thumb down during the injection. This is okay.What do do if did not hear click after pushing the device down on my skin for 15 secondsIf you did not hear click, you can confirm complete injection by checking that the window has turned yellow. Whom do contact if need help with the autoinjector or my injectionIf you have any questions about the autoinjector, its storage, or about your injection, contact your healthcare provider or visit www.enbrel.com or call 1-888-4ENBREL (1-888-436-2735) for help.This Instructions for Use has been approved by the U.S. Food and Drug Administration.AMGEN(R)Manufactured by:Immunex Corporation Thousand Oaks, CA 91320-1799U.S. License Number 1132(C)1998 2016, 2019-2020 Immunex Corporation. All rights reserved.<part number>Revised: 03/2020 v14This printed material is recyclable.. Store the Enbrel SureClick autoinjector in the refrigerator at 36F to 46F (2C to 8C).. Store the Enbrel SureClick autoinjector in the original carton to protect from light or physical damage. If needed, you may store the Enbrel SureClick autoinjector at room temperature at 68F to 77F (20C to 25C) for up to 14 days. Once Enbrel has reached room temperature, do not put it back in the refrigerator. Once Enbrel has reached room temperature, do not put it back in the refrigerator.. Throw away any Enbrel SureClick autoinjector that has been stored at room temperature after 14 days.. Do not store the Enbrel SureClick autoinjector in extreme heat or cold. For example, avoid storing the Enbrel SureClick autoinjector in your vehicles glove box or trunk.. Do not freeze.. Do not shake.. Keep the Enbrel SureClick autoinjector and all medicines out of the reach of children. It is important that you do not try to give the injection unless you or your caregiver has received training from your healthcare provider.. Do not use an Enbrel SureClick autoinjector after the expiration date on the label.. Do not shake the Enbrel SureClick autoinjector.. Do not remove the white cap from the Enbrel SureClick autoinjector until you are ready to inject.. Do not use an Enbrel SureClick autoinjector if it has been dropped on hard surface. Part of the Enbrel SureClick autoinjector may be broken even if you cannot see the break. Use new Enbrel SureClick autoinjector, and call 1-888-4ENBREL (1-888-436-2735). The white needle cap on the Enbrel SureClick autoinjector contains dry natural rubber, which is made from latex. Tell your healthcare provider if you are allergic to latex.. Children must weigh at least 138 pounds to use the Enbrel SureClick autoinjector. Children who weigh less than 138 pounds should use different form of Enbrel.. Do not put the autoinjector back in the refrigerator once it has reached room temperature.. Do not try to warm the autoinjector by using heat source such as hot water or microwave.. Do not shake the autoinjector.. Do not remove the white cap from the autoinjector yet.. Do not use the autoinjector if:The medicine is cloudy or discolored or contains large lumps, flakes, or colored particles.Any part appears cracked or broken.The white cap is missing or not securely attached.The expiration date printed on the label has passed. The medicine is cloudy or discolored or contains large lumps, flakes, or colored particles.. Any part appears cracked or broken.. The white cap is missing or not securely attached.. The expiration date printed on the label has passed.. New autoinjector Alcohol wipes. Cotton ball or gauze pad. Adhesive bandage. Sharps disposal container. See Step 4: Finish Your thigh. Stomach area (abdomen), except for 2 inch area right around your navel (belly button). Outer area of upper arm (only if someone else is giving you the injection). Do not touch this area again before injecting.. Choose different site each time you give yourself an injection. If you need to use the same injection site, just make sure it is not the same spot on that site you used last time.Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.. If you have psoriasis, you should avoid injecting directly into raised, thick, red, or scaly skin patch or lesion.. Do not twist or bend the white cap.. Do not put the white cap back onto the autoinjector.. Do not put fingers into the green safety guard.. Do not remove the white cap from the autoinjector until you are ready to inject.. Put the used SureClick autoinjector in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the SureClick autoinjector in your household trash.. If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. made of heavy-duty plastic,. can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. upright and stable during use,. leak-resistant, and. properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. Do not reuse the autoinjector.. Do not recycle the autoinjector or sharps disposal container or throw them into household trash.. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image.

LACTATION SECTION.

8.2 Lactation. Risk SummaryLimited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by breastfed infant. No data are available on the effects of etanercept on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Enbrel and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. TNF is naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of RA, polyarticular JIA, PsA, and AS and the resulting joint pathology. In addition, TNF plays role in the inflammatory process of PsO. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, JIA, PsA, AS, and PsO.Two distinct receptors for TNF (TNFRs), 55 kilodalton protein (p55) and 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR.Etanercept is dimeric soluble form of the p75 TNF receptor that can bind TNF molecules. Etanercept inhibits binding of TNF- and TNF- (lymphotoxin alpha [LT-]) to cell surface TNFRs, rendering TNF biologically inactive. In in vitro studies, large complexes of etanercept with TNF- were not detected and cells expressing transmembrane TNF (that binds Enbrel) are not lysed in the presence or absence of complement.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been conducted to evaluate the carcinogenic potential of etanercept or its effect on fertility.

OVERDOSAGE SECTION.

10 OVERDOSAGE. No dose-limiting toxicities have been observed during clinical trials of Enbrel. Single IV doses up to 60 mg/m2 (approximately twice the recommended dose) have been administered to healthy volunteers in an endotoxemia study without evidence of dose-limiting toxicities.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

etanercept. Label Image.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Enbrel has been studied in 69 children with moderately to severely active polyarticular JIA aged to 17 years.Enbrel has been studied in 211 pediatric patients with moderate to severe PsO aged to 17 years.Enbrel has not been studied in children 2 years of age with JIA and 4 years of age with PsO. For pediatric specific safety information concerning malignancies and inflammatory bowel disease [see Warnings and Precautions (5.3) and Adverse Reactions (6.2)].The clinical significance of infant exposure to Enbrel in utero is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to exposed infants. For pediatric specific safety information concerning vaccinations [see Warnings and Precautions (5.8) and Drug Interactions (7.1)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. After administration of 25 mg of Enbrel by single SC injection to 25 patients with RA, mean +- standard deviation half-life of 102 +- 30 hours was observed with clearance of 160 +- 80 mL/hr. maximum serum concentration (Cmax) of 1.1 +- 0.6 mcg/mL and time to Cmax of 69 +- 34 hours was observed in these patients following single 25 mg dose. After months of twice weekly 25 mg doses in these same RA patients, the mean Cmax was 2.4 +- 1.0 mcg/mL (N 23). Patients exhibited 2- to 7-fold increase in peak serum concentrations and approximately 4-fold increase in AUC0-72 hr (range 1- to 17-fold) with repeated dosing. Serum concentrations in patients with RA have not been measured for periods of dosing that exceed months. In another study, serum concentration profiles at steady-state were comparable among patients with RA treated with 50 mg Enbrel once weekly and those treated with 25 mg Enbrel twice weekly. The mean (+- standard deviation) Cmax, Cmin, and partial AUC were 2.4 +- 1.5 mcg/mL, 1.2 +- 0.7 mcg/mL, and 297 +- 166 mcgoh/mL, respectively, for patients treated with 50 mg Enbrel once weekly (N 21); and 2.6 +- 1.2 mcg/mL, 1.4 +- 0.7 mcg/mL, and 316 +- 135 mcgoh/mL for patients treated with 25 mg Enbrel twice weekly (N 16).Patients with JIA (ages to 17 years) were administered 0.4 mg/kg of Enbrel twice weekly (up to maximum dose of 50 mg per week) for up to 18 weeks. The mean serum concentration after repeated SC dosing was 2.1 mcg/mL, with range of 0.7 to 4.3 mcg/mL. Limited data suggest that the clearance of etanercept is reduced slightly in children ages to years. Population pharmacokinetic analyses predict that the pharmacokinetic differences between the regimens of 0.4 mg/kg twice weekly and 0.8 mg/kg once weekly in JIA patients are of the same magnitude as the differences observed between twice weekly and weekly regimens in adult RA patients. The mean (+- SD) serum steady-state trough concentrations for the 50 mg QW dosing in adult PsO subjects were 1.5 +- 0.7 mcg/mL. Pediatric PsO patients (age to 17 years) were administered 0.8 mg/kg of Enbrel once weekly (up to maximum dose of 50 mg per week) for up to 48 weeks. The mean (+- SD) serum steady-state trough concentrations ranged from 1.6 +- 0.8 to 2.1 +- 1.3 mcg/mL at weeks 12, 24, and 48.In clinical studies with Enbrel, pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. The pharmacokinetics of etanercept were unaltered by concomitant MTX in RA patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on etanercept disposition.

POSTMARKETING EXPERIENCE SECTION.

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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 painHepatobiliary disorders:autoimmune hepatitis, elevated transaminases, hepatitis reactivationImmune disorders:macrophage activation syndrome, systemic vasculitis, sarcoidosisMusculoskeletal and connective tissue disorders:lupus-like syndromeNeoplasms 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, scleritisRespiratory, thoracic and mediastinal disorders:interstitial lung diseaseSkin 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable 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 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). 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 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 major birth defect and about 15-20% of pregnancies end in miscarriage, regardless of drug exposure.. Clinical Considerations Fetal/Neonatal adverse reactionsThe 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 Use in Specific Populations (8.4)].. Data. Human DataA 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 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.Three case reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, were between 3% and 32% of the maternal serum level.. Animal DataIn embryofetal development studies with etanercept administered during the period of organogenesis to pregnant rats from gestation day (GD) through 20 or pregnant rabbits from GD 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 peri-and post-natal development study with pregnant rats that received etanercept during organogenesis and the later gestational period from GD through 21, development of pups through post-natal day 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).

REFERENCES SECTION.

15 REFERENCES. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 13 Registries, 1992-2002.Broms G, Granath F, Ekbom A, et al. Low Risk of Birth Defects for Infants Whose Mothers Are Treated With Anti-Tumor Necrosis Factor Agents During Pregnancy. Clin Gastroenterol Hepatol. 2016;14:234-241.e5. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 13 Registries, 1992-2002.. Broms G, Granath F, Ekbom A, et al. Low Risk of Birth Defects for Infants Whose Mothers Are Treated With Anti-Tumor Necrosis Factor Agents During Pregnancy. Clin Gastroenterol Hepatol. 2016;14:234-241.e5.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 03/2020Medication GuideEnbrel(R) (en-brel) (etanercept)injection, for subcutaneous useEnbrel(R) (en-brel) (etanercept) for injection, for subcutaneous useRead the Medication Guide that comes with Enbrel before you start using it and each time you get refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment. It is important to remain under your healthcare providers care while using Enbrel.Enbrel is prescription medicine called Tumor Necrosis Factor (TNF) blocker that affects your immune system.What is the most important information should know about EnbrelEnbrel may cause serious side effects, including:1. Risk of Infection2. Risk of Cancer1. Risk of infectionEnbrel can lower the ability of your immune system to fight infections. Some people have serious infections while taking Enbrel. These infections include tuberculosis (TB), and infections caused by viruses, fungi, or bacteria that spread throughout their body. Some people have died from these infections. Your healthcare provider should test you for TB before starting Enbrel.Your healthcare provider should monitor you closely for symptoms of TB during treatment with Enbrel even if you tested negative for TB. Your healthcare provider should check you for symptoms of any type of infection before, during, and after your treatment with Enbrel.You should not start taking Enbrel if you have any kind of infection unless your healthcare provider says it is okay. 2. Risk of cancerThere have been cases of unusual cancers, some resulting in death, in children and teenage patients who started using TNF-blocking agents at less than 18 years of age.For children, teenagers, and adults taking TNF-blocker medicines, including Enbrel, the chances of getting lymphoma or other cancers may increase.People with rheumatoid arthritis, especially those with very active disease, may be more likely to get lymphoma.Before starting Enbrel, be sure to talk to your healthcare provider:Enbrel may not be right for you. Before starting Enbrel, tell your healthcare provider about all of your medical conditions, including: Infections. Tell your healthcare provider if you: have an infection. See What is the most important information should know about Enbrel are being treated for an infection.think you have an infection.have symptoms of an infection such as fever, sweats or chills, cough or flu-like symptoms, shortness of breath, blood in your phlegm, weight loss, muscle aches, warm, red or painful areas on your skin, sores on your body, diarrhea or stomach pain, burning when you urinate or urinating more often than normal, and feel very tired. have any open cuts on your body.get lot of infections or have infections that keep coming back.have diabetes, HIV, or weak immune system. People with these conditions have higher chance for infections. have TB, or have been in close contact with someone with TB.were born in, lived in, or traveled to countries where there is risk for getting TB. Ask your healthcare provider if you are not sure. live, have lived in, or traveled to certain parts of the country (such as the Ohio and Mississippi River valleys, or the Southwest) where there is greater risk for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis). These infections may happen or become more severe if you use Enbrel. Ask your healthcare provider if you do not know if you live or have lived in an area where these infections are common.have or have had hepatitis B. Also, before starting Enbrel, tell your healthcare provider: About all the medicines you take including prescription and over-the-counter medicines, vitamins and herbal supplements including:Orencia (abatacept) or Kineret (anakinra). You have higher chance for serious infections when taking Enbrel with Orencia or Kineret.Cyclophosphamide (Cytoxan). You may have higher chance for getting certain cancers when taking Enbrel with cyclophosphamide.Anti-diabetic medicines. If you have diabetes and are taking medication to control your diabetes, your healthcare provider may decide you need less anti-diabetic medicine while taking Enbrel.Keep list of all your medications with you to show your healthcare provider and pharmacist each time you get new medicine. Ask your healthcare provider if you are not sure if your medicine is one listed above. Other important medical information you should tell your healthcare provider before starting Enbrel, includes if you: have or had nervous system problem such as multiple sclerosis or Guillain-Barre syndrome. have or had heart failure.are scheduled to have surgery.have recently received or are scheduled to receive vaccine.All vaccines should be brought up-to-date before starting Enbrel.People taking Enbrel should not receive live vaccines.Ask your healthcare provider if you are not sure if you received live vaccine. are allergic to rubber or latex. The needle covers on the single-dose prefilled syringes, the needle covers within the white caps on the single-dose prefilled SureClick autoinjectors, and within the purple caps of the Enbrel Mini cartridges contain dry natural rubber. have been around someone with varicella zoster (chicken pox).are pregnant or plan to become pregnant. It is not known if Enbrel will harm your unborn baby. If you took Enbrel during pregnancy, talk to your healthcare provider prior to administration of live vaccines to your infant.are breastfeeding or plan to breastfeed. Enbrel can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Enbrel. See the section What are the possible side effects of Enbrel below for more information.What is EnbrelEnbrel is prescription medicine called Tumor Necrosis Factor (TNF) blocker. Enbrel is used to treat: moderately to severely active rheumatoid arthritis (RA). Enbrel can be used alone or with medicine called methotrexate.moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in children ages years and older.psoriatic arthritis (PsA). Enbrel can be used alone or with methotrexate. ankylosing spondylitis (AS).chronic moderate to severe plaque psoriasis (PsO) in children years and older and adults who may benefit from taking injections or pills (systemic therapy) or phototherapy (ultraviolet light).You may continue to use other medicines that help treat your condition while taking Enbrel, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and prescription steroids, as recommended by your healthcare provider. Enbrel can help reduce joint damage and the signs and symptoms of the above-mentioned diseases. People with these diseases have too much of protein called tumor necrosis factor (TNF), which is made by your immune system. Enbrel can reduce the effect of TNF in the body and block the damage that too much TNF can cause, but it can also lower the ability of your immune system to fight infections. See What is the most important information should know about Enbrel and What are the possible side effects of Enbrel Who should not use EnbrelDo not use Enbrel if you:have an infection that has spread through your body (sepsis).How should use EnbrelEnbrel is given as an injection under the skin (subcutaneous or SC).If your healthcare provider decides that you or caregiver can give the injections of Enbrel at home, you or your caregiver should receive training on the right way to prepare and inject Enbrel. Do not try to inject Enbrel until you have been shown the right way by your healthcare provider or nurse. Enbrel is available in the forms listed below. Your healthcare provider will prescribe the type that is best for you. Single-dose Prefilled SyringeSingle-dose Prefilled SureClick AutoinjectorSingle-dose VialMultiple-dose VialEnbrel Mini single-dose cartridge for use with the AutoTouch reusable autoinjector See the detailed Instructions for Use with this Medication Guide for instructions about the right way to store, prepare, and give your Enbrel injections at home.Your healthcare provider will tell you how often you should use Enbrel. Do not miss any doses of Enbrel. If you forget to use Enbrel, inject your dose as soon as you remember. Then, take your next dose at your regular(ly) scheduled time. In case you are not sure when to inject Enbrel, call your healthcare provider or pharmacist. Do not use Enbrel more often than as directed by your healthcare provider. Your childs dose of Enbrel depends on his or her weight. Your childs healthcare provider will tell you which form of Enbrel to use and how much to give your child.What are the possible side effects of Enbrel Enbrel can cause serious side effects, including:See What is the most important information should know about EnbrelInfections. Enbrel can make you more likely to get infections or make any infection that you have worse. Call your healthcare provider right away if you have any symptoms of an infection. See Before starting Enbrel, be sure to talk to your healthcare provider for list of symptoms of infection.Previous Hepatitis infection. If you have been previously infected with the hepatitis virus (a virus that affects the liver), the virus can become active while you use Enbrel. Your healthcare provider may do blood test before you start treatment with Enbrel and while you use Enbrel. Nervous system problems. Rarely, people who use TNF-blocker medicines have developed nervous system problems such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes. Tell your healthcare provider right away if you get any of these symptoms: numbness or tingling in any part of your body, vision changes, weakness in your arms and legs, and dizziness.Blood problems. Low blood counts have been seen with other TNF-blocker medicines. Your body may not make enough of the blood cells that help fight infections or help stop bleeding. Symptoms include fever, bruising or bleeding very easily, or looking pale. Heart failure including new heart failure or worsening of heart failure you already have. New or worse heart failure can happen in people who use TNF-blocker medicines like Enbrel. If you have heart failure your condition should be watched closely while you take Enbrel. Call your healthcare provider right away if you get new or worsening symptoms of heart failure while taking Enbrel, such as shortness of breath or swelling of your lower legs or feet. Psoriasis. Some people using Enbrel developed new psoriasis or worsening of psoriasis they already had. Tell your healthcare provider if you develop red scaly patches or raised bumps that may be filled with pus. Your healthcare provider may decide to stop your treatment with Enbrel. Allergic reactions. Allergic reactions can happen to people who use TNF-blocker medicines. Call your healthcare provider right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction include severe rash, swollen face, or trouble breathing. Autoimmune reactions, including:Lupus-like syndrome. Symptoms include rash on your face and arms that gets worse in the sun. Tell your healthcare provider if you have this symptom. Symptoms may go away when you stop using Enbrel.Autoimmune hepatitis. Liver problems can happen in people who use TNF-blocker medicines, including Enbrel. These problems can lead to liver failure and death. Call your healthcare provider right away if you have any of these symptoms: feel very tired, skin or eyes look yellow, poor appetite or vomiting, pain on the right side of your stomach (abdomen).Common side effects of Enbrel include:Injection site reactions such as redness, itching, pain, swelling, bleeding or bruising. These symptoms usually go away within to days. If you have pain, redness, or swelling around the injection site that does not go away or gets worse, call your healthcare provider. Upper respiratory infections (sinus infections). These are not all the side effects with Enbrel. Tell your healthcare provider about any side effect that bothers you or does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store EnbrelStore Enbrel in the refrigerator between 36F to 46F (2C to 8C).Store Enbrel in the original carton to protect from light or damage.If needed, you may store the Enbrel prefilled syringe, SureClick autoinjector, single-dose vial, Enbrel Mini cartridge, or the dose tray for the multiple-dose vial at room temperature between 68F to 77F (20C to 25C) for up to 14 days. When Enbrel has reached room temperature, do not put it back in the refrigerator. Throw away Enbrel that has been stored at room temperature after 14 days.Mixed Enbrel multiple-dose vials should be used right away or kept in the refrigerator between 36F to 46F (2C to 8C) for up to 14 days.Do not store Enbrel in extreme heat or cold such as in your vehicles glove box or trunk. Do not shake.Do not freeze.Keep Enbrel and all medicines out of the reach of children.General information about the safe and effective use of Enbrel.Medicines are sometimes prescribed for purposes not mentioned in Medication Guide. Do not use Enbrel for condition for which it was not prescribed. Do not give Enbrel to other people, even if they have the same condition. It may harm them.This Medication Guide summarizes the most important information about Enbrel. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Enbrel that was written for healthcare professionals.What are the ingredients in Enbrel Single-dose Prefilled Syringe, Single-dose Prefilled SureClick Autoinjector, Single-dose Vial and Enbrel Mini single-dose cartridge: Active Ingredient: etanercept Inactive Ingredients: L-arginine hydrochloride, sodium chloride, and sucrose Multiple-dose Vial: Active Ingredient: etanercept Inactive Ingredients: mannitol, sucrose, tromethamine AMGEN (R) Manufactured by: Immunex Corporation, Thousand Oaks, CA 91320-1799, U.S. License Number 1132Immunex Corporation. All rights reserved.1XXXXXX v19For more information, call 888 4ENBREL (1 888 436 2735) or www.enbrel.com. This printed material is recyclable. Your healthcare provider should test you for TB before starting Enbrel.. Your healthcare provider should monitor you closely for symptoms of TB during treatment with Enbrel even if you tested negative for TB. Your healthcare provider should check you for symptoms of any type of infection before, during, and after your treatment with Enbrel.. There have been cases of unusual cancers, some resulting in death, in children and teenage patients who started using TNF-blocking agents at less than 18 years of age.. For children, teenagers, and adults taking TNF-blocker medicines, including Enbrel, the chances of getting lymphoma or other cancers may increase.. People with rheumatoid arthritis, especially those with very active disease, may be more likely to get lymphoma.. have an infection. See What is the most important information should know about Enbrel are being treated for an infection.. think you have an infection.. have symptoms of an infection such as fever, sweats or chills, cough or flu-like symptoms, shortness of breath, blood in your phlegm, weight loss, muscle aches, warm, red or painful areas on your skin, sores on your body, diarrhea or stomach pain, burning when you urinate or urinating more often than normal, and feel very tired. have any open cuts on your body.. get lot of infections or have infections that keep coming back.. have diabetes, HIV, or weak immune system. People with these conditions have higher chance for infections. have TB, or have been in close contact with someone with TB.. were born in, lived in, or traveled to countries where there is risk for getting TB. Ask your healthcare provider if you are not sure. live, have lived in, or traveled to certain parts of the country (such as the Ohio and Mississippi River valleys, or the Southwest) where there is greater risk for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis). These infections may happen or become more severe if you use Enbrel. Ask your healthcare provider if you do not know if you live or have lived in an area where these infections are common.. have or have had hepatitis B.. About all the medicines you take including prescription and over-the-counter medicines, vitamins and herbal supplements including:Orencia (abatacept) or Kineret (anakinra). You have higher chance for serious infections when taking Enbrel with Orencia or Kineret.Cyclophosphamide (Cytoxan). You may have higher chance for getting certain cancers when taking Enbrel with cyclophosphamide.Anti-diabetic medicines. If you have diabetes and are taking medication to control your diabetes, your healthcare provider may decide you need less anti-diabetic medicine while taking Enbrel.. Orencia (abatacept) or Kineret (anakinra). You have higher chance for serious infections when taking Enbrel with Orencia or Kineret.. Cyclophosphamide (Cytoxan). You may have higher chance for getting certain cancers when taking Enbrel with cyclophosphamide.. Anti-diabetic medicines. If you have diabetes and are taking medication to control your diabetes, your healthcare provider may decide you need less anti-diabetic medicine while taking Enbrel.. have or had nervous system problem such as multiple sclerosis or Guillain-Barre syndrome. have or had heart failure.. are scheduled to have surgery.. have recently received or are scheduled to receive vaccine.All vaccines should be brought up-to-date before starting Enbrel.People taking Enbrel should not receive live vaccines.Ask your healthcare provider if you are not sure if you received live vaccine. All vaccines should be brought up-to-date before starting Enbrel.. People taking Enbrel should not receive live vaccines.. Ask your healthcare provider if you are not sure if you received live vaccine.. are allergic to rubber or latex. The needle covers on the single-dose prefilled syringes, the needle covers within the white caps on the single-dose prefilled SureClick autoinjectors, and within the purple caps of the Enbrel Mini cartridges contain dry natural rubber. The needle covers on the single-dose prefilled syringes, the needle covers within the white caps on the single-dose prefilled SureClick autoinjectors, and within the purple caps of the Enbrel Mini cartridges contain dry natural rubber.. have been around someone with varicella zoster (chicken pox).. are pregnant or plan to become pregnant. It is not known if Enbrel will harm your unborn baby. If you took Enbrel during pregnancy, talk to your healthcare provider prior to administration of live vaccines to your infant.. are breastfeeding or plan to breastfeed. Enbrel can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Enbrel.. moderately to severely active rheumatoid arthritis (RA). Enbrel can be used alone or with medicine called methotrexate.. moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in children ages years and older.. psoriatic arthritis (PsA). Enbrel can be used alone or with methotrexate. ankylosing spondylitis (AS).. chronic moderate to severe plaque psoriasis (PsO) in children years and older and adults who may benefit from taking injections or pills (systemic therapy) or phototherapy (ultraviolet light).. have an infection that has spread through your body (sepsis).. Enbrel is given as an injection under the skin (subcutaneous or SC).. If your healthcare provider decides that you or caregiver can give the injections of Enbrel at home, you or your caregiver should receive training on the right way to prepare and inject Enbrel. Do not try to inject Enbrel until you have been shown the right way by your healthcare provider or nurse. Enbrel is available in the forms listed below. Your healthcare provider will prescribe the type that is best for you. Single-dose Prefilled SyringeSingle-dose Prefilled SureClick AutoinjectorSingle-dose VialMultiple-dose VialEnbrel Mini single-dose cartridge for use with the AutoTouch reusable autoinjector Single-dose Prefilled Syringe. Single-dose Prefilled SureClick Autoinjector. Single-dose Vial. Multiple-dose Vial. Enbrel Mini single-dose cartridge for use with the AutoTouch reusable autoinjector See the detailed Instructions for Use with this Medication Guide for instructions about the right way to store, prepare, and give your Enbrel injections at home.. Your healthcare provider will tell you how often you should use Enbrel. Do not miss any doses of Enbrel. If you forget to use Enbrel, inject your dose as soon as you remember. Then, take your next dose at your regular(ly) scheduled time. In case you are not sure when to inject Enbrel, call your healthcare provider or pharmacist. Do not use Enbrel more often than as directed by your healthcare provider. Your childs dose of Enbrel depends on his or her weight. Your childs healthcare provider will tell you which form of Enbrel to use and how much to give your child.. See What is the most important information should know about Enbrel. Infections. Enbrel can make you more likely to get infections or make any infection that you have worse. Call your healthcare provider right away if you have any symptoms of an infection. See Before starting Enbrel, be sure to talk to your healthcare provider for list of symptoms of infection.. Previous Hepatitis infection. If you have been previously infected with the hepatitis virus (a virus that affects the liver), the virus can become active while you use Enbrel. Your healthcare provider may do blood test before you start treatment with Enbrel and while you use Enbrel. Nervous system problems. Rarely, people who use TNF-blocker medicines have developed nervous system problems such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes. Tell your healthcare provider right away if you get any of these symptoms: numbness or tingling in any part of your body, vision changes, weakness in your arms and legs, and dizziness.. Blood problems. Low blood counts have been seen with other TNF-blocker medicines. Your body may not make enough of the blood cells that help fight infections or help stop bleeding. Symptoms include fever, bruising or bleeding very easily, or looking pale. Heart failure including new heart failure or worsening of heart failure you already have. New or worse heart failure can happen in people who use TNF-blocker medicines like Enbrel. If you have heart failure your condition should be watched closely while you take Enbrel. Call your healthcare provider right away if you get new or worsening symptoms of heart failure while taking Enbrel, such as shortness of breath or swelling of your lower legs or feet. Psoriasis. Some people using Enbrel developed new psoriasis or worsening of psoriasis they already had. Tell your healthcare provider if you develop red scaly patches or raised bumps that may be filled with pus. Your healthcare provider may decide to stop your treatment with Enbrel. Allergic reactions. Allergic reactions can happen to people who use TNF-blocker medicines. Call your healthcare provider right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction include severe rash, swollen face, or trouble breathing. Autoimmune reactions, including:Lupus-like syndrome. Symptoms include rash on your face and arms that gets worse in the sun. Tell your healthcare provider if you have this symptom. Symptoms may go away when you stop using Enbrel.Autoimmune hepatitis. Liver problems can happen in people who use TNF-blocker medicines, including Enbrel. These problems can lead to liver failure and death. Call your healthcare provider right away if you have any of these symptoms: feel very tired, skin or eyes look yellow, poor appetite or vomiting, pain on the right side of your stomach (abdomen).. Lupus-like syndrome. Symptoms include rash on your face and arms that gets worse in the sun. Tell your healthcare provider if you have this symptom. Symptoms may go away when you stop using Enbrel.. Autoimmune hepatitis. Liver problems can happen in people who use TNF-blocker medicines, including Enbrel. These problems can lead to liver failure and death. Call your healthcare provider right away if you have any of these symptoms: feel very tired, skin or eyes look yellow, poor appetite or vomiting, pain on the right side of your stomach (abdomen).. Injection site reactions such as redness, itching, pain, swelling, bleeding or bruising. These symptoms usually go away within to days. If you have pain, redness, or swelling around the injection site that does not go away or gets worse, call your healthcare provider. Upper respiratory infections (sinus infections). Store Enbrel in the refrigerator between 36F to 46F (2C to 8C).. Store Enbrel in the original carton to protect from light or damage.. If needed, you may store the Enbrel prefilled syringe, SureClick autoinjector, single-dose vial, Enbrel Mini cartridge, or the dose tray for the multiple-dose vial at room temperature between 68F to 77F (20C to 25C) for up to 14 days. When Enbrel has reached room temperature, do not put it back in the refrigerator. When Enbrel has reached room temperature, do not put it back in the refrigerator.. Throw away Enbrel that has been stored at room temperature after 14 days.. Mixed Enbrel multiple-dose vials should be used right away or kept in the refrigerator between 36F to 46F (2C to 8C) for up to 14 days.. Do not store Enbrel in extreme heat or cold such as in your vehicles glove box or trunk. Do not shake.. Do not freeze.. Keep Enbrel and all medicines out of the reach of children.. Image.

SPL UNCLASSIFIED SECTION.

SERIOUS INFECTIONSPatients 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 patient develops 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.. 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable 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 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). 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 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 major birth defect and about 15-20% of pregnancies end in miscarriage, regardless of drug exposure.. Clinical Considerations Fetal/Neonatal adverse reactionsThe 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 Use in Specific Populations (8.4)].. Data. Human DataA 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 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.Three case reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, were between 3% and 32% of the maternal serum level.. Animal DataIn embryofetal development studies with etanercept administered during the period of organogenesis to pregnant rats from gestation day (GD) through 20 or pregnant rabbits from GD 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 peri-and post-natal development study with pregnant rats that received etanercept during organogenesis and the later gestational period from GD through 21, development of pups through post-natal day 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 SummaryLimited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by breastfed infant. No data are available on the effects of etanercept on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Enbrel and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.. 8.4 Pediatric Use. Enbrel has been studied in 69 children with moderately to severely active polyarticular JIA aged to 17 years.Enbrel has been studied in 211 pediatric patients with moderate to severe PsO aged to 17 years.Enbrel has not been studied in children 2 years of age with JIA and 4 years of age with PsO. For pediatric specific safety information concerning malignancies and inflammatory bowel disease [see Warnings and Precautions (5.3) and Adverse Reactions (6.2)].The clinical significance of infant exposure to Enbrel in utero is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to exposed infants. For pediatric specific safety information concerning vaccinations [see Warnings and Precautions (5.8) and Drug Interactions (7.1)].. 8.5 Geriatric Use. total of 480 RA patients ages 65 years or older have been studied in clinical trials. In PsO randomized clinical trials, 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 higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.. 8.6 Use in Diabetics. There have been reports of hypoglycemia following initiation of Enbrel therapy in patients receiving medication for diabetes, necessitating reduction in anti-diabetic medication in some of these patients.

WARNINGS AND PRECAUTIONS SECTION.

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 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 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). 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 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 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). 5.1Serious 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 history of an opportunistic infection;Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; orWith 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 patient develops serious infection or sepsis. patient who develops new infection during treatment with Enbrel should be closely monitored, undergo prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.. With chronic or recurrent infection;. Who have been exposed to tuberculosis;. With 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)].. TuberculosisCases 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 mm or greater with tuberculin skin testing should be considered 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 past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with 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 new infection during Enbrel treatment, especially in patients who have previously or recently traveled to countries with high prevalence of tuberculosis, or who have had close contact with person with active tuberculosis.. Invasive Fungal InfectionsCases 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 serious systemic illness. Appropriate empiric anti-fungal therapy should be considered while 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 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 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.. 5.2Neurologic 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)].. 5.3Malignancies. LymphomasIn the controlled portions of clinical trials of TNF-blocking agents, more cases of lymphoma have been observed among patients receiving TNF-blocker compared to control patients. During the controlled portions of Enbrel trials in adult patients with RA, AS, and PsA, lymphomas were observed among 3306 Enbrel-treated patients versus among 1521 control patients (duration of controlled treatment ranged from 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.. LeukemiaCases 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, cases of leukemia were observed among 5445 (0.06 cases per 100 patient-years) Enbrel-treated patients versus among 2890 (0%) control patients (duration of controlled treatment ranged from 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 MalignanciesInformation 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 PatientsMalignancies, 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 Hodgkins and non-Hodgkins lymphoma. The other cases represented 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 median of 30 months of therapy (range to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from 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 UseIn global postmarketing adult and pediatric use, lymphoma and other malignancies have been reported.. 5.4Patients with Heart Failure. Two clinical trials evaluating the use of Enbrel in the treatment of heart failure were terminated early due to lack of efficacy. One of these studies suggested higher mortality in Enbrel-treated patients compared to placebo [see Adverse Reactions (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.. 5.5Hematologic Reactions. Rare (< 0.1%) reports of pancytopenia, including very rare (< 0.01%) reports of aplastic anemia, some with 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 previous history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g. persistent fever, bruising, bleeding, pallor) while on Enbrel. Discontinuation of Enbrel therapy should be considered in patients with confirmed significant hematologic abnormalities.Two percent of patients treated concurrently with Enbrel and anakinra developed neutropenia (ANC 1 109/L). While neutropenic, one patient developed cellulitis that resolved with antibiotic therapy.. 5.6Hepatitis Reactivation. Reactivation of hepatitis in patients who were previously infected with the hepatitis virus (HBV) and had received concomitant TNF-blocking agents, including very rare cases (< 0.01%) with Enbrel, has been reported. In some instances, hepatitis 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 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.. 5.7Allergic 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.. 5.8Immunizations. 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)].. 5.9Autoimmunity. Treatment with Enbrel may result in the formation of autoantibodies [see Adverse Reactions (6.1)] and, rarely (< 0.1%), in the development of lupus-like syndrome or autoimmune hepatitis [see Adverse Reactions (6.2)], which may resolve following withdrawal of Enbrel. If patient develops symptoms and findings suggestive of lupus-like syndrome or autoimmune hepatitis following treatment with Enbrel, treatment should be discontinued and the patient should be carefully evaluated.. 5.10Immunosuppression. 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 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)].. 5.11Use in Granulomatosis with Polyangiitis Patients. The use of Enbrel in patients with granulomatosis with polyangiitis receiving immunosuppressive agents is not recommended. In study of patients with granulomatosis with polyangiitis, the addition of Enbrel to standard therapy (including cyclophosphamide) was associated with 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)].. 5.12Use with Anakinra or Abatacept Use of Enbrel with anakinra or abatacept is not recommended [see Drug Interactions (7.2)].. 5.13Use in Patients with Moderate to Severe Alcoholic Hepatitis. In 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 month but significantly higher after months. Physicians should use caution when using Enbrel in patients with moderate to severe alcoholic hepatitis.