1 ML etanercept 50 MG/ML Prefilled Syringe

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.

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 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 t

WARNINGS AND PRECAUTIONS Do not start Enbrel during an active infection. If an infection develops, monitor carefully and stop Enbrel if infection becomes serious. ( 5.1 ) Consider empiric anti-fungal therapy for patients at risk for invasive fungal infections who develop a severe systemic illness on Enbrel (those who reside or travel to regions where mycoses are endemic). ( 5.1 ) Demyelinating disease, exacerbation or new onset, may occur. ( 5.2 ) Cases of lymphoma have been observed in patients receiving TNF-blocking agents. ( 5.3 ) Congestive heart failure, worsening or new onset, may occur. ( 5.4 ) Advise patients to seek immediate medical attention if symptoms of pancytopenia or aplastic anemia develop, and consider stopping Enbrel. ( 5.5 ) Monitor patients previously infected with hepatitis B virus for reactivation during and several months after therapy. If reactivation occurs, consider stopping Enbrel and beginning anti-viral therapy. ( 5.6 ) Anaphylaxis or serious allergic reactions may occur. ( 5.7 ) Stop Enbrel if lupus-like syndrome or autoimmune hepatitis develops. ( 5.9 ) 5.1 Serious Infections Patients treated with Enbrel are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease. Treatment with Enbrel should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients: With chronic or recurrent infection; Who have been exposed to tuberculosis; With a history of an opportunistic infection; Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or With underlying conditions that may predispose them to infection, such as advanced or poorly controlled diabetes [see Adverse Reactions (6.1) ] . Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Enbrel. Enbrel should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with Enbrel should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated. Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving Enbrel, including patients who have previously received treatment for latent or active tuberculosis. Data from clinical trials and preclinical studies suggest that the risk of reactivation of latent tuberculosis infection is lower with Enbrel than with TNF-blocking monoclonal antibodies. Nonetheless, postmarketing cases of tuberculosis reactivation have been reported for TNF-blockers, including Enbrel. Tuberculosis has developed in patients who tested negative for latent tuberculosis prior to initiation of therapy. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating Enbrel and periodically during therapy. Tests for latent tuberculosis infection may be falsely negative while on therapy with Enbrel. Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating Enbrel, even for patients previously vaccinated with Bacillus Calmette-Guerin (BCG). Anti-tuberculosis therapy should also be considered prior to initiation of Enbrel in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Tuberculosis should be strongly considered in patients who develop a new infection during Enbrel treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. Invasive Fungal Infections Cases of serious and sometimes fatal fungal infections, including histoplasmosis, have been reported with TNF-blockers, including Enbrel. For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric anti-fungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric anti-fungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of anti-fungal therapy. In 38 Enbrel clinical trials and 4 cohort studies in all approved indications representing 27,169 patient-years of exposure (17,696 patients) from the United States and Canada, no histoplasmosis infections were reported among patients treated with Enbrel. 5.2 Neurologic Reactions Treatment with TNF-blocking agents, including Enbrel, has been associated with rare (< 0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barre syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with Enbrel therapy. Prescribers should exercise caution in considering the use of Enbrel in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders [see Postmarketing Experience (6.3) ] . 5.3 Malignancies Lymphomas In the controlled portions of clinical trials of TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF-blocker compared to control patients. During the controlled portions of Enbrel trials in adult patients with RA, AS, and PsA, 2 lymphomas were observed among 3306 Enbrel-treated patients versus 0 among 1521 control patients (duration of controlled treatment ranged from 3 to 36 months). Among 6543 adult rheumatology (RA, PsA, AS) patients treated with Enbrel in controlled and uncontrolled portions of clinical trials, representing approximately 12,845 patient-years of therapy, the observed rate of lymphoma was 0.10 cases per 100 patient-years. This was 3-fold higher than the rate of lymphoma expected in the general U.S. population based on the Surveillance, Epidemiology, and End Results (SEER) Database. An increased rate o

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

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.