ENBREL

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

4 CONTRAINDICATIONS Enbrel is contraindicated in patients with sepsis. Enbrel is contraindicated in patients with sepsis. ( 4 )

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

2 DOSAGE AND ADMINISTRATION Enbrel is administered by subcutaneous injection. Patient Population Recommended Dose and Frequency Adult RA and PsA ( 2.1 ) 50 mg once weekly with or without methotrexate (MTX) AS ( 2.1 ) 50 mg once weekly Adult PsO ( 2.1 ) 50 mg twice weekly for 3 months, followed by 50 mg once weekly pJIA, Pediatric PsO and JPsA ( 2.2 ) 0.8 mg/kg weekly, with a maximum of 50 mg per week 2.1 Testing and Procedures Prior to Treatment Initiation Perform the following evaluations and procedures prior to initiating treatment with Enbrel: Prior to initiating Enbrel and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5.1) ]. Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with Enbrel [see Warnings and Precautions (5.8) ]. 2.2 Important Administration Instructions Administration of one 50 mg Enbrel single - dose prefilled syringe, one single - dose prefilled Enbrel SureClick autoinjector, or one Enbrel Mini single - dose prefilled cartridge (for use with the AutoTouch reusable autoinjector only), provides a dose equivalent to two 25 mg Enbrel single-dose prefilled syringes, two 25 mg single - dose vials, or two multiple-dose vials of lyophilized Enbrel, when multiple - dose vials are reconstituted and administered as recommended. 2.3 Recommended Dosage in Adult Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic Arthritis, and Plaque Psoriasis Enbrel is administered by subcutaneous injection (Table 1). Table 1. Recommended Dosage for Adult Patients with RA, AS, PsA and PsO Patient Population Recommended Dosage Adult RA, AS, and PsA 50 mg weekly Adult PsO Starting Dose : 50 mg twice weekly for 3 months Maintenance Dose : 50 mg once weekly See the Enbrel (etanercept) "Instructions for Use" insert for detailed information on injection site selection and dose administration [see Dosage and Administration (2.3) and Patient Counseling Information (17) ] . Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients Methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be continued during treatment with Enbrel. Based on a study of 50 mg Enbrel twice weekly in patients with RA that suggested higher incidence of adverse reactions but similar American College of Rheumatology (ACR) response rates, doses higher than 50 mg per week are not recommended. Adult Plaque Psoriasis Patients In addition to the 50 mg twice weekly recommended starting dose, starting doses of 25 mg or 50 mg per week were shown to be efficacious. The proportion of responders was related to Enbrel dosage [see Clinical Studies (14.5) ] . 2.4 Recommended Dosage for Pediatric Patients with Polyarticular Juvenile Idiopathic Arthritis, Plaque Psoriasis, and Juvenile Psoriatic Arthritis The recommended weight-based dosage for pediatric patients is administered by subcutaneous injection (Table 2). Table 2. Recommended Dosage for Pediatric Patients with pJIA, PsO and JPsA Body Weight Recommended Dosage 63 kg (138 pounds) or more 50 mg weekly Less than 63 kg (138 pounds) 0.8 mg/kg weekly To achieve pediatric doses other than 25 mg or 50 mg, use Enbrel solution in a single-dose vial or reconstituted lyophilized powder in a multiple-dose vial. Dosages of Enbrel higher than those described in Table 2 have not been studied in pediatric patients. In pJIA patients, glucocorticoids, NSAIDs, or analgesics may be continued during treatment with Enbrel. 2.5 Preparation Instructions for 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. Administer injections subcutaneously in the thigh, abdomen or outer area of the upper arm. The Enbrel devices are not made with natural rubber latex. The Enbrel (etanercept) "Instructions for Use" insert for each presentation contains more detailed instructions on injection site selection and the preparation of Enbrel. Preparation of Enbrel Single-dose Prefilled Syringe For a more comfortable injection, leave Enbrel prefilled syringes at room temperature for about 15 to 30 minutes before injecting. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature. Inspect visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present. When using the Enbrel single-dose prefilled syringe, check to see if the amount of liquid in the prefilled syringe falls between the two purple fill level indicator lines on the syringe. If the syringe does not have the right amount of liquid, DO NOT USE THAT SYRINGE. Preparation of Enbrel Single-dose Prefilled SureClick Autoinjector Leave the autoinjector at room temperature for at least 30 minutes before injecting. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature. Inspect visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present. Preparation of Enbrel Single-dose Vial For a more comfortable injection, leave Enbrel vial(s) at room temperature for at least 30 minutes before injecting. DO NOT remove the vial cap while allowing the vial to reach room temperature. Inspect visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present. When using the Enbrel single-dose vial, administer the correct dose of solution using the following recommended materials: A 1 mL Luer-Lock syringe. A withdrawal needle with Luer-Lock connection, sterile, 22-gauge, length 1 ½ inch. An injection needle with Luer-Lock connection, sterile, 27-gauge, length ½ inch. Two vials may be required to administer the total prescribed dose. Use the same syringe for each vial. The vial does not contain preservatives; therefore, discard unused portions. Preparation of Enbrel Lyophilized Powder in a Multiple-dose Vial Enbrel lyophilized powder should be reconstituted aseptically with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol), giving a solution of 1 mL containing 25 mg of Enbrel. A vial adapter is supplied for use when reconstituting the lyophilized powder. However, the vial adapter should not be used if multiple doses are going to be withdrawn from the vial. If the vial will be used for multiple doses, a 25-gauge needle should be used for reconstituting and withdrawing Enbrel, and the supplied "Mixing Date:" sticker should be attached to the vial and the date of reconstitution entered. Reconstituted solution must be refrigerated at 36°F to 46°F (2°C to 8°C) and used within 14 days. Discard reconstituted solution after 14 days because product stability and sterility cannot be assured after 14 days. DO NOT store reconstituted Enbrel solution at room temperature. For a more comfortable injection, leave the Enbrel dose tray at room temperature for about 15 to 30 minutes before injecting. If using the vial adapter, twist the vial adapter onto the diluent syringe. Then, place the vial adapter over the Enbrel vial and insert the vial adapter into the vial stopper. Push down on the plunger to inject the diluent into the Enbrel vial. If using a 25-gauge needle to reconstitute and withdraw Enbrel, the diluent should be injected very slowly into the Enbrel vial. It is normal for some foaming to occur. Keeping the diluent syringe in place, gently swirl the contents of the Enbrel vial during dissolution. To avoid excessive foaming, do not shake or vigorously agitate. Generally, dissolution of Enbrel takes less than 10 minutes. Do not use the solution if discolored or cloudy, or if particulate matter remains. Withdraw the correct dose of reconstituted solution into the syringe. Some foam or bubbles may remain in the vial. Remove the syringe from the vial adapter or remove the 25-gauge needle from the syringe. Attach a 27-gauge needle to inject Enbrel. The contents of one vial of Enbrel solution should not be mixed with, or transferred into, the contents of another vial of Enbrel. No other medications should be added to solutions containing Enbrel, and do not reconstitute Enbrel with other diluents. Do not filter reconstituted solution during preparation or administration. Preparation of Enbrel Mini ® single-dose prefilled cartridge using the AutoTouch ® reusable autoinjector Leave Enbrel Mini single-dose prefilled cartridge at room temperature for at least 30 minutes before injecting. DO NOT remove the purple cap while allowing the cartridge to reach room temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present. To use AutoTouch reusable autoinjector, open the door by pushing the door button and inserting Enbrel Mini single-dose prefilled cartridge into AutoTouch. When inserted correctly, Enbrel Mini single-dose prefilled cartridge will slide freely and completely into the door. Close the door and AutoTouch reusable autoinjector is ready for injection.

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

10 OVERDOSAGE No dose-limiting toxicities have been observed during clinical trials of Enbrel. Single IV doses up to 60 mg/m 2 (approximately twice the recommended dose) have been administered to healthy volunteers in an endotoxemia study without evidence of dose-limiting toxicities.

7 DRUG INTERACTIONS Specific drug interaction studies have not been conducted with Enbrel. Live vaccines – Avoid concurrent administration with Enbrel ( 5.8 , 7.1 ) Anakinra – Increased risk of serious infection ( 5.12 , 7.2 ) Abatacept – Increased risk of serious adverse events, including infections ( 5.12 , 7.2 ) Cyclophosphamide – Not recommended for use with Enbrel. ( 7.3 ) 7.1 Vaccines Most PsA patients receiving Enbrel were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and fewer patients had 2-fold rises in titers compared to patients not receiving Enbrel. The clinical significance of this is unknown. Patients receiving Enbrel may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving Enbrel. Patients with a significant exposure to varicella virus should temporarily discontinue Enbrel therapy and be considered for prophylactic treatment with varicella zoster immune globulin [see Warnings and Precautions (5.8 , 5.10) ] . 7.2 Immune-Modulating Biologic Products In a study in which patients with active RA were treated for up to 24 weeks with concurrent Enbrel and anakinra therapy, a 7% rate of serious infections was observed, which was higher than that observed with Enbrel alone (0%) [see Warnings and Precautions (5.12) ] and did not result in higher ACR response rates compared to Enbrel alone. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure. Two percent of patients treated concurrently with Enbrel and anakinra developed neutropenia (ANC < 1 × 10 9 /L). In clinical studies, concurrent administration of abatacept and Enbrel resulted in increased incidences of serious adverse events, including infections, and did not demonstrate increased clinical benefit [see Warnings and Precautions (5.12) ] . 7.3 Cyclophosphamide The use of Enbrel in patients receiving concurrent cyclophosphamide therapy is not recommended [see Warnings and Precautions (5.11) ] . 7.4 Sulfasalazine Patients in a clinical study who were on established therapy with sulfasalazine, to which Enbrel was added, were noted to develop a mild decrease in mean neutrophil counts in comparison to groups treated with either Enbrel or sulfasalazine alone. The clinical significance of this observation is unknown.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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 RA, polyarticular JIA, PsA, and AS and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of PsO. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, JIA, PsA, AS, and PsO. Two distinct receptors for TNF (TNFRs), 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 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. 12.2 Pharmacodynamics Etanercept can modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (e.g. E-selectin, and to 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. 12.3 Pharmacokinetics After administration of 25 mg of Enbrel by a single SC injection to 25 patients with RA, a mean ± standard deviation half-life of 102 ± 30 hours was observed with a clearance of 160 ± 80 mL/hr. A maximum serum concentration (C max ) of 1.1 ± 0.6 mcg/mL and time to C max of 69 ± 34 hours was observed in these patients following a single 25 mg dose. After 6 months of twice weekly 25 mg doses in these same RA patients, the mean C max was 2.4 ± 1.0 mcg/mL (N = 23). Patients exhibited a 2- to 7-fold increase in peak serum concentrations and approximately 4-fold increase in AUC 0-72 hr (range 1- to 17-fold) with repeated dosing. Serum concentrations in patients with RA have not been measured for periods of dosing that exceed 6 months. In another study, serum concentration profiles at steady-state were comparable among patients with RA treated with 50 mg Enbrel once weekly and those treated with 25 mg Enbrel twice weekly. The mean (± standard deviation) C max , C min , and partial AUC were 2.4 ± 1.5 mcg/mL, 1.2 ± 0.7 mcg/mL, and 297 ± 166 mcg∙h/mL, respectively, for patients treated with 50 mg Enbrel once weekly (N = 21); and 2.6 ± 1.2 mcg/mL, 1.4 ± 0.7 mcg/mL, and 316 ± 135 mcg∙h/mL for patients treated with 25 mg Enbrel twice weekly (N = 16). Patients with JIA (ages 4 to 17 years) were administered 0.4 mg/kg of Enbrel twice weekly (up to a maximum dose of 50 mg per week) for up to 18 weeks. The mean serum concentration after repeated SC dosing was 2.1 mcg/mL, with a range of 0.7 to 4.3 mcg/mL. Limited data suggest that the clearance of etanercept is reduced slightly in children ages 4 to 8 years. Population pharmacokinetic analyses predict that the pharmacokinetic differences between the regimens of 0.4 mg/kg twice weekly and 0.8 mg/kg once weekly in JIA patients are of the same magnitude as the differences observed between twice weekly and weekly regimens in adult RA patients. The mean (± SD) serum steady-state trough concentrations for 50 mg QW dosing in adult PsA subjects were 2.1 ± 1.2 mcg/mL and 2.1 ± 1.4 mcg/mL at weeks 24 and 48, respectively. The mean (± SD) serum steady-state trough concentrations for the 50 mg QW dosing in adult PsO subjects were 1.5 ± 0.7 mcg/mL. Pediatric PsO patients (age 4 to 17 years) were administered 0.8 mg/kg of Enbrel once weekly (up to a maximum dose of 50 mg per week) for up to 48 weeks. The mean (± SD) serum steady-state trough concentrations ranged from 1.6 ± 0.8 to 2.1 ± 1.3 mcg/mL at weeks 12, 24, and 48. Overall, the observed etanercept concentrations in patients with JIA and pediatric PsO were within the range of those observed for adult RA, PsA and PsO after administration of Enbrel. In clinical studies with Enbrel, pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. The pharmacokinetics of etanercept were unaltered by concomitant MTX in RA patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on etanercept disposition.

12.1 Mechanism of Action 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 RA, polyarticular JIA, PsA, and AS and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of PsO. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, JIA, PsA, AS, and PsO. Two distinct receptors for TNF (TNFRs), 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 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.

12.2 Pharmacodynamics Etanercept can modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (e.g. E-selectin, and to 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.

12.3 Pharmacokinetics After administration of 25 mg of Enbrel by a single SC injection to 25 patients with RA, a mean ± standard deviation half-life of 102 ± 30 hours was observed with a clearance of 160 ± 80 mL/hr. A maximum serum concentration (C max ) of 1.1 ± 0.6 mcg/mL and time to C max of 69 ± 34 hours was observed in these patients following a single 25 mg dose. After 6 months of twice weekly 25 mg doses in these same RA patients, the mean C max was 2.4 ± 1.0 mcg/mL (N = 23). Patients exhibited a 2- to 7-fold increase in peak serum concentrations and approximately 4-fold increase in AUC 0-72 hr (range 1- to 17-fold) with repeated dosing. Serum concentrations in patients with RA have not been measured for periods of dosing that exceed 6 months. In another study, serum concentration profiles at steady-state were comparable among patients with RA treated with 50 mg Enbrel once weekly and those treated with 25 mg Enbrel twice weekly. The mean (± standard deviation) C max , C min , and partial AUC were 2.4 ± 1.5 mcg/mL, 1.2 ± 0.7 mcg/mL, and 297 ± 166 mcg∙h/mL, respectively, for patients treated with 50 mg Enbrel once weekly (N = 21); and 2.6 ± 1.2 mcg/mL, 1.4 ± 0.7 mcg/mL, and 316 ± 135 mcg∙h/mL for patients treated with 25 mg Enbrel twice weekly (N = 16). Patients with JIA (ages 4 to 17 years) were administered 0.4 mg/kg of Enbrel twice weekly (up to a maximum dose of 50 mg per week) for up to 18 weeks. The mean serum concentration after repeated SC dosing was 2.1 mcg/mL, with a range of 0.7 to 4.3 mcg/mL. Limited data suggest that the clearance of etanercept is reduced slightly in children ages 4 to 8 years. Population pharmacokinetic analyses predict that the pharmacokinetic differences between the regimens of 0.4 mg/kg twice weekly and 0.8 mg/kg once weekly in JIA patients are of the same magnitude as the differences observed between twice weekly and weekly regimens in adult RA patients. The mean (± SD) serum steady-state trough concentrations for 50 mg QW dosing in adult PsA subjects were 2.1 ± 1.2 mcg/mL and 2.1 ± 1.4 mcg/mL at weeks 24 and 48, respectively. The mean (± SD) serum steady-state trough concentrations for the 50 mg QW dosing in adult PsO subjects were 1.5 ± 0.7 mcg/mL. Pediatric PsO patients (age 4 to 17 years) were administered 0.8 mg/kg of Enbrel once weekly (up to a maximum dose of 50 mg per week) for up to 48 weeks. The mean (± SD) serum steady-state trough concentrations ranged from 1.6 ± 0.8 to 2.1 ± 1.3 mcg/mL at weeks 12, 24, and 48. Overall, the observed etanercept concentrations in patients with JIA and pediatric PsO were within the range of those observed for adult RA, PsA and PsO after administration of Enbrel. In clinical studies with Enbrel, pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. The pharmacokinetics of etanercept were unaltered by concomitant MTX in RA patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on etanercept disposition.

20231024

205

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

ENBREL etanercept ETANERCEPT ETANERCEPT ARGININE HYDROCHLORIDE SODIUM CHLORIDE SUCROSE ENBREL etanercept ETANERCEPT ETANERCEPT ARGININE HYDROCHLORIDE SODIUM CHLORIDE SUCROSE ENBREL etanercept ENBREL etanercept ETANERCEPT ETANERCEPT MANNITOL SUCROSE TROMETHAMINE Sterile Bacteriostatic Water Sterile Bacteriostatic Water BENZYL ALCOHOL WATER ENBREL etanercept ETANERCEPT ETANERCEPT ARGININE HYDROCHLORIDE SODIUM CHLORIDE SUCROSE ENBREL etanercept ETANERCEPT ETANERCEPT ARGININE HYDROCHLORIDE SODIUM CHLORIDE SUCROSE ENBREL etanercept ETANERCEPT ETANERCEPT ARGININE HYDROCHLORIDE SODIUM CHLORIDE SUCROSE ENBREL etanercept ETANERCEPT ETANERCEPT ARGININE HYDROCHLORIDE SODIUM CHLORIDE SUCROSE ENBREL etanercept ETANERCEPT ETANERCEPT ARGININE HYDROCHLORIDE SODIUM CHLORIDE SUCROSE ENBREL etanercept ETANERCEPT ETANERCEPT ARGININE HYDROCHLORIDE SODIUM CHLORIDE SUCROSE ENBREL etanercept ETANERCEPT ETANERCEPT ARGININE HYDROCHLORIDE SODIUM CHLORIDE SUCROSE ENBREL etanercept ETANERCEPT ETANERCEPT ARGININE HYDROCHLORIDE SODIUM CHLORIDE SUCROSE

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

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

BLA103795

ENBREL

etanercept

58406-055

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

PRINCIPAL DISPLAY PANEL Contains 4 Single-Dose Prefilled Syringes NDC 58406-455-04 Enbrel ® etanercept 25 mg/0.5 mL Single-Dose Prefilled Syringe 25 mg/0.5 mL Attention: Not for use in pediatric patients under 31 kg (68 pounds). For Subcutaneous Use Only Sterile Solution – No Preservative Refrigerate at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Carton contents (4 single-dose prefilled syringes, 1 package insert with attached Medication Guide) are intended to be dispensed as a unit. ATTENTION: Enclosed Medication Guide is required for each patient. This Product Contains Dry Natural Rubber. AMGEN ® Rx Only Manufactured by Immunex Corporation, Thousand Oaks, CA 91320 PRINCIPAL DISPLAY PANEL Contains 4 Single-Dose Prefilled Syringes NDC 58406-455-04 Enbrel® etanercept 25 mg/0.5 mL Single-Dose Prefilled Syringe 25 mg/0.5 mL Attention: Not for use in pediatric patients under 31 kg (68 pounds). For Subcutaneous Use Only Sterile Solution – No Preservative Refrigerate at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Carton contents (4 single-dose prefilled syringes, 1 package insert with attached Medication Guide) are intended to be dispensed as a unit. ATTENTION: Enclosed Medication Guide is required for each patient. This Product Contains Dry Natural Rubber. AMGEN® Rx Only Manufactured by Immunex Corporation, Thousand Oaks, CA 91320

Indications and Usage, Juvenile Psoriatic Arthritis ( 1.6 ) 10/2023 Dosage and Administration, Pediatric Patients ( 2.2 ) 10/2023

AMGEN ® Enbrel ® (etanercept) Manufactured by: Immunex Corporation Thousand Oaks, CA 91320-1799 U.S. License Number 1132 Patent: http://pat.amgen.com/enbrel/ © 1998-2023 Immunex Corporation. All rights reserved. 1XXXXXX – v70 This printed material is recyclable. Image

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

Instructions for Use Enbrel ® (en-brel) (etanercept) injection, for subcutaneous use Single-Dose Prefilled SureClick ® Autoinjector 50 mg/mL This Instructions for Use contains information on how to inject ENBREL. Guide to parts Before use After use Important: Needle is inside the green safety guard. Important Important Information You Need to Know Before Injecting ENBREL: It is important that you do not try to give yourself or someone else the injection unless you have received training from your healthcare provider. Storing your Enbrel SureClick autoinjector: Keep the autoinjector and all medicines out of the reach of children. Keep the autoinjector in the original carton to protect from light. Keep the autoinjector in the refrigerator at 36°F to 46°F (2°C to 8°C). After removing from the refrigerator, the autoinjector may be kept at room temperature between 68°F to 77°F (20°C to 25°C) and must be used within 30 days. Do not put it back in the refrigerator after it has reached room temperature. Throw away Enbrel that has been stored at room temperature for more than 30 days. Do not store the autoinjector in extreme heat or cold. For example, avoid storing the autoinjector in your vehicle's glove box or trunk. Do not freeze or use the autoinjector if it has been frozen. Using your Enbrel SureClick autoinjector: Do not use the autoinjector after the expiration date on the label. Do not shake the autoinjector. Do not remove the white cap from the autoinjector until you are ready to inject. Leaving the cap off for more than 5 minutes can dry out the medicine. Do not use the autoinjector if it has been dropped on a hard surface. Part of the autoinjector may be broken even if you cannot see the break. Use a new autoinjector and call 1-888-4ENBREL (1-888-436-2735). The autoinjector is not made with natural rubber latex. Children must weigh at least 138 pounds to use the Enbrel SureClick autoinjector. Children who weigh less than 138 pounds should use a different form of Enbrel. For more information or help, contact your healthcare provider, visit www.enbrel.com or call 1-888-4ENBREL (1-888-436-2735). Step 1: Preparing to inject ENBREL 1A Remove the autoinjector from the carton. Carefully lift the autoinjector straight up out of the carton. Before you inject, always check the label of the autoinjector to make sure you have the correct medicine and the correct dose of ENBREL. Put the original carton with any unused autoinjectors back in the refrigerator. Wait at least 30 minutes for the autoinjector to reach room temperature before injecting. This is important for administering the entire dose and helps minimize discomfort. ENBREL may take longer to inject if it has not reached room temperature. Do not heat the autoinjector. Let it come to room temperature naturally. 30 minutes Do not put the autoinjector back in the refrigerator after it has reached room temperature. Do not try to warm the autoinjector by using a heat source such as hot water or microwave. Do not leave the autoinjector in direct sunlight. Do not shake the autoinjector. Do not remove the white cap from the autoinjector yet. 1B Inspect the Enbrel SureClick autoinjector. Make sure the medicine in the window is clear and colorless. It is okay if you see small white particles in the medicine. Do not use the autoinjector if the medicine is cloudy or discolored or contains large lumps, flakes, or colored particles. Do not use the autoinjector if any part appears cracked or broken. Do not use the autoinjector if the autoinjector has been dropped. Do not use the autoinjector if the white cap is missing or not securely attached. Do not use the autoinjector if the expiration date printed on the label has passed. In all cases, use a new autoinjector and call 1-888-4ENBREL (1-888-436-2735). 1C Gather all materials needed for your injection. Wash your hands thoroughly with soap and water. On a clean, well-lit work surface, place the: New autoinjector Alcohol wipes Cotton balls or gauze pads Adhesive bandages Sharps disposal container ( see Step 4: Finish ) 1D Prepare and clean your injection site. Only use these injection sites: Thigh Stomach (abdomen), except for a 2 inch area around your navel (belly button) Outer area of upper arm (only if someone else is giving you the injection) Clean your injection site with an alcohol wipe. Let your skin dry. Do not touch this area again before injecting. Choose a different site each time you give yourself an injection. If you want to use the same injection site, make sure it is not the same spot you used for the last injection. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. Avoid injecting directly into raised, thick, red, or scaly skin patch or lesion. Step 2: Get ready 2A Pull the white cap straight off only when you are ready to inject. Do not leave the white cap off for more than 5 minutes . This can dry out the medicine. 5 minutes It is normal to see a drop of liquid at the end of the needle or green safety guard. Do not twist, bend, or wiggle the white cap. Do not put the white cap back onto the autoinjector. Do not put fingers into the green safety guard. Do not remove the white cap from the autoinjector until you are ready to inject. If you are unable to inject, please contact your healthcare provider. 2B Create a firm surface at the selected injection site (thigh, stomach, or outer areas of the upper arm), by using either the Stretch method or the Pinch method. Stretch method: Stretch the skin firmly by moving your thumb and fingers in opposite directions, creating an area about 2 inches wide. Pinch method: Pinch the skin firmly between your thumb and fingers, creating an area about 2 inches wide. Important: Keep skin stretched or pinched while injecting. Step 3: Inject 3A Keep holding the stretched or pinched skin. With the white cap off, put the green safety guard on your skin at 90 degrees. The needle is inside the green safety guard. Do not touch the purple start button yet. 3B Firmly push down the autoinjector onto the skin until it stops moving. Important: You must push all the way down but do not touch the purple start button until you are ready to inject. 3C When you are ready to inject, press the purple start button. You will hear a click. 3D Keep pushing the autoinjector down on your skin. Then lift your thumb while still holding the autoinjector on your skin. Your injection could take about 15 seconds to complete. Window turns from clear to yellow when the injection is done. You may hear a second click. NOTE: After you remove the autoinjector from your skin, the needle will be automatically covered. Important: When you remove the autoinjector, if the window has not turned yellow, or if it looks like the medicine is still injecting, this means you have not received a full dose. Call your healthcare provider immediately. Step 4: Finish 4A Throw away the used autoinjector and white needle cap. Put the used autoinjector and white needle cap in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the autoinjector or white cap in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Do not reuse the autoinjector. Do not recap the autoinjector or put fingers into the green safety guard. Important: Always keep the sharps disposal container out of the reach of children. 4B Check the injection site. If there is blood, press a cotton ball or gauze pad on your injection site. Apply an adhesive bandage if needed. Do not rub the injection site. Commonly Asked Questions This Instructions for Use has been approved by the U.S. Food and Drug Administration. What will happen if I press the purple start button before I am ready to do the injection on my skin? Even when you press the purple start button, the injection will only happen when the green safety guard is also pushed into the autoinjector. Can I move the autoinjector around on my skin while I am choosing an injection site? It is okay to move the autoinjector around on the injection site as long as you do not press the purple start button. However, if you press the purple start button and the green safety guard is pushed into the autoinjector, the injection will begin. Can I release the purple start button after I start my injection? You can release the purple start button, but continue to hold the autoinjector firmly against your skin during the injection. Will the purple start button pop up after I release my thumb? The purple start button may not pop up after you release your thumb if you held your thumb down during the injection. This is okay. What do I do if I did not hear a second click? If you did not hear a second click, you can confirm a complete injection by checking that the window has turned yellow. Whom do I contact if I need help with the autoinjector or my injection? A healthcare provider familiar with ENBREL should be able to answer your questions. For more information, call 1-888-4ENBREL (1-888-436-2735) or visit www.enbrel.com. AMGEN ® Manufactured by: Immunex Corporation Thousand Oaks, CA 91320-1799 U.S. License Number 1132 ©1998 – 2016, 2019-2023 Immunex Corporation. All rights reserved. Revised: 06/2023 v18 This printed material is recyclable. Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 10/2023 Medication Guide Enbrel ® (en-brel) (etanercept) injection, for subcutaneous use Enbrel ® (en-brel) (etanercept) for injection, for subcutaneous use Read the Medication Guide that comes with Enbrel before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment. It is important to remain under your healthcare provider's care while using Enbrel. Enbrel is a prescription medicine called a Tumor Necrosis Factor (TNF) blocker that affects your immune system. What is the most important information I should know about Enbrel? Enbrel may cause serious side effects, including: 1. Risk of Infection 2. Risk of Cancer 1. Risk of infection Enbrel can lower the ability of your immune system to fight infections. Some people have serious infections while taking Enbrel. These infections include tuberculosis (TB), and infections caused by viruses, fungi, or bacteria that spread throughout their body. Some people have died from these infections. Your healthcare provider should test you for TB before starting Enbrel. Your healthcare provider should monitor you closely for symptoms of TB during treatment with Enbrel even if you tested negative for TB. Your healthcare provider should check you for symptoms of any type of infection before, during, and after your treatment with Enbrel. You should not start taking Enbrel if you have any kind of infection unless your healthcare provider says it is okay. 2. Risk of cancer There have been cases of unusual cancers, some resulting in death, in children and teenagers who started using TNF-blocking agents at less than 18 years of age. For children, teenagers, and adults taking TNF-blocker medicines, including Enbrel, the chances of getting lymphoma or other cancers may increase. People with rheumatoid arthritis, especially those with very active disease, may be more likely to get lymphoma. Before starting Enbrel, be sure to talk to your healthcare provider: Enbrel may not be right for you. Before starting Enbrel, tell your healthcare provider about all of your medical conditions, including: Infections. Tell your healthcare provider if you: have an infection. See " What is the most important information I should know about Enbrel? " are being treated for an infection. think you have an infection. have symptoms of an infection such as fever, sweats or chills, cough or flu-like symptoms, shortness of breath, blood in your phlegm, weight loss, muscle aches, warm, red or painful areas on your skin, sores on your body, diarrhea or stomach pain, burning when you urinate or urinating more often than normal, and feel very tired. have any open cuts on your body. get a lot of infections or have infections that keep coming back. have diabetes, HIV, or a weak immune system. People with these conditions have a higher chance for infections. have TB, or have been in close contact with someone with TB. were born in, lived in, or traveled to countries where there is a risk for getting TB. Ask your healthcare provider if you are not sure. live, have lived in, or traveled to certain parts of the country (such as the Ohio and Mississippi River valleys, or the Southwest) where there is a greater risk for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis). These infections may happen or become more severe if you use Enbrel. Ask your healthcare provider if you do not know if you live or have lived in an area where these infections are common. have or have had hepatitis B. Also, before starting Enbrel, tell your healthcare provider: About all the medicines you take including prescription and over-the-counter medicines, vitamins and herbal supplements including: Orencia (abatacept) or Kineret (anakinra). You have a higher chance for serious infections when taking Enbrel with Orencia or Kineret. Cyclophosphamide (Cytoxan). You may have a higher chance for getting certain cancers when taking Enbrel with cyclophosphamide. Anti-diabetic medicines. If you have diabetes and are taking medicine to control your diabetes, your healthcare provider may decide you need less anti-diabetic medicine while taking Enbrel. Keep a list of all your medicines with you to show your healthcare provider and pharmacist each time you get a new medicine. Ask your healthcare provider if you are not sure if your medicine is one listed above. Other important medical information you should tell your healthcare provider before starting Enbrel, includes if you: have or had a nervous system problem such as multiple sclerosis or Guillain-Barré syndrome. have or had heart failure. are scheduled to have surgery. have recently received or are scheduled to receive a vaccine. All vaccines should be brought up-to-date before starting Enbrel. People taking Enbrel should not receive live vaccines. Ask your healthcare provider if you are not sure if you received a live vaccine. have been around someone with varicella zoster (chicken pox). are pregnant or plan to become pregnant. It is not known if Enbrel will harm your unborn baby. If you took Enbrel during pregnancy, talk to your healthcare provider prior to administration of live vaccines to your infant. are breastfeeding or plan to breastfeed. Enbrel can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Enbrel. See the section " What are the possible side effects of Enbrel? " below for more information. What is Enbrel? Enbrel is a prescription medicine called a Tumor Necrosis Factor (TNF) blocker. Enbrel is used to treat: moderately to severely active rheumatoid arthritis (RA). Enbrel can be used alone or with a medicine called methotrexate. moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA) in children 2 years of age or older. psoriatic arthritis (PsA) in adults. Enbrel can be used alone or with methotrexate. active juvenile psoriatic arthritis (JPsA) in children 2 years of age or older. ankylosing spondylitis (AS). chronic moderate to severe plaque psoriasis (PsO) in children 4 years of age or older and adults who may benefit from taking injections or pills (systemic therapy) or phototherapy (ultraviolet light). You may continue to use other medicines that help treat your condition while taking Enbrel, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and prescription steroids, as recommended by your healthcare provider. Enbrel can help reduce joint damage and the signs and symptoms of the above-mentioned diseases. People with these diseases have too much of a protein called tumor necrosis factor (TNF), which is made by your immune system. Enbrel can reduce the effect of TNF in the body and block the damage that too much TNF can cause, but it can also lower the ability of your immune system to fight infections. See " What is the most important information I should know about Enbrel? " and " What are the possible side effects of Enbrel? " Who should not use Enbrel? Do not use Enbrel if you: have an infection that has spread through your body (sepsis). How should I use Enbrel? Enbrel is given as an injection under the skin (subcutaneous or SC). If your healthcare provider decides that you or a caregiver can give the injections of Enbrel at home, you or your caregiver should receive training on the right way to prepare and inject Enbrel. Do not try to inject Enbrel until you have been shown the right way by your healthcare provider or nurse. Enbrel is available in the forms listed below. Your healthcare provider will prescribe the type that is best for you. Single-dose Prefilled Syringe Single-dose Prefilled SureClick Autoinjector Single-dose Vial Multiple-dose Vial Enbrel Mini single-dose cartridge for use with the AutoTouch reusable autoinjector See the detailed Instructions for Use with this Medication Guide for instructions about the right way to store, prepare, and give your Enbrel injections at home. Your healthcare provider will tell you how often you should use Enbrel. Do not miss any doses of Enbrel. If you forget to use Enbrel, inject your dose as soon as you remember. Then, take your next dose at your regular(ly) scheduled time. In case you are not sure when to inject Enbrel, call your healthcare provider or pharmacist. Do not use Enbrel more often than as directed by your healthcare provider. Your child's dose of Enbrel depends on his or her weight. Your child's healthcare provider will tell you which form of Enbrel to use and how much to give your child. What are the possible side effects of Enbrel? Enbrel can cause serious side effects, including: See " What is the most important information I should know about Enbrel? " Infections. Enbrel can make you more likely to get infections or make any infection that you have worse. Call your healthcare provider right away if you have any symptoms of an infection. See " Before starting Enbrel, be sure to talk to your healthcare provider " for a list of symptoms of infection. Previous Hepatitis B infection. If you have been previously infected with the hepatitis B virus (a virus that affects the liver), the virus can become active while you use Enbrel. Your healthcare provider may do a blood test before you start treatment with Enbrel and while you use Enbrel. Nervous system problems. Rarely, people who use TNF-blocker medicines have developed nervous system problems such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes. Tell your healthcare provider right away if you get any of these symptoms: numbness or tingling in any part of your body, vision changes, weakness in your arms and legs, and dizziness. Blood problems. Low blood counts have been seen with other TNF-blocker medicines. Your body may not make enough of the blood cells that help fight infections or help stop bleeding. Symptoms include fever, bruising or bleeding very easily, or looking pale. New heart failure or worsening of heart failure you already have. New or worse heart failure can happen in people who use TNF-blocker medicines like Enbrel. If you have heart failure your condition should be watched closely while you take Enbrel. Call your healthcare provider right away if you get new or worsening symptoms of heart failure while taking Enbrel, such as shortness of breath or swelling of your lower legs or feet. Psoriasis. Some people using Enbrel developed new psoriasis or worsening of psoriasis they already had. Tell your healthcare provider if you develop red scaly patches or raised bumps that may be filled with pus. Your healthcare provider may decide to stop your treatment with Enbrel. Allergic reactions. Allergic reactions can happen to people who use TNF-blocker medicines. Call your healthcare provider right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction include a severe rash, a swollen face, or trouble breathing. Autoimmune reactions, including: Lupus-like syndrome. Symptoms include a rash on your face and arms that gets worse in the sun. Tell your healthcare provider if you have this symptom. Symptoms may go away when you stop using Enbrel. Autoimmune hepatitis. Liver problems can happen in people who use TNF-blocker medicines, including Enbrel. These problems can lead to liver failure and death. Call your healthcare provider right away if you have any of these symptoms: feel very tired, skin or eyes look yellow, poor appetite or vomiting, pain on the right side of your stomach (abdomen). Common side effects of Enbrel include: Injection site reactions such as redness, itching, pain, swelling, bleeding or bruising. These symptoms usually go away within 3 to 5 days. If you have pain, redness, or swelling around the injection site that does not go away or gets worse, call your healthcare provider. Upper respiratory infections (sinus infections). These are not all the side effects with Enbrel. Tell your healthcare provider about any side effect that bothers you or does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Enbrel? Store Enbrel in the refrigerator between 36°F to 46°F (2°C to 8°C). Store Enbrel in the original carton to protect from light or damage. If needed, you may store your dose tray for the multiple-dose vial at room temperature between 68°F to 77°F (20°C to 25°C) for up to 14 days. When the dose tray has reached room temperature, do not put it back in the refrigerator. Throw away the dose tray that has been stored at room temperature after 14 days. Mixed Enbrel multiple-dose vials should be used right away or kept in the refrigerator between 36°F to 46°F (2°C to 8°C) for up to 14 days. If needed, you may store the Enbrel prefilled syringe, SureClick autoinjector, single-dose vial, or Enbrel Mini cartridge at room temperature between 68°F to 77°F (20°C to 25°C) for up to 30 days. When Enbrel has reached room temperature, do not put it back in the refrigerator. Throw away Enbrel that has been stored at room temperature after 30 days. Do not store Enbrel in extreme heat or cold such as in your vehicle's glove box or trunk. Do not shake. Do not freeze. Keep Enbrel and all medicines out of the reach of children. General information about the safe and effective use of Enbrel. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Enbrel for a condition for which it was not prescribed. Do not give Enbrel to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about Enbrel. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Enbrel that was written for health professionals. What are the ingredients in Enbrel? Single-dose Prefilled Syringe, Single-dose Prefilled SureClick Autoinjector, Single-dose Vial and Enbrel Mini single-dose cartridge: Active Ingredient: etanercept Inactive Ingredients: L-arginine hydrochloride, sodium chloride, and sucrose Multiple-dose Vial: Active Ingredient: etanercept Inactive Ingredients: mannitol, sucrose, tromethamine AMGEN ® Manufactured by: Immunex Corporation, Thousand Oaks, CA 91320-1799, U.S. License Number 1132 Immunex Corporation. All rights reserved. 1XXXXXX – v22 For more information, call 1 888 4ENBREL (1 888 436 2735) or www.enbrel.com. This printed material is recyclable Image

14 CLINICAL STUDIES 14.1 Adult Rheumatoid Arthritis The safety and efficacy of Enbrel were assessed in four randomized, double-blind, controlled studies. The results of all four trials were expressed in percentage of patients with improvement in RA using ACR response criteria. Study I evaluated 234 patients with active RA who were ≥ 18 years old, had failed therapy with at least one but no more than four disease-modifying antirheumatic drugs (DMARDs) (e.g. hydroxychloroquine, oral or injectable gold, MTX, azathioprine, D-penicillamine, sulfasalazine), and had ≥ 12 tender joints, ≥ 10 swollen joints, and either erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr, C-reactive protein (CRP) > 2.0 mg/dL, or morning stiffness for ≥ 45 minutes. Doses of 10 mg or 25 mg Enbrel or placebo were administered SC twice a week for 6 consecutive months. Study II evaluated 89 patients and had similar inclusion criteria to Study I except that patients in Study II had additionally received MTX for at least 6 months with a stable dose (12.5 to 25 mg/week) for at least 4 weeks and they had at least 6 tender or painful joints. Patients in Study II received a dose of 25 mg Enbrel or placebo SC twice a week for 6 months in addition to their stable MTX dose. Study III compared the efficacy of Enbrel to MTX in patients with active RA. This study evaluated 632 patients who were ≥ 18 years old with early (≤ 3 years disease duration) active RA, had never received treatment with MTX, and had ≥ 12 tender joints, ≥ 10 swollen joints, and either ESR ≥ 28 mm/hr, CRP > 2.0 mg/dL, or morning stiffness for ≥ 45 minutes. Doses of 10 mg or 25 mg Enbrel were administered SC twice a week for 12 consecutive months. The study was unblinded after all patients had completed at least 12 months (and a median of 17.3 months) of therapy. The majority of patients remained in the study on the treatment to which they were randomized through 2 years, after which they entered an extension study and received open-label 25 mg Enbrel. MTX tablets (escalated from 7.5 mg/week to a maximum of 20 mg/week over the first 8 weeks of the trial) or placebo tablets were given once a week on the same day as the injection of placebo or Enbrel doses, respectively. Study IV evaluated 682 adult patients with active RA of 6 months to 20 years duration (mean of 7 years) who had an inadequate response to at least one DMARD other than MTX. Forty-three percent of patients had previously received MTX for a mean of 2 years prior to the trial at a mean dose of 12.9 mg. Patients were excluded from this study if MTX had been discontinued for lack of efficacy or for safety considerations. The patient baseline characteristics were similar to those of patients in Study I. Patients were randomized to MTX alone (7.5 to 20 mg weekly, dose escalated as described for Study III; median dose 20 mg), Enbrel alone (25 mg twice weekly), or the combination of Enbrel and MTX initiated concurrently (at the same doses as above). The study evaluated ACR response, Sharp radiographic score, and safety. Clinical Response A higher percentage of patients treated with Enbrel and Enbrel in combination with MTX achieved ACR 20, ACR 50, and ACR 70 responses and Major Clinical Responses than in the comparison groups. The results of Studies I, II, and III are summarized in Table 6. The results of Study IV are summarized in Table 7. Table 6. ACR Responses in Placebo- and Active-Controlled Trials (Percent of Patients) Placebo-Controlled Active-Controlled Study I Study II Study III Placebo Enbrel 25 mg Enbrel SC twice weekly. MTX/Placebo MTX/Enbrel MTX Enbrel Response N = 80 N = 78 N = 30 N = 59 N = 217 N = 207 ACR 20 Month 3 23% 62% p < 0.01, Enbrel versus placebo. 33% 66% 56% 62% Month 6 11% 59% 27% 71% 58% 65% Month 12 NA NA NA NA 65% 72% ACR 50 Month 3 8% 41% 0% 42% 24% 29% Month 6 5% 40% 3% 39% 32% 40% Month 12 NA NA NA NA 43% 49% ACR 70 Month 3 4% 15% 0% 15% 7% 13% p < 0.05, Enbrel versus MTX. Month 6 1% 15% 0% 15% 14% 21% Month 12 NA NA NA NA 22% 25% Table 7. Study IV Clinical Efficacy Results: Comparison of MTX versus Enbrel versus Enbrel in Combination with MTX in Patients with Rheumatoid Arthritis of 6 Months to 20 Years Duration (Percent of Patients) Endpoint MTX (N = 228) Enbrel (N = 223) Enbrel/MTX (N = 231) ACR N Values are medians. , ACR N is the percent improvement based on the same core variables used in defining ACR 20, ACR 50, and ACR 70. Month 12 40% 47% 63% p < 0.05 for comparisons of Enbrel/MTX versus Enbrel alone or MTX alone. ACR 20 Month 12 59% 66% 75% ACR 50 Month 12 36% 43% 63% ACR 70 Month 12 17% 22% 40% Major Clinical Response Major clinical response is achieving an ACR 70 response for a continuous 6-month period. 6% 10% 24% The time course for ACR 20 response rates for patients receiving placebo or 25 mg Enbrel in Studies I and II is summarized in Figure 1. The time course of responses to Enbrel in Study III was similar. Figure 1. Time Course of ACR 20 Responses 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 in Studies I and III: 25 mg Enbrel was more effective than 10 mg (10 mg was not evaluated in Study II). Enbrel was significantly better than placebo in all components of the ACR criteria as well as other measures of RA disease activity not included in the ACR response criteria, such as morning stiffness. In Study III, ACR response rates and improvement in all the individual ACR response criteria were maintained through 24 months of Enbrel therapy. Over the 2-year study, 23% of Enbrel patients achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period. The results of the components of the ACR response criteria for Study I are shown in Table 8. Similar results were observed for Enbrel-treated patients in Studies II and III. Table 8. Components of ACR Response in Study I Placebo N = 80 Enbrel 25 mg Enbrel SC twice weekly. N = 78 Parameter (median) Baseline 3 Months Baseline 3 Months Results at 6 months showed similar improvement. Number of tender joints Scale 0-71. 34.0 29.5 31.2 10.0 p < 0.01, Enbrel versus placebo, based on mean percent change from baseline. Number of swollen joints Scale 0-68. 24.0 22.0 23.5 12.6 Physician global assessment Visual analog scale: 0 = best; 10 = worst. 7.0 6.5 7.0 3.0 Patient global assessment 7.0 7.0 7.0 3.0 Pain 6.9 6.6 6.9 2.4 Disability index Health Assessment Questionnaire: 0 = best; 3 = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. 1.7 1.8 1.6 1.0 ESR (mm/hr) 31.0 32.0 28.0 15.5 CRP (mg/dL) 2.8 3.9 3.5 0.9 After discontinuation of Enbrel, symptoms of arthritis generally returned within a month. Reintroduction of treatment with Enbrel after discontinuations of up to 18 months resulted in the same magnitudes of response as in patients who received Enbrel without interruption of therapy, based on results of open-label studies. Continued durable responses were seen for over 60 months in open-label extension treatment trials when patients received Enbrel without interruption. A substantial number of patients who initially received concomitant MTX or corticosteroids were able to reduce their doses or discontinue these concomitant therapies while maintaining their clinical responses. Figure 1 Physical Function Response In Studies I, II, and III, physical function and disability were assessed using the Health Assessment Questionnaire (HAQ). Additionally, in Study III, patients were administered the SF-36 Health Survey. In Studies I and II, patients treated with 25 mg Enbrel twice weekly showed greater improvement from baseline in the HAQ score beginning in month 1 through month 6 in comparison to placebo (p < 0.001) for the HAQ disability domain (where 0 = none and 3 = severe). In Study I, the mean improvement in the HAQ score from baseline to month 6 was 0.6 (from 1.6 to 1.0) for the 25 mg Enbrel group and 0 (from 1.7 to 1.7) for the placebo group. In Study II, the mean improvement from baseline to month 6 was 0.6 (from 1.5 to 0.9) for the Enbrel/MTX group and 0.2 (from 1.3 to 1.2) for the placebo/MTX group. In Study III, the mean improvement in the HAQ score from baseline to month 6 was 0.7 (from 1.5 to 0.7) for 25 mg Enbrel twice weekly. All subdomains of the HAQ in Studies I and III were improved in patients treated with Enbrel. In Study III, patients treated with 25 mg Enbrel twice weekly showed greater improvement from baseline in SF-36 physical component summary score compared to Enbrel 10 mg twice weekly and no worsening in the SF-36 mental component summary score. In open-label Enbrel studies, improvements in physical function and disability measures have been maintained for up to 4 years. In Study IV, median HAQ scores improved from baseline levels of 1.8, 1.8, and 1.8 to 1.1, 1.0, and 0.6 at 12 months in the MTX, Enbrel, and Enbrel/MTX combination treatment groups, respectively (combination versus both MTX and Enbrel, p < 0.01). Twenty-nine percent of patients in the MTX alone treatment group had an improvement of HAQ of at least 1 unit versus 40% and 51% in the Enbrel alone and the Enbrel/MTX combination treatment groups, respectively. Radiographic Response In Study III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score. Radiographs of hands/wrists and forefeet were obtained at baseline, 6 months, 12 months, and 24 months and scored by readers who were unaware of treatment group. The results are shown in Table 9. A significant difference for change in erosion score was observed at 6 months and maintained at 12 months. Table 9. Mean Radiographic Change Over 6 and 12 Months in Study III MTX 25 mg Enbrel MTX/Enbrel (95% Confidence Interval 95% confidence intervals for the differences in change scores between MTX and Enbrel. ) P Value 12 Months Total Sharp Score 1.59 1.00 0.59 (-0.12, 1.30) 0.1 Erosion Score 1.03 0.47 0.56 (0.11, 1.00) 0.002 JSN Score 0.56 0.52 0.04 (-0.39, 0.46) 0.5 6 Months Total Sharp Score 1.06 0.57 0.49 (0.06, 0.91) 0.001 Erosion Score 0.68 0.30 0.38 (0.09, 0.66) 0.001 JSN Score 0.38 0.27 0.11 (-0.14, 0.35) 0.6 Patients continued on the therapy to which they were randomized for the second year of Study III. Seventy-two percent of patients had x-rays obtained at 24 months. Compared to the patients in the MTX group, greater inhibition of progression in TSS and erosion score was seen in the 25 mg Enbrel group, and, in addition, less progression was noted in the JSN score. In the open-label extension of Study III, 48% of the original patients treated with 25 mg Enbrel have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage, as measured by the TSS, and 55% of them had no progression of structural damage. Patients originally treated with MTX had further reduction in radiographic progression once they began treatment with Enbrel. In Study IV, less radiographic progression (TSS) was observed with Enbrel in combination with MTX compared with Enbrel alone or MTX alone at month 12 (Table 10). In the MTX treatment group, 55% of patients experienced no radiographic progression (TSS change ≤ 0.0) at 12 months compared to 63% and 76% in the Enbrel alone and the Enbrel/MTX combination treatment groups, respectively. Table 10. Mean Radiographic Change in Study IV at 12 Months (95% Confidence Interval) MTX (N = 212) Analyzed radiographic ITT population. Enbrel (N = 212) Enbrel/MTX (N = 218) Total Sharp Score (TSS) 2.80 (1.08, 4.51) 0.52 p < 0.05 for comparison of Enbrel versus MTX. (-0.10, 1.15) -0.54 p < 0.05 for comparison of Enbrel/MTX versus MTX. , p < 0.05 for comparison of Enbrel/MTX versus Enbrel. (-1.00, -0.07) Erosion Score (ES) 1.68 (0.61, 2.74) 0.21 (-0.20, 0.61) -0.30 (-0.65, 0.04) Joint Space Narrowing (JSN) Score 1.12 (0.34, 1.90) 0.32 (0.00, 0.63) -0.23 , (-0.45, -0.02) Once Weekly Dosing 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. Fifty-three patients received placebo, 214 patients received 50 mg Enbrel once weekly, and 153 patients received 25 mg Enbrel twice weekly. The safety and efficacy profiles of the two Enbrel treatment groups were similar. 14.2 Polyarticular Juvenile Idiopathic Arthritis (JIA) The safety and efficacy of Enbrel were assessed in a 2-part study in 69 children with polyarticular JIA who had a variety of JIA onset types. Patients ages 2 to 17 years with moderately to severely active polyarticular JIA refractory to or intolerant of MTX were enrolled; patients remained on a stable dose of a single nonsteroidal anti-inflammatory drug and/or prednisone (≤ 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received 0.4 mg/kg (maximum 25 mg per dose) Enbrel SC twice weekly. In part 2, patients with 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 JIA Definition of Improvement (DOI), defined as ≥ 30% improvement in at least three of six and ≥ 30% worsening in no more than one of the six JIA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and ESR. Disease flare was defined as a ≥ 30% worsening in three of the six JIA core set criteria and ≥ 30% improvement in not more than one of the six JIA core set criteria and 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 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. Each component of the JIA core set criteria worsened in the arm that received placebo and remained stable or improved in the arm that continued on Enbrel. The data suggested the possibility of 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 Enbrel continued to improve from month 3 through month 7, while those who received placebo did not improve. The majority of JIA patients who developed a disease flare in part 2 and reintroduced Enbrel treatment up to 4 months after discontinuation re-responded to Enbrel therapy in open-label studies. Most of the responding patients who continued Enbrel therapy without interruption have maintained responses for up to 48 months. Studies have not been done in patients with polyarticular JIA to assess the effects of continued Enbrel therapy in patients who do not respond within 3 months of initiating Enbrel therapy, or to assess the combination of Enbrel with MTX. 14.3 Psoriatic Arthritis The safety and efficacy of Enbrel were assessed in a randomized, double-blind, placebo-controlled study in 205 patients with PsA. Patients were between 18 and 70 years of age and had active PsA (≥ 3 swollen joints and ≥ 3 tender joints) in one or more of the following forms: (1) distal interphalangeal (DIP) involvement (N = 104); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis; N = 173); (3) arthritis mutilans (N = 3); (4) asymmetric psoriatic arthritis (N = 81); or (5) ankylosing spondylitis-like (N = 7). Patients also had plaque psoriasis with a qualifying target lesion ≥ 2 cm in diameter. Patients on MTX therapy at enrollment (stable for ≥ 2 months) could continue at a stable dose of ≤ 25 mg/week MTX. Doses of 25 mg Enbrel or placebo were administered SC twice a week during the initial 6-month double-blind period of the study. Patients continued to receive blinded therapy in an up to 6-month maintenance period until all patients had completed the controlled period. Following this, patients received open-label 25 mg Enbrel twice a week in a 12-month extension period. Compared to placebo, treatment with Enbrel resulted in significant improvements in measures of disease activity (Table 11). Table 11. Components of Disease Activity in Psoriatic Arthritis Placebo N = 104 Enbrel p < 0.001 for all comparisons between Enbrel and placebo at 6 months. N = 101 Parameter (median) Baseline 6 Months Baseline 6 Months Number of tender joints Scale 0-78. 17.0 13.0 18.0 5.0 Number of swollen joints Scale 0-76. 12.5 9.5 13.0 5.0 Physician global assessment Likert scale: 0 = best; 5 = worst. 3.0 3.0 3.0 1.0 Patient global assessment 3.0 3.0 3.0 1.0 Morning stiffness (minutes) 60 60 60 15 Pain 3.0 3.0 3.0 1.0 Disability index Health Assessment Questionnaire: 0 = best; 3 = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. 1.0 0.9 1.1 0.3 CRP (mg/dL) Normal range: 0-0.79 mg/dL. 1.1 1.1 1.6 0.2 Among patients with PsA 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. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. At 6 months, the ACR 20/50/70 responses were achieved by 50%, 37%, and 9%, respectively, of patients receiving Enbrel, compared to 13%, 4%, and 1%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of PsA, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. The results of this study were similar to those seen in an earlier single-center, randomized, placebo-controlled study of 60 patients with PsA. The skin lesions of psoriasis were also improved with Enbrel, relative to placebo, as measured by percentages of patients achieving improvements in the Psoriasis Area and Severity Index (PASI). Responses increased over time, and at 6 months, the proportions of patients achieving a 50% or 75% improvement in the PASI were 47% and 23%, respectively, in the Enbrel group (N = 66), compared to 18% and 3%, respectively, in the placebo group (N = 62). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. Radiographic Response Radiographic changes were also assessed in the PsA study. Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24. A modified Total Sharp Score (TSS), which included distal interphalangeal joints (i.e., not identical to the modified TSS used for RA) was used by readers blinded to treatment group to assess the radiographs. Some radiographic features specific to PsA (e.g. pencil-and-cup deformity, joint space widening, gross osteolysis, and ankylosis) were included in the scoring system, but others (e.g. phalangeal tuft resorption, juxta-articular and shaft periostitis) were not. Most patients showed little or no change in the modified TSS during this 24-month study (median change of 0 in both patients who initially received Enbrel or placebo). More placebo-treated patients experienced larger magnitudes of radiographic worsening (increased TSS) compared to Enbrel treatment during the controlled period of the study. At 12 months, in an exploratory analysis, 12% (12 of 104) of placebo patients compared to none of the 101 Enbrel-treated patients had increases of 3 points or more in TSS. Inhibition of radiographic progression was maintained in patients who continued on Enbrel during the second year. Of the patients with 1-year and 2-year x-rays, 3% (2 of 71) had increases of 3 points or more in TSS at 1 and 2 years. Physical Function Response In the PsA study, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 25 mg Enbrel twice weekly showed greater improvement from baseline in the HAQ-DI score (mean decreases of 54% at both months 3 and 6) in comparison to placebo (mean decreases of 6% at both months 3 and 6) (p < 0.001). At months 3 and 6, patients treated with Enbrel showed greater improvement from baseline in the SF-36 physical component summary score compared to patients treated with placebo, and no worsening in the SF-36 mental component summary score. Improvements in physical function and disability measures were maintained for up to 2 years through the open-label portion of the study. 14.4 Ankylosing Spondylitis The safety and efficacy of Enbrel were assessed in a randomized, double-blind, placebo-controlled study in 277 patients with active AS. Patients were between 18 and 70 years of age and had AS as defined by the modified New York Criteria for Ankylosing Spondylitis. Patients were to have evidence of active disease based on values of ≥ 30 on a 0-100 unit Visual Analog Scale (VAS) for the average of morning stiffness duration and intensity, and two of the following three other parameters: a) patient global assessment, b) average of nocturnal and total back pain, and c) the average score on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients with complete ankylosis of the spine were excluded from study participation. Patients taking hydroxychloroquine, sulfasalazine, methotrexate, or prednisone (≤ 10 mg/day) could continue these drugs at stable doses for the duration of the study. Doses of 25 mg Enbrel or placebo were administered SC twice a week for 6 months. The primary measure of efficacy was a 20% improvement in the Assessment in Ankylosing Spondylitis (ASAS) response criteria. Compared to placebo, treatment with Enbrel resulted in improvements in the ASAS and other measures of disease activity (Figure 2 and Table 12). Figure 2. ASAS 20 Responses in Ankylosing Spondylitis At 12 weeks, the ASAS 20/50/70 responses were achieved by 60%, 45%, and 29%, respectively, of patients receiving Enbrel, compared to 27%, 13%, and 7%, respectively, of patients receiving placebo (p ≤ 0.0001, Enbrel versus placebo). Similar responses were seen at Week 24. Responses were similar between those patients receiving concomitant therapies at baseline and those who were not. The results of this study were similar to those seen in a single-center, randomized, placebo-controlled study of 40 patients and a multicenter, randomized, placebo-controlled study of 84 patients with AS. Table 12. Components of Ankylosing Spondylitis Disease Activity Placebo N = 139 Enbrel p < 0.0015 for all comparisons between Enbrel and placebo at 6 months. P values for continuous endpoints were based on percent change from baseline. N = 138 Median values at time points Baseline 6 Months Baseline 6 Months ASAS response criteria Patient global assessment Measured on a Visual Analog Scale (VAS) with 0 = "none" and 100 = "severe". 63 56 63 36 Back pain Average of total nocturnal and back pain scores, measured on a VAS with 0 = "no pain" and 100 = "most severe pain". 62 56 60 34 BASFI Bath Ankylosing Spondylitis Functional Index (BASFI), average of 10 questions. 56 55 52 36 Inflammation Inflammation represented by the average of the last 2 questions on the 6-question Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 64 57 61 33 Acute phase reactants CRP (mg/dL) C-reactive protein (CRP) normal range: 0-1.0 mg/dL. 2.0 1.9 1.9 0.6 Spinal mobility (cm): Modified Schober's test 3.0 2.9 3.1 3.3 Chest expansion 3.2 3.0 3.3 3.9 Occiput-to-wall measurement 5.3 6.0 5.6 4.5 Figure 2 14.5 Adult Plaque Psoriasis The safety and efficacy of Enbrel were assessed in two randomized, double-blind, placebo-controlled studies in adults with chronic stable PsO involving ≥ 10% of the body surface area, a minimum Psoriasis Area and Severity Index (PASI) score of 10 and who had received or were candidates for systemic antipsoriatic therapy or phototherapy. Patients with guttate, erythrodermic, or pustular psoriasis and patients with severe infections within 4 weeks of screening were excluded from study. No concomitant major antipsoriatic therapies were allowed during the study. Study I evaluated 672 subjects who received placebo or Enbrel SC at doses of 25 mg once a week, 25 mg twice a week, or 50 mg twice a week for 3 months. After 3 months, subjects continued on blinded treatments for an additional 3 months during which time subjects originally randomized to placebo began treatment with blinded Enbrel at 25 mg twice weekly (designated as placebo/Enbrel in Table 13); subjects originally randomized to Enbrel continued on the originally randomized dose (designated as Enbrel/Enbrel groups in Table 13). Study II evaluated 611 subjects who received placebo or Enbrel SC at doses of 25 mg or 50 mg twice a week for 3 months. After 3 months of randomized, blinded treatment, subjects in all three arms began receiving open-label Enbrel at 25 mg twice weekly for 9 additional months. Response to treatment in both studies was assessed after 3 months of therapy and was defined as the proportion of subjects who achieved a reduction in PASI score of at least 75% from baseline. The PASI is a composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of psoriatic changes within the affected regions (induration, erythema and scaling). Other evaluated outcomes included the proportion of subjects who achieved a score of "clear" or "minimal" by the Static Physician Global Assessment (sPGA) and the proportion of subjects with a reduction of PASI of at least 50% from baseline. The sPGA is a 6-category scale ranging from "5 = severe" to "0 = none" indicating the physician's overall assessment of the PsO severity focusing on induration, erythema and scaling. Treatment success of "clear" or "minimal" consisted of none or minimal elevation in plaque, up to faint red coloration in erythema and none or minimal fine scale over < 5% of the plaque. Subjects in all treatment groups and in both studies had a median baseline PASI score ranging from 15 to 17, and the percentage of subjects with baseline sPGA classifications ranged from 54% to 66% for moderate, 17% to 26% for marked and 1% to 5% for severe. Across all treatment groups, the percentage of subjects who previously received systemic therapy for PsO ranged from 61% to 65% in Study I and 71% to 75% in Study II, and those who previously received phototherapy ranged from 44% to 50% in Study I and 72% to 73% in Study II. More subjects randomized to Enbrel than placebo achieved at least a 75% reduction from baseline PASI score (PASI 75) with a dose response relationship across doses of 25 mg once a week, 25 mg twice a week and 50 mg twice a week (Tables 13 and 14). The individual components of the PASI (induration, erythema and scaling) contributed comparably to the overall treatment-associated improvement in PASI. Table 13. Study I Outcomes at 3 and 6 Months Placebo/Enbrel Enbrel/Enbrel 25 mg BIW 25 mg QW 25 mg BIW 50 mg BIW (N = 168) (N = 169) (N = 167) (N = 168) 3 Months PASI 75 n (%) 6 (4%) 23 (14%) p = 0.001 compared with placebo. 53 (32%) p < 0.0001 compared with placebo. 79 (47%) Difference (95% CI) 10% (4, 16) 28% (21, 36) 43% (35, 52) sPGA, "clear" or "minimal" n (%) 8 (5%) 36 (21%) 53 (32%) 79 (47%) Difference (95% CI) 17% (10, 24) 27% (19, 35) 42% (34, 50) PASI 50 n (%) 24 (14%) 62 (37%) 90 (54%) 119 (71%) Difference (95% CI) 22% (13, 31) 40% (30, 49) 57% (48, 65) 6 Months PASI 75 n (%) 55 (33%) 36 (21%) 68 (41%) 90 (54%) Table 14. Study II Outcomes at 3 Months Placebo Enbrel 25 mg BIW 50 mg BIW (N = 204) (N = 204) (N = 203) PASI 75 n (%) 6 (3%) 66 (32%) p < 0.0001 compared with placebo. 94 (46%) Difference (95% CI) 29% (23, 36) 43% (36, 51) sPGA, "clear" or "minimal" n (%) 7 (3%) 75 (37%) 109 (54%) Difference (95% CI) 34% (26, 41) 50% (43, 58) PASI 50 n (%) 18 (9%) 124 (61%) 147 (72%) Difference (95% CI) 52% (44, 60) 64% (56, 71) Among PASI 75 achievers in both studies, the median time to PASI 50 and PASI 75 was approximately 1 month and approximately 2 months, respectively, after the start of therapy with either 25 or 50 mg twice a week. In Study I, subjects who achieved PASI 75 at month 6 were entered into a study drug withdrawal and retreatment period. Following withdrawal of study drug, these subjects had a median duration of PASI 75 of between 1 and 2 months. In Study I, among subjects who were PASI 75 responders at 3 months, retreatment with their original blinded Enbrel dose after discontinuation of up to 5 months resulted in a similar proportion of responders as in the initial double-blind portion of the study. In Study II, most subjects initially randomized to 50 mg twice a week continued in the study after month 3 and had their Enbrel dose decreased to 25 mg twice a week. Of the 91 subjects who were PASI 75 responders at month 3, 70 (77%) maintained their PASI 75 response at month 6. 14.6 Pediatric Plaque Psoriasis A 48-week, randomized, double-blind, placebo-controlled study enrolled 211 pediatric subjects 4 to 17 years of age, with moderate to severe plaque psoriasis (PsO) (as defined by a sPGA score ≥ 3 [moderate, marked, or severe], involving ≥ 10% of the body surface area, and a PASI score ≥ 12) who were candidates for phototherapy or systemic therapy, or were inadequately controlled on topical therapy. Subjects in all treatment groups had a median baseline PASI score of 16.4, and the percentage of subjects with baseline sPGA classifications was 65% for moderate, 31% for marked, and 3% for severe. Across all treatment groups, the percentage of subjects who previously received systemic or phototherapy for PsO was 57%. Subjects received Enbrel 0.8 mg/kg (up to a maximum of 50 mg per dose) or placebo once weekly for the first 12 weeks. After 12 weeks, subjects entered a 24-week open-label treatment period, in which all subjects received Enbrel at the same dose. This was followed by a 12-week withdrawal-retreatment period. Response to treatment was assessed after 12 weeks of therapy and was defined as the proportion of subjects who achieved a reduction in PASI score of at least 75% from baseline. The PASI is a composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of psoriatic changes within the affected regions (induration, erythema and scaling). Other evaluated outcomes included the proportion of subjects who achieved a score of "clear" or "almost clear" by the sPGA and the proportion of subjects with a reduction in PASI score of at least 90% from baseline. The sPGA is a 6-category scale ranging from "5 = severe" to "0 = none" indicating the physician's overall assessment of the PsO severity focusing on induration, erythema and scaling. Treatment success of "clear" or "almost clear" consisted of none or minimal elevation in plaque, up to faint red coloration in erythema and none or minimal fine scale over < 5% of the plaque. Efficacy results are summarized in Table 15. Table 15. Pediatric Plaque Psoriasis Outcomes at 12 Weeks Placebo (N = 105) Enbrel 0.8 mg/kg Once Weekly (N = 106) PASI 75, n (%) 12 (11%) 60 (57%) PASI 90, n (%) 7 (7%) 29 (27%) sPGA "clear" or "almost clear" n (%) 14 (13%) 55 (52%) Maintenance of Response To evaluate maintenance of response, subjects who achieved PASI 75 response at Week 36 were re-randomized to either Enbrel or placebo during a 12-week randomized withdrawal period. The maintenance of PASI 75 response was evaluated at Week 48. The proportion of subjects who maintained PASI 75 response at Week 48 was higher for subjects treated with Enbrel (65%) compared to those treated with placebo (49%).

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

8.5 Geriatric Use A total of 480 RA patients ages 65 years or older have been studied in clinical trials. In PsO randomized clinical trials, a total of 138 out of 1965 patients treated with Enbrel or placebo were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but the number of geriatric PsO patients is too small to determine whether they respond differently from younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.

8.4 Pediatric Use Polyarticular Juvenile Idiopathic Arthritis The safety and effectiveness of Enbrel have been established in pediatric patients 2 years of age and older with pJIA. Enbrel has been studied in 69 children with moderately to severely active polyarticular JIA 2 to 17 years of age. The safety and effectiveness of Enbrel in pediatric patients less than 2 years of age with pJIA have not been established. Juvenile Psoriatic Arthritis The safety and effectiveness of Enbrel have been established in pediatric patients 2 years to 17 years old with JPsA. Use of Enbrel in JPsA is supported by evidence from adequate and well controlled studies of Enbrel in adults with PsA; pharmacokinetic data from adult patients with PsA, RA, and PsO; and pharmacokinetic data from pediatric patients with active JIA and PsO. Safety of Enbrel in JPsA is supported by a clinical study in 69 pediatric patients with moderately to severely active JIA aged 2 to 17 years; a clinical study in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years; and an open-label extension study in 182 pediatric patients with moderate to severe PsO aged 4 to 17 years. The observed pre-dose (trough) concentrations are generally comparable between adults with RA and PsA and pediatric patients with active JIA, as well as adults with PsO and pediatric patients with PsO. The PK exposure is expected to be comparable between adults with PsA and pediatric patients with JPsA [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1 , 14.2 , 14.3 , 14.5 , 14.6) ] . The safety and effectiveness in pediatric patients below the age of 2 years have not been established in JPsA. Plaque Psoriasis The safety and effectiveness of Enbrel for plaque psoriasis have been established in pediatric patients 4 years of age and older. Enbrel has been studied in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years. The safety and effectiveness of Enbrel in pediatric patients below the age of 4 years with PsO have not been established. Malignancies in Pediatric Patients Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy at ≤ 18 years of age), including Enbrel [see Warnings and Precautions (5.3) ] .

8.1 Pregnancy Risk Summary Available studies with use of etanercept during pregnancy do not reliably support an association between etanercept and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS) Enbrel Pregnancy Registry in women with rheumatic diseases or psoriasis and a Scandinavian study in pregnant women with chronic inflammatory disease. Both the OTIS Registry and the Scandinavian study showed the proportion of liveborn infants with major birth defects was higher for women exposed to etanercept compared to diseased etanercept unexposed women. However, the lack of pattern of major birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects (see Data ). In animal reproduction studies with pregnant rats and rabbits, no fetal harm or malformations were observed with subcutaneous administration of etanercept during the period of organogenesis at doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (see Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the United States, about 2-4% of liveborn babies have a major birth defect and about 15-20% of pregnancies end in miscarriage, regardless of drug exposure. Clinical Considerations Fetal/Neonatal Adverse Reactions The risk of fetal/neonatal adverse reactions with in utero exposure to Enbrel is unknown. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to Enbrel in utero [see Warnings and Precautions (5.8) and Drug Interactions (7.1) ] . Data Human Data A prospective cohort pregnancy registry conducted by OTIS in the US and Canada between 2000 and 2012 compared the risk of major birth defects in liveborn infants of women with rheumatic diseases or psoriasis exposed to etanercept in the first trimester. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 319) and diseased etanercept unexposed cohorts (N = 144) was 9.4% and 3.5%, respectively. The findings showed no statistically significant increased risk of minor birth defects and no pattern of major or minor birth defects. A Scandinavian study compared the risk of major birth defects in liveborn infants of women with chronic inflammatory disease (CID) exposed to TNF-inhibitors during early pregnancy. Women were identified from the Danish (2004-2012) and Swedish (2006-2012) population-based health registers. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 344) and CID etanercept unexposed cohorts (N = 21,549) was 7.0% and 4.7%, respectively. Overall, while both the OTIS Registry and Scandinavian study show a higher proportion of major birth defects in etanercept-exposed patients compared to diseased etanercept unexposed patients, the lack of pattern of birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects. Three case reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, were between 3% and 32% of the maternal serum level. Animal Data In embryofetal development studies with etanercept administered during the period of organogenesis to pregnant rats from gestation day (GD) 6 through 20 or pregnant rabbits from GD 6 through 18, there was no evidence of fetal malformations or embryotoxicity in rats or rabbits at respective doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day in rats and 40 mg/kg/day in rabbits). In a peri-and post-natal development study with pregnant rats that received etanercept during organogenesis and the later gestational period from GD 6 through 21, development of pups through post-natal day 4 was unaffected at doses that achieved exposures 48 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available studies with use of etanercept during pregnancy do not reliably support an association between etanercept and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS) Enbrel Pregnancy Registry in women with rheumatic diseases or psoriasis and a Scandinavian study in pregnant women with chronic inflammatory disease. Both the OTIS Registry and the Scandinavian study showed the proportion of liveborn infants with major birth defects was higher for women exposed to etanercept compared to diseased etanercept unexposed women. However, the lack of pattern of major birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects (see Data ). In animal reproduction studies with pregnant rats and rabbits, no fetal harm or malformations were observed with subcutaneous administration of etanercept during the period of organogenesis at doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (see Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the United States, about 2-4% of liveborn babies have a major birth defect and about 15-20% of pregnancies end in miscarriage, regardless of drug exposure. Clinical Considerations Fetal/Neonatal Adverse Reactions The risk of fetal/neonatal adverse reactions with in utero exposure to Enbrel is unknown. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to Enbrel in utero [see Warnings and Precautions (5.8) and Drug Interactions (7.1) ] . Data Human Data A prospective cohort pregnancy registry conducted by OTIS in the US and Canada between 2000 and 2012 compared the risk of major birth defects in liveborn infants of women with rheumatic diseases or psoriasis exposed to etanercept in the first trimester. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 319) and diseased etanercept unexposed cohorts (N = 144) was 9.4% and 3.5%, respectively. The findings showed no statistically significant increased risk of minor birth defects and no pattern of major or minor birth defects. A Scandinavian study compared the risk of major birth defects in liveborn infants of women with chronic inflammatory disease (CID) exposed to TNF-inhibitors during early pregnancy. Women were identified from the Danish (2004-2012) and Swedish (2006-2012) population-based health registers. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 344) and CID etanercept unexposed cohorts (N = 21,549) was 7.0% and 4.7%, respectively. Overall, while both the OTIS Registry and Scandinavian study show a higher proportion of major birth defects in etanercept-exposed patients compared to diseased etanercept unexposed patients, the lack of pattern of birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects. Three case reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, were between 3% and 32% of the maternal serum level. Animal Data In embryofetal development studies with etanercept administered during the period of organogenesis to pregnant rats from gestation day (GD) 6 through 20 or pregnant rabbits from GD 6 through 18, there was no evidence of fetal malformations or embryotoxicity in rats or rabbits at respective doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day in rats and 40 mg/kg/day in rabbits). In a peri-and post-natal development study with pregnant rats that received etanercept during organogenesis and the later gestational period from GD 6 through 21, development of pups through post-natal day 4 was unaffected at doses that achieved exposures 48 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day). 8.2 Lactation Risk Summary Limited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by a breastfed infant. No data are available on the effects of etanercept on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Enbrel and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. 8.4 Pediatric Use Polyarticular Juvenile Idiopathic Arthritis The safety and effectiveness of Enbrel have been established in pediatric patients 2 years of age and older with pJIA. Enbrel has been studied in 69 children with moderately to severely active polyarticular JIA 2 to 17 years of age. The safety and effectiveness of Enbrel in pediatric patients less than 2 years of age with pJIA have not been established. Juvenile Psoriatic Arthritis The safety and effectiveness of Enbrel have been established in pediatric patients 2 years to 17 years old with JPsA. Use of Enbrel in JPsA is supported by evidence from adequate and well controlled studies of Enbrel in adults with PsA; pharmacokinetic data from adult patients with PsA, RA, and PsO; and pharmacokinetic data from pediatric patients with active JIA and PsO. Safety of Enbrel in JPsA is supported by a clinical study in 69 pediatric patients with moderately to severely active JIA aged 2 to 17 years; a clinical study in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years; and an open-label extension study in 182 pediatric patients with moderate to severe PsO aged 4 to 17 years. The observed pre-dose (trough) concentrations are generally comparable between adults with RA and PsA and pediatric patients with active JIA, as well as adults with PsO and pediatric patients with PsO. The PK exposure is expected to be comparable between adults with PsA and pediatric patients with JPsA [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1 , 14.2 , 14.3 , 14.5 , 14.6) ] . The safety and effectiveness in pediatric patients below the age of 2 years have not been established in JPsA. Plaque Psoriasis The safety and effectiveness of Enbrel for plaque psoriasis have been established in pediatric patients 4 years of age and older. Enbrel has been studied in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years. The safety and effectiveness of Enbrel in pediatric patients below the age of 4 years with PsO have not been established. Malignancies in Pediatric Patients Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy at ≤ 18 years of age), including Enbrel [see Warnings and Precautions (5.3) ] . 8.5 Geriatric Use A total of 480 RA patients ages 65 years or older have been studied in clinical trials. In PsO randomized clinical trials, a total of 138 out of 1965 patients treated with Enbrel or placebo were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but the number of geriatric PsO patients is too small to determine whether they respond differently from younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly. 8.6 Use in Patients with Diabetes There have been reports of hypoglycemia following initiation of Enbrel therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

16 HOW SUPPLIED/STORAGE AND HANDLING Enbrel (etanercept) injection is supplied as a clear and colorless sterile, preservative-free solution for subcutaneous administration in single-dose prefilled syringes, an Enbrel single-dose prefilled SureClick autoinjector with a 27-gauge, ½-inch needle, or a single-dose vial. The prefilled syringe and SureClick autoinjector are not made with natural rubber latex. Each Enbrel ® Mini single-dose prefilled cartridge for use with the AutoTouch ® reusable autoinjector contains 1.0 mL of 50 mg/mL of etanercept. The AutoTouch reusable autoinjector and Enbrel Mini single-dose prefilled cartridge are not made with natural rubber latex. The AutoTouch reusable autoinjector contains no drug and must use an Enbrel Mini single-dose prefilled cartridge. In addition, the AutoTouch Connect ® reusable autoinjector would allow for data connectivity via Bluetooth wireless technology. 50 mg/mL single-dose prefilled syringe Carton of 4 NDC 58406-435-04 NDC 58406-021-04 50 mg/mL single-dose prefilled SureClick autoinjector Carton of 4 NDC 58406-445-04 NDC 58406-032-04 25 mg/0.5 mL single-dose prefilled syringe Carton of 4 NDC 58406-455-04 NDC 58406-010-04 50 mg/mL Enbrel Mini single-dose prefilled cartridge for use with the AutoTouch reusable autoinjector only Cartridges: Carton of 4 NDC 58406-456-04 NDC 58406-044-04 AutoTouch Reusable Autoinjector: Carton of 1 NDC 58406-470-01 AutoTouch Connect Reusable Autoinjector: Carton of 1 NDC 58406-480-01 25 mg/0.5 mL single-dose vial Carton of 4 NDC 58406-055-04 Enbrel should be refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light or physical damage. Do not store Enbrel in extreme heat or cold. DO NOT SHAKE. DO NOT FREEZE. For convenience, storage of individual single-dose prefilled syringes, SureClick autoinjectors, single-dose vials, or Enbrel Mini cartridges at room temperature at 68°F to 77°F (20°C to 25°C) for a maximum single period of 30 days is permissible, with protection from light and sources of heat. Once a single-dose prefilled syringe, SureClick autoinjector, single-dose vial, or Enbrel Mini cartridge has been stored at room temperature, it should not be placed back into the refrigerator. If not used within 30 days at room temperature, the single-dose prefilled syringe, SureClick autoinjector, single-dose vial, or Enbrel Mini cartridge should be discarded. Do not use Enbrel beyond the expiration date stamped on the carton or barrel/cartridge label. Keep out of the reach of children. The AutoTouch reusable autoinjector should be stored at room temperature. Do not refrigerate the AutoTouch reusable autoinjector. Enbrel Lyophilized Powder (Used for Weight-based Dosing) Enbrel (etanercept) for Injection is supplied as lyophilized powder for reconstitution in a multiple-dose vial. Each vial is supplied in a carton containing four dose trays. Each dose tray contains one 25 mg vial of etanercept lyophilized powder, one diluent syringe (1 mL Sterile Bacteriostatic Water for Injection, USP, containing 0.9% benzyl alcohol), one 27-gauge ½-inch needle, one vial adapter, and one plunger. Each carton contains four "Mixing Date:" stickers. 25 mg multiple-dose vial Carton of 4 NDC 58406-425-34 Enbrel should be refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light or physical damage. Do not store Enbrel in extreme heat or cold. DO NOT SHAKE. DO NOT FREEZE. For convenience, storage of an individual dose tray containing Enbrel multiple-dose vial and diluent syringe at room temperature at 68°F to 77°F (20°C to 25°C) for a maximum single period of 14 days is permissible, with protection from light, sources of heat, and humidity. Once the dose tray has been stored at room temperature, it should not be placed back into the refrigerator. If not used within 14 days at room temperature, the dose tray should be discarded. Once a vial has been reconstituted, the solution must be used immediately or may be refrigerated for up to 14 days. Do not use Enbrel beyond the expiration date stamped on the dose tray. Keep out of the reach of children.

Enbrel should be refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light or physical damage. Do not store Enbrel in extreme heat or cold. DO NOT SHAKE. DO NOT FREEZE. For convenience, storage of individual single-dose prefilled syringes, SureClick autoinjectors, single-dose vials, or Enbrel Mini cartridges at room temperature at 68°F to 77°F (20°C to 25°C) for a maximum single period of 30 days is permissible, with protection from light and sources of heat. Once a single-dose prefilled syringe, SureClick autoinjector, single-dose vial, or Enbrel Mini cartridge has been stored at room temperature, it should not be placed back into the refrigerator. If not used within 30 days at room temperature, the single-dose prefilled syringe, SureClick autoinjector, single-dose vial, or Enbrel Mini cartridge should be discarded. Do not use Enbrel beyond the expiration date stamped on the carton or barrel/cartridge label. Keep out of the reach of children. The AutoTouch reusable autoinjector should be stored at room temperature. Do not refrigerate the AutoTouch reusable autoinjector.

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