Enbrel

Etanercept.

Each ENBREL pre-filled syringe contains 25 mg or 50 mg of etanercept (active ingredient). Each pre-filled pen contains 50 mg of etanercept.
ENBREL (etanercept) is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons.
MYCLIC is the tradename for the pre-filled pen.
Solution for injection in pre-filled syringe and pre-filled pen: The solution for injection in the pre-filled syringe and the pre-filled pen is clear to opalescent, colorless to yellow or pale brown, and liquid may contain trace levels of translucent to white amorphous particles, with a pH of 6.3 ± 0.2.
Excipients/Inactive Ingredients: sucrose, sodium chloride, L-arginine hydrochloride, sodium phosphate monobasic dihydrate, sodium phosphate dibasic dihydrate, and water.

Pharmacotherapeutic group: TNF-alpha Inhibitor. ATC code: L04AB01.
Pharmacology: Pharmacodynamics: Geriatric use: No specific dosage adjustments of etanercept are recommended based on patient age.
Mechanism of action: Etanercept binds specifically to tumor necrosis factor (TNF) and blocks its interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of rheumatoid arthritis (RA), polyarticular-course juvenile idiopathic arthritis (JIA), psoriatic arthritis and ankylosing spondylitis and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of plaque psoriasis. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, JIA, psoriatic arthritis, ankylosing spondylitis (AS) and plaque psoriasis.
Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 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 a dimeric soluble form of the p75 TNF receptor that can bind TNF molecules. Etanercept inhibits binding of both TNF-α and TNF-β (lymphotoxin alpha [LT-α]) to cell surface TNFRs, rendering TNF biologically inactive. In in-vitro studies, large complexes of etanercept with TNF-α were not detected and cells expressing transmembrane TNF (that binds ENBREL) are not lysed in the presence or absence of complement.
Etanercept can also modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (i.e., E-selectin and to a 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.
Clinical efficacy: This section presents data from four trials in adults with rheumatoid arthritis, 3 studies in juvenile idiopathic arthritis, 1 study in adults with psoriatic arthritis, 4 studies in adults with ankylosing spondylitis, 1 study in adults with non-radiographic axial spondyloarthritis, 3 studies in adults with plaque psoriasis and 2 studies in pediatric subjects with plaque psoriasis.
Adult patients with rheumatoid arthritis: The efficacy of ENBREL was assessed in a randomized, double-blind, placebo-controlled study. The study evaluated 234 adult patients with active rheumatoid arthritis who had failed therapy with at least one, but no more than four, disease-modifying anti-rheumatic drugs (DMARDs). Doses of 10 mg or 25 mg ENBREL or placebo were administered subcutaneously (SC) twice a week for 6 consecutive months. The results of this controlled trial were expressed in percentage improvement in rheumatoid arthritis using American College of Rheumatology (ACR) response criteria.
ACR 20 and 50 responses were higher in patients treated with ENBREL at 3 and 6 months than in patients treated with placebo (ACR 20: ENBREL 62% and 59%, placebo 23% and 11% at 3 and 6 months, respectively; ACR 50: ENBREL 41% and 40%, placebo 8% and 5% at months 3 and 6, respectively; p<0.01 ENBREL vs. placebo at all timepoints for both ACR 20 and ACR 50 responses).
Approximately 15% of subjects who received ENBREL achieved an ACR 70 response at month 3 and month 6 compared to fewer than 5% of subjects in the placebo arm. Among patients receiving ENBREL, the clinical responses generally appeared within 1 to 2 weeks after initiation of therapy and nearly always occurred by 3 months. A dose response was seen; results with 10 mg were intermediate between placebo and 25 mg. ENBREL was significantly better than placebo in all components of the ACR criteria, as well as other measures of rheumatoid arthritis disease activity not included in the ACR response criteria, such as morning stiffness. A Health Assessment Questionnaire (HAQ), which included disability, vitality, mental health, general health status, and arthritis-associated health status subdomains, was administered every 3 months during the trial. All subdomains of the HAQ were improved in patients treated with ENBREL compared to controls at 3 and 6 months.
After discontinuation of ENBREL, symptoms of arthritis generally returned within a month. Re-introduction of treatment with ENBREL after discontinuations of up to 24 months resulted in the same magnitudes of responses as patients who received ENBREL without interruption of therapy based on results of open-label studies. Continued durable responses have been seen for up to 10 years in open-label extension treatment trials when patients received ENBREL without interruption.
The efficacy of ENBREL was compared to methotrexate in a second randomized, active-controlled study with blinded radiographic evaluations as a primary endpoint in 632 adult patients with active rheumatoid arthritis (<3 years duration) who had never received treatment with methotrexate. Doses of 10 mg or 25 mg ENBREL were administered SC twice a week for up to 24 months. Methotrexate doses were escalated from 7.5 mg/week to a maximum of 20 mg/week over the first 8 weeks of the trial and continued for up to 24 months. Clinical improvement including onset of action within 2 weeks with ENBREL 25 mg was similar to that seen in the previous trials, and was maintained for up to 24 months. At baseline, patients had a moderate degree of disability, with mean HAQ scores of 1.4 to 1.5. Treatment with ENBREL 25 mg resulted in substantial improvement at 12 months, with about 44% of patients achieving a normal HAQ score (less than 0.5). This benefit was maintained in Year 2 of this study.
In this study, 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 score (JSN). Radiographs of hands/wrists and feet were read at baseline and 6, 12, and 24 months. The 10 mg ENBREL dose had consistently less effect on structural damage than the 25 mg dose. ENBREL 25 mg was significantly superior to methotrexate for erosion scores at both 12 and 24 months. The differences in TSS and JSN were not statistically significant between methotrexate and ENBREL 25 mg. The results are shown in the figure as follows. (See Figure 1.)

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In another active-controlled, double-blind, randomized study, clinical efficacy, safety, and radiographic progression in RA patients treated with ENBREL alone (25 mg twice weekly), methotrexate alone (7.5 to 20 mg weekly, median dose 20 mg), and of the combination of ENBREL and methotrexate initiated concurrently were compared in 682 adult patients with active rheumatoid arthritis of 6 months to 20 years duration (median 5 years) who had a less than satisfactory response to at least 1 DMARD other than methotrexate.
Patients in the ENBREL in combination with methotrexate therapy group had significantly higher ACR 20, ACR 50, ACR 70 responses and improvement for DAS and HAQ scores at both 24 and 52 weeks than patients in either of the single therapy groups (results shown in table as follows). Significant advantages for ENBREL in combination with methotrexate compared with ENBREL monotherapy and methotrexate monotherapy were also observed after 24 months. (See Table 1.)

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Radiographic progression at 12 months was significantly less in the ENBREL group than in the methotrexate group, while the combination was significantly better than either monotherapy at slowing radiographic progression (see figure as follows). (Figure 2.)

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Significant advantages for ENBREL in combination with methotrexate compared with ENBREL monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for ENBREL monotherapy compared with methotrexate monotherapy were also observed after 24 months.
In an analysis in which all patients who dropped out of the study for any reason were considered to have progressed, the percentage of patients without progression (TSS change ≤0.5) at 24 months was higher in the ENBREL in combination with methotrexate group compared with the ENBREL alone and methotrexate alone groups (62%, 50%, and 36%, respectively; p<0.05). The difference between ENBREL alone and methotrexate alone was also significant (p<0.05). Among patients who completed a full 24 months of therapy in the study, the non-progression rates were 78%, 70%, and 61%, respectively.
The safety and efficacy of 50 mg ENBREL (two 25 mg SC injections) administered once weekly were evaluated in a double-blind, placebo-controlled study of 420 patients with active RA. In this study, 53 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 regimens were comparable at week 8 in their effect on signs and symptoms of RA; data at week 16 did not show comparability (non-inferiority) between the two regimens.
Pediatric population with juvenile idiopathic arthritis: The safety and efficacy of etanercept were assessed in a two-part study in 69 children with polyarticular-course juvenile idiopathic arthritis who had a variety of juvenile idiopathic arthritis onset types (polyarthritis, pauciarthritis, systemic-onset). Patients ages 4 to 17 years with moderately to severely active polyarticular course juvenile idiopathic arthritis refractory to or intolerant of methotrexate were enrolled; patients remained on a stable dose of a single non-steroidal 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) etanercept subcutaneously twice weekly. In part 2, patients with a clinical response at day 90 were randomized to remain on etanercept or receive placebo for four months and assessed for disease flair. Responses were measured using the ACR Pedi 30, defined as ≥30% improvement in at least three of six and ≥30% worsening in no more than one of six JRA 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 a ≥30% worsening in three of six JRA core set criteria and ≥30% improvement in not more than one of the six JRA core set criteria and a minimum of two active joints.
In part 1 of the study, 51 of 69 (74%) patients demonstrated a clinical response and entered part 2. In part 2, 6 of 25 (24%) patients remaining on etanercept experienced a 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 etanercept and 28 days for patients who received placebo. Each component of the JRA core set criteria worsened in the arm that received placebo and remained stable or improved in the arm that continued on etanercept. The data suggested the possibility of a higher flare rate among those patients with a higher baseline ESR. Of patients who demonstrated a clinical response at 90 days and entered part 2 of the study, some of the patients remaining on etanercept continued to improve from month 3 through month 7, while those who received placebo did not improve.
In an open-label, safety extension study, 58 pediatric patients from the previously mentioned study (from the age of 4 years at time of enrolment) continued to receive etanercept for up to 10 years. Rates of serious adverse events and serious infections did not increase with long-term exposure.
In another open-label single-arm study, 60 patients with extended oligoarthritis (15 patients aged 2 to 4, 23 patients aged 5 to 11 and 22 patients aged 12 to 17 years old), 38 patients with enthesitis-related arthritis (12 to 17 years old), and 29 patients with psoriatic arthritis (12 to 17 years old) were treated with etanercept at a dose of 0.8 mg/kg (up to a maximum of 50 mg per dose) administered weekly for 12 weeks. In each of the JIA subtypes, the majority of patients met ACR Pedi 30 criteria and demonstrated clinical improvement in secondary endpoints such as number of tender joints and physician global assessment. The safety profile was consistent with that observed in other JIA studies.
Studies have not been done in patients with juvenile idiopathic arthritis to assess the effects of continued etanercept therapy in patients who do not respond within 3 months of initiating etanercept therapy. Additionally, studies have not been conducted to assess the effects of discontinuing or reducing the recommended dose of etanercept following its long-term use in patients with JIA.
Long-term safety of etanercept monotherapy (n=103), etanercept plus methotrexate (n=294), or methotrexate monotherapy (n=197) were assessed for up to 3 years in a registry of 594 children aged 2 to 18 years with juvenile idiopathic arthritis, 39 of whom were 2 to 3 years of age. Overall, infections were more commonly reported in patients treated with etanercept compared to methotrexate alone (3.8% versus 2%), and the infections associated with etanercept use were of amore severe nature.
Adult patients with psoriatic arthritis: The efficacy of ENBREL was assessed in a randomized, double-blind, placebo-controlled study in 205 patients with psoriatic arthritis. Patients were between 18 and 70 years of age and had active psoriatic arthritis (≥3 swollen joints and ≥3 tender joints) in at least one of the following forms: distal interphalangeal (DIP) involvement; polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); arthritis mutilans; asymmetric psoriatic arthritis; or spondylitis-like ankylosis. Patients also had plaque psoriasis with a qualifying target lesion ≥2 cm in diameter. Patients had previously been treated with NSAIDs (86%), DMARDs (80%), and corticosteroids (24%). Patients currently on methotrexate therapy (stable for ≥2 months) could continue at a stable dose of ≤25 mg/week methotrexate. Doses of 25 mg ENBREL (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered SC twice a week for 6 months. At the end of the double-blind study, patients could enter a long-term open-label extension study for a total duration of up to 2 years.
Clinical responses were expressed as percentages of patients achieving the ACR 20, 50, and 70 response and percentages with improvement in Psoriatic Arthritis Response Criteria (PsARC). Results are summarized in the table as follows. (See Table 2.)

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Among patients with psoriatic arthritis who received ENBREL, the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. ENBREL was significantly better than placebo in all measures of disease activity (p<0.001), and responses were similar with and without concomitant methotrexate therapy. Quality of life in psoriatic arthritis patients was assessed at every timepoint using the disability index of the HAQ. The disability index score was significantly improved at all timepoints in psoriatic arthritis patients treated with ENBREL, relative to placebo (p<0.001).
Radiographic changes were assessed in the psoriatic arthritis study. Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24. The modified TSS at 12 months is presented in the table as follows. In an analysis in which all patients who dropped out of the study for any reason were considered to have progressed, the percentage of patients without progression (TSS change ≤0.5) at 12 months was higher in the ENBREL group compared with the placebo group (73% vs. 47%, respectively, p≤0.001). The effect of ENBREL on radiographic progression was maintained in patients who continued on treatment during the second year. The slowing of peripheral joint damage was observed in patients with polyarticular symmetrical joint involvement. (See Table 3.)

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ENBREL treatment resulted in improvement in physical function during the double-blind period, and this benefit was maintained during the longer-term exposure of up to 2 years.
There is insufficient evidence of the efficacy of ENBREL in patients with ankylosing spondylitis-like and arthritis mutilans psoriatic arthropathies due to the small number of patients studied.
No study has been performed in patients with psoriatic arthritis using the 50 mg, once-weekly dosing regimen. Evidence of efficacy for the once-weekly dosing regimen in this patient population has been based on data from the study in patients with ankylosing spondylitis.
Adult patients with ankylosing spondylitis: The efficacy of ENBREL in ankylosing spondylitis was assessed in 3 randomized, double-blind studies comparing twice-weekly administration of 25 mg ENBREL with placebo. A total of 401 patients were enrolled, from which 203 were treated with ENBREL. The largest of these trials (n=277) enrolled patients who were between 18 and 70 years of age and had active ankylosing spondylitis defined as visual analog scale (VAS) scores of ≥30 for average of duration and intensity of morning stiffness plus VAS scores of ≥30 for at least 2 of the following 3 parameters: patient global assessment; average of VAS values for nocturnal back pain and total back pain; average of 10 questions on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients receiving DMARDs, NSAIDs, or corticosteroids could continue them on stable doses. Patients with complete ankylosis of the spine were not included in the study. Doses of 25 mg of ENBREL (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered subcutaneously twice a week for 6 months in 138 patients.
The primary measure of efficacy (ASAS 20) was a ≥20% improvement in at least 3 of the 4 Assessment in Ankylosing Spondylitis (ASAS) domains (patient global assessments, back pain, BASFI, and inflammation) and absence of deterioration in the remaining domain. ASAS 50 and 70 responses used the same criteria with a 50% improvement or a 70% improvement, respectively.
Compared to placebo, treatment with ENBREL resulted in significant improvements in the ASAS 20, ASAS 50 and ASAS 70 as early as 2 weeks after the initiation of therapy. (See Table 4.)

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Among patients with ankylosing spondylitis who received ENBREL, the clinical responses were apparent at the time of the first visit (2 weeks) and were maintained through 6 months of therapy. Responses were similar in patients who were or were not receiving concomitant therapies at baseline.
Similar results were obtained in the 2 smaller ankylosing spondylitis trials.
In a fourth study, the safety and efficacy of 50 mg ENBREL (two 25 mg SC injections) administered once weekly vs. 25 mg ENBREL administered twice weekly were evaluated in a double-blind, placebo-controlled study of 356 patients with active ankylosing spondylitis. The safety and efficacy profiles of the 50 mg once-weekly and 25 mg twice-weekly regimens were similar.
Adult patients with non-radiographic axial spondyloarthritis: The efficacy of ENBREL in patients with non-radiographic axial spondyloarthritis (nr-AxSpa) was assessed in a randomized, 12-week double-blind, placebo-controlled study. The study evaluated 215 adult patients (modified intent-to-treat population) with active nr-AxSpa (18 to 49 years of age), defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but did not meet the modified New York criteria for AS. Patients were also required to have an inadequate response to two or more NSAIDs. In the double-blind period, patients received ENBREL 50 mg weekly or placebo for 12 weeks. The primary measure of efficacy (ASAS 40) was a 40% improvement in at least three of the four ASAS domains and absence of deterioration in the remaining domain. MRIs of the sacroiliac joint and spine were obtained to assess inflammation at baseline and at week 12. The double-blind period was followed by an open-label period during which all patients receive ENBREL 50 mg weekly for up to an additional 92 weeks.
Compared to placebo, treatment with ENBREL resulted in statistically significant improvement in the ASAS 40, ASAS 20 and ASAS 5/6. Significant improvement was also observed for the ASAS partial remission and BASDAI 50. Week 12 results are shown in the table as follows. (See Table 5.)

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At week 12, there was a statistically significant improvement in the SPARCC (Spondyloarthritis Research Consortium of Canada) score for the sacroiliac joint as measured by MRI for patients receiving ENBREL. Adjusted mean change from baseline was 3.8 for ENBREL treated (n=95) versus 0.8 for placebo treated (n=105) patients (p<0.001).
Health-related quality of life and physical function were assessed using the BASFI (Bath Ankylosing Spondylitis Functional Index), EuroQol 5D and the SF-36 questionnaires. ENBREL showed statistically significantly greater improvement in the BASFI, EQ5D Overall Health State Score and the SF-36 Physical Component Score (PCS) from baseline to week 12 compared to placebo.
Clinical responses among nr-AxSpa patients who received ENBREL were apparent at the time of the first visit (2 weeks) and were maintained through 2 years of therapy. Improvements in health-related quality of life and physical function were also maintained through 2 years of therapy. The 2 year data did not reveal any new safety findings.
Adult patients with plaque psoriasis: The safety and efficacy of ENBREL in patients with plaque psoriasis were assessed in three randomized, double-blind, placebo-controlled studies. The primary efficacy endpoint in all three studies was the proportion of patients in each treatment group who achieved the PASI 75 (i.e., at least a 75% improvement in the Psoriasis Area and Severity Index score from baseline) at 12 weeks.
Study 1 was a Phase 2 study in patients with active, but clinically stable plaque psoriasis involving ≥10% of the body surface area who were ≥18 years old. One hundred and twelve (112) patients were randomized to receive a dose of 25 mg of ENBREL (n=57) or placebo (n=55) twice a week for 24 weeks.
Study 2 evaluated 652 patients with chronic plaque psoriasis, using the same inclusion criteria as study 1, with the addition of a minimum psoriasis area and severity index (PASI) of 10 at screening. ENBREL was administered at doses of 25 mg once a week, 25 mg twice a week or 50 mg twice a week for 6 consecutive months. During the first 12 weeks of the double-blind treatment period, patients received placebo or one of the previously mentioned three ENBREL doses. After 12 weeks of treatment, patients in the placebo group began treatment with blinded ENBREL (25 mg twice a week); patients in the active treatment groups continued to week 24 on the dose to which they were originally randomized.
Study 3 evaluated 583 patients and had the same inclusion criteria as study 2. Patients in this study received a dose of 25 mg or 50 mg ENBREL, or placebo twice a week for 12 weeks, and then all patients received open-label 25 mg ENBREL twice weekly for an additional 24 weeks.
In study 1, the ENBREL-treated group had a significantly higher proportion of patients with a PASI 75 response at week 12 (30%) compared to the placebo-treated group (2%) [p<0.0001]. At 24 weeks, 56% of patients in the ENBREL-treated group had achieved the PASI 75 compared to 5% of placebo-treated patients. Key results of studies 2 and 3 are shown as follows. (See Table 6.)

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Among patients with plaque psoriasis who received ENBREL, significant responses relative to placebo were apparent at the time of the first visit (2 weeks) and were maintained through 24 weeks of therapy.
Study 2 also had a drug withdrawal period, during which patients who achieved a PASI improvement of at least 50% at week 24 had treatment stopped. Patients were observed off treatment for the occurrence of rebound (PASI ≥150% of baseline) and for the time to relapse (defined as a loss of at least half of the improvement achieved between baseline and week 24). During the withdrawal period, symptoms of psoriasis gradually returned with a median time to disease relapse of 3 months. No rebound flare of disease and no psoriasis-related serious adverse events were observed. There was some evidence to support a benefit of re-treatment with ENBREL in patients initially responding to treatment.
In study 3, the majority of patients (77%) who were initially randomized to 50 mg twice weekly and had their ENBREL dose decreased at week 12 to 25 mg twice weekly maintained their PASI 75 response through week 36. For patients who received 25 mg twice weekly throughout the study, the PASI 75 response continued to improve between weeks 12 and 36.
In long-term (up to 34 months), open-label studies where ENBREL was given without interruption, clinical responses were sustained and safety was comparable to shorter-term studies.
Pediatric patients with plaque psoriasis: The efficacy of ENBREL was assessed in a randomized, double-blind, placebo-controlled study in 211 pediatric patients aged 4 to 17 years with moderate to severe plaque psoriasis (as defined by a sPGA score ≥3, involving ≥10% of the BSA, and PASI ≥12). Eligible patients had a history of receiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy.
Patients received ENBREL 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients randomized to ENBREL had positive efficacy responses (e.g., PASI 75) than those randomized to placebo. (See Table 7.)

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After the 12-week double-blind treatment period, all patients who entered the open-label period received ENBREL 0.8 mg/kg (up to 50 mg) once weekly for additional 24 weeks. Responses observed during the open-label period were similar to those observed in the double-blind period.
During a randomized withdrawal period, significantly more patients re-randomized to placebo experienced disease relapse (loss of PASI 75 response) compared with patients re-randomized to ENBREL. With continued therapy, responses were maintained up to 48 weeks.
The long-term safety and effectiveness of ENBREL 0.8 mg/kg (up to 50 mg) once weekly was assessed in an open-label extension study of 181 pediatric subjects with plaque psoriasis for up to 2 years beyond the 48 week study discussed previously. Long-term experience with ENBREL was generally comparable to the original 48-week study and did not reveal any new safety findings.
Pharmacokinetics: Absorption: Etanercept is slowly absorbed from the site of SC injection, reaching maximum concentration approximately 48 hours after a single dose. The absolute bioavailability is 76%.
Distribution: After a single SC dose of 25 mg etanercept, the average maximum serum concentration observed in healthy volunteers was 1.65 ± 0.66 μg/mL, and the area under the curve was 235 ± 96.6 μg·hr/mL. Dose proportionality has not been formally evaluated, but there is no apparent saturation of clearance across the dosing range.
The volume of distribution at steady-state after subcutaneous administration is 13.9 ± 9.4 L.
After continued dosing of RA patients (n=25) with etanercept for 6 months with 25 mg twice weekly, the median observed level was 3.0 μg/mL (range 1.7 to 5.6 μg/mL). Based on the available data, individual patients may undergo a two- to five-fold increase in serum levels with repeated dosing.
Elimination: Etanercept is cleared slowly from the body. The half-life is approximately 80 hours.
The clearance is approximately 175 ± 116 mL/hr in patients with rheumatoid arthritis and 131 ± 81 mL/hr in healthy volunteers.
Radioactivity is eliminated in urine after administration of radiolabeled etanercept to patients and volunteers.
Renal impairment or hepatic impairment: Although there is elimination of radioactivity in urine after administration of radiolabeled etanercept to patients and volunteers, increased etanercept concentrations were not observed in patients with acute renal or hepatic failure. The presence of renal or hepatic impairment should not require a change in dosage.
Gender: There is no apparent pharmacokinetic difference between men and women.
Concentration-effect relationship: Steady-state serum concentrations of 1 to 2 mg/L of etanercept are associated with optimal effect and are obtained with doses of 25 mg twice weekly. In an open-label, single-dose, two-treatment, crossover study in 28 healthy volunteers, etanercept, administered as a single 50 mg/mL injection, was found to be bioequivalent to two simultaneous injections of 25 mg/mL.
Toxicology: PRECLINICAL SAFETY DATA: Carcinogenicity, Mutagenicity, and Impairment of Fertility: Long-term animal studies have not been conducted to evaluate the carcinogenic potential of etanercept or its effect on fertility. Long-term animal studies are not feasible because animals can develop antibodies to etanercept, which is a human protein. Mutagenesis studies were conducted in vitro and in vivo, and no evidence of mutagenic activity was observed.

Rheumatoid Arthritis: Etanercept is indicated for reducing signs and symptoms and inhibiting the progression of structural damage in patients with moderately to severely active rheumatoid arthritis. Etanercept can be initiated in combination with methotrexate (MTX) or used alone.
Psoriatic Arthritis: Etanercept is indicated for reducing signs and symptoms of active psoriatic arthritis in patients with psoriatic arthritis. Etanercept can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.
Axial Spondyloarthritis: Ankylosing spondylitis (AS): Etanercept is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
Non-radiographic axial spondyloarthritis: Etanercept is indicated for the treatment of adults with severe non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated CRP and/or MRI evidence, who have had an inadequate response to, or are intolerant to, conventional therapy.
Plaque Psoriasis: Etanercept is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
Juvenile Idiopathic Arthritis: Treatment of polyarticular-course juvenile idiopathic arthritis (JIA) in children and adolescents from the age of 2 years when the response to one or more DMARDs has proved inadequate.
Treatment of polyarthritis (rheumatoid factor positive or negative) and extended oligoarthritis in children and adolescents from the age of 2 years who have had an inadequate response to, or who have proved intolerant of, methotrexate.
Treatment of psoriatic arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, methotrexate.
Treatment of enthesitis-related arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, conventional therapy.
Pediatric Plaque Psoriasis: Etanercept is indicated for the treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.

Use in Adults: Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis: Patients aged 18 years or older: 50 mg etanercept per week administered once weekly as one subcutaneous injection.
Methotrexate, glucocorticoids, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), or analgesics may be continued during treatment with etanercept in adults.
Plaque psoriasis: The dose of etanercept is 50 mg once weekly (as one subcutaneous injection using a 50 mg syringe or as two 25 mg injections given at approximately the same time) or 25 mg twice weekly (72 to 96 hours apart) as a subcutaneous injection. Higher responses may be achieved from initial treatment with a dose of 50 mg twice weekly for up to 12 weeks, followed, by a dose of 50 mg once weekly or 25 mg twice weekly.
Adult patients may be treated intermittently or continuously, based on physician judgment and individual patient needs. Treatment should be discontinued in patients who show no response after 12 weeks. With intermittent use, treatment cycles subsequent to the initial cycle should use a dose of 50 mg once weekly or 25 mg twice weekly.
Pediatric Population: The dosage of etanercept is based on body weight for pediatric patients. Patients weighing less than 62.5 kg should be accurately dosed on a mg/kg basis using ENBREL 25 mg/mL powder and solvent for solution for injection (see following text for dosing for specific indications). Patients weighing 62.5 kg or more may be dosed using a fixed-dose pre-filled syringe or pre-filled pen.
Juvenile idiopathic arthritis (age 2 years and above): Children (≥2 to <18 years): 0.4 mg/kg (up to a maximum of 25 mg per dose) twice weekly (72 to 96 hours apart), or 0.8 mg/kg (up to a maximum of 50 mg per dose) given once weekly.
Glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), or analgesics may be continued during treatment with etanercept in children.
Etanercept has not been studied in children <2 years of age.
Pediatric plaque psoriasis (age 6 years and above): Children (≥6 to <18 years): 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly for up to 24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks.
If re-treatment with etanercept is indicated, the previously mentioned guidance on treatment duration should be followed. The dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.
Elderly (≥65 years): No dosage adjustment is required.
Renal Impairment: No dosage adjustment is required.
Hepatic Impairment: No dosage adjustment is required.
Preparation of ENBREL: ENBREL is intended for use under the guidance and supervision of a 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.
Solution for injection in pre-filled syringe: Before injection, etanercept single-use pre-filled syringe should be allowed to reach room temperature (approximately 15 to 30 minutes). The needle cover should not be removed while allowing the pre-filled syringe to reach room temperature. The solution should be clear to opalescent, colorless to yellow or pale brown and liquid may contain trace levels of translucent to white amorphous particles.
Solution for injection in pre-filled pen: Before injection, Enbrel single-use pre-filled pens should be allowed to reach room temperature (approximately 15 to 30 minutes). The needle cover should not be removed while allowing the pre-filled pen to reach room temperature. By looking through the inspection window, the solution should be clear to opalescent, colorless to yellow or pale brown, and liquid may contain trace levels of translucent to white amorphous particles.
Prior to administration, visually inspect the solution for particulate matter and discoloration. The solution should not be used if discolored or cloudy, or if particulate matter is present. Check to see if the amount of liquid in the pre-filled 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.
If a patient or caregiver is to self-administer ENBREL, he/she should be instructed in injection techniques and how to measure the correct dose to help ensure the proper administration of ENBREL. The first injection should be performed under the supervision of a qualified health care professional. The patient's or caregiver's ability to self-inject subcutaneously should be assessed.
A puncture-resistant container for disposal of needles and syringes should be used. Patients and caregivers should be instructed in the technique as well as proper syringe and needle disposal, and be cautioned against reuse of these items.
Method of Administration: Administer etanercept as subcutaneous injections in the thigh, abdomen, or upper arm. Give each new injection at least 3 cm from a previous site. Do NOT inject into areas where the skin is tender, bruised, red, or hard.
Pediatric Use: Etanercept has not been studied in children <2 years of age (see INDICATIONS/USES). For pediatric specific safety information concerning malignancies, vaccinations and inflammatory bowel disease, see PRECAUTIONS and ADVERSE REACTIONS.

The maximum tolerated dose of etanercept has not been established in humans. Single intravenous doses up to 60 mg/m² have been administered to healthy volunteers in an endotoxemia study without evidence of dose-limiting toxicities. The highest dose level evaluated in rheumatoid arthritis patients has been an intravenous loading dose of 32 mg/m² followed by subcutaneous doses of 16 mg/m² (~25 mg) administered twice weekly.
Etanercept did not induce lethality or notable signs of toxicity in mice or rats following a single subcutaneous dose of 2000 mg/kg or a single intravenous dose of 1000 mg/kg. Etanercept did not elicit dose-limiting or target organ toxicity in cynomolgus monkeys following twice weekly subcutaneous administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AUC-based serum drug concentrations that were over 27-fold higher than that obtained in humans at the recommended human dose of 25 mg.
No dose-limiting toxicities were observed during clinical trials of rheumatoid arthritis patients.
There is no known antidote to etanercept.

Hypersensitivity to etanercept or to any component of the product formulation.
Sepsis or risk of sepsis (see PRECAUTIONS AND ADVERSE REACTIONS).
Treatment with ENBREL should not be initiated in patients with serious active infections, including chronic or localized infections.

Infections: Serious infections, including sepsis and tuberculosis (TB), have been reported with the use of etanercept (see ADVERSE REACTIONS). Some of these infections have been fatal. These infections were due to bacteria, mycobacteria, fungi, viruses and parasites (including protozoa). Opportunistic infections have also been reported (including listeriosis and legionellosis). Patients who develop a new infection while undergoing treatment with etanercept should be monitored closely. Administration of etanercept should be discontinued if a patient develops a serious infection. Caution should be exercised when considering the use of etanercept in patients with a history of recurring or chronic infections or with underlying conditions which may pre-dispose patients to infections (see CONTRAINDICATIONS, FOLLOWING TEXT and ADVERSE REACTIONS).
Patients should be evaluated for infections before, during and after treatment with etanercept, taking into consideration that the mean elimination half-life of etanercept is 80 hours (standard deviation of 28 hours; range from 7 to 300 hours).
Opportunistic infections, including invasive fungal infections, have been reported in patients receiving etanercept. In some cases, fungal and other opportunistic infections are not recognized, and this has resulted in delays in appropriate treatment, sometimes resulting in death. In many of the reports, patients have also received concomitant medicines including immunosuppressants. In evaluating patients for infections, healthcare providers should consider the patient's risk for relevant opportunistic infections (e.g., exposure to endemic mycoses).
Worsening of Hepatitis C: There have been reports of worsening of hepatitis C in patients receiving etanercept, although a causal relationship with etanercept has not been established.
Concurrent Treatment with Anakinra: Concurrent administration of etanercept and anakinra has been associated with an increased risk of serious infections and neutropenia. This combination has not demonstrated increased clinical benefit; such use is not recommended (see INTERACTIONS).
Concurrent Treatment with Abatacept: In clinical studies, concurrent administration of abatacept and etanercept therapy resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended (see INTERACTIONS).
Wegener's Granulomatosis: In a placebo-controlled study of 180 patients with Wegener's granulomatosis, the addition of etanercept to standard treatment (including cyclophosphamide and high-dose steroids) was no more efficacious than standard treatment alone. The group of patients who received etanercept experienced more non-cutaneous malignancies of various types than the patient group receiving standard treatment alone. The use of etanercept for treatment of Wegener's granulomatosis is not recommended.
Alcoholic Hepatitis: In a study of 48 hospitalized patients treated with etanercept or placebo for moderate to severe alcoholic hepatitis [mean Model of End-stage Liver Disease (MELD) score = 25], etanercept was not efficacious and the mortality rate in patients treated with etanercept was significantly higher after 6 months. Infections were also higher in the group treated with etanercept. The use of etanercept in patients for the treatment of alcoholic hepatitis is not recommended. Physicians should use caution when using etanercept in patients who also have moderate to severe alcoholic hepatitis.
The needle cover of the pre-filled syringe contains latex (dry natural rubber). Patients or caregivers should contact their doctor before using etanercept if the needle cover will be handled by or if etanercept will be given to someone with a known or possible hypersensitivity (allergy) to latex.
Allergic Reactions: Allergic reactions associated with etanercept administration have been reported. If any serious allergic or anaphylactic reaction occurs, discontinue administration of etanercept immediately (see ADVERSE REACTIONS).
Immunosuppression: Anti-TNF therapies, including etanercept, may affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses.
Malignancies and Lymphoproliferative Disorders: Solid and hematopoietic malignancies (excluding skin cancers): Reports of malignancies affecting various sites have been received in the post-marketing period. In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare, and the follow-up period for placebo patients was shorter than for patients receiving TNF-antagonist therapy. Cases of leukemia have been reported in patients treated with TNF-antagonists. There is an increased background risk for lymphoma and leukemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation. Post-hoc analyses of rheumatoid arthritis clinical trials with etanercept have neither confirmed nor excluded an increased risk for malignancies.
Malignancies (particularly Hodgkin's and non-Hodgkin's lymphomas), some fatal, have been reported among children and adolescents who received treatment with TNF-antagonists, including etanercept. Most of the patients were receiving concomitant immunosuppressants.
Based on current knowledge, a possible risk for the development of lymphomas or other hematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded.
Skin Cancers: Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF-antagonists including etanercept. Post-marketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with etanercept. Periodic skin examination is recommended for all patients who are at increased risk for skin cancer.
Combining the results of controlled portions of clinical trials of etanercept, more cases of NMSC were observed in patients receiving etanercept compared with control patients, particularly in patients with psoriasis.
Hematologic Reactions: Rare cases of pancytopenia and very rare cases of aplastic anaemia, some with fatal outcome, have been reported in patients treated with etanercept. Caution should be exercised in patients being treated with etanercept who have a previous history of blood dyscrasias. All patients should be advised that if they develop signs and symptoms suggestive of blood dyscrasias or infections (e.g., persistent fever, sore throat, bruising, bleeding, paleness) whilst on etanercept, they should seek immediate medical advice. Such patients should be evaluated urgently, including full blood count; if blood dyscrasias are confirmed, etanercept should be discontinued.
Autoantibody Formation: Treatment with etanercept may be associated with the formation of autoimmune antibodies (see Autoantibodies under ADVERSE REACTIONS).
Vaccinations: In a double-blind, placebo-controlled, randomized clinical study in patients with psoriatic arthritis, 184 patients also received a multivalent pneumococcal polysaccharide vaccine at week 4. In this study most psoriatic arthritis patients receiving ENBREL were able to mount effective B-cell immune response to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and fewer patients had two-fold rises in titers compared to patients not receiving ENBREL. The clinical significance of this is unknown. Live vaccines should not be given concurrently with etanercept. If possible, bring pediatric patients up to date with immunizations according to current local guidelines before beginning etanercept therapy.
Neurological Disorders: Although no clinical trials have been performed evaluating etanercept therapy in patients with multiple sclerosis, clinical trials of other TNF antagonists in patients with multiple sclerosis have shown increases in disease activity. There have been rare post-marketing reports of central nervous system (CNS) demyelinating disorders in patients treated with etanercept (see ADVERSE REACTIONS). Additionally, there have been rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barré syndrome). A careful risk/benefit evaluation, including a neurological assessment, is recommended when prescribing etanercept therapy to patients with pre-existing or recent onset of demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.
Congestive Heart Failure (Cardiac Failure Congestive): There have been post-marketing reports of worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking etanercept. There have also been rare (<0.1%) reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. Two large clinical trials evaluating the use of etanercept in the treatment of CHF were terminated early due to lack of efficacy. Although not conclusive, data from one of these trials suggest a possible tendency toward worsening CHF in those patients assigned to etanercept treatment. In addition, a clinical trial evaluating the use of infliximab (a monoclonal antibody that binds to TNF-alpha) in the treatment of CHF was terminated early due to an increase in mortality among infliximab treated patients. Physicians should use caution when using etanercept in patients who also have CHF.
Tuberculosis (TB): Tuberculosis (including disseminated or extrapulmonary presentation) has been observed in patients receiving TNF-blocking agents, including etanercept. Tuberculosis may be due to reactivation of latent TB infection or to new infection.
Before initiation of therapy with etanercept, any patient at increased risk for TB should be evaluated for active or latent infection. Prophylaxis of latent TB infection should be initiated prior to therapy with etanercept. Some patients who tested negative for latent TB prior to receiving etanercept have developed active TB. Physicians should monitor patients receiving etanercept for signs and symptoms of active TB, including patients who tested negative for latent TB infection. Applicable local guidelines should be consulted. Patients with RA appear to have an increased rate of TB infection.
Hepatitis B Reactivation: Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant anti-TNF agents including etanercept has been reported. The majority of these reports have occurred in patient concomitantly receiving other medications that suppress the immune system, which may also contribute to hepatitis B reactivation. Patients at risk for hepatitis B infection should be evaluated for prior evidence of HBV infection before initiating anti-TNF therapy.
Caution should be exercised when administering etanercept in patients previously infected with HBV. These patients should be monitored for signs and symptoms of active HBV infection.
Hypoglycemia in Patients Treated for Diabetes: There have been reports of hypoglycemia following initiation of etanercept in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.
Inflammatory Bowel Disease (IBD) in Patients with Juvenile Idiopathic Arthritis (JIA): There have been reports of IBD in JIA patients being treated with etanercept, which is not effective for the treatment of IBD. A causal relationship with etanercept is unclear because clinical manifestations of bowel inflammation have also been observed in untreated JIA patients.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: No studies on the effects on the ability to drive and use machines have been performed.

Pregnancy: The effects of etanercept on pregnancy outcomes have been investigated in two observational cohort studies. One pregnancy registry compared rates of major birth defects in live born infants of mothers with rheumatic diseases or psoriasis exposed to ENBREL in the first trimester (n=319) versus those unexposed to ENBREL during pregnancy (n=144). The all-inclusive adjusted odds ratio for major birth defects was 2.77 (95% CI 1.04-7.35) and when chromosomal and known genetic disorders were removed was 2.49 (95% CI 0.92-6.68). The findings showed no increased rate of minor malformations, and no pattern of major or minor malformations. In addition, there was no increase in rates of intrauterine or post-natal growth deficits or delayed post-natal development. In a second observational multi-country registry study comparing the risk of adverse pregnancy outcomes in women exposed to etanercept (n=522) to those exposed to non-biologic drugs (n=3508), there was no observed increased risk of major birth defects (adjusted odds ratio 0.96, 95% CI 0.58-1.60). This study also showed no increased risks of minor birth defects, preterm birth, stillbirth or infections in the first year of life for infants born to women exposed to etanercept during pregnancy. ENBREL should only be used during pregnancy if the potential benefits to the mother outweigh the potential risks to the fetus.
Preclinical data about peri- and post-natal toxicity of etanercept and of effects of etanercept on fertility and general reproductive performance are not available. Developmental toxicity studies have been performed in rats and rabbits. The AUC-based systemic exposures of etanercept in rats and rabbits are 21- to 25-times higher than in humans at the usual human therapeutic dose of 50 mg weekly, and are approximately 10- to 13-times higher than in humans at the maximum recommended human dose of etanercept of 50 mg twice weekly (for psoriasis). No evidence of harm to the fetus in rats or rabbits or neonatal rats due to etanercept was observed. Animal reproduction studies are not always predictive of human response.
Etanercept crosses the placenta and has been detected in the serum of infants born to female patients treated with etanercept during pregnancy. The clinical impact of this is unknown, however, infants may be at increased risk of infection. Administration of live vaccines to infants for 16 weeks after the mother's last dose of etanercept is generally not recommended.
Lactation: The safe use of etanercept during lactation has not been established. Etanercept has been reported to be excreted in human milk following subcutaneous administration. In lactating rats following subcutaneous administration, etanercept was excreted in the milk and detected in the serum of the pups. Because many medicinal products and immunoglobulins are excreted in human, a decision should be made whether to discontinue nursing or to discontinue etanercept while nursing.

Adult Patients: The proportion of patients who discontinued treatment due to adverse reactions in controlled clinical studies in patients with rheumatoid arthritis was the same in both the etanercept and placebo treatment groups.
Injection site reactions: Patients in controlled clinical studies treated with etanercept had a significantly higher incidence of injection site reactions (erythema and/or itching, pain, or swelling) compared with placebo-treated patients. The frequency of injection site reactions was greatest in the first month and subsequently decreased in frequency. In clinical trials, these reactions were generally transient with a mean duration of 4 days. Some patients who experienced injection site reactions also experienced reactions at previous injection sites.
In post-marketing experience, injection site bleeding and bruising have also been observed in conjunction with etanercept therapy.
Infections: Serious and fatal infections have been reported; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses, and fungi. Opportunistic infections have also been reported including invasive fungal, parasitic (including protozoal), viral (including herpes zoster), bacterial (including Listeria and Legionella), and atypical mycobacterial infections (see PRECAUTIONS). The most commonly reported invasive fungal infections included Candida, Pneumocystis, Aspergillus, and Histoplasma.
In controlled trials in patients with rheumatoid arthritis, the rates of reported serious (fatal, life threatening, or required hospitalisation or intravenous antibiotics) and non-serious infections were similar for etanercept and placebo when adjusted for duration of exposure. Upper respiratory infections were the most commonly reported non-serious infections.
Data from a clinical trial in patients with established sepsis suggest that etanercept treatment may increase mortality in these patients.
Malignancies and lymphoproliferative disorders: Reports of malignancies affecting various sites have been received in the post-marketing period.
There have been reports of malignancies in a clinical trial of patients being treated for Wegener's granulomatosis (see PRECAUTIONS).
Interstitial lung disease: In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of interstitial lung disease in patients receiving etanercept without concomitant methotrexate was 0.06% (frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of interstitial lung disease was 0.47% (frequency uncommon). There have been postmarketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.
Elevated liver enzymes: In the double-blind periods of controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of adverse events of elevated liver enzymes in patients receiving etanercept without concomitant methotrexate was 0.54% (frequency uncommon). In the double-blind periods of controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of adverse events of elevated liver enzymes was 4.18% (frequency common).
Autoimmune hepatitis: In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of autoimmune hepatitis in patients receiving etanercept without concomitant methotrexate was 0.02% (frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of autoimmune hepatitis was 0.24% (frequency uncommon).
Autoantibodies: In controlled trials, the percentage of patients who developed new positive antinuclear antibodies (ANA) (≥1:40), new positive anti-double-stranded DNA antibodies, and new anticardiolipin antibodies was increased compared to placebo-treated patients. The impact of long-term treatment with etanercept on the development of autoimmune disease is unknown.
Rare reports have been described in patients, including those with rheumatoid factor positive RA, who have developed additional autoantibodies in conjunction with a lupus-like syndrome or rashes compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy (see Other Adverse Reactions in table as follows).
Other Adverse Reactions: See Table 8.

Click on icon to see table/diagram/image

The following table of suspected undesirable effects is based on clinical trials and/or spontaneous post-marketing reporting rates: See Table 9.

Click on icon to see table/diagram/image

Pediatric Population: In general, the adverse events in pediatric patients were similar in frequency and types to those seen in adult patients.
Undesirable effects in pediatric patients with juvenile idiopathic arthritis: Infection was the most common adverse event reported in pediatric patients taking etanercept and occurred at an incidence similar to placebo. The types of infections reported in juvenile idiopathic arthritis patients were generally mild and consistent with those commonly seen in outpatient pediatric populations.
In clinical trials, two cases of varicella infection with signs and symptoms suggestive of aseptic meningitis have been reported among juvenile idiopathic arthritis patients treated with etanercept.
There were 4 reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials.
Undesirable effects in pediatric patients with plaque psoriasis: In a 48-week study of 211 children aged 4 to 17 years with pediatric plaque psoriasis, the adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.

Concurrent Treatment with Anakinra: Patients treated with etanercept and anakinra were observed to have a higher rate of serious infection when compared with patients who were treated with etanercept alone (historical data). In addition, in a double-blind placebo-controlled trial in patients receiving background methotrexate, patients treated with etanercept and anakinra were observed to have a higher rate of serious infections and neutropenia than patients treated with etanercept alone (see PRECAUTIONS).
Concurrent Treatment with Abatacept: In clinical studies, concurrent administration of abatacept and etanercept therapy resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended (see PRECAUTIONS).
Concurrent Treatment with Sulfasalazine: In a clinical study of patients who were receiving established doses of sulfasalazine, to which etanercept was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with etanercept or sulfasalazine alone. The clinical significance of this interaction is unknown.
Non-interactions: No interactions have been observed when etanercept was administered with glucocorticoids, salicylates (except sulfasalazine), non-steroidal anti-inflammatory drugs (NSAIDs), analgesic, or methotrexate in clinical trials with adult rheumatoid arthritis patients.
Methotrexate has no effect on the pharmacokinetics of etanercept.
No clinically significant pharmacokinetic drug-drug interactions were observed in studies with digoxin and warfarin.

INCOMPATIBILITIES: In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products.
SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING: The needle cover of the pre-filled syringe and the needle cap of the pre-filled pen contain latex (dry natural rubber). Patients or caregivers should contact their doctor before using etanercept if the needle cover will be handled by or if etanercept will be given to someone with a known or possible hypersensitivity (allergy) to latex.
Patients or caregivers who are to administer etanercept must be instructed in proper syringe and needle disposal, and be cautioned against reuse of these items.
Unused etanercept, syringes, or waste materials should be disposed of according to local requirements.

ENBREL must be refrigerated at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE.
Keep the pre-filled syringe and pre-filled pen in the original carton to protect from light until the time of use.
Do not shake.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs) / Immunosuppressants

L04AB01 - etanercept ; Belongs to the class of tumor necrosis factor alpha (TNF-alpha) inhibitors. Used as immunosuppressants.

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