Enbrel - instructions for use, dose, side effects, contraindications

Active substanceEtanerceptEtanercept

Similar drugsTo uncover

Enbrel®

lyophilizate PC

Pfizer Inc. USA

Enbrel®

solution PC

Pfizer Inc. USA

Enbrel®

lyophilizate PC

Pfizer Inc. USA

Dosage form: & nbsplyophilizate for the preparation of a solution for subcutaneous administration

Composition:

1 bottle with lyophilizate contains:

active substance: etanercept 25.0 mg;

Excipients: mannitol 40.0 mg, sucrose 10.0 mg, trometamol 1.2 mg (as a mixture of trometamol and trometamol hydrochloride until a pH of 7.4).

1 syringe with solvent contains: water for injection 1.0 ml.

Description:

White lyophilized powder or porous mass.

Pharmacotherapeutic group:Tumor necrosis factor-alpha (TNF-alpha) inhibitors

ATX: & nbsp

L.04.A.B.01 Etanercept

Pharmacodynamics:

Tumor Necrosis Factor (TNF-α, TNF) is the main cytokine that supports the inflammatory process in rheumatoid arthritis. Increasing concentrations of TNF are also found in the synovium and psoriatic plaques of patients with psoriatic arthritis and in serum and synovial tissue of patients with ankylosing spondylitis. Etanercept is a competitive inhibitor of the binding of TNF to its receptors on the cell surface, and thus inhibits the biological activity of TNF.TNF and lymphotoxin relate to pro-inflammatory cytokines that bind to two distinct receptors of tumor necrosis factor (TNFR) on the cell surface: 55-kilodalton (p55) and 75-kilodalton (p75). Both PNOM are present in the body in membrane-bound and free forms. Soluble FNOR regulate the biological activity of TNF.

TNF and lymphotoxin exist predominantly as homotrimers, their biological activity depends on the cross-linking of the TNFR on the surface of the cell. Dimeric soluble receptors, such as etanercept, have a greater affinity for TNF than monomeric receptors, and therefore are significantly stronger competitive inhibitors of TNFα binding to their cellular receptors. In addition, the use of Fcimmunoglobulin fragment as a binding element in the dimeric receptor structure prolongs the half-life of serum.

A significant part of the pathological changes in joints with rheumatoid arthritis and ankylosing spondylitis, as well as changes in the skin in the form of psoriatic plaques, arise due to the action of pro-inflammatory molecules involved in a system controlled by TNF.The mechanism of action of etanercept appears to be a competitive inhibition of the binding of TNF to TNF receptors on the cell surface. In this way, etanercept prevents the cellular response mediated by TNF, facilitating the biological inactivation of TNF. Etanercept can also modulate biological responses controlled by additional molecules that transmit the signal downward (for example, cytokines, adhesion molecules or proteinases). And these answers can either stimulate or control TNF.

In patients with psoriatic arthritis, Enbrel® improves physical activity and reduces the likelihood of developing peripheral joint damage.

After the termination of therapy with the drug Enbrel®, the disease may worsen within a month. The effectiveness of re-appointment of the drug within 24 months after discontinuation of therapy is comparable to that for patients who did not interrupt treatment.

Pharmacokinetics:

Etanercept is slowly absorbed from the subcutaneous injection site, reaching a maximum concentration approximately 48 hours after a single dose of Enbrel®. Absolute bioavailability is 76%.With the administration of a dose of Enbrel® twice weekly, double equilibrium concentrations are achieved twice that observed after a single dose. After a single subcutaneous injection of 25 mg of Enbrel®, the average maximum concentration of etanercept in the blood plasma was 1.65 ± 0.66 μg / ml, the area under the concentration-time curve (AUC) was 235 ± 96.6 μg / hr / ml . Visible saturation of clearance in the dose limits was not observed. The dependence of the ethanercept concentration on time is described by the biexponential curve. The average value of the volume of distribution is 7.6 liters, while the volume of distribution at the equilibrium state is 10.4 liters.

From the body etanercept output slowly. The half-life (T_1/2) is about 70 hours. In patients with rheumatoid arthritis, clearance is approximately 0.066 L / h, which is somewhat lower than its value of 0.11 L / h in healthy volunteers. The pharmacokinetic characteristics of etanercept in patients with rheumatoid arthritis, ankylosing spondylitis and psoriasis are similar.

The dose of Enbrel® 50 mg, administered once, is bioequivalent to the dose obtained by two injections of 25 mg of the drug, made almost simultaneously.Despite the fact that in patients and healthy volunteers after the introduction of labeled etanercept, the radioactive label is eliminated through the kidneys, in patients with acute renal or hepatic insufficiency, there was no increase in the concentration of etanercept in the blood plasma. In patients with acute renal or hepatic insufficiency, an increase in the concentration of etanercept is not observed.

There are no obvious differences in the pharmacokinetics of etanercept in men and women.

Elderly patients

The clearance and apparent volumes of etanercept distribution in the group of patients from 65 to 87 years are similar to those in patients younger than 65 years.

Children

Juvenile idiopathic polyarthritis

The serum concentration profile is similar to that in adult patients with rheumatoid arthritis. Modeling suggests that in older children (10-17 years) and adult patients, the concentration of etanercept in plasma is approximately the same, and in younger children it will be significantly lower.

Psoriasis

Equilibrium concentrations of etanercept in the blood serum of children aged 4 to 17 years with psoriasis and children with juvenile idiopathic polyarthritis who received Enbrel®,respectively, at a dose of 0.8 mg / kg once a week (maximum dose of 50 mg per week) and 0.4 mg / kg twice a week (maximum dose of 50 mg per week) for 48 and 12 weeks were similar (1.6-2.1 μg / ml). The value of this indicator coincided with that in adult patients with psoriasis, which Enbrel® was administered at a dose of 25 mg twice a week.

Indications:

Rheumatoid arthritis

In combination with methotrexate, Enbrel® is prescribed to adults for the treatment of active rheumatoid arthritis of medium and high severity, when the response to basic anti-inflammatory drugs (CPAP), including methotrexate, was inadequate. Enbrel® can be given as a monotherapy in the case of ineffectiveness or intolerance to methotrexate.

Enbrel® is indicated for the treatment of severe, active and progressive rheumatoid arthritis in adults who have not previously received methotrexate therapy.

Juvenile idiopathic polyarthritis

Treatment of active juvenile idiopathic polyarthritis (seropositive and seronegative) in children and adolescents aged 2-17 years who had insufficient efficacy or intolerance to methotrexate.

Treatment of advanced oligoarthritis in children and adolescents over 2 years of age who have had insufficient efficacy or intolerance to methotrexate. Treatment of psoriatic arthritis in adolescents over the age of 12 years who have had insufficient efficacy or intolerance to methotrexate.

Treatment of arthritis associated with enthesitis in adolescents over the age of 12 years who have experienced inadequate efficacy or intolerance to standard therapy.

Psoriatic arthritis

Treatment of active and progressive psoriatic arthritis in adults, when the response to therapy with BPVP was inadequate.

Axial form of spondyloarthritis

Ankylosing spondylitis

Treatment of adults with severe active ankylosing spondylitis, in whom traditional therapy did not lead to significant improvement.

Dorsiatological stage of axial form of spondyloarthritis

Etanercept is indicated for the treatment of adult patients with severe course of the dorotgenological stage of the axial form of spondyloarthritis who have an inadequate response or resistance to standard therapy,and there are objective signs of disease activity, confirmed by an increase in the concentration of C-reactive protein (CRP) and / or MRI scan data.

Psoriasis

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

Treatment of children aged 6 years and older with chronic high-grade psoriasis who have had intolerance or insufficient response to other systemic or phototherapy.

Contraindications:

Hypersensitivity to etanercept or any other component of the drug.

Sepsis or the risk of sepsis.

Active infection, including chronic or localized infections.

Pregnancy and the period of breastfeeding.

The efficacy and safety of Enbrel® for the treatment of juvenile idiopathic polyarthritis (seropositive and seronegative) and advanced oligoarthritis in children under 2 years of age have not been studied.

The efficacy and safety of Enbrel® for the treatment of psoriasis in children under the age of 6 years have not been studied.

The efficacy and safety of Enbrel® for the treatment of psoriatic arthritis and arthritis associated with enthesitis in children under the age of 12 years have not been studied.

Carefully:

Demyelinating diseases, chronic heart failure (CHF), conditions of immunodeficiency, diseases predisposing to the development or activation of infections (diabetes mellitus, hepatitis), alcoholic hepatitis of moderate and severe course, hepatitis C, blood dyscrasia, nerve diseases (multiple sclerosis, optic neuritis , transverse myelitis).

Pregnancy and lactation:

The safety of Enbrel® during pregnancy is not established. The available data did not show an increase in the frequency of congenital malformations, fetal development. In addition, no increase in the frequency of intrauterine or postnatal growth deficits or postnatal developmental delays in children. The use of Enbrel® is contraindicated during pregnancy and in women planning pregnancy, since there is no experience of using this drug in pregnant women. Etanercept penetrates into the placenta.In newborns whose mothers received etanercept therapy during pregnancy, they detected it in blood plasma. The clinical significance of this is unknown, but such children may have increased sensitivity to infections.

It is not recommended to administer live vaccines to newborns within 16 weeks after their mothers received the last dose of etanercept.

Women of childbearing age should use a reliable method contraception during therapy with the drug Enbrel®, and also within three weeks after its withdrawal.

Etanercept is excreted in breast milk after subcutaneous injection. Should either stop breastfeeding or stop taking Enbrel® during breastfeeding, taking into account the importance of therapy for the mother and the risk to the baby.

Dosing and Administration:

Subcutaneously.

Treatment with Enbrell® should 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 a dosage form of lyophilizate for the preparation of a solution in a dosage of 25 mg is recommended for patients weighing less than 62.5 kg, including children.

Before preparing the reconstituted solution and administering the preparation, it is necessary to carefully study the instructions for its use, which is at the end of this section.

Adults

Rheumatoid arthritis

The recommended dose is 25 mg of Enbrel® twice a week at intervals of 3-4 days. An alternative dose is 50 mg once a week, which can be administered by a single subcutaneous injection of 50 mg or two injections of 25 mg of the drug taken almost simultaneously.

The use of the drug at a dose of 25 mg once a week can be less effective and gives a slower effect.

Psoriatic arthritis

The recommended dose is 25 mg of Enbrel® twice a week with an interval of 3-4 days. An alternative dose is 50 mg once a week, which can be administered by a single subcutaneous injection of 50 mg or two injections of 25 mg of the drug taken almost simultaneously.

Ankylosing spondylitis

Dorsiatological stage of axial form of spondyloarthritis

Psoriasis

The recommended dose is 25 mg of Enbrel® twice a week with an interval of 3-4 days. It is possible to administer 50 mg of the drug once a week by a single subcutaneous injection or two injections of 25 mg of the drug taken almost simultaneously.

Alternatively, Enbrel® can be administered 50 mg twice a week for no more than 12 weeks. If it is necessary to continue treatment, Enbrel® should be administered at a dose of 25 mg twice a week or 50 mg once a week. Therapy should be performed before remission is achieved and, as a rule, not more than 24 weeks. The drug should be discontinued if there is no positive symptom dynamics after 12 weeks of treatment. In some cases, the duration of treatment may be more than 24 weeks.

In adult patients, depending on the evaluation of the doctor and the individual characteristics of the patient, therapy can be carried out continuously or intermittently.

If it is necessary to re-administer Enbrel®, the duration of treatment indicated above should be observed. It is recommended to prescribe a dose of 25 mg twice a week or 50 mg once a week.

Elderly patients (65 years and older)

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

Children

In children, the dose of Enbrel® is calculated based on the patient's body weight.

In children weighing less than 62.5 kg, Enbrel®, in the form of a medicinal lyophilizate, should be used to prepare a solution for subcutaneous administration that allows a dose of less than 25 mg to be administered.

Children weighing 62.5 kg or more can use Enbrel® in their dosage form as a hypodermic solution in the form of syringes or disposable syringes.

Juvenile idiopathic polyarthritis (children 2 years and older)

The dose is determined from the calculation of 0.4 mg / kg of body weight (maximum single dose of 25 mg). The drug is administered twice a week at intervals of 3-4 days. Treatment with the drug should be discontinued if after 4 months of therapy there is no positive dynamics of symptoms.

It is possible to administer a dose of 0.8 mg / kg body weight (maximum single dose of 50 mg) once a week.

Common oligoarthritis (children over 2 years old)

It is possible to administer a dose of 0.8 mg / kg body weight (maximum single dose of 50 mg) once a week.

Psoriatic arthritis (adolescents over 12 years old)

It is possible to administer a dose of 0.8 mg / kg body weight (maximum single dose of 50 mg) once a week.

Arthritis associated with enthesitis (adolescents over 12 years old)

It is possible to administer a dose of 0.8 mg / kg body weight (maximum single dose of 50 mg) once a week.

Psoriasis (children aged 6 years and over)

The dose is determined from the calculation of 0.8 mg / kg of body weight (maximum single dose of 50 mg). The drug is administered once a week, the duration of therapy is no more than 24 weeks. The drug should be discontinued if, after 12 weeks of treatment, there is no response to ongoing therapy.

If it is necessary to re-administer Enbrel®, the duration of treatment indicated above should be observed. The dose of the drug is 0.8 mg / kg of body weight (maximum single dose of 50 mg) once a week.

In case of missing the dose at the due time, it is necessary to enter the drug immediately, as soon as this was remembered, but provided that the next injection should be no earlier than a day later. Otherwise, you must skip the forgotten injection and make another injection in time.

Impaired liver and kidney function: there is no need to adjust the dose.

INSTRUCTION FOR THE PREPARATION AND INTRODUCTION OF THE SOLUTION FOR THE SUBORDINATE ADMINISTRATION OF THE ENBREL® PREPARATION

Introduction

Do not try to use Enbrel® unless you are sure you understand how to prepare and administer it properly.

Patients or their parents / caregivers who will inject should be informed about how to properly administer the injection.In the event that further injections are carried out by the patient or his parents / guardian, the first administration should be carried out under the supervision of qualified medical personnel.

Do not mix this drug for injection with another drug in one syringe or vial!

Instructions for storing the Enbrel® preparation, including the reconstituted solution, are in the section "Storage conditions".

Preparation for the administration of the drug

- Wash your hands thoroughly.

- Choose a clean, well-lit flat working surface.

- Plastic packaging for the introduction of a single dose of the drug should contain the items listed below. (If there is not enough of an item in the plastic package, do not use it and contact the pharmacist). Use only the listed items.

DO NOT USE other syringes.

1 bottle containing the lyophilizate of Enbrel®

1 syringe containing a clear, colorless solvent (water for injection)

1 Injection Needle

1 bottle adapter

2 alcohol wipes

Check the expiration date (month and year) on the labeling of the vial and syringe. They should not be used after the specified period.

Preparation of a dose of Enbrel® for injection

- Remove the contents of the plastic packaging.

- Remove the plastic cap from the vial (see Figure 1). DO NOT REMOVE a rubber stopper and an aluminum ring around the neck of the vial.

- Using a clean alcohol wipe, wipe the rubber stopper on a bottle of Enbrel®. After handling, do not touch it with hands or allow it to come into contact with any surface.

- Place the bottle in a vertical position on a clean flat surface.

- Remove the paper coating from the packaging with the bottle adapter.

- Without removing the adapter from the plastic bag, place it on the Enbrel® bottle in such a way that the point of the adapter is in the center of the raised circle on the lid of the bottle (see Figure 2).

- With one hand, firmly hold the bottle on a flat surface. With the other hand, push the package with the adapter in the direction of STRETCH DOWN until you feel that the point of the adapter has passed through the lid of the bottle and DO NOT FEEL and DO NOT HEAR how the ADAPTER RIPE CAME TO PLACE (see Figure 3). DO NOT over-tighten the adapter at an angle (see Figure 4). It is important that the tip of the adapter completely passes through the lid of the vial.

- Holding the vial in one hand, remove the plastic packaging from the bottle adapter (see Figure 5).

- Break off the protective cap of the syringe with the solvent in place of the perforation of the cap. Do this by alternately bending the cap up and down until the cap is broken off at the perforation site (see Figure 6). DO NOT remove part of the white cap remaining on the syringe.

- Do not use a syringe if the tip of the cap is already broken off on the perforated line. Take the other packing.

- Holding the syringe by the glass cylinder (but not the white cap) in one hand and the adapter for the vial (but not the vial itself) in the other, connect the syringe to the bottle adapter by inserting the tip into the hole and turning it clockwise until it is fully connected (see (See Figure 7).

Addition of solvent

- Holding the bottle vertically on a flat surface, VERY SLOWLY push the plunger until all the solvent is in the vial. This will help to reduce the formation of foam (a lot of bubbles) (see Figure 8).

- After adding the solvent to the Enbrel® preparation, the piston can rise independently. This is normal and is related to air pressure.

- Without disconnecting the syringe, gently rotate the vial to dissolve the powder (see Figure 9). DO NOT shake the bottle.Wait until the powder is completely dissolved (usually it takes less than 10 minutes). The solution should be clear and colorless, without lumps, flakes or particles. A little white foam may remain in the vial, this is normal.

DO NOT USE Enbrel®, if the powder in the vial did not dissolve within 10 minutes. Take a new plastic packaging with the drug.

How to dial Enbrell® from the bottle

- Without disconnecting the syringe from the vial and adapter for the vial, lift the vial to eye level, keeping it upside down. Press the plunger so that it fully enters the syringe (see Figure 10).

- Then slowly pull the piston to draw liquid into the syringe (see Figure 11). For adult patients, type the entire solution if your doctor did not recommend you to a different dosage. For children - only get the necessary part of the solution, as indicated by your child's doctor. After you have collected the required dose of Enbrel®, air may remain in the syringe. Do not worry about it, as you remove air from the syringe later.

- Holding the bottle upside down, unscrew the syringe from the adapter by turning it counter-clockwise (see Figure 12).

- Place the filled syringe on a clean, level surface. Make sure that the tip of the syringe does not touch anything. Be careful not to push the plunger. (Note: after completion of these actions, a small amount of liquid may remain in the vial - this is normal).

How to put a needle on a syringe

- The needle is placed in a plastic container to preserve its sterility.

- To open the plastic container, hold its short wide end in one hand. With the other hand, take the longer part of the container.

- To break the seal, pull the longer part down, and then up until it breaks (see Figure 13).

- After the seal is broken, remove the short wide part of the plastic container.

- The needle will remain in the long part of the package.

- Holding the needle and container in one hand, take the syringe and insert the tip of the syringe into the needle hole.

- Attach the syringe to the needle by turning it clockwise until it is fully connected (see Figure 14).

- Remove the cap from the needle by pulling it; try not to touch the needle and prevent the needle from touching anything (see Figure 15). Try not to bend or twist the cap when removing, so as not to damage the needle.

- Holding the syringe upright, remove the air bubbles, slowly pressing the piston until all air is released from the syringe (see Figure 16).

Selection of injection site

- Three places for the administration of Enbrel® are recommended: (1) the anterior surface of the middle third of the thigh; (2) the stomach, except for a 5 cm area around the navel; (3) the outer surface of the shoulder (see Figure 17). If you are injecting yourself, do not use the outer surface of the shoulder.

- Each injection should be performed in a new location. The location of each new injection should be at least 3 cm away from the site of previous injections. DO NOT inject the drug into areas where there is soreness, redness of the skin, bruising, or constriction. Do not enter into areas with scars or stretch marks. (It may be useful to record the places of previous injections).

- If you or your child has psoriasis, try not to inject the drug directly into areas that are raised above the surface of the skin, thickened, reddened or in the outbreaks (psoriatic plaques).

Preparation of injection site and injection of Enbrel solution®

- In a circular motion, wipe the skin area into which you will inject Enbrel®, with a clean alcohol sponge. DO NOT touch this area before performing the injection.

- When the cleared area of the skin is completely dry, with one hand, assemble the skin into the crease and hold it. With the second hand, hold the syringe like a pencil. Try not to touch the cleaned surface of the skin.

- With a short, short movement, direct the needle into the skin at an angle of 45 ° to 90 ° (see Figure 18). Over time, you will find the angle most comfortable for the child. Try not to inject the needle into the skin too slowly or with excessive force.

- After the needle has completely entered the skin, release the fold of the skin that you were holding. Hold the base of the syringe with your free hand to stabilize the position of the syringe. Then press the plunger to enter the entire solution at a slow constant rate (see Figure 19).

- When the syringe becomes empty, remove the needle from the skin; try to keep it under the same angle at which it was injected.

- Press down with a cotton swab at the injection site for 10 seconds. There may be slight bleeding. DO NOT wipe the injection site. You can impose a bandage.

Disposal of consumables

- NEVER use the syringe and needles again. Dispose of needles and syringes following the recommendations of your doctor, nurse or pharmacist.

If you have questions, please contact your doctor or nurse who work with Enbrel®.

Storage of Enbrel® solution in the period between injections

Enbrel® solution is recommended to be used immediately after dilution. AT If the solution is not used immediately, it can be stored in the refrigerator (2-8 ° C) for 6 hours. AT If the solution is not used after 6 hours, it should be destroyed.

After storage in the refrigerator, allow the solution to warm to room temperature.

Side effects:

Adverse reactions, depending on the frequency of occurrence, were grouped as follows: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000), isolated cases (it is impossible to determine the frequency).

Infectious and parasitic diseases: Often - infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections); infrequently - Serious infections (including pneumonia, phlegmon, septic arthritis, sepsis and parasitic infections); rarely Mycobacterial infections, including tuberculosis, opportunistic infections (including invasive fungal, protozoal, bacterial,atypical mycobacterial, viral infections and diseases caused by Legionella); isolated cases - infections caused by Listeria, hepatitis B activation. Benign, malignant and unspecified neoplasms (including cysts and polyps): infrequently - Skin cancer not related to melanoma (FCNM); rarely - Lymphoma, melanoma; single cases - leukemia, Merkel's carcinoma.

Violations from the blood and lymphatic system: infrequently - thrombocytopenia; rarely - Anemia, leukopenia, neutropenia, pancytopenia; aboutchen rarely aplastic anemia.

Immune system disorders: often - Allergic reactions (see subsection "Infringements from the skin and subcutaneous tissues"), the formation of autoantibodies; infrequently - systemic vasculitis (including ANCA-associated vasculitis); rarely - Serious allergic / anaphylactic reactions (including bronchospasm), sarcoidosis; isolated cases - Macrophage activation syndrome.

Impaired nervous system: rarely - convulsions, demyelination phenomena in the central nervous system (CNS), similar to those observed with multiple sclerosis or local demyelination conditions, such as optic neuritis and transverse myelitis (see section "Special instructions"); rarely - peripheral demyelinating diseases (including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, multiofocal motor neuropathy).

Disorders from the side of the organ of vision: infrequently - uveitis, scleritis.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - interstitial lung diseases (including pneumonitis and pulmonary fibrosis).

Disorders from the liver and bile ducts: rarely increased activity of "hepatic" enzymes, autoimmune hepatitis.

Disturbances from the skin and subcutaneous tissues: often - skin itching; infrequently - angioedema, urticaria, rash, psoriasis-like rash, psoriasis (including the debut of the disease or worsening and pustular lesions, mainly soles and palms); rarely - cutaneous forms of vasculitis, Stevens-Johnson syndrome, erythema multiforme; rarely - toxic epidermal necrolysis. Disturbances from the musculoskeletal system and connective tissue: rarely - cutaneous manifestations of subacute lupus erythematosus, discoid lupus erythematosus, lupus-like syndrome.

General disorders and disorders at the site of administration: Often - local reactions after injection (including bleeding, subcutaneous hematoma, erythema, pruritus, pain, swelling); often - fever.

Disorders from the cardiovascular system: rarely - worsening of the course of chronic heart failure (CHF) (see section "Special instructions").

Additional Information

Adverse reactions in adults

The frequency of drug withdrawal due to the development of adverse reactions during controlled clinical trials in patients with rheumatoid arthritis was similar in patients receiving Enbrel® and receiving placebo. Against the background of treatment with the drug Enbrel® the most common were the reactions at the site of administration of the drug. The frequency of these reactions reached a peak in the first month of application of the drug, and then gradually decreased. In clinical studies, these reactions were predominantly transient and lasted for an average of 4 days. In some patients who experienced the development of the reaction at the site of administration, reactions were also noted at the sites of the previous administration. During postregistration observations of the drug Enbrel®, the development of bleeding and the appearance of hematomas at the injection sites were noted.

Adverse reactions in children

In general, the frequency and types of adverse reactions in children were similar to those observed in adult patients. Infections were the most frequent adverse reactions. Infections that were observed in clinical studies in children with juvenile idiopathic polyarthritis aged 2 to 18 years were of mild to moderate severity, and their species did not conflict with those commonly found among outpatients. Reports of severe adverse events included chicken pox with symptoms of aseptic meningitis that resolved without complications (see section "Special instructions"), appendicitis, gastroenteritis, depression / personality disorders, skin ulcers, esophagitis / gastritis, septic shock caused by group A streptococci, type 1 diabetes mellitus and soft tissue infections and postoperative wounds.

4 reports on macrophage activation syndrome were recorded in these patients.

Cases of inflammatory bowel disease have been reported in patients with juvenile idiopathic polyarthritis receiving Enbrel® therapy, including a very small number of observations of recurrence of symptoms upon resumption of therapy.There was no clear cause-effect relationship, since cases of inflammatory bowel disease were also seen in patients with juvenile idiopathic arthritis who were not treated.

The frequency and types of adverse reactions in children with psoriasis were similar to those observed in adult patients.

Overdose:

When an overdose of the drug Enbrel®, immediately inform your doctor or pharmacist.

Keep the carton pack of Enbrel® even if it is empty.

The maximum dose of Enbrel® is not established. In the clinical study, healthy volunteers received a dose of 60 mg / m², once, which did not lead to the development of a dose-limiting toxicity.

In the treatment of patients with rheumatoid arthritis, there were no cases of excess of the toxic dose limit. The highest dose administered intravenously was 32 mg / m² with subsequent subcutaneous injection of 16 mg / m² twice a week. The specific antidote for the drug Enbrel® is unknown.

Interaction:

Anakinra

Against the background of combined therapy with the drug Enbrel® and anakinra, there was a significant increase in the incidence of serious infections and neutropenia compared to patients given only Enbrel® or anakinra alone.

The combined use of the drug Enbrel® and anakinra has not shown clinical benefit and is therefore not recommended.

Abatacept

The simultaneous use of abatacept and Enbrel® was accompanied by an increase in the incidence of serious adverse events. This combination of drugs has not demonstrated clinical benefits and is therefore not recommended.

Sulfasalazine

Patients who were treated with Enbrel® during the treatment with sulfasalazine reported a significant reduction in the number of white blood cells compared to those who received only Enbrel® or only sulfasalazine.

Lack of interaction

There were no undesirable interactions in patients with rheumatoid arthritis, while using Enbrel® with glucocorticosteroids, salicylates (with the exception of sulfasalazine), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics or methotrexate.

Methotrexate

Methotrexate does not affect the pharmacokinetics of etanercept. The effect of Enbrel® on the pharmacokinetics of methotrexate in humans has not been studied.

Digoxin

There was no clinically significant mutual effect on the pharmacokinetics of etanercept.

Warfarin

There was no clinically significant mutual effect on the pharmacokinetics of etanercept.

Vaccination

Live vaccines should not be administered against the background of treatment with the drug Enbrel®. There is no evidence of secondary transmission of infection through live vaccine to patients receiving Enbrel®. It is recommended that before the initiation of treatment with Enbrell®, children and adolescents, if possible, receive all the necessary vaccinations in accordance with the current national vaccination calendar. In most patients with psoriatic arthritis receiving Enbrel®, an increase in the B-cell immune response to pneumococcal polysaccharide vaccine was observed, but the titres were generally somewhat lower, a 2-fold increase in titers was observed in fewer patients compared to patients not receiving Enbrel ®.

Special instructions:

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

Infections

Patients should be screened for infections prior to the use of Enbrel®, during treatment and after the course of therapy, taking into account the average duration of the half-life of etanercept, equal to approximately 70 hours (7-300 hours).

With the use of the drug Enbrel®, sepsis, tuberculosis, parasitic infections (including those caused by protozoan organisms) and severe infections, including opportunistic infections, including invasive fungal infections, listeriosis and legionellosis (some with fatal outcome), viral infections (including those caused by herpes zoster). The most frequently reported invasive fungal infections were caused by Candida Pneumocystis, Aspergillus and Histoplasma. Incorrect diagnosis of these infections, especially fungal and other opportunistic infections, resulted in a delay in the appointment of treatment and, in some cases, death. In many cases, patients received therapy with other drugs, including immunosuppressants. When examining patients, it is necessary to take into account the possibility of developing opportunistic infections, for example, endemic mycoses. Patients in whom new infections develop against the background of Enbrel® treatment should be carefully monitored. The use of Enbrel® should be discontinued if the patient develops a severe infection. The use of Enbrel® requires caution in patients with frequent or chronic infections in the anamnesis or having co-morbidities that may contribute to the development of infections (eg, severe or poorly controlled diabetes mellitus).

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

Tuberculosis

Against the background of therapy with the drug Enbrel®, cases of active tuberculosis, including miliary tuberculosis and tuberculosis of extrapulmonary localization, were reported. Among patients with rheumatoid arthritis, there appears to be a higher incidence of tuberculosis infection.

The development of tuberculosis infection can be associated with the reactivation of a latent infection, as well as the development of a new infection.

Before the start of therapy, all patients should be examined for active or latent tuberculosis. Prevention of latent tuberculosis should begin before the initiation of therapy with the drug Enbrel®. Examination should include a detailed study of history in relation to tuberculosis or having contact with TB patients in the past and data about previous or current immunosuppressive therapy.All patients should have the necessary screening tests that meet local requirements, and necessarily include: tuberculin skin test and lung radiography. The possibility of a false-negative tuberculin test should be taken into account, especially in patients with a severe condition or in patients with impaired immunity. It is also necessary to take into account the possibility of developing tuberculosis in patients who had no evidence of tuberculosis infection prior to initiation of Enbrel® therapy. The attending physician should monitor the patient's condition for signs of tuberculosis, incl. In patients with initially negative results of tests for the presence of tuberculosis infection.

Do not use Enbrel if the patient has active tuberculosis. In the case of inactive tuberculosis, the initiation of therapy with the Enbrel® drug requires the appointment of a standard anti-tuberculosis therapy in accordance with local recommendations. In this case, the relationship between the benefits and risks of treatment with Enbrel® should be carefully analyzed.

All patients should be informed of the need to see a doctor if they appear on the background of treatment with the drug Enbrel® or after it complaints or symptoms characteristic of tuberculosis (for example, persistent cough, weight loss, subfebrile condition).

Activation of the hepatitis B virus

There have been reports of cases of activation of the hepatitis B virus in carrier patients who received TNF inhibitors, including Enbrel®. Most of these cases have occurred in patients who simultaneously receive other drugs that suppress the immune system, which can also contribute to the reactivation of the hepatitis B virus. Before using Enbrel® in patients at high risk for hepatitis B, it is necessary to conduct an appropriate diagnostic search . Special care must be taken when using Enbrel® in patients with hepatitis B virus. Patients should be monitored for signs of hepatitis B. If they develop symptoms of this disease, the possibility of specific therapy should be discussed.

Exacerbation of hepatitis C

The cases of exacerbation of hepatitis C in patients receiving Enbrel® therapy are reported, but the causal relationship with the use of etanercept is not proved. Nevertheless, caution should be exercised when using Enbrel® in patients with history of hepatitis C.

Allergic reactions

Allergic reactions are often accompanied by the ingestion of Enbrel®. For any severe allergic or anaphylactic reactions, you should immediately stop taking Enbrel® and begin appropriate treatment.

Immunosuppression

In the treatment of TNF inhibitors, including Enbrel®, there is the possibility of inhibiting the protective mechanisms of the human body against infections and malignant tumors, as TNF participates in inflammation processes and modulates the cellular immune response. However, in adults with rheumatoid arthritis, there were no cases of oppression of delayed hypersensitivity reactions, a decrease in the level of immunoglobulin, or a change in the number of the effector cell population, despite the treatment with Enbrel®.

In children with juvenile idiopathic polyarthritis, chicken pox and the symptoms of aseptic meningitis rarely resolved, which were resolved without complications. Patients who were in contact with patients with chickenpox should temporarily stop taking Enbrell® and prescribe prophylactic immunoglobulin against the virus Varicella Zoster.

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

Malignant and lymphoproliferative diseases

In the postmarketing period (see the "Side effect" section), reports were received of various malignant neoplasms (including breast and lung carcinomas, as well as lymphoma).

In a number of controlled clinical trials, lymphoma was more often diagnosed in patients taking TNF inhibitors than patients who did not receive them. On the other hand, these cases were rare, and the observation period for patients from the placebo group was shorter than for patients receiving treatment with TNF inhibitors. There have been reports of the development of leukemia in the background of therapy with TNF inhibitors.There is a high risk of lymphoma and leukemia in patients with rheumatoid arthritis, which is a long-term disease characterized by active inflammation, which in itself complicates the risk assessment. The subsequent analysis of clinical studies of etanercept in patients with rheumatoid arthritis did not confirm and did not rule out an increased risk of oncological diseases when etanercept is used. In accordance with modern data, the possible risk of developing lymphoma, leukemia or other malignancies in patients receiving TNF inhibitors can not be ruled out.

There are reports of the development of malignant neoplasms (half the cases of Hodgkin's and non-Hodgkin's lymphomas), some of which were fatal, in children and adolescents treated with TNF inhibitors, including Enbrel®. Most patients received concomitant therapy with immunosuppressants. In other cases, there were various malignant neoplasms, including rare variants associated with immunosuppression. When using the drug, it is necessary to take into account the risk of developing malignant neoplasms.

Skin cancer

Melanoma and non-melanoma skin cancer (FCNM) have been reported in patients treated with TNF inhibitors, including Enbrel®. Most often, the FCNM is diagnosed in patients with psoriasis. There are reports of the development of Merkel's carcinoma.

For all patients at risk, periodic examination of the skin is recommended.

Formation of autoimmune antibodies

Treatment with the drug Enbrel® can be accompanied by the formation of autoimmune antibodies (see section "Side effect"). These antibodies do not belong to neutralizers and usually disappear quickly. There was no correlation between the formation of antibodies and the clinical efficacy of the drug, as well as the incidence of adverse reactions.

Single cases of the formation of additional autoantibodies in combination with lupus-like syndrome or a rash similar to a subacute form of lupus erythematosus or a discoid form of lupus erythematosus (clinical examination and biopsy data) were noted in patients, including patients with rheumatoid rheumatoid arthritis.

Hematologic reactions

There have been reports of rare cases of pancytopenia and very rare cases of aplastic anemia, including fatal cases, in patients receiving Enbrel®.Caution should be exercised when using Enbrel® in patients with an indication of a history of blood disease. All patients, their relatives / caregivers should be aware that if the patient develops signs and symptoms characteristic of infection or hematologic disorders (eg, prolonged fever, sore throat, bruises, bleeding, pallor) while taking Enbrell®, should immediately seek medical help. In such patients, it is recommended that an examination be performed urgently, including a complete blood test. When confirming the diagnosis of hematologic disease, treatment with the drug Enbrel® should be discontinued.

CNS lesion

There are rare reports of the development of demyelinating CNS diseases in patients receiving etanercept therapy. There were also very rare reports of the development of peripheral demyelinating polyneuropathies (including Guillain-Barre syndrome). Studies of Enbrel® in patients with multiple sclerosis have not been conducted, but studies of other TNF inhibitors in this disease have shown the possibility of exacerbation.Before the initiation of therapy with the drug Enbrel®, it is recommended that the risk / benefit ratio, neurological status in patients with demyelinating diseases, incl. recently emerged, as well as in patients who have an increased risk of developing a demyelinating disease.

Exacerbation of chronic heart failure (CHF)

Care should be taken with regard to the use of Enbrel® in patients with CHF. A number of studies suggest the possibility of worsening of the course of CHF in patients receiving Enbrel®.

Combination Therapy

The combination of Enbrel® and methotrexate did not give unexpected results in a safety study. Long-term study of this indicator continues. The safety data for the Enbrel® preparation, which was prescribed in combination with methotrexate, were similar to those reported for the use of Enbrel® and methotrexate alone. The long-term safety of Enbrel® in combination with other basic anti-inflammatory drugs has not been investigated.

Studies of the use of Enbrel® in combination with other systemic therapy or phototherapy for psoriasis have not been conducted.

Wegener's granulomatosis

The incidence of various types of malignant tumors in the subcutaneous localization was significantly higher in patients with Wegener's granulomatosis who received Enbrel® than in the control group.

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

Alcoholic Hepatitis

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

Hypoglycemia in patients with diabetes mellitus

There have been reports of hypoglycemia in combination with Enbrel® in patients taking antidiabetic drugs, which required a reduction in their dose.

Effect on the ability to drive transp. cf. and fur:The study of the effect on the ability to drive a car and use complex techniques with Enbrel® was not carried out. In this regard, to drive a car or use sophisticated technology should be carefully.

Form release / dosage:

Lyophilizate for the preparation of a solution for subcutaneous administration, 25 mg.

Packaging:

25.0 mg etanercept in a vial of colorless glass (type I), sealed with a rubber stopper and rolled up with an aluminum cap, equipped with a plastic tear-off cap of the "flip-off" type.

1.0 ml of solvent in a disposable syringe made of colorless glass (type I) with a rubber stopper and a system for monitoring the first opening.

1 bottle complete with 1 syringe containing solvent, 1 injection needle, 1 bottle adapter and 2 individually packaged alcohol wipes are placed in a plastic bag and sealed with adhesive paper. 4 plastic bags together with instructions for use are placed in a cardboard box.

Storage conditions:

Store at a temperature of 2 to 8 ° C.

Do not freeze.

The reconstituted solution should be used within 6 hours.

Unused medication is subject to destruction.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-006031/09

Date of registration:23.07.2009 / 18.09.2014