Registration number: LSR-006652/09

Invented name: Enbrel^®

International non-proprietary name: etanercept

Pharmaceutical form: solution for subcutaneous injection

Composition

Composition per 1 mL of solution

active substance:etanercept 50.0 mg;

excipients: L-arginine hydrochloride 5.3 mg, sodium chloride 5.8 mg, sucrose 10.0 mg, sodium hydrogen phosphate dihydrate 1.2 mg, sodium dihydrogen phosphate dihydrate 2.9 mg, water for injection to 1.0 mL.

Description

Clear or opalescent from colorless to yellow or light brown liquid. Small transparent to white amorphous particles are permissible.

Pharmacotherapeutic group: tumor necrosis factor-α (TNF-α) inhibitor

ATC Code: L04AB01

Rheumatoid arthritis

In combination with methotrexate, Enbrel^® is prescribed to adults for the treatment of moderate and severe active rheumatoid arthritis when response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, has been inadequate.

Enbrel^® may be prescribed as monotherapy in case of inefficacy or intolerance of methotrexate. Enbrel^® is indicated for the treatment of severe active and progressive rheumatoid arthritis in adults who have not been previously treated with methotrexate.

Juvenile idiopathic polyarthritis

Treatment of active juvenile idiopathic polyarthritis (seropositive and seronegative) in children and adolescents aged 12 years and older with a body weight of more than 62.5 kg (for Enbrel^® in the pharmaceutical form of a solution for subcutaneous injection), who have had an ineffective response or intolerance to methotrexate.

Treatment of extended oligoarthritis in children and adolescents aged 12 years and older with a body weight of more than 62.5 kg (for Enbrel^® in the pharmaceutical form of a “solution for subcutaneous injection”), who have had an ineffective response or intolerance to methotrexate.

Treatment of psoriatic arthritis in adolescents aged 12 years and older with a body weight of more than 62.5 kg (for Enbrel^® in the pharmaceutical form of a “solution for subcutaneous injection”), who have had an ineffective response or intolerance to methotrexate.

Treatment of arthritis associated with enthesitis in adolescents aged 12 years and older with a body weight of more than 62.5 kg (for Enbrel^® in the pharmaceutical form of a “solution for subcutaneous injection”), who have had an ineffective response or intolerance to standard therapy.

Psoriatic arthritis

Treatment of active and progressive psoriatic arthritis in adults who have had an inadequate response to DMARDs.

Axial spondylarthritis Ankylosing spondylitis

Treatment of severe active ankylosing spondylitis in adults for whom conventional therapy has not resulted in substantial improvement.

Non-radiographic of axial spondylarthritis

Etanercept is indicated for treatment of adult patients with severe course of axial spondylarthritis in the non-radiographic stage, in whom an inadequate response or resistance to standard treatment has been observed and who also have objective signs of active disease confirmed by an increased concentration of C-reactive protein (CRP) and/or MRI scan data.

Psoriasis

Treatment of adults with moderate and severe psoriasis, who have contraindications or intolerance to other systemic treatments, including cyclosporine, methotrexate or PUVA therapy.

Treatment of children aged 12 years and older with a body weight of more than 62.5 kg (for Enbrel^® in the pharmaceutical form of a “solution for subcutaneous injection”) with severe chronic psoriasis, who have had an intolerance or inadequate response to other systemic therapy or phototherapy.

Hypersensitivity to etanercept or any other component of the medication. Sepsis or risk of sepsis.

Active infection, including chronic or localized infections.

Patients aged under 12 years with a body weight of less than 62.5 kg (for Enbrel^® in the pharmaceutical form of a “solution for subcutaneous injection”).

Demyelinating diseases, chronic heart failure (CHF), immunodeficiency conditions, diseases that cause predisposition to the development or activation of infections (diabetes, hepatitis), moderate and severe alcoholic hepatitis, hepatitis C, blood dyscrasia, diseases of the nervous system (multiple sclerosis, optic neuritis, transverse myelitis).

Women of childbearing potential should consider the use of appropriate contraception to avoid becoming pregnant during therapy with Enbrel^® and for three weeks after the discontinuation of the therapy.

The effects of etanercept on pregnancy outcomes have been investigated in two observational cohort studies. A higher rate of major birth defects was observed in one observational study comparing pregnancies exposed to etanercept during the first trimester, with pregnancies not exposed to etanercept or other TNF-antagonists. The types of major birth defects were consistent with those most commonly reported in the general population and no particular pattern of abnormalities was identified. No change in the rate of spontaneous abortion, stillbirth, or minor malformations was observed. In another observational multi-country registry study comparing the risk of adverse pregnancy outcomes in women exposed to etanercept during the first 90 days of pregnancy to those exposed to non-biologic medications, there was no observed increased risk of major birth defects. That study also showed no increased risks of minor birth defects, preterm birth, stillbirth, or infections in the first year of life for infants born to women exposed to etanercept during pregnancy. Enbrel^® should only be used during pregnancy if clearly needed.

Etanercept penetrates the placenta and is detected in the serum of infants born to female patients treated with Enbrel^® during pregnancy. The clinical impact of this is unknown, however, infants

may be at increased risk of infection. The administration of live vaccines to infants for 16 weeks after the mother’s last dose of etanercept is generally not recommended.

Limited information from the published literature indicates that etanercept has been detected at low levels in human milk. Etanercept could be considered for use during breast-feeding taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Although systemic exposure in a breastfed infant is expected to be low because etanercept is largely degraded in the gastrointestinal tract, limited data regarding systemic exposure in the breastfed infant are available. Therefore, the administration of live vaccines (eg, BCG) to a breastfed infant when the mother is receiving etanercept may be considered 16 weeks after stopping breast-feeding (or at an earlier timepoint if the infant’s etanercept serum levels are undetectable).

Preclinical data on the peri- and postnatal toxicity of etanercept and of effects of etanercept on fertility and overall reproductive performance are not available.

Subcutaneously.

Treatment with Enbrel^® must be prescribed and monitored by a physician experienced in the diagnosis and treatment of rheumatoid arthritis, juvenile idiopathic polyarthritis, psoriatic arthritis, ankylosing spondylitis or psoriasis.

Enbrel^® in the form of a 25 mg ready-for-use solution (a single-use syringe containing 0.5 mL of the medicinal product) and 50 mg (a single-use syringe containing 1.0 mL of the medicinal product) or 50 mg (injection pen containing 1 mL of the medicinal product) is used for patients with a body weight of more than 62.5 kg. For patients with a body weight of less than 62.5 kg, lyophilizate for the preparation of a solution should be used.

Rheumatoid arthritis

The recommended dose is 25 mg of Enbrel^® twice a week with an interval of three to four days. An alternative dose is 50 mg once a week, which can be administered as a single subcutaneous injection of 50 mg or two practically simultaneous injections of 25 mg.

Psoriatic arthritis

The recommended dose is 25 mg of Enbrel^® twice a week with an interval of three to four days. An alternative dose is 50 mg once a week, which can be administered as a single subcutaneous injection of 50 mg or two practically simultaneous injections of 25 mg.

Ankylosing spondylitis

The recommended dose is 25 mg of Enbrel^® twice a week with an interval of three to four days. An alternative dose is 50 mg once a week, which can be administered as a single subcutaneous injection of 50 mg or two practically simultaneous injections of 25 mg.

Pre-radiographic axial spondylarthritis

The recommended dose is 25 mg of Enbrel^® twice a week with an interval of three to four days. An alternative dose is 50 mg once a week, which can be administered as a single subcutaneous injection of 50 mg or two practically simultaneous injections of 25 mg.

Psoriasis

The recommended dose is 25 mg of Enbrel^® twice a week with an interval of three to four days. It is possible to administer 50 mg of the medicinal product once a week as a single subcutaneous injection or two practically simultaneous injections of 25 mg.

As an alternative, 50 mg of Enbrel^® can be used twice a week for a period of not more than 12 weeks. If treatment needs to be continued, Enbrel^® should be administered at a dose of 25 mg twice a week or 50 mg once a week. Treatment should be continued until remission is reached and, as a rule, for not more than 24 weeks. The administration of the medicinal product should be discontinued if, after 12 weeks of treatment, no improvement in symptoms is observed. In some cases, the length of treatment may be more than 24 weeks.

In adult patients, depending on the physician’s evaluation and individual peculiarities of the patient, therapy can be either continuous or intermittent.

If repeated administration of Enbrel^® is needed, the duration of treatment stated above should be observed. It is recommended to prescribe a dose of 25 mg twice a week or 50 mg once a week.

The duration of treatment for some patients may exceed 24 weeks.

Elderly patients (65 years and older)

There is no need to adjust the dose or method of administration.

In children aged under 12 years with a body weight of less than 62.5 kg (see “Contraindications” section), Enbrel^® in the pharmaceutical form of a lyophilizate for solution for subcutaneous injection should be used, making it possible to administer a dose of less than 25 mg.

Children aged 12 years and older with a body weight of more than 62.5 kg can be administered Enbrel^® in the pharmaceutical form of a solution for subcutaneous injection in single-use syringes or injection pens.

Juvenile idiopathic polyarthritis (children aged 12 years and older with a body weight of more than 62.5 kg [for Enbrel ^® in the pharmaceutical form of a “solution for subcutaneous injection”]) Enbrel^® in the pharmaceutical form of a “solution for subcutaneous injection” is administered in this patient group in the same way as in adult patients: a single 25 mg dose. The medicinal product is injected twice a week with an interval of three to four days. Treatment should be discontinued if, after four months of therapy, no improvement in symptoms is observed.

The administration of a 50 mg dose once per week is possible.

Extended oligoarthritis (children aged 12 years and older with a body weight of more than 62.5 kg [for Enbrel ^® in the pharmaceutical form of a “solution for subcutaneous injection”])

Enbrel^® in the pharmaceutical form of a “solution for subcutaneous injection” is administered in this patient group in the same way as in adult patients: a single 25 mg dose. The medicinal product is injected twice a week with an interval of three to four days. Treatment should be discontinued if, after four months of therapy, no improvement in symptoms is observed.

The administration of a 50 mg dose once per week is possible.

Psoriatic arthritis (adolescents aged 12 years and older, and with a body weight greater than 62.5 kg [for Enbrel ^® in the pharmaceutical form of a “solution for subcutaneous injection”])

Enbrel^® in the pharmaceutical form of a “solution for subcutaneous injection” is administered in this patient group in the same way as in adult patients: a single 25 mg dose. The medicinal product is injected twice a week with an interval of three to four days. Treatment should be discontinued if, after four months of therapy, no improvement in symptoms is observed.

The administration of a 50 mg dose once per week is possible.

Arthritis associated with enthesitis (adolescents aged 12 years and older with a body weight of more than 62.5 kg [for Enbrel ^® in the pharmaceutical form of a “solution for subcutaneous injection”])

Enbrel^® in the pharmaceutical form of a “solution for subcutaneous injection” is administered in this patient group in the same way as in adult patients: a single 25 mg dose. The medicinal product

is injected twice a week with an interval of three to four days. Treatment should be discontinued if, after four months of therapy, no improvement in symptoms is observed.

The administration of a 50 mg dose once per week is possible.

Psoriasis (children aged 12 years and older with a body weight of more than 62.5 kg [for Enbrel ^® in the pharmaceutical form of a “solution for subcutaneous injection”])

The single dose of the medicinal product is 50 mg. The medicinal product is injected once a week, and the duration of therapy is not more than 24 weeks. The injections of the medicinal product should be discontinued if, after 12 weeks of treatment, no response to the therapy is observed.

If repeated administration of Enbrel^® is needed, the duration of treatment stated above should be observed. The single dose of the medicinal product is 50 mg once a week.

If a dose is missed at the appointed time, the drug must be injected as soon as remembered, but only on condition that the next injection will not be earlier than a day later. Otherwise, the forgotten dose should be skipped. Patients should continue to inject the medicine on the usual day (days). If a patient does not remember the day that the next injection is due, instruct the patient not to take a double dose.

Impaired hepatic and renal function: there is no need to adjust the dose.

selecting-a-site-for-injection

• Three sites are recommended for the injection of Enbrel ^®: (1) the front surface of the middle third of the thigh; (2) the abdomen, except for an area 5 cm in diameter around the navel;

(3) the outer surface of the shoulder (see Fig. 1). If you are administering an injection to yourself, you should not use the outer surface of the shoulder.

Fig. 1

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• Each injection should be administered in a different site. The site of each new injection should be at least 3 cm away from the site of the previous injection. DO NOT INJECT the medicinal product into areas where there is pain, skin redness, bruising or induration. Do not inject in areas with scars or stretch marks. (It may be useful to write down the sites of previous injections).

• If a child has psoriasis, try not to inject the medicinal product directly into raised, thickened or red areas or lesions with flaking (psoriatic plaques).

1) INSTRUCTIONS FOR PREPARATION AND INJECTION OF A SOLUTION FOR SUBCUTANEOUS INJECTION OF ENBREL^® IN A SYRINGE

Patients or their parents/guardians who are going to perform injections should be informed of how to do it correctly. In cases where the patient or his/her parent/guardian performs the future injections by him-/herself, the first injection must be performed under the supervision of qualified medical personnel.

Preparation for Injection

This medicinal product must not be mixed with any other medicinal products in a single syringe or vial!

• Remove the carton with pre-filled syringes of Enbrel^® from the refrigerator and place it on a clean, well-lit, flat work surface. Take one pre-filled syringe. Do not shake the syringe. Put the carton with the remaining pre-filled syringes back in the refrigerator.

• Leave the syringe with a solution of Enbrel^® for 15 to 30 minutes to allow it to reach room temperature. DO NOT REMOVE the cap from the syringe needle until it reaches room temperature. Do not warm up Enbrel^® by any other means (for example, in a microwave oven or in hot water).

• Wash your hands with soap and warm water.

• Make sure that the solution in the syringe is clear or opalescent, colorless to yellow or to light brown, it may contain a small amount of semi-transparent or white amorphous particles. If this is not the case, do not inject the solution. Use a different pre-filled syringe of Enbrel^®.

• You will also need: an alcohol wipe, which is included in the kit, and a cotton ball or gauze pad.

Preparation of the skin site and injection of the solution of Enbrel^®

• Wipe the skin site where you will inject Enbrel^® in circular motions with a clean alcohol wipe. DO NOT TOUCH this area until you have completed the injection.

• Remove the cap from the needle by pulling it forcefully from the syringe (see Fig. 2). Be careful not to bend or over-twist the cap while removing, so as not to damage the needle.

• When removing the cap, a drop of fluid may appear on the tip of the needle; this is permissible.

  • Do not touch the needle and do not let it touch any other surface.

Do not touch or press on the plunger. This can lead to fluid leaking from the syringe.

Fig. 2

​

• When a cleaned skin area is completely dry, pinch the skin into a fold with one hand and hold it. With the other hand, hold the syringe like a pencil.

• With a quick, short motion, direct the needle into the skin at an angle between 45° and 90° (see Fig. 3). In time you will find the angle that is most comfortable for the injection. Try not to push the needle into the skin too slowly or with excessive force.

Fig. 3

​

• After the needle has fully entered the skin, release the fold of skin you have been holding.

With your free hand, hold the base of the syringe to stabilize its position. Then press the plunger to inject all of the solution at a slow, constant speed (see Fig. 4).

Fig. 4

​

• When the syringe is empty, remove the needle from the skin, being careful to keep it at the same angle as when it was inserted.

• Press on the injection site with a cotton ball or gauze pad for 10 seconds. A small amount of bleeding may occur. DO NOT WIPE the injection site. A bandage may be applied.

Waste disposal

• The pre-filled syringe is intended for single use only. NEVER reuse the syringe and needle. NEVER recap the needle. Dispose of the needle and syringe as instructed by your physician or nurse.

If you have questions, please contact a physician or nurse who works with Enbrel^®.

2) INSTRUCTIONS FOR PREPARATION AND INJECTION OF A SOLUTION FOR SUBCUTANEOUS INJECTION OF ENBREL^®IN AN INJECTION PEN

Do not attempt to perform an injection by yourself if you have not understood how to use the injection pen properly. If you have questions regarding injections, please ask your physician or nurse.

Fig. 5

Pre-filled injection pen

​

• Select a clean, well-lit, flat working surface.

Gather the following items needed for the injection and place them on the working surface:

1. One pre-filled injection pen and one alcohol wipe (take them out of the carton of injection pens that you store in the refrigerator). Do not shake the injection pen.

2. One cotton ball or gauze pad.

   • Check the expiry date on the injection pen. Do not use the injection pen if the date is past. Consult with your treating physician.

   • Assess the condition of the solution in the injection pen through the transparent inspection window.

It is only permissible to inject a clear or opalescent, colorless to yellow or light brown solution, which may contain a small quantity of semi-transparent or white amorphous particles. If this is not the case, you should use a different injection pen and then ask a pharmacist for assistance.

• Without removing the white needle cap, wait approximately 15 to 30 minutes for the Enbrel^® solution in the injection pen to warm up to room temperature. This will make the injection more comfortable. Do not warm the injection pen by any other method. Always keep the injection pen out of reach of children.

• While the solution in the injection pen is warming up to room temperature, read the information on Step 2 activities (below) and select an injection site.

• After warming the solution up to room temperature for approximately 15 to 30 minutes, wash your hands with soap and water.

• With circular motions, wipe the area of skin where you are going to inject Enbrel^® with a clean alcohol wipe and allow to dry. DO NOT TOUCH this area until you have completed the injection.

• Take the injection pen and remove the white cap by pulling it straight toward yourself (see Fig. 7). To avoid damaging the needle, which is covered by the cap, do not tilt the cap when removing it, and do not attempt to put it back on after removing. After removing the needle cap, you will see a purple protective screen, which protrudes slightly from the edge of the injection pen. The needle itself will remain inside the injection pen until the moment it is activated. Do not use the injection pen if it dropped on the floor after you had removed the protective cap from the needle.

Fig. 7

​

• Carefully pinch the skin into a fold between the thumb and index finger of your free hand; this will make it easier to administer the medicinal product and make it more comfortable. Try not to touch the prepared surface of the skin.

• Place the injection pen at a right angle (90º) to the injection site and press the open end firmly against the skin, so that the protective screen goes fully inside the injection pen. You will see a slight indentation of the skin (Fig. 8). The injection pen will be activated only when the protective screen of the needle has fully gone into the injection pen.

Fig. 8

​

• Press the injection pen firmly against the skin and make sure that the purple protective screen has gone completely inside it. To inject, press at the center of the green button located on the upper part of the injection pen (Fig. 9). After pressing the button, you will hear a click. Continue to hold the injection pen pressed firmly to the skin either until the second click or for 10 seconds after the first click (whichever occurs first).

Note: if you cannot start the injection as described above, press the injection pen more tightly against the skin and press the green button again.

Fig. 9

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• After the second click (or in 10 seconds), the injection is complete (Fig. 10), and you can release the pressure on the skin (Fig. 11); the purple protective screen will automatically come out and cover the needle.

Fig. 10

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Fig. 11

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• When this is done, the color of the inspection window of the injection pen will change to purple (see Fig. 12), which confirms that the dose has been injected correctly. If this does not occur, you should ask a physician, nurse or pharmacist for assistance, as there is no guarantee in this situation that the full dose of Enbrel^® has been injected. Do not attempt to reuse this injection pen, and do not use a new injection pen without consulting with a nurse or pharmacist.

Fig. 12

​

• If drops of blood appear at the injection site, press a cotton ball or gauze pad against the site and hold it for 10 seconds. Do not rub the injection site.

• The injection pen is intended for single use only; therefore, its reuse is not permissible. Used injection pens should be disposed of as instructed by a physician, nurse or pharmacist. Do not try to re-attach the needle protective cap.

Summary of the safety profile

The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infections, bronchitis, bladder infections and skin infections), allergic reactions, development of autoantibodies, itching, and fever.

Serious adverse reactions have also been reported during the use of Enbrel^®. TNF-antagonists, such as etanercept, negatively affect the immune system and their use may have a negative effect on the body’s defenses against infections and malignancies. Serious infections affect fewer than one in 100 patients treated with Enbrel^®. Reports have included fatal and life-threatening infections and sepsis. Various malignancies have also been reported with the use of Enbrel^®, including cancers of the breast, lung, skin and lymph glands (lymphoma).

Serious hematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia and very rare reports of aplastic anemia. Central and peripheral demyelinating events have been seen rarely and very rarely, respectively, with the use of Enbrel^®. There have been rare reports of lupus, lupus-related conditions, and vasculitis.

In the case of an overdose of Enbrel ^®, contact a physician or pharmacist immediately.

Save the carton of Enbrel^®, even if it is empty.

The maximum dose of Enbrel^® has not been established. In a clinical study, a single 60 mg/m2 dose was administered to healthy volunteers, which did not lead to the development of dose- limiting toxicity.

In the treatment of patients with rheumatoid arthritis, no cases of the toxic dose limit being exceeded were documented. The highest dose injected intravenously was 32 mg/m2, with a subsequent subcutaneous injection of 16 mg/m2 twice a week. There is no known specific antidote for Enbrel^®.

Anakinra

During combined therapy with etanercept and anakinra, a significant increase in the frequency of serious infections and neutropenia was observed as compared with patients who were injected with only etanercept or only anakinra.

Combined therapy with etanercept and anakinra did not show any clinical benefit and, therefore, is not recommended.

Abatacept

The simultaneous use of abatacept and etanercept was accompanied by an increase in the frequency of serious undesirable events. This drug combination did not show any clinical benefits and, therefore, is not recommended.

Sulfasalazine

In patients administered etanercept during treatment with sulfasalazine, a significant reduction in leukocyte count was documented compared to patients who received only etanercept or only sulfasalazine.

Absence of interaction

No adverse interactions were observed during the simultaneous use of etanercept with glucocorticosteroids, salicylates (with the exception of sulfasalazine), non-steroidal anti- inflammatory drugs (NSAIDs), analgesics or methotrexate.

Methotrexate

Methotrexate has no effect on the pharmacokinetics of etanercept. The effect of etanercept on the pharmacokinetics of methotrexate in humans has not been studied.

Digoxin

No clinically significant cross-effect on the pharmacokinetics of etanercept has been found.

Warfarin

No clinically significant cross-effect on the pharmacokinetics of etanercept has been found.

Vaccination

Live vaccines should not be administered during treatment with etanercept. There is no data on the secondary transmission of an infection through a live vaccine to patients receiving etanercept. Before beginning treatment with etanercept, it is recommended that children and adolescents receive all necessary vaccinations according to the current national vaccination calendar, if possible.

An increase in B-cell immune response to the pneumococcal polysaccharide vaccine was observed in the majority of patients with psoriatic arthritis who had received etanercept, even if titers were slightly lower on the whole. A twofold increase in titers was observed in a lower number of patients in comparison with patients not receiving etanercept.

After the discontinuation of Enbrel^®, disease symptoms may recur.

Infections

Patients should be examined for infections before starting treatment with Enbrel^®, during treatment and after completing the course of treatment, taking into account the mean half-life of etanercept, which is approximately 70 hours (seven to 300 hours).

During treatment with Enbrel^®, sepsis, tuberculosis, parasitic infections (including those caused by protozoa organisms) and severe infections, including opportunistic infections, such as invasive fungal infections, listeriosis and legionellosis (some with lethal outcomes), and viral infections (including caused by herpes zoster) were reported. The most commonly reported invasive fungal infections were caused by Candida Pneumocystis, Aspergillus and Histoplasma. Incorrect diagnosis of the above-mentioned infections, especially fungal and other opportunistic infections, led to the delayed prescription of necessary treatment and, in some cases, to lethal outcomes. In many cases, patients received treatment with other medicinal products, including immunosuppressants. When examining patients, it is important to consider the possible development of opportunistic infections, for example, endemic mycoses. Patients who develop new infections during treatment with Enbrel^® should be kept under close observation. The administration of Enbrel^® should be discontinued if a patient develops a severe infection. The administration of Enbrel^® requires caution in patients with a history of frequent or chronic infections or underlying diseases, which may facilitate the development of infections (such as severe or poorly controlled diabetes mellitus).

The safety and efficacy of Enbrel^® in patients with chronic infections have not been evaluated.

Tuberculosis

During treatment with Enbrel^®, cases of active tuberculosis have been reported, including miliary tuberculosis and extrapulmonary tuberculosis. Among rheumatoid arthritis patients, there is apparently a higher frequency of the development of tuberculosis infection.

The development of tuberculosis infection may be connected with the reactivation of a latent infection or with the development of a new infection.

Before starting treatment, all patients should be screened for the presence of active or latent tuberculosis. The screening should include a detailed examination of the patient’s medical history with regard to contraction of tuberculosis or contact with tuberculosis patients in the past and information on previous or current immunosuppressive therapy. All patients should undergo necessary screenings in accordance with local requirements. These must include: a tuberculin skin test and a chest x-ray. The possibility of a false negative tuberculin skin test should be considered, especially in patients in a serious condition or in immunocompromised patients. It is also necessary to consider the possibility of the development of tuberculosis in patients in whom signs of tuberculosis infection were not found before beginning treatment with Enbrel^®. The attending physician should monitor the condition of the patient for any signs of tuberculosis, including patients who originally tested negative for tuberculosis infection.

Enbrel^® should not be used if a patient has active tuberculosis. If inactive tuberculosis is present before beginning the treatment with Enbrel^®, a standard anti-tuberculosis therapy should be prescribed in accordance with local recommendations. In this case, the benefit-to-risk ratio of treatment with Enbrel^® should be thoroughly analyzed.

All patients should be advised to contact a physician if symptoms typical of tuberculosis (for example, persistent cough, weight loss, low-grade fever) appear during or after treatment with Enbrel^®.

Activation of hepatitis B virus

Cases of the activation of hepatitis B virus in carrier patients who received TNF inhibitors, including Enbrel^®, have been reported. The majority of these cases took place in patients who had simultaneously been receiving other medicinal products that suppress the immune system and could also promote the reactivation of hepatitis B virus. Before using Enbrel^® in patients with a high risk of contracting hepatitis B, appropriate diagnostic screening should be conducted. Despite the fact that no connection with the use of Enbrel^® has been proven, special care should be taken when using Enbrel^® in patients who are carriers of hepatitis B virus. It is necessary to monitor the condition of patients for signs of hepatitis B. If symptoms of the disease appear, the possibility of specific therapy should be discussed.

Exacerbation of hepatitis C

Cases of the exacerbation of hepatitis C have been documented in patients receiving treatment with Enbrel^®; however, no cause-and-effect relationship with the use of etanercept has been proven. Nevertheless, caution should be exercised when administering Enbrel^® to patients with a history of hepatitis C.

Allergic reactions

The use of Enbrel^® is frequently accompanied by allergic reactions. In case of any severe allergic or anaphylactic reactions, treatment with Enbrel^® should be discontinued immediately, and appropriate treatment should be started.

The protective cap of the injection pen contains latex (dry natural rubber). Patients or caregivers should consult their physician before taking Enbrel^® when the needle protective cap is handled by or when Enbrel^® is administered to a patient with known or possible latex sensitivity (allergy).

Immunosuppression

During treatment with TNF inhibitors, including Enbrel^®, there is a possibility of suppressing the body’s defense mechanisms against infections and malignant neoplasms, since TNF is involved in inflammation processes and modulates cellular immune responses. However, in adult patients with rheumatoid arthritis, there was no evidence of depressed delayed-type hypersensitivity reactions, decreased immunoglobulin levels or changes in the effector cell population size during treatment with Enbrel^®.

In rare cases, children with juvenile idiopathic polyarthritis developed varicella infection and symptoms of aseptic meningitis, which resolved with no complications. Patients who have been in contact with varicella virus should temporarily discontinue Enbrel^® and start prophylactic treatment with immune globulin to Varicella Zoster .

The efficacy and safety of Enbrel^® in patients with immunosuppression have not been studied.

Malignant and lymphoproliferative diseases

In the post-marketing period (see “Side effects” section), reports of various malignant neoplasms (including breast and lung carcinoma and lymphoma) were received.

In a number of controlled clinical studies, lymphoma was diagnosed more frequently in patients taking TNF inhibitors compared to patients who did not receive them. However, these cases were rare, and the observation period for the patients in the placebo group was shorter than for the patients receiving treatment with TNF inhibitors. There are reports of the development of leukemia in patients undergoing treatment with TNF inhibitors. There is a high risk of lymphoma and leukemia developing in patients with rheumatoid arthritis – a long-term disease characterized by active inflammation, which in itself complicates risk evaluation. A subsequent analysis of the clinical studies of etanercept in patients with rheumatoid arthritis did not confirm or exclude an

increase in the risk of developing cancers in patients who receive etanercept. However, based on current data, the possible risk of developing lymphomas, leukemia or other malignant neoplasms cannot be ruled out in patients receiving TNF inhibitors.

Malignant neoplasms (in half of the cases, Hodgkin’s and non-Hodgkin’s lymphomas), some of which had lethal outcomes, were reported in children and adolescents who had received treatment with TNF inhibitors, including Enbrel^®. The majority of patients received concomitant treatment with immunosuppressants. In other cases, there were various malignant neoplasms, including rare varieties, linked with immunosuppression. During the use of the medicinal product, it is necessary to consider the risk of developing malignant neoplasms.

Skin cancer

Melanoma and non-melanoma skin cancer (NMSC) were documented in patients who had received treatment with TNF inhibitors, including Enbrel^®. NMSC is most frequently diagnosed in psoriasis patients. The development of Merkel cell carcinoma has been reported.

For all patients at high risk, periodic skin examinations are recommended.

Formation of autoimmune antibodies

Treatment with Enbrel^® may be accompanied by the formation of autoimmune antibodies (see “Side effects” section). These are not neutralizing antibodies and usually disappear shortly. No correlation has been observed between the formation of antibodies and the clinical efficacy of the medicinal product or the frequency of adverse reactions.

Isolated cases of the formation of additional autoantibodies in conjunction with lupus-like syndrome or rash similar to a subacute form of lupus erythematosus or a discoid form of lupus erythematosus (data from clinical examination and biopsy) were observed in patients, including those with rheumatoid arthritis with a positive rheumatoid factor.

Hematological reactions

Rare cases of pancytopenia and very rare cases of aplastic anemia were reported, including lethal cases, in patients who had received Enbrel^®. Caution should be exercised when using Enbrel^® in patients with a history of blood disorders. All patients and their relatives/caregivers should be advised to seek medical attention immediately if a patient develops signs or symptoms typical of an infection or hematological disorders (for example, persistent fever, tonsillitis, bruises, bleeding, pallor) when taking Enbrel^®. These patients should undergo examination immediately, including a complete blood count. If the diagnosis of a hematological disorder is confirmed, treatment with Enbrel^® should be discontinued.

CNS disorders

There have been rare reports of demyelinating diseases of the CNS in patients receiving treatment with etanercept. There have also been very rare reports of peripheral demyelinating

polyneuropathies (including Guillain-Barré syndrome). The studies of treatment with Enbrel^® in patients with multiple sclerosis have not been conducted; however, studies of other TNF inhibitors in patients with this condition showed the possibility of its exacerbation. Before beginning the treatment with Enbrel^®, a thorough evaluation of the risk-to-benefit ratio and a neurological assessment are recommended in patients with pre-existing or recent-onset demyelinating diseases as well as patients with a high risk of developing a demyelinating disease.

CHF

Caution should be exercised in prescribing Enbrel^® for patients with CHF. Rare (< 0.1%) cases of CHF were reported, including those in patients without a confirmed underlying cardiovascular disease. Some patients were under 50 years old. The data from a number of studies suggest the possibility of exacerbation of CHF in patients receiving Enbrel^®.

Combination therapy

The combination of Enbrel^® and methotrexate yielded no unexpected results in safety testing. The long-term study of this combination continues. Data on the safety of Enbrel^® prescribed in combination with methotrexate were similar to those from reports on the use of either Enbrel^® or methotrexate alone. The long-term safety of taking Enbrel^® in combination with other disease- modifying anti-rheumatic drugs has not been studied.

No studies on Enbrel^® in combination with other systemic therapy or phototherapy for psoriasis have been conducted.

Wegener’s granulomatosis

The frequency of developing various types of malignant extracutaneous tumors was significantly higher in patients with Wegener’s granulomatosis who had received Enbrel ^® than in the control group.

Therefore, Enbrel ^® is not recommended for the treatment of Wegener’s granulomatosis patients.

Alcoholic hepatitis

The administration of etanercept for the treatment of alcoholic hepatitis is not recommended.

Hypoglycemia in patients with diabetes mellitus

There have been reports of hypoglycemia during treatment with Enbrel^® in patients taking hypoglycemic medications, requiring their dose adjustment.

Effect on the ability to drive and operate machinery

No studies on the effect of Enbrel^® on the ability to drive motor vehicles and operate complex machinery have been conducted. Therefore, caution should be exercised when driving or operating machinery.

50 mg/mL solution for subcutaneous injection.

1. 0.5 mL (25 mg) or 1.0 mL (50 mg) of the medicinal product in colorless glass (type I) single- use syringes fitted with a stainless-steel needle covered with a two-layer cap, a plastic finger grip and a plunger rod with a rubber seal.

   Four syringes in a set with four individually wrapped alcohol wipes in a plastic package with a ventilation hole.

   One, two or six plastic packages (25 mg) or one, two or three plastic packages (50 mg) along with Instructions for Use in a carton with or without a tamper-evident seal.

2. 1.0 mL (50 mg) of the drug in a single-use injection pen with a white plastic needle cap and a purple protective screen. The syringe inside the pen is of colorless glass (type I) and is fitted with a stainless-steel needle.

   Four injection pens in a set with four individually wrapped alcohol wipes in a plastic package with an air vent. One plastic package with Instructions for Use in a carton with or without a tamper-evident seal.

Store between 2 °C and 8 °C. Do not freeze.

Keep out of reach of children!

Three years.

Do not use after the expiry date indicated on the package!

Dispensed by prescription.

Pfizer Manufacturing Belgium NV, Belgium

Address: 12 Rijksweg, 2870 Puurs-Sint-Amands, Belgium

Pfizer Inc, USA

Organization receiving consumer claims

Pfizer Innovations LLC

123112, Moscow, Presnenskaya nab., d. 10,

BTs [Business Centre] “Bashnya na Naberezhnoy” (Blok C)

Phone: + 7 (495) 287-5000

Fax: +7 (495) 287-5300/287-5067