ENBREL

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.

Rheumatoid arthritis, arthritis in the shell, and the prevention of joint damage from these infections.

Medically supervised use in the following cases: VAA, HIV or AIDS, tuberculosis, or any type of repeated infection.

Active symptoms such as fever, influenza, diarrhoea, or painful urination.

Open or skin lesions.

Congestive heart failure.

Neuropathy, such as multiple lubricant, optics, or epilepsy.

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 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 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 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.

PsO patients (age 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.

The immune system of people with autoimmune disorders produces a lot of tumor necrosis, and attacks healthy cells by mistake.

Do you have questions on this subject? Ask Sina, artificial intelligence to answer all your medical questions, write your question here, and we'll prepare the answer for you.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious.

Infections Neurologic Reactions Malignancies Patients with Heart Failure Hematologic Reactions Hepatitis B Reactivation Allergic Reactions Autoimmunity Immunosuppression Most common adverse reactions (incidence > 5%): infections and injection site reactions.

To report SUSPECTED ADVERSE

REACTIONS, contact Amgen Inc.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.

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.

In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients.

In a 48-week clinical study in 211 children aged 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 to 4 years were similar to adverse reactions reported in older children.

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 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.

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.

JIA patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae.

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 to 5 days.

Seven percent of patients experienced redness at a previous injection site when subsequent injections were given.

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.

• 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 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 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 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 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.

III, no pattern of increased autoantibody development was seen in Enbrel patients compared to MTX patients. 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 Cardiac disorders: congestive heart failure Gastrointestinal disorders: inflammatory bowel disease (IBD) General disorders: angioedema, chest pain Hepatobiliary disorders: autoimmune hepatitis, elevated trans.

No dose-limiting toxicities have been observed during clinical trials of Enbrel.

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.

Enbrel is contraindicated in patients with sepsis.

Enbrel is administered by subcutaneous injection.

Patient Population Recommended Dose and Frequency Adult RA and PsA 50 mg once weekly with or without methotrexate (MTX) AS 50 mg once weekly Adult PsO 50 mg twice weekly for 3 months, followed by 50 mg once weekly pJIA, Pediatric PsO and JPsA 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.

Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with Enbrel. 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.

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.

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. 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.

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.

Enbrel devices are not made with natural rubber latex.

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 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.

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.

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 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.

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.

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.

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.

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.

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.

AutoTouch reusable autoinjector should be stored at room temperature.

Do not refrigerate the

AutoTouch reusable autoinjector.

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.

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.

Enbrel beyond the expiration date stamped on the dose tray.

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.

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.

AutoTouch reusable autoinjector should be stored at room temperature.

Do not refrigerate the

AutoTouch reusable autoinjector.

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.

Reports of etanercept use during the third trimester of pregnancy demonstrated that placental transfer of etanercept was low in infants at birth.

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.

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 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly.

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.

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.

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.

Data Human Data A prospective cohort pregnancy registry conducted by OTIS in the US and Canada between 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 and Swedish 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.

Reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, varied from undetectable to 32% of the maternal serum level.

In a cohort study of 30 pregnant women with RA, 29 were treated with etanercept until 30 weeks of gestation and was treated until 36 weeks of gestation.

Etanercept was not detected in the cord blood sample from any infant at delivery.

In three published case reports, etanercept was detected in cord blood at levels of 3.3, 3.6, and 7.4% of the maternal concentration, when etanercept was administered at 50 mg every 7-12 days in pregnancy until 4 days prior to delivery, 25 mg twice weekly until 36 weeks of gestation, and 25 mg subcutaneous every week through the third trimester, respectively.

There was one post-marketing safety report of a pregnant woman who received etanercept 25 mg once to twice weekly throughout pregnancy, and etanercept was detected in cord blood at 32% of the maternal concentration.

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 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 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).

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 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 to 17 years; a clinical study in 211 pediatric patients with moderate to severe PsO aged to 17 years; and an open-label extension study in 182 pediatric patients with moderate to severe PsO aged 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.

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 to 17 years.

Enbrel in pediatric patients below the age of 4 years with PsO have not been established.

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.

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.