ENBREL

Indications and Usage, Juvenile Psoriatic Arthritis ( 1.6 ) 10/2023 Dosage and Administration, Pediatric Patients ( 2.4 ) 10/2023

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.

2 DOSAGE AND ADMINISTRATION Enbrel is administered by subcutaneous injection. Patient Population Recommended Dose and Frequency Adult RA and PsA ( 2.3 ) 50 mg once weekly with or without methotrexate (MTX) AS ( 2.3 ) 50 mg once weekly Adult PsO ( 2.3 ) 50 mg twice weekly for 3 months, followed by 50 mg once weekly pJIA, Pediatric PsO and JPsA ( 2.4 ) 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 …

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 )

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

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 …

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.

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 ). Reports of etanercept use during the third trimester of pregnancy demonstrated that placental transfer of etanercept was low in infants at birth (see Data ) . There are risks to the mother and fetus associated with active rheumatoid arthritis. The theoretical risks of administration of live or live-attenuated vaccines to the infants exposed in utero to Enbrel should be weighed against the benefits of vaccinations (see Clinical Considerations ) . 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 Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis is correlated with maternal disease activity and that active disease increases the risk of adverse pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) and small for gestational age birth. 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 …

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.

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

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.

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, 1⁄2-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 58406-021-04 50 mg/mL single-dose prefilled SureClick autoinjector Carton of 4 NDC 58406-032-04 25 mg/0.5 mL single-dose prefilled syringe Carton of 4 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 58406-044-04 NDC 58406-044-24 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 1⁄2-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 …