Enbrel 50 mg solution for injection in pre-filled syringe

Rheumatoid Arthritis

Enbrel 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe can be initiated in combination with methotrexate (MTX) or used alone.

Polyarticular Juvenile Idiopathic Arthritis

Enbrel 50 mg solution for injection in pre-filled syringe is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients ages 2 and older.

Psoriatic Arthritis

Enbrel 50 mg solution for injection in pre-filled syringe is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis (PsA). Enbrel 50 mg solution for injection in pre-filled syringe can be used with or without methotrexate.

Ankylosing Spondylitis

Enbrel 50 mg solution for injection in pre-filled syringe is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS).

Plaque Psoriasis

Enbrel 50 mg solution for injection in pre-filled syringe 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.

DOSAGE AND ADMINISTRATION

Adult Patients

Enbrel 50 mg solution for injection in pre-filled syringe is administered by subcutaneous injection.

Table 1. Dosing and Administration for Adult Patients

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 50 mg solution for injection in pre-filled syringe.

Based on a study of 50 mg Enbrel 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe dosage.

Pediatric Patients

Enbrel 50 mg solution for injection in pre-filled syringe is administered by subcutaneous injection.

Table 2. Dosing and Administration for Pediatric Patients (PsO or JIA)

To achieve pediatric doses other than 25 mg or 50 mg, use reconstituted Enbrel 50 mg solution for injection in pre-filled syringe lyophilized powder.

Doses of Enbrel 50 mg solution for injection in pre-filled syringe higher than those described in Table 2 have not been studied in pediatric patients.

In JIA patients, glucocorticoids, NSAIDs, or analgesics may be continued during treatment with Enbrel 50 mg solution for injection in pre-filled syringe.

Preparation Of Enbrel 50 mg solution for injection in pre-filled syringe

Enbrel 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe (Enbrel 50 mg solution for injection in pre-filled syringe) “Instructions for Use” insert for each presentation contains more detailed instructions on injection site selection and the preparation of Enbrel 50 mg solution for injection in pre-filled syringe.

Preparation Of Enbrel 50 mg solution for injection in pre-filled syringe Single-Dose Prefilled Syringe

For a more comfortable injection, leave Enbrel 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe Lyophilized Powder In A Multiple-Dose Vial

Enbrel 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe.

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 50 mg solution for injection in pre-filled syringe, 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 50 mg solution for injection in pre-filled syringe solution at room temperature.

For a more comfortable injection, leave the Enbrel 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe vial and insert the vial adapter into the vial stopper. Push down on the plunger to inject the diluent into the Enbrel 50 mg solution for injection in pre-filled syringe vial. If using a 25-gauge needle to reconstitute and withdraw Enbrel 50 mg solution for injection in pre-filled syringe, the diluent should be injected very slowly into the Enbrel 50 mg solution for injection in pre-filled syringe vial. It is normal for some foaming to occur. Keeping the diluent syringe in place, gently swirl the contents of the Enbrel 50 mg solution for injection in pre-filled syringe vial during dissolution. To avoid excessive foaming, do not shake or vigorously agitate. Generally, dissolution of Enbrel 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe.

The contents of one vial of Enbrel 50 mg solution for injection in pre-filled syringe solution should not be mixed with, or transferred into, the contents of another vial of Enbrel 50 mg solution for injection in pre-filled syringe. No other medications should be added to solutions containing Enbrel 50 mg solution for injection in pre-filled syringe, and do not reconstitute Enbrel 50 mg solution for injection in pre-filled syringe with other diluents. Do not filter reconstituted solution during preparation or administration.

Monitoring To Assess Safety

Prior to initiating Enbrel 50 mg solution for injection in pre-filled syringe and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection.

Enbrel 50 mg solution for injection in pre-filled syringe injection is used to reduce signs and symptoms of active arthritis, rheumatoid arthritis, or psoriatic arthritis, such as joint swelling, pain, tiredness, and duration of morning stiffness. Enbrel 50 mg solution for injection in pre-filled syringe may also slow the progression of damage to the body from active arthritis or rheumatoid arthritis. It may also be used to treat plaque psoriasis or a condition known as ankylosing spondylitis.

Enbrel 50 mg solution for injection in pre-filled syringe is also used in children 2 years of age and older for juvenile idiopathic arthritis.

Enbrel 50 mg solution for injection in pre-filled syringe is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in the product labeling, Enbrel 50 mg solution for injection in pre-filled syringe is used in certain patients with the following medical condition:

• Inflammatory bowel disease arthritis.
• Reactive arthritis.

​See the Enbrel 50 mg solution for injection in pre-filled syringe(Enbrel 50 mg solution for injection in pre-filled syringe) “Instructions for Use” insert for detailed information on injection site selection and dose administration.

Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients

MTX, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be continued during treatment with Enbrel 50 mg solution for injection in pre-filled syringe.

Based on a study of 50 mg Enbrel 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe dosage.

JIA Patients

In JIA patients, glucocorticoids, NSAIDs, or analgesics may be continued during treatment with Enbrel 50 mg solution for injection in pre-filled syringe. Higher doses of Enbrel 50 mg solution for injection in pre-filled syringe have not been studied in pediatric patients.

Preparation of Enbrel 50 mg solution for injection in pre-filled syringe

Enbrel 50 mg solution for injection in pre-filled syringe 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. Injections should occur in the thigh, abdomen or outer area of the upper arm.

​The Enbrel 50 mg solution for injection in pre-filled syringe (Enbrel 50 mg solution for injection in pre-filled syringe) “Instructions for Use” insert for each presentation contains more detailed instructions on injection site selection and the preparation of Enbrel 50 mg solution for injection in pre-filled syringe.

Preparation of Enbrel 50 mg solution for injection in pre-filled syringe Using the Single-use Prefilled Syringe

For a more comfortable injection, leave Enbrel 50 mg solution for injection in pre-filled syringe 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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present.

When using the Enbrel 50 mg solution for injection in pre-filled syringe single-use 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 50 mg solution for injection in pre-filled syringe Using the Single-use 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.

​Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present.

Preparation of Enbrel 50 mg solution for injection in pre-filled syringe Using the Multiple-use Vial

Enbrel 50 mg solution for injection in pre-filled syringe should be reconstituted aseptically with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol), giving a solution of 1.0 mL containing 25 mg of Enbrel 50 mg solution for injection in pre-filled syringe.

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 50 mg solution for injection in pre-filled syringe, 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 50 mg solution for injection in pre-filled syringe solution at room temperature.

For a more comfortable injection, leave the Enbrel 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe vial and insert the vial adapter into the vial stopper. Push down on the plunger to inject the diluent into the Enbrel 50 mg solution for injection in pre-filled syringe vial. If using a 25‑gauge needle to reconstitute and withdraw Enbrel 50 mg solution for injection in pre-filled syringe, the diluent should be injected very slowly into the Enbrel 50 mg solution for injection in pre-filled syringe vial. It is normal for some foaming to occur. Keeping the diluent syringe in place, gently swirl the contents of the Enbrel 50 mg solution for injection in pre-filled syringe vial during dissolution. To avoid excessive foaming, do not shake or vigorously agitate.

Generally, dissolution of Enbrel 50 mg solution for injection in pre-filled syringe 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 50 mg solution for injection in pre-filled syringe.

The contents of one vial of Enbrel 50 mg solution for injection in pre-filled syringe solution should not be mixed with, or transferred into, the contents of another vial of Enbrel 50 mg solution for injection in pre-filled syringe. No other medications should be added to solutions containing Enbrel 50 mg solution for injection in pre-filled syringe, and do not reconstitute Enbrel 50 mg solution for injection in pre-filled syringe with other diluents. Do not filter reconstituted solution during preparation or administration.

Monitoring to Assess Safety

Prior to initiating Enbrel 50 mg solution for injection in pre-filled syringe and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection.

See also:
What is the most important information I should know about Enbrel 50 mg solution for injection in pre-filled syringe?

Some people using Enbrel 50 mg solution for injection in pre-filled syringe have developed a rare fast-growing type of lymphoma (cancer). This condition affects the liver, spleen, and bone marrow, and it can be fatal. This has occurred mainly in teenagers and young adults using Enbrel 50 mg solution for injection in pre-filled syringe or similar medicines to treat Crohn's disease or ulcerative colitis.

Call your doctor at once if you have any of the following symptoms: fever, night sweats, itching, loss of appetite, weight loss, tiredness, feeling full after eating only a small amount, pain in your upper stomach that may spread to your shoulder, nausea, easy bruising or bleeding, pale skin, feeling light-headed or short of breath, rapid heart rate, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Enbrel 50 mg solution for injection in pre-filled syringe can lower blood cells that help your body fight infections. Your blood may need to be tested often. Serious and sometimes fatal infections may occur during treatment with Enbrel 50 mg solution for injection in pre-filled syringe. Contact your doctor right away if you have signs of infection such as: fever, cough, sweating, tired feeling, or if you feel short of breath.

Children using this medication should be current on all childhood immunizations before starting treatment with Enbrel 50 mg solution for injection in pre-filled syringe.

Use Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes refilled.
• Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes are given as an injection under the skin. If you will be using Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes at home, a health care provider will teach you how to use it. Be sure you understand how to use Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.
• Wash your hands with soap and warm water before using Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes.
• Remove 1 prefilled syringe of Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes from the refrigerator. To make the injection more comfortable, you may leave the prefilled syringe at room temperature for 15 to 30 minutes before using. Do NOT remove the needle cover while allowing it to reach room temperature. Do not warm Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes in any other way (eg, in a microwave or in hot water).
• Do not shake Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes.
• Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes may contain small white particles. Do not use Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes if it contains large lumps, flakes, or other particles. Do not use if cloudy or discolored, or if the syringe is cracked or damaged.
• Use the proper technique taught to you by your doctor. Inject deep under the skin, NOT into muscle or a vein.
• Injection sites within an injection area (stomach area, thigh, outer area of the upper arm) must be rotated from one injection to the next. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid areas with scars or stretch marks. If you have psoriasis, try not to inject directly into any raised, red, thick, or scaly skin patches.
• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• Do not miss any doses of Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes. If you miss a dose of Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once. If you are not sure what to do if you miss a dose, call your doctor.

Ask your health care provider any questions you may have about how to use Enbrel 50 mg solution for injection in pre-filled syringe prefilled syringes.

Use: Labeled Indications

Ankylosing spondylitis: Reducing signs and symptoms in patients with active ankylosing spondylitis.

Plaque psoriasis (Enbrel 50 mg solution for injection in pre-filled syringe): Treatment of patients ≥4 years of age with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Polyarticular juvenile idiopathic arthritis: Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ≥2 years of age.

Psoriatic arthritis (Enbrel 50 mg solution for injection in pre-filled syringe): Reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis. Enbrel 50 mg solution for injection in pre-filled syringe can be used with or without methotrexate.

Rheumatoid arthritis: 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 50 mg solution for injection in pre-filled syringe can be initiated in combination with methotrexate or used alone.

Off Label Uses

Acute graft-versus-host disease (treatment)

Data from a small pilot/phase 2 study support the use of Enbrel 50 mg solution for injection in pre-filled syringe (in combination with methylprednisolone) for initial treatment of acute graft-versus-host disease (GVHD).

See also:
What other drugs will affect Enbrel 50 mg solution for injection in pre-filled syringe?

Concurrent Treatment with Abatacept: In clinical studies, concurrent administration of abatacept and Enbrel 50 mg solution for injection in pre-filled syringe therapy resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended.

Concurrent Treatment with Methotrexate: Enbrel 50 mg solution for injection in pre-filled syringe may be administered in combination with methotrexate for the treatment of rheumatoid arthritis. In a safety and efficacy clinical trial, methotrexate had no effect on the pharmacokinetics of Enbrel 50 mg solution for injection in pre-filled syringe. The effect of Enbrel 50 mg solution for injection in pre-filled syringe on the human pharmacokinetics of methotrexate has not been investigated. The safety and efficacy of Enbrel 50 mg solution for injection in pre-filled syringe in combination with methotrexate for the treatment of psoriasis have not been studied. Enbrel 50 mg solution for injection in pre-filled syringe should not be administered in combination with methotrexate for the treatment of psoriasis.

Concurrent Treatment with Anakinra: Patients treated with Enbrel 50 mg solution for injection in pre-filled syringe and anakinra were observed to have a higher rate of serious infection when compared with patients who were treated with Enbrel 50 mg solution for injection in pre-filled syringe alone (historical data). In addition, in a double-blind, placebo-controlled trial, in patients receiving background methotrexate, patients treated with Enbrel 50 mg solution for injection in pre-filled syringe and anakinra were observed to have a higher rate of serious infections and neutropenia than patients treated with Enbrel 50 mg solution for injection in pre-filled syringe alone.

Concurrent Treatment with Sulfasalazine: In a clinical study of patients who were receiving established doses of sulfasalazine, to which Enbrel 50 mg solution for injection in pre-filled syringe was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with Enbrel 50 mg solution for injection in pre-filled syringe or sulfasalazine alone. The clinical significance of this interaction is unknown.

Live Vaccines: No safety data are available on the effects of live vaccine when used in combination with Enbrel 50 mg solution for injection in pre-filled syringe. Live vaccines should therefore not be given concurrently with Enbrel 50 mg solution for injection in pre-filled syringe.

Other: Product information for methotrexate should be referenced when Enbrel 50 mg solution for injection in pre-filled syringe is administered with methotrexate. Interactions between Enbrel 50 mg solution for injection in pre-filled syringe and other drugs have not been evaluated in formal studies. No interactions have been observed when Enbrel 50 mg solution for injection in pre-filled syringe was administered with glucocorticoids, salicylates (except sulfasalazine), non-steroidal antiinflammatory drugs (NSAIDs), analgesics or methotrexate in clinical trials with adult rheumatoid arthritis patients.

No clinically significant pharmacokinetic drug-drug interactions were observed in studies with digoxin and warfarin.

Effects on Laboratory Tests: No effects on laboratory tests have been reported in adults. An analysis of 54 JCA patients in an open-label study demonstrated low haemoglobin, low albumin and low lymphocyte counts in 63%, 39% and 30% of juvenile patients, respectively. These observations, however, appear to be attributed to the underlying disease, rather than treatment with Enbrel 50 mg solution for injection in pre-filled syringe.

See also:
What are the possible side effects of Enbrel 50 mg solution for injection in pre-filled syringe?

Enbrel 50 mg solution for injection in pre-filled syringe has been studied in 2680 patients with rheumatoid arthritis (RA) in double-blind and open-label trials. This experience includes 2 placebo-controlled studies (349 Enbrel 50 mg solution for injection in pre-filled syringe patients and 152 placebo patients) and 2 active-controlled trials, 1 active-controlled trial comparing Enbrel 50 mg solution for injection in pre-filled syringe to methotrexate (415 Enbrel 50 mg solution for injection in pre-filled syringe patients and 217 methotrexate patients) and another active-controlled trial comparing Enbrel 50 mg solution for injection in pre-filled syringe (223 patients), methotrexate (228 patients) and Enbrel 50 mg solution for injection in pre-filled syringe in combination with methotrexate (231 patients). The proportion of patients who discontinued treatment due to adverse events was the same in both the Enbrel 50 mg solution for injection in pre-filled syringe and placebo treatment groups; in the 1st active-controlled trial, the dropout rate was significantly higher for methotrexate (10%) than for Enbrel 50 mg solution for injection in pre-filled syringe (5%). In the 2nd active-controlled trial, the rate of discontinuation for adverse events was similar among all 3 treatment groups, Enbrel 50 mg solution for injection in pre-filled syringe (16%), methotrexate (21%) and Enbrel 50 mg solution for injection in pre-filled syringe in combination with methotrexate (17%). Additionally, Enbrel 50 mg solution for injection in pre-filled syringe has been studied in 131 psoriatic arthritis patients who participated in 2 double-blind, placebo-controlled studies and an open-label extension study. Two hundred and three (203) ankylosing spondylitis patients were treated with Enbrel 50 mg solution for injection in pre-filled syringe in 3 double-blind, placebo-controlled studies. Enbrel 50 mg solution for injection in pre-filled syringe has also been studied in 1084 patients with plaque psoriasis for up to 6 months in 3 double-blind, placebo-controlled studies.

In double-blind clinical trials comparing Enbrel 50 mg solution for injection in pre-filled syringe to placebo, injection site reactions were the most frequent adverse events among Enbrel 50 mg solution for injection in pre-filled syringe-treated patients. Among patients with RA treated in placebo-controlled trials, serious adverse events occurred at a frequency of 4% in 349 patients treated with Enbrel 50 mg solution for injection in pre-filled syringe compared with 5% of 152 placebo-treated patients. In the 1st active-controlled trial, serious adverse events occurred at a frequency of 6% in 415 patients treated with Enbrel 50 mg solution for injection in pre-filled syringe compared with 8% of 217 methotrexate-treated patients. In the 2nd active-controlled trial, the rate of serious adverse events were similar among the 3 treatment group (Enbrel 50 mg solution for injection in pre-filled syringe 11%, methotrexate 12% and Enbrel 50 mg solution for injection in pre-filled syringe in combination with methotrexate 8%). Among patients with plaque psoriasis treated in placebo-controlled trials, the frequency of serious adverse events was about 1% of 933 patients treated with Enbrel 50 mg solution for injection in pre-filled syringe compared with 1% of 414 placebo-treated patients.

The adverse reactions as follows is based on experience from clinical trials in adults and on post-marketing experience.

Within the organ system classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the categories as follows: Very Common: >1/10; common: >1/100, <1/10; uncommon: >1/1000, <1/100; rare: >1/10,000, <1/1000; very rare: <1/10,000; not known: Frequency could not be accurately estimated from clinical studies.

Infections and Infestations: Very Common: Infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections)*. Uncommon: Serious infections (including pneumonia, cellulitis, septic arthritis, sepsis)*. Rare: Tuberculosis.

Blood and Lymphatic System Disorders: Uncommon: Thrombocytopenia. Rare: Anaemia, leukopenia, neutropenia, pancytopenia*. Very Rare: Aplastic anaemia*.

Immune System Disorders: Common: Allergic reactions, autoantibody formation*. Rare: Serious allergic/anaphylactic reactions (including angioedema, bronchospasm). Not Known: Macrophage activation syndrome, ANCA positive vasculitis.

Nervous System Disorders: Rare: Seizures. CNS demyelinating events suggestive of multiple sclerosis or localised demyelinating conditions eg, optic neuritis and transverse myelitis.

Eye Disorders: Uncommon: Uveitis.

Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Interstitial lung disease (including pulmonary fibrosis and pneumonitis).

Skin and Subcutaneous Tissue Disorders: Common: Pruritus. Uncommon: Angioedema, urticaria, rash, psoriasis and psoriasiform rash, non-melanoma skin cancers. Rare: Cutaneous vasculitis (including leukocytoclastic vasculitis), Stevens-Johnson syndrome, erythema multiforme. Very Rare: Toxic epidermal necrolysis.

Musculoskeletal, Connective Tissue and Bone Disorders: Rare: Subacute cutaneous lupus erythematosus and discoid lupus erythematosus, lupus-like syndrome.

General Disorders and Administration Site Conditions: Very Common: Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling)*. Common: Fever.

Cardiac Disorders: Rare: There have been reports of worsening of congestive heart failure.

Hepatobiliary Disorders: Rare: Elevated liver enzymes, autoimmune hepatitis.

Note: *See Additional Information as follows.

Additional Information: Serious Adverse Events Reported in Clinical Trials: Among RA, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis patients in placebo-controlled, active-controlled and open-label trials of Enbrel 50 mg solution for injection in pre-filled syringe, serious adverse events reported included malignancies, asthma, infections, heart failure, myocardial infarction, myocardial ischaemia, chest pain, syncope, cerebral ischaemia, hypertension, hypotension, cholecystitis, pancreatitis, gastrointestinal haemorrhage, bursitis, confusion, depression, dyspnoea, abnormal healing, renal insufficiency, kidney calculus, deep vein thrombosis, pulmonary embolism, membranous glomerulonephropathy, polymyositis, thrombophlebitis, liver damage, leucopenia, paresis, paresthesia, vertigo, allergic alveolitis, angioedema, scleritis, bone fracture, lymphadenopathy, ulcerative colitis, intestinal obstruction, eosinophilia, haematuria and sarcoidosis.

Malignancies: Thirty-eight (38) new malignancies of various types were observed in 2680 RA patients treated in clinical trials with Enbrel 50 mg solution for injection in pre-filled syringe for up to 48 months, including 231 patients treated with Enbrel 50 mg solution for injection in pre-filled syringe in combination with methotrexate in the 1-year active-controlled study. No psoriatic arthritis patients developed malignancies in the double-blind, placebo-controlled studies of up to 6 months duration involving 131 Enbrel 50 mg solution for injection in pre-filled syringe-treated patients. Twenty-three (23) malignancies were reported in plaque psoriasis patients treated with Enbrel 50 mg solution for injection in pre-filled syringe in double-blind and open-label studies of up to 15 months involving 1261 Enbrel 50 mg solution for injection in pre-filled syringe-treated patients. Reports of various malignancies (including breast and lung carcinoma and lymphoma) have also been received in the post-marketing period.

There have been reports of malignancies in a clinical trial of patients being treated for Wegener's granulomatosis.

Injection Site Reactions: Compared to placebo, patients with rheumatic diseases treated with Enbrel 50 mg solution for injection in pre-filled syringe had a significantly higher incidence of injection site reactions (36% vs 9%). Injection site reactions usually occurred in the 1st month. Mean duration was approximately 3-5 days. No treatment was given for the majority of injection site reactions in the Enbrel 50 mg solution for injection in pre-filled syringe treatment groups and the majority of patients who were given treatment received topical preparations eg, corticosteroids or oral antihistamines. Additionally, some patients developed recall injection site reactions characterised by a skin reaction at the most recent site of injection along with the simultaneous appearance of injection site reactions at previous injection sites. These reactions were generally transient and did not recur with treatment. In post-marketing experience, injection site bleeding and bruising have also been observed in conjunction with Enbrel 50 mg solution for injection in pre-filled syringe therapy.

In controlled trials in patients with plaque psoriasis, approximately 14% of patients treated with Enbrel 50 mg solution for injection in pre-filled syringe developed injection site reactions compared with 6% of placebo-treated patients during the first 12 weeks of treatment.

Infections: In clinical trials in rheumatic disorders, upper respiratory infections (colds) and sinusitis were the most frequently reported infections in patients receiving Enbrel 50 mg solution for injection in pre-filled syringe or placebo. In placebo-controlled trials, the incidence of upper respiratory tract infections was 17% in the placebo treatment group and 22% in the group treated with Enbrel 50 mg solution for injection in pre-filled syringe. In RA patients participating in placebo-controlled trials, there were 0.68 events/patient-year in the placebo group and 0.82 events/patient-year in the group treated with Enbrel 50 mg solution for injection in pre-filled syringe when the longer observation of patients on Enbrel 50 mg solution for injection in pre-filled syringe was accounted for. In placebo-controlled trials evaluating Enbrel 50 mg solution for injection in pre-filled syringe, no increase in the incidence of serious infections (fatal, life-threatening or requiring hospitalization or IV antibiotics) was observed. Among the 2680 RA patients treated with Enbrel 50 mg solution for injection in pre-filled syringe for up to 48 months, including 231 patients treated with Enbrel 50 mg solution for injection in pre-filled syringe in combination with methotrexate in the 1-year active-controlled study, 170 serious infections were observed. These serious infections included abscess (at various sites), bacteraemia, bronchitis, bursitis, cellulitis, cholecystitis, diarrhoea, diverticulitis, endocarditis (suspected), gastroenteritis, hepatitis B, herpes zoster, leg ulcer, mouth infection, osteomyelitis, otitis, peritonitis, pneumonia, pyelonephritis, sepsis, septic arthritis, sinusitis, skin infection, skin ulcer, urinary tract infection, vasculitis and wound infection. In the 1-year active-controlled study where patients were treated with either Enbrel 50 mg solution for injection in pre-filled syringe alone, methotrexate alone or Enbrel 50 mg solution for injection in pre-filled syringe in combination with methotrexate, the rates of serious infections were similar among the treatment groups. However, it cannot be excluded that the combination of Enbrel 50 mg solution for injection in pre-filled syringe with methotrexate could be associated with an increase in the rate of infections.

In the placebo-controlled psoriatic arthritis and plaque psoriasis trials, there were no differences in rates of infection among patients treated with Enbrel 50 mg solution for injection in pre-filled syringe and those treated with placebo. In the psoriatic arthritis trials, no serious infections occurred in patients treated with Enbrel 50 mg solution for injection in pre-filled syringe. In the double-blind and open-label plaque psoriasis trials of up to 15 months, serious infections experienced by Enbrel 50 mg solution for injection in pre-filled syringe-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis and abscess.

Serious and fatal infections have been reported during use of Enbrel 50 mg solution for injection in pre-filled syringe; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses and fungi. Opportunistic infections have also been reported. Some have occurred within a few weeks after initiating treatment with Enbrel 50 mg solution for injection in pre-filled syringe in patients who have underlying conditions (eg, diabetes, congestive heart failure, history of active or chronic infections) in addition to their RA. Data from a sepsis clinical trial not specifically in patients with RA suggest that Enbrel 50 mg solution for injection in pre-filled syringe treatment may increase mortality in patients with established sepsis.

Autoantibodies: Patients had serum tested for autoantibodies at multiple timepoints. Of the RA patients evaluated for antinuclear antibodies (ANA), the percentage of patients who developed new positive ANA (≥1:40) was higher in patients treated with Enbrel 50 mg solution for injection in pre-filled syringe (11%) than in placebo-treated patients (5%). The percentage of patients who developed new positive antidouble-stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with Enbrel 50 mg solution for injection in pre-filled syringe compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with Enbrel 50 mg solution for injection in pre-filled syringe compared to none of placebo-treated patients). The proportion of patients treated with Enbrel 50 mg solution for injection in pre-filled syringe who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The impact of long-term treatment with Enbrel 50 mg solution for injection in pre-filled syringe on the development of autoimmune diseases is unknown.

There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a lupus-like syndrome or rashes that are compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy.

Pancytopenia and Aplastic Anaemia: There have been post-marketing reports of pancytopenia and aplastic anaemia, some of which had fatal outcomes.

Laboratory Evaluations: Based on the results of clinical studies, normally no special laboratory evaluations are necessary in addition to careful medical management and supervision of patients.

Concurrent Enbrel 50 mg solution for injection in pre-filled syringe and Anakinra Treatment: Patients treated with Enbrel 50 mg solution for injection in pre-filled syringe and anakinra were observed to have a higher rate of serious infection when compared with patients treated with either Enbrel 50 mg solution for injection in pre-filled syringe or anakinra alone (historical data). In addition, in a double-blind, placebo-controlled trial in patients receiving background methotrexate, patients treated with Enbrel 50 mg solution for injection in pre-filled syringe and anakinra were observed to have a higher rate of serious infections (7%) and neutropenia than patients treated with Enbrel 50 mg solution for injection in pre-filled syringe. The combination Enbrel 50 mg solution for injection in pre-filled syringe and anakinra has not demonstrated increased clinical benefit and is therefore not recommended.

Paediatrics with Juvenile Chronic Arthritis: In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients. Differences from adults and other special considerations are discussed as follows.

Severe adverse events reported in a trial in 69 juvenile chronic arthritis patients 4-17 years included varicella with signs and symptoms of aseptic meningitis which resolved without sequelae, gastroenteritis, depression/personality disorder, cutaneous ulcer, oesophagitis/gastritis, group A streptococcal septic shock, type I diabetes mellitus and soft tissue and postoperative wound infection.

There were 4 reports of macrophage activation syndrome in juvenile chronic arthritis clinical trials.

Forty-three of 69 (62%) children with juvenile chronic arthritis experienced an infection while receiving Enbrel 50 mg solution for injection in pre-filled syringe during 3 months of the study (part 1 open-label) and the frequency and severity of infections was similar in 58 patients completing 12 months of open-label extension therapy. The types of infections reported in juvenile chronic arthritis patients were generally mild and consistent with those commonly seen in outpatient paediatric populations. The types and proportion of adverse events in juvenile chronic arthritis patients were similar to those seen in trials of Enbrel 50 mg solution for injection in pre-filled syringe in adult patients with RA, and the majority were wild. Several adverse events were reported more commonly in 69 juvenile chronic arthritis patients receiving 3 months of Enbrel 50 mg solution for injection in pre-filled syringe compared to 349 adult RA patients. These included headache (19% of patients, 1.7 events/patient-year), nausea (9%, 1 event/patient-year), abdominal pain (19%, 0.74 events/patient-year), and vomiting (13%, 0.74 events/patient-year).

Enbrel 50 mg solution for injection in pre-filled syringe (INN): Enbrel 50 mg solution for injection in pre-filled syringe (Enbrel 50 mg solution for injection in pre-filled syringe) is a human tumour necrosis factor receptor (TNFR) p75 Fc fusion protein produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian expression system. Enbrel 50 mg solution for injection in pre-filled syringe is a dimer of a chimeric protein genetically engineered by fusing the extracellular ligand binding domain of human tumour necrosis factor receptor-2 (TNFR2/p75) to the Fc domain of human IgG1. This Fc component contains the hinge, CH₂ and CH₃ regions but not the CH₁ region of the IgG1. Enbrel 50 mg solution for injection in pre-filled syringe contains 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. The potency is determined by measuring the ability of Enbrel 50 mg solution for injection in pre-filled syringe to neutralise the TNFα-mediated growth inhibition of A375 cells. The specific activity of Enbrel 50 mg solution for injection in pre-filled syringe is 1.7 x 10⁶ units/mg.

Reconstituted Enbrel 50 mg solution for injection in pre-filled syringe solution is clear to slightly opalescent and colorless to slightly yellow, with a pH of 7.4 ± 0.3.

The solution for injection in the pre-filled syringe and pen is clear to opalescent, colourless to yellow, and liquid may contain trace levels of translucent to white particles of protein, with a pH of 6.3 ± 0.2.

Excipients/Inactive Ingredients: Enbrel 50 mg solution for injection in pre-filled syringe Lyophilized Powder: Mannitol, nitrogen, sucrose, trometamol (tromethamine) and water for injections.

Enbrel 50 mg solution for injection in pre-filled syringe Pre-Filled Syringe: Sucrose, sodium chloride, L-arginine hydrochloride, sodium phosphate monobasic dihydrate, sodium phosphate dibasic dihydrate and water for injections.