ALTEBREL

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. 7, 5 The Fc component of etanercept contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 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.

It is used to treat or manage a variety of inflammatory conditions including rheumatoid arthritis (RA), ankylosing spondylitis (AS), and juvenile idiopathic poly-articular arthritis (JIA).

Etanercept is indicated for the treatment of moderately to severely active rheumatoid arthritis in adults and in chronic moderate to severe plaque psoriasis in patients 4 years of age and older. 7, 8 It is also used to manage signs and symptoms of polyarticular idiopathic arthritis and Juvenile Psoriatic Arthritis in those aged 2 years and older.

Etanercept is also used to manage the symptoms of psoriatic arthritis and ankylosing spondylitis.

Etanercept binds specifically to tumor necrosis factor (TNF) and thereby modulates biological processes that are induced or regulated by TNF. 7, 5 Such processes or molecules affected include the level of adhesion molecules expressed, as well as serum levels of cytokines and matrix metalloproteinases.

Population pharmacokinetic modeling in adults with

RA, AS, or who were healthy showed a subcutaneous bioavailability of 56.9% with a Ka of 0.0223/h.

Another model in pediatric JIA patients showed an increased Ka of 0.05/h with a high mean interindividual variability of 215%.

Cmax after a single 25 mg subcutaneous dose of Enbrel is reported as 1.1 mcg/L with a Tmax of 69 h.

Cmax after repeated dosing is reported as 2.4 mcg/L in adult RA patients with a dosage of 25 mg twice weekly and 2.1 mcg in pediatric JIA patients with a dosage of 0.4 mg/kg twice weekly.

Population pharmacokinetic modeling predicts a total

Vd of 5.49 L with a peripheral compartment of 1.24 L in adults with RA and an apparent Vd with subcutaneous administration in pediatric JIA patients of 7.88 L. 2, 3.

As etanercept is a fusion protein antibody, it is assumed to be metabolized via proteinases similarly to endogenous proteins.

Etanercept has a mean half-life of elimination of 102 hours in RA patients.

Population models have shown a mean half-life of 68 hours in healthy adults and 70.7-94.8 hours in pediatric JIA patients. 4, 3.

Etanercept has a mean apparent clearance of 160 mL/h in RA patients.

Population models predict a mean apparent clearance of 132 mL/h in healthy adults and 0.0576 L/h in pediatric JIA patients. 4, 3.

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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.