Enbrel

Etanercept.

Each pre-filled syringe also contains the following excipients: Sucrose, sodium chloride, L-arginine hydrochloride, sodium phosphate dibasic anhydrous, sodium phosphate monobasic monohydrate and water for injection.
Etanercept is a human tumour necrosis factor receptor (TNFR) p75 Fc fusion protein produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian expression system. Etanercept is a dimer of a chimeric protein genetically engineered by fusing the extracellular ligand-binding domain of human tumour necrosis factor receptor-2 (TNFR2/p75) to the Fc domain of human IgG1. This Fc component contains the hinge, CH2 and CH3 regions but not the CH1 region of IgG1. Etanercept contains 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. The potency is determined by measuring the ability of etanercept to neutralize the TNFα-mediated growth inhibition of A375 cells. The specific activity of etanercept is 1.7 x 10⁶ units/mg.

Pharmacotherapeutic Group: TNF-α inhibitor. ATC Code: L04AB01.
Pharmacology: Pharmacodynamics: Tumour necrosis factor (TNF) is a dominant cytokine in the inflammatory process of rheumatoid arthritis (RA). Elevated levels of TNF are also found in the synovium and psoriatic plaques of patients with psoriatic arthritis and in serum and synovial tissue of patients with ankylosing spondylitis. In plaque psoriasis, infiltration by inflammatory cells including T-cells leads to increased TNF levels in psoriatic lesions compared with levels in uninvolved skin. Etanercept is a competitive inhibitor of TNF-binding to its cell surface receptors and thereby inhibits the biological activity of TNF. TNF and lymphotoxin are pro-inflammatory cytokines that bind to 2 distinct cell surface receptors: The 55-kilodalton (p55) and 75-kilodalton (p75) TNFRs. Both TNFRs exist naturally in membrane-bound and soluble forms. Soluble TNFRs are thought to regulate TNF biological activity.
TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on cross-linking of cell surface TNFRs. Dimeric soluble receptors eg, etanercept possess a higher affinity for TNF than monomeric receptors and are considerably more potent competitive inhibitors of TNF-binding to its cellular receptors. In addition, use of an immunoglobulin Fc region as a fusion element in the construction of a dimeric receptor imparts a longer serum half-life.
Mechanism of Action: Much of the joint pathology in RA and ankylosing spondylitis and skin pathology in plaque psoriasis is mediated by pro-inflammatory molecules that are linked in a network controlled by TNF. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF-binding to cell surface TNFR, preventing TNF-mediated cellular responses by rendering TNF biologically inactive. Etanercept may also modulate biologic responses controlled by additional downstream molecules (eg, cytokines, adhesion molecules or proteinases) that are induced or regulated by TNF.
Clinical Trials: This section presents data from 4 randomized controlled trials in RA, 1 study in polyarticular-course juvenile chronic arthritis, 1 study in psoriatic arthritis, 1 study in ankylosing spondylitis and 3 studies in plaque psoriasis.
Rheumatoid Arthritis: The efficacy of Enbrel was assessed in a randomized, double-blind, placebo-controlled study. The study evaluated 234 adult patients with active RA who had failed therapy with at least 1 but no more than 4 disease-modifying antirheumatic drugs (DMARDs). Doses of Enbrel 10 or 25 mg or placebo were administered SC twice a week for 6 consecutive months.
The results of this controlled trial were expressed in percentage improvement in RA 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 3 and 6 months, respectively; p<0.01 Enbrel versus placebo at all time points for both ACR 20 and 50 responses).
Approximately 15% of subjects who received Enbrel achieved an ACR 70 response at months 3 and 6 compared to fewer than 5% of subjects in the placebo arm. Among patients receiving Enbrel, the clinical responses generally appeared within 1-2 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 RA disease activity not included in the ACR response criteria eg, 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. Reintroduction of treatment with Enbrel after discontinuation 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; longer-term experience is not available.
The efficacy of Enbrel was compared to methotrexate in a randomized, active-controlled study with blinded radiographic evaluations as a primary endpoint in 632 adult patients with active RA (<3 years duration) who had never received treatment with methotrexate. Doses of Enbrel 10 or 25 mg 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 1.4-1.5. Treatment with Enbrel 25 mg resulted in substantial improvement at 12 months, with about 44% of patients achieving a normal HAQ scores (<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 following figure. (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 (7.5-20 mg weekly, median dose 20 mg), and of the combination of Enbrel and methotrexate initiated concurrently were compared in 682 adult patients with active RA 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, 50 and 70 responses, and improvement for DAS and HAQ scores at both 24 and 52 weeks than patients in either of the single therapy groups (see Table 1).


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Radiographic progression at week 52 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 2).


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The percentage of patients without progression (TSS change ≤0.5) was higher in the Enbrel in combination with methotrexate and Enbrel groups compared with methotrexate at week 24 (74%, 68% and 56%, respectively; p<0.05) and week 52 (80%, 68% and 57%, respectively; p<0.05).
The safety and efficacy of Enbrel 50 mg (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 Enbrel 50 mg once weekly, and 153 patients received Enbrel 25 mg twice weekly. The safety and efficacy profiles of the 2 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 2 regimens. A single 50 mg/mL injection of Enbrel was found to be equivalent to 2 simultaneous injection of 25 mg/mL.
Polyarticular-Course Juvenile Chronic Arthritis/Juvenile Rheumatoid Arthritis (JRA): The safety and efficacy of Enbrel were assessed in a 2-part study in 69 children with polyarticular-course JRA who had a variety of JRA onset types. Patients 4-17 years with moderately to severely active polyarticular-course JRA refractory to or intolerant of methotrexate were enrolled; patients remained on a stable dose of a single nonsteroidal anti-inflammatory drug (NSAID) and/or prednisone (≤0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received Enbrel 0.4 mg/kg (maximum 25 mg/dose) SC twice weekly. In part 2, patients with a clinical response at day 90 were randomized to remain on Enbrel or receive placebo for 4 months and assessed for disease flare. Responses were measured using the JRA Definition of Improvement (DOI), defined as ≥30% improvement in at least 3 of 6 and ≥30% worsening in no more than 1 of 6 JRA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment and erythrocyte sedimentation rate (ESR). Disease flare was defined as a ≥30% worsening in 3 of 6 JRA core set criteria and ≥30% improvement in not more than 1 of the 6 JRA core set criteria and a minimum of 2 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 Enbrel 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 Enbrel and 28 days for patients who received placebo. Of patients who demonstrated a clinical response at 90 days and entered part 2 of the study, some of the patients remaining on Enbrel continued to improve from month 3 through month 7, while those who received placebo did not improve.
Studies have not been done in patients with polyarticular-course juvenile chronic arthritis to assess the effects of continued Enbrel therapy in patients who do not respond within 3 months of initiating Enbrel therapy or to assess the combination of Enbrel with methotrexate.
Adults 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 and had active psoriatic arthritis (≥3 swollen joints and ≥3 tender joints) in at least 1 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 methotrexate ≤25 mg/week. Doses of Enbrel 25 mg (based on dose-finding studies in patients with RA) or placebo were administered SC twice a week for 6 months.
The results were expressed as percentages of patients achieving the ACR 20, 50 and 70 responses and percentages with improvement in Psoriatic Arthritis Response Criteria (PsARC). Results are summarized in Table 2. (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 1st 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). There is insufficient evidence of the efficacy of Enbrel in patients with ankylosing spondylitis-like psoriatic arthropathy due to the small number of patients studied.
Adults with Ankylosing Spondylitis: The efficacy of Enbrel was assessed in 3 randomized, double-blind, placebo-controlled studies in 401 patients with ankylosing spondylitis from which 203 were treated with Enbrel. The largest of these trials (n=277) enrolled patients 18-70 years 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 noctural 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 Enbrel 25 mg (based on dose-finding studies in patients with RA) or placebo were administered SC 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% or a 70% improvement, respectively.
Compared to placebo, treatment with Enbrel resulted in significant improvements in the ASAS 20, 50 and 70 as early as 2 weeks after the initiation of therapy. (See Table 3.)


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Among patients with ankylosing spondylitis who received Enbrel, the clinical responses were apparent at the time of the 1st 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.
Adults with Plaque Psoriasis: Enbrel is recommended for use in patients as defined in Indications. Patients who "failed to respond to" in the target population is defined by insufficient response (Psoriasis Area and Severity Index (PASI) <50 or PGA less than good), or worsening of the disease while on treatment, and who were adequately dosed for a sufficiently long duration to assess response with at least each of the 3 major systemic therapies as available.
The efficacy of Enbrel versus other systemic therapies in patients with moderate to severe psoriasis (responsive to other systemic therapies) has not been evaluated in studies directly comparing Enbrel with other systemic therapies. Instead, the safety and efficacy of Enbrel were assessed in 3 randomized, double-blind, placebo-controlled studies. The primary efficacy endpoint in all 3 studies was the proportion of patients in each treatment group who achieved the PASI 75 (ie, at least a 75% improvement in the PASI score from baseline) at 12 weeks.
Study 1 was a phase II study in patients with active but clinically stable plaque psoriasis involving ≥10% of the body surface area that were ≥18 years old. One hundred and twelve (112) patients were randomized to receive a dose of Enbrel 25 mg (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 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 1 of the previously mentioned 3 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 Enbrel 25 or 50 mg, or placebo twice a week for 12 weeks and then all patients received open-label Enbrel 25 mg 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 4.)


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Among patients with plaque psoriasis who received Enbrel, significant responses relative to placebo were apparent at the time of the 1st 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 psoriasis-related serious adverse events were observed. There was some evidence to support a benefit of retreatment 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.
Antibodies to Enbrel: Antibodies to Enbrel, all non-neutralizing, were detected in 4 out of 96 RA patients who received Enbrel at a dose of 25 mg twice a week for up to 3 months in a placebo-controlled trial. In the active-controlled trial, 11 (2.8%) of 400 etanercept-treated patients had at least 1 positive result but none of these patients had a positive neutralizing antibody test. Results from JCA patients were similar to those seen in adult RA patients treated with Enbrel. Of 98 patients with psoriatic arthritis who have been tested, no patient has developed antibodies to Enbrel at 24 weeks. Among 175 ankylosing spondylitis patients treated with Enbrel, 3 patients were reported with antibodies to Enbrel, none were neutralizing. In double-blind studies up to 6 months duration in plaque psoriasis, about 1% of the 1084 patients developed antibodies to Enbrel, none were neutralizing.
Although the experience does not exclude the possibility that a clinically relevant effect might occur, no apparent correlation of antibody development to clinical response or adverse event was seen.
Pharmacokinetics: Etanercept serum values were determined by an ELISA method, which may detect ELISA-reactive degradation products as well as the parent compound.
Etanercept is slowly absorbed from the site of SC injection, reaching maximum concentration approximately 48 hrs after a single dose. The absolute bioavailability is 76%. With twice weekly doses, it is anticipated that steady-state concentrations are approximately twice as high as those observed after single doses. After a single SC dose of Enbrel 25 mg, the average maximum serum concentration observed in healthy volunteers was 1.65±0.66 mcg/mL, and the area under the curve (AUC) was 235±96.6 mcg·hr/mL. Dose proportionality has not been formally evaluated, but there is no apparent saturation of clearance across the dosing range.
A biexponential curve is required to describe the concentration-time curve of etanercept. The central volume of distribution of etanercept is 7.6 L, while the volume of distribution at steady-state is 10.4 L.
Etanercept is cleared slowly from the body. The half-life is long, approximately 80 hrs.
Clearance is approximately 175±116 mL/hr in patients with RA, somewhat lower than the value of 131±81 mL/hr observed in healthy volunteers. Additionally, the pharmacokinetics of Enbrel in RA, ankylosing spondylitis and plaque psoriasis patients are similar.
Mean serum concentration profiles at steady state in treated RA patients were C_max of 2.4 mg/L versus 2.6 mg/L, C_min of 1.2 mg/L versus 1.4 mg/L, and partial AUC of 297 mg·hr/L versus 316 mg·hr/L for Enbrel 50 mg once weekly (n=21) versus Enbrel 25 mg twice weekly (n=16), respectively.
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 and hepatic impairment should not require a change in dosage. There is no apparent pharmacokinetic difference between men and women.
Methotrexate has no effect on the pharmacokinetics of etanercept. The effect of Enbrel on the human pharmacokinetics of methotrexate has not been investigated.
Elderly Patients: The impact of advanced age was studied in the population pharmacokinetic analysis of etanercept serum concentrations. Clearance and volume estimates in patients 65-87 years were similar to estimates in patients <65 years.
Patients with Renal 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 concentration of 1-2 mg/L of etanercept are associated with optimal effect, and are obtained with doses of 25 mg twice weekly.
Patients with Polyarticular-Course Juvenile Chronic Arthritis/Juvenile Rheumatoid Arthritis (JRA): In a polyarticular-course juvenile chronic arthritis trial with Enbrel, 69 patients (aged 4-17 years) were administered Enbrel 0.4 mg/kg twice weekly for 3 months. Serum concentration profiles were similar to those seen in adult RA patients. The youngest children (aged 4 years) had reduced clearance (increased clearance when normalized by weight) compared with older children (aged 12 years) and adults. Simulation of dosing suggests that while older children (aged 10-17 years) will have serum levels close to those seen in adults, younger children will have appreciably lower levels.
Toxicology: Preclinical Safety Data: In the toxicological studies with Enbrel, no dose-limiting or target organ toxicity was evident. Enbrel was considered to be non-genotoxic from a battery of in vitro and in vivo studies. Carcinogenicity studies, and standard assessments of fertility and postnatal toxicity were not performed with Enbrel due to the development of neutralizing antibodies in rodents.
Enbrel did not induce lethality or notable signs of toxicity in mice or rats following a single SC dose of 2000 mg/kg or a single IV dose of 1000 mg/kg. Enbrel did not elicit dose-limiting or target organ toxicity in cynomolgus monkeys following twice-weekly SC administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AUC-based serum drug concentrations that were >27-fold higher than that obtained in humans at the recommended dose of 25 mg.

Treatment of active RA in adults when the response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate (unless contraindicated), has been inadequate. Enbrel has been shown to halt disease-associated structural damage when used in combination with methotrexate.
Treatment of severe, active and progressive RA in adults not previously treated with methotrexate.
In patients with RA, Enbrel used alone or in combination with methotrexate has been shown to slow the progression of disease-associated structural damage as measured by x-ray.
Treatment of active polyarticular-course juvenile chronic arthritis in children 4-17 years who have had an inadequate response to, or who have proved intolerant of, methotrexate. Enbrel has not been studied in children <4 years.
Treatment of active and progressive psoriatic arthritis in adults when the response to previous DMARDs therapy has been inadequate.
Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to previous DMARDs therapy. Treatment of adults with moderate to severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA (see Pharmacology under Actions).

Enbrel treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of RA, psoriatic arthritis, ankylosing spondylitis or psoriasis.
Each vial of Enbrel 50 mg must be reconstituted with 1 mL of water for injection before use and administered by SC injection. Adults (18-64 years): Rheumatoid Arthritis: Recommended Dose: Enbrel 25 mg administered twice weekly. Alternatively, 50 mg administered once weekly (as two 25-mg injections given at approximately the same time) has been shown to be safe and effective (see Pharmacology under Actions).
Psoriatic Arthritis and Ankylosing Spondylitis: Recommended Dose: Enbrel 25 mg administered twice weekly or 50 mg once weekly.
Plaque Psoriasis: Recommended Dose: Enbrel 25 mg administered twice weekly. Alternatively, 50 mg given twice weekly may be used for up to 12 weeks followed, if necessary, by a dose of 25 mg twice weekly.
Treatment with Enbrel should continue until remission is achieved, for up to 24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks.
If re-treatment with Enbrel is indicated, guidance on treatment duration should be followed. The dose should be 25 mg twice weekly.
Methotrexate, glucocorticoids, salicylates, NSAIDs or analgesics may be continued during treatment with Enbrel in adults.
Children and Adolescents (≥4 to <18 years): 0.4 mg/kg (up to a maximum of 25 mg/dose) after reconstitution of Enbrel 25 mg in 1 mL of water for injection, given twice weekly as SC injection with an interval of 3-4 days between doses.
Enbrel has not been studied in children <4 years.
Elderly (≥65 years): No dose adjustment is required. Dosage and administration are the same as for adults 18-64 years.
Renal and Hepatic Impairment: No dose adjustment is required.
Administration: Administer Enbrel as SC injection 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.
Patients or caregivers who are to administer Enbrel must be instructed in mixing the powder with the liquid and in injection techniques. The 1st injection should be performed under the supervision of a qualified healthcare professional if Enbrel is to be administered by a patient or caregiver.
Before injection, Enbrel single-use pre-filled syringe should be allowed to reach room temperature (approximately 15-30 min). The needle cover should not be removed while allowing the pre-filled syringe to reach room temperature. The solution should be clear and colorless or pale yellow and practically free from visible particles.

The maximum tolerated dose of Enbrel has not been established in humans. Single IV 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 RA patients has been an IV loading dose of 32 mg/m² followed by SC doses of 16 mg/m² (~25 mg) administered twice weekly.
Enbrel did not induce lethality or notable signs of toxicity in mice or rats following a single SC dose of 2000 mg/kg or a single IV dose of 1000 mg/kg. Enbrel did not elicit dose-limiting or target organ toxicity in cynomolgus monkeys following twice weekly SC administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AUC-based serum drug concentrations that were >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 RA patients.
There is no known antidote to Enbrel.

Hypersensitivity to etanercept or to any component of Enbrel. Sepsis or risk of sepsis.
Treatment with Enbrel should not be initiated in patients with serious active infections including chronic or localized infections.
Concurrent Enbrel and anakinra treatment (see Warnings).

Infections: Sepsis and serious infections (fatal, life-threatening, or requiring hospitalization or IV antibiotics) have been reported with the use of Enbrel (see Adverse Reactions). Many of these serious events have occurred in patients with underlying diseases that in addition to their RA could predispose them to infections. Patients who develop a new infection while undergoing treatment with Enbrel should be monitored closely. Administration of Enbrel should be discontinued if a patient develops a serious infection. Physicians should exercise caution when considering the use of Enbrel in patients with a history of recurring or chronic infections or with underlying conditions which may predispose patients to infections eg, advanced or poorly controlled diabetes.
Patients should be evaluated for infections before, during and after treatment with Enbrel, taking into consideration that the mean elimination half-life of etanercept is 80 hrs (standard deviation of 28 hrs; range from 7-300 hrs).
Concurrent Enbrel and Anakinra Treatment: Concurrent administration of Enbrel and anakinra has been associated with an increased risk of serious infections and neutropenia compared to Enbrel alone. This combination has not demonstrated increased clinical benefit. Thus, the combined use of Enbrel and anakinra is not recommended (see Interactions and Adverse Reactions).
In 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.
Allergic Reactions: The needle cover of the pre-filled syringe contains latex (dry natural rubber) that may cause hypersensitivity reactions when handled by or when Enbrel is administered to persons with known or possible latex sensitivity.
Allergic reactions associated with Enbrel administration have been reported commonly. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, Enbrel therapy should be discontinued immediately and appropriate therapy initiated.
Immunosuppression: The possibility exists for anti-TNF therapies, including Enbrel, to affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. Reports of various malignancies (including breast and lung carcinoma and lymphoma) have been received in the post-marketing period (see Adverse Reactions). In a study of 49 patients with RA treated with Enbrel, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels or change in enumeration of effector cell populations. Whether treatment with Enbrel might influence the development and course of malignancies and active and/or chronic infections is unknown. The safety and efficacy of Enbrel in patients with immunosuppression or chronic infections have not been evaluated.
Two juvenile chronic arthritis patients developed varicella infection and signs and symptoms of aseptic meningitis which resolved without sequelae. Patients with a significant exposure to varicella virus should temporarily discontinue Enbrel therapy and be considered for prophylactic treatment with varicella zoster immune globulin.
Vaccinations: Most psoriatic arthritis patients receiving Enbrel were able to mount effective β-cell immune response 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.
Live vaccines should not be given concurrently with Enbrel. No data are available on the secondary transmission of infection by live vaccines in patients receiving Enbrel. It is recommended that juvenile chronic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Enbrel therapy.
Autoantibody Formation: Treatment with Enbrel may be associated with the formation of autoimmune antibodies (see Adverse Reactions). Hematologic Reactions: Rare cases of pancytopenia and very rare cases of aplastic anemia, some with fatal outcome, have been reported in patients treated with Enbrel. Caution should be exercised in patients being treated with Enbrel 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 (eg, persistent fever, sore throat, bruising, bleeding, paleness) whilst on Enbrel, they should seek immediate medical advice. Such patients should be evaluated urgently, including full blood count; if blood dyscrasias are confirmed, Enbrel should be discontinued.
CNS Disorders: Although no clinical trials have been performed evaluating Enbrel 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 reports of CNS demyelinating disorders in patients treated with Enbrel (see Adverse Reactions); the causal relationship to Enbrel therapy remains unclear. A careful risk/benefit evaluation including a neurological assessment, is recommended when prescribing Enbrel to patients with preexisting or recent onset of CNS demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.
Congestive Heart Failure (CHF): Physicians should use caution when using Enbrel in patients who also have CHF. There have been post-marketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking Enbrel. Two large clinical trials evaluating the use of Enbrel 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 Enbrel treatment. In addition, a clinical trial evaluating the use of infliximab (a monoclonal antibody that binds to TNFα) in the treatment of CHF was terminated early due to an increase in mortality among infliximab-treated patients.
Tuberculosis (TB): Before initiation of therapy with Enbrel, 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 Enbrel therapy. Applicable local guidelines should be consulted. Patients with RA appear to have an increased rate of TB infection. It is not known whether Enbrel therapy increases this risk.
Hepatitis B Virus (HBV) Reactivation: Reactivation of HBV in patients who are chronic carriers of this virus receiving anti-TNF agents including etanercept has been reported. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating anti-TNF therapy.
Although a causal relationship has not been established for etanercept, caution should be exercised when administering etanercept in patients identified as carriers of HBV. If etanercept is used in carriers of HBV, the patients should be monitored for signs and symptoms of active HBV infection.
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.
Combination Therapy: In a controlled clinical trial of 1-year duration in RA patients, the combination of Enbrel and methotrexate did not result in unexpected safety findings, and the safety profile of Enbrel when given in combination with methotrexate was similar to the profiles reported in studies of Enbrel and methotrexate alone. Long-term studies to assess the safety of the combination are ongoing. The long-term safety of Enbrel in combination with other DMARDs has not been established.
The use of Enbrel in combination with other systemic therapies or phototherapy for the treatment of psoriasis has not been studied.
Renal and Hepatic Impairment: Based on pharmacokinetic data (see Pharmacokinetics under Actions), no dosage adjustment is needed in patients with renal or hepatic impairment; clinical experience in such patients is limited.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
Use in pregnancy: The safe use of etanercept during pregnancy has not been established. Use etanercept during pregnancy only if clearly needed.
Developmental toxicity studies have been performed in rats and rabbits at doses resulting in AUC-based systemic exposure levels of etanercept that were at least 21- to 25-fold higher than in humans at the recommended therapeutic dose of 50 mg weekly, and are approximately 10- to 13-fold higher than in humans at the maximum recommended human dose of 50 mg twice weekly (for psoriasis) have revealed no evidence of harm to the fetus or neonatal rat due to etanercept. Preclinical data about peri- and postnatal toxicity of etanercept and of effects of etanercept on fertility and general reproductive performance are not available.
Use in lactation: The safe use of etanercept during lactation has not been established.
It is not known whether etanercept is excreted in human milk. Because immunoglobulins and many medicinal products can be excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue Enbrel while nursing.

Use in pregnancy: The safe use of etanercept during pregnancy has not been established. Use etanercept during pregnancy only if clearly needed.
Developmental toxicity studies have been performed in rats and rabbits at doses resulting in AUC-based systemic exposure levels of etanercept that were at least 21- to 25-fold higher than in humans at the recommended therapeutic dose of 50 mg weekly, and are approximately 10- to 13-fold higher than in humans at the maximum recommended human dose of 50 mg twice weekly (for psoriasis) have revealed no evidence of harm to the fetus or neonatal rat due to etanercept. Preclinical data about peri- and postnatal toxicity of etanercept and of effects of etanercept on fertility and general reproductive performance are not available.
Use in lactation: The safe use of etanercept during lactation has not been established.
It is not known whether etanercept is excreted in human milk. Because immunoglobulins and many medicinal products can be excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue Enbrel while nursing.

The following list of adverse reactions is based on experience from clinical trials in adults and on post-marketing experience.
Within the organ system classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: Very common: ≥1/10; common: ≥1/100, <1/10; uncommon: ≥1/1000, <1/100; rare: ≥1/10,000, <1/1000; very rare: <1/10,000.
Blood and Lymphatic System Disorders: Uncommon: Thrombocytopenia. Rare: Anemia, leukopenia, neutropenia, pancytopenia*. Very Rare: Aplastic anemia*. (See Precautions.)
Immune System Disorders: Common: Allergic reactions (see Skin and Subcutaneous Disorders as follows), autoantibody formation*. Uncommon: Systemic vasculitis (ANCA positive vasculitis). Rare: Serious allergic/anaphylactic reactions (including angioedema, bronchospasm).
Nervous System Disorders: Rare: Seizures, CNS demyelinating events including multiple sclerosis and localized demyelinating conditions eg, optic neuritis and transverse myelitis (see Precautions).
Skin and Subcutaneous Tissue Disorders: Common: Pruritus. Uncommon: Urticaria, rash, psoriasis and psoriasiform rash. Rare: Cutaneous vasculitis (including leukocytoclastic vasculitis), Stevens-Johnson syndrome, erythema multiforme.
Musculoskeletal, Connective Tissue and Bone Disorders: Rare: Subacute cutaneous lupus erythematosus, discoid lupus erythematosus, lupus-like syndrome.
General Disorders and Administration Site Conditions: Common: Fever.
Cardiac Disorders: Rare: There have been reports of worsening of congestive heart failure (see Precautions).
Hepatobiliary Disorders: Rare: Elevated liver enzymes, autoimmune hepatitis.
*See Additional Information as follows.
Additional Information: Serious Adverse Events Reported in Clinical Trials: Among RA, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis patients in placebo-controlled, active-controlled and open-label trials of Enbrel, serious adverse events reported included malignancies, asthma, infections, heart failure, myocardial infarction, myocardial ischemia, chest pain, syncope, cerebral ischemia, hypertension, hypotension, cholecystitis, pancreatitis, gastrointestinal hemorrhage, bursitis, confusion, depression, dyspnea, abnormal healing, renal insufficiency, kidney calculus, deep vein thrombosis, pulmonary embolism, membranous glomerulonephropathy, polymyositis, thrombophlebitis, liver damage, leucopenia, paresis, paresthesia, vertigo, allergic alveolitis, angioedema, scleritis, bone fracture, lymphadenopathy, ulcerative colitis and intestinal obstruction.
Malignancies: Thirty-eight (38) new malignancies of various types were observed in 2680 RA patients treated in clinical trials with Enbrel for up to 48 months, including 231 patients treated with Enbrel in combination with methotrexate in the 1-year active-controlled study. The observed rates and incidences in these clinical trials were similar to those expected for the population studied. No psoriatic arthritis patients developed malignancies in the double-blind, placebo-controlled studies of up to 6 months duration involving 131 Enbrel-treated patients. Twenty-three (23) malignancies were reported in plaque psoriasis patients treated with Enbrel in double-blind and open-label studies of up to 15 months involving 1261 Enbrel-treated patients.
Reports of malignancies affecting various sites have been received in the post-marketing period (see Precautions).
There have been reports of malignancies in a clinical trial of patients being treated for Wegener's granulomatosis.
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 1st month and subsequently decreased in frequency. Some patients who experienced injection site reactions also experienced reactions at previous injection sites.
In controlled trials in patients with plaque psoriasis, approximately 14% of patients treated with Enbrel developed injection site reactions compared with 6% of placebo-treated patients during the first 12 weeks of treatment.
In post-marketing experience, injection site bleeding and bruising have also been observed in conjunction with Enbrel therapy.
Infections: In controlled trials in patients with RA, the rates of reported serious (fatal, life-threatening, or required hospitalization or IV antibiotics) and non-serious infection were similar for Enbrel and placebo when adjusted for duration of exposure. Upper respiratory tract infections were the most commonly reported non-serious infections.
In placebo-controlled psoriatic arthritis and plaque psoriasis trials, there were no differences in rates of infection among patients treated with Enbrel and those treated with placebo. In the psoriatic arthritis trials, no serious infections occurred in patients treated with Enbrel. In the double-blind and open-label plaque psoriasis trials of up to 15 months, serious infections experienced by Enbrel-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis and abscess.
Serious and fatal infections have been reported during use of Enbrel; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred within a few weeks after initiating treatment with Enbrel in patients who have underlying conditions (eg, diabetes, CHF, history of active or chronic infections) in addition to their RA (see Precautions). Data from a sepsis clinical trial, not specifically in patients with RA, suggest that Enbrel treatment may increase mortality in patients with established sepsis.
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 Enbrel on the development of autoimmune diseases 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.
Pancytopenia and Aplastic Anemia: There have been post-marketing reports of pancytopenia and aplastic anemia, some of which had fatal outcomes (see Precautions).
Laboratory Evaluations: Based on the results of clinical studies, normally no special laboratory evaluations are necessary in addition to careful medical management and supervision of patients.
Concurrent Enbrel and Anakinra Treatment: In studies when patients received concurrent treatment with Enbrel plus anakinra, a higher rate of serious infections compared to Enbrel alone was observed and 2% of patients (3/139) developed neutropenia (absolute neutrophil count <1000/mm³). While neutropenic, 1 patient developed cellulitis that resolved after hospitalization (see Warnings and Interactions).
Undesirable Effects in Pediatric Patients with Juvenile Chronic Arthritis: In general the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients.
Juvenile chronic arthritis patients treated with Enbrel had a significantly higher incidence of injectionsite reactions (erythema and/or itching, pain or swelling) compared with placebo-treated patients in controlled clinical trials.
Infection was the most common adverse event reported in pediatric patients taking Enbrel and occurred at an incidence similar to placebo. The types of infections reported in juvenile chronic arthritis patients were generally mild and consistent with those commonly seen in outpatient pediatric populations.
In clinical trials, 2 cases of varicella infection with signs and symptoms suggestive of aseptic meningitis have been reported among juvenile chronic arthritis patients treated with Enbrel.
The most frequent non-infectious adverse events seen in each age group were as follows: 4-8 years: Abdominal pain (29%); 9-12 years: vomiting and accidental injury (27% each); and 13-17 years: headache (27%). Five events occurred in >10% of the patients: Abdominal pain, headache, rhinitis, vomiting, rash. The majority of patients (53%) who experienced adverse events had events considered unrelated to drug.

In clinical trials, no interactions have been observed when Enbrel was administered with glucocorticoids, salicylates, NSAIDs, analgesics or methotrexate. No data are available on the effects of vaccination in patients receiving Enbrel (see Precautions).
In a clinical study of patients who were receiving established doses of sulfasalazine, to which Enbrel was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with Enbrel or sulfasalazine alone. The clinical significance of this interaction is unknown.
Concurrent Enbrel and Anakinra Treatment: Patients treated with Enbrel and anakinra were observed to have a higher rate of serious infection when compared with patients treated with Enbrel alone (historical data). In addition, in a double-blind placebo-controlled trial in patients receiving background methotrexate, patients treated with Enbrel and anakinra were observed to have a higher rate of serious infections (7%) and neutropenia than patients treated with Enbrel alone (see Precautions and Adverse Reactions). The combination of Enbrel and anakinra has not demonstrated increased clinical benefit and is therefore not recommended.
Incompatibilities: In the absence of incompatibility studies, Enbrel must not be mixed with other medicinal products.

Instructions for Use, Handling and Disposal: The needle cover of the diluent syringe contains latex (dry natural rubber). Patient or caregivers should contact the doctor before using Enbrel if the needle cover will be handled by or if Enbrel will be given to someone with a known or possible hypersensitivity (allergy) to latex.
Patients or caregivers who are to administer Enbrel must be instructed in proper syringe and needle disposal, and be cautioned against reuse of these items. Any unused product or waste material should be disposed of in accordance with local requirements.

Store at 2°-8°C before reconstitution. Do not freeze.
The reconstituted Enbrel should be used immediately (ie, within 6 hrs if stored at 2°-8°C).
Shelf-Life: Pre-Filled Syringe: 36 months.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

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

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