Enbrel (Solution, Lyophilisate) Instructions for Use

ATC Code

L04AB01 (Etanercept)

Active Substance

Etanercept (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Drug with anti-inflammatory action. Tumor necrosis factor-alpha (TNF-α) inhibitor

Pharmacotherapeutic Group

Immunosuppressive agent

Pharmacological Action

Tumor necrosis factor (TNF-α, TNF) is a key cytokine that sustains the inflammatory process in rheumatoid arthritis. Elevated TNF levels have also been found in the synovial membranes and psoriatic plaques of patients with psoriatic arthritis, as well as in the plasma and synovial tissues of patients with ankylosing spondylitis. Etanercept is a competitive inhibitor of TNF binding to its cell surface receptors, and thus inhibits the biological activity of TNF.

TNF and lymphotoxin are pro-inflammatory cytokines that bind to two distinct tumor necrosis factor receptors (TNFR) on the cell surface: the 55-kilodalton (p55) and 75-kilodalton (p75) receptors. Both TNFRs exist in the body in membrane-bound and soluble forms. Soluble TNFRs regulate the biological activity of TNF.

TNF and lymphotoxin exist predominantly as homotrimers; their biological activity depends on cross-linking of TNFRs located on the cell surface. Dimeric soluble receptors, such as Etanercept, have a greater affinity for TNF than monomeric receptors and are therefore significantly more potent competitive inhibitors of TNF binding to their cellular receptors. Furthermore, the use of the Fc region of immunoglobulin as a binding element in the structure of the dimeric receptor prolongs the serum half-life.

A significant portion of the pathological changes in the joints in rheumatoid arthritis and ankylosing spondylitis, as well as skin changes in the form of psoriatic plaques, occur due to the action of pro-inflammatory molecules involved in the system controlled by TNF. The mechanism of action of etanercept appears to be the competitive inhibition of TNF binding to TNF receptors on the cell surface. Thus, Etanercept prevents TNF-mediated cellular responses by promoting the biological inactivation of TNF. Etanercept may also modulate biological responses controlled by additional downstream signaling molecules (e.g., cytokines, adhesion molecules, or proteinases). And these responses may either stimulate or be controlled by TNF.

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

Pharmacokinetics

Absorption

Etanercept is slowly absorbed from the site of s.c. injection, reaching C_max approximately 48 hours after a single dose of Enbrel. The absolute bioavailability is 76%. When Enbrel is administered twice a week, steady-state concentrations are achieved that are twice as high as after a single dose. After a single s.c. administration of 25 mg Enbrel, the mean C_max in plasma is 1.65±0.66 µg/ml, AUC – 235±96.6 µg×h/ml. No apparent saturation of clearance within the dose range was observed.

Distribution

The concentration-time profile of etanercept is described by a biexponential curve. The mean V_d is 7.6 L, while the V_d at steady state is 10.4 L.

Elimination

Etanercept is slowly eliminated from the body. T_1/2 is about 80 hours. In patients with rheumatoid arthritis, the clearance is approximately 0.066 L/h, which is somewhat lower than the 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.

A dose of Enbrel 50 mg once a week is bioequivalent to a dose of 25 mg administered twice a week.

Pharmacokinetics in special clinical cases

No increase in etanercept concentration is observed in patients with acute renal or hepatic impairment.

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

The clearance and apparent V_d of etanercept in the group of patients aged 65 to 87 years are similar to those in patients under 65 years of age.

In children with juvenile idiopathic polyarthritis, the serum concentration profile is similar to that in adult patients with rheumatoid arthritis. Modeling suggests that serum etanercept levels are approximately the same in older children (10-17 years) and adult patients, and will be significantly lower in younger children.

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

Indications

Rheumatoid arthritis

In combination with methotrexate, Enbrel is indicated for adults in the treatment of moderate to severe active rheumatoid arthritis when the response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate, has been inadequate.

Enbrel may be prescribed as monotherapy in case of inefficacy or intolerance to methotrexate.

Enbrel is indicated for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.

Juvenile idiopathic polyarthritis

Treatment of active juvenile idiopathic polyarthritis in children and adolescents aged 4-17 years who have had an inadequate response or intolerance to methotrexate.

Psoriatic arthritis

Treatment of active and progressive psoriatic arthritis in adults when the response to DMARD therapy has been inadequate.

Ankylosing spondylitis

Treatment of adults with severe active ankylosing spondylitis who have not responded significantly to conventional therapy.

Psoriasis

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

Treatment of children 8 years of age and older with severe chronic psoriasis who have had intolerance or an inadequate response to other systemic or phototherapy.

ICD codes

Dosage Regimen

Lyophilisate

The drug is administered s.c. Treatment with Enbrel 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 the dosage form of lyophilisate for solution, in the 25 mg dosage is recommended for patients weighing less than 62.5 kg, including children.

Before preparing the reconstituted solution, and before the initial and subsequent administration of the drug, carefully read the instructions for its use, which are at the end of this section.

Adults

For rheumatoid arthritis the recommended dose is 25 mg twice a week with an interval of 3-4 days. An alternative dose is 50 mg once a week.

For ankylosing spondylitis the recommended dose is 25 mg twice a week or 50 mg once a week.

For psoriatic arthritis the recommended dose is 25 mg twice a week with an interval of 3-4 days or 50 mg once a week.

For psoriasis the recommended dose is 25 mg twice a week or 50 mg once a week. Alternatively, Enbrel can be prescribed at 50 mg twice a week for no more than 12 weeks. If continuation of treatment is necessary, Enbrel may be prescribed at a dose of 25 mg twice a week or 50 mg once a week. Therapy with Enbrel should be continued until remission is achieved, usually no more than 24 weeks. Administration of the drug should be discontinued if no positive dynamics of symptoms are observed after 12 weeks of treatment.

If re-prescribing Enbrel is necessary, the duration of treatment specified above should be observed. A dose of 25 mg twice a week or 50 mg once a week is recommended.

The duration of therapy in some patients may exceed 24 weeks.

In elderly patients (65 years and older) there is no need to adjust either the dose or the method of administration.

Children

For juvenile idiopathic arthritis in children 4 years and older the dose is determined at the rate of 0.4 mg/kg of body weight (maximum single dose 25 mg). The drug is administered twice a week with intervals of 3-4 days between doses.

For psoriasis in children 8 years and older the dose is determined at the rate of 0.8 mg/kg of body weight (maximum single dose 50 mg). The drug is administered once a week until remission is achieved, usually no more than 24 weeks. Treatment with the drug should be discontinued if no positive dynamics of symptoms are observed after 12 weeks of therapy.

If re-prescribing Enbrel is necessary, the duration of treatment specified above should be observed. The drug dose is 0.8 mg/kg of body weight (maximum single dose 50 mg) once a week. In some cases, the duration of treatment may be more than 24 weeks.

In cases of renal and hepatic impairment there is no need to adjust the dose.

Rules for using the drug

Preparing for the injection

This drug must not be mixed in the same syringe or vial with any other drugs!

Instructions for storing Enbrel, including the reconstituted solution, are in the “Storage Conditions” section.

Select a clean, well-lit, flat work surface. Remove one tray with the Enbrel injection kit from the refrigerator. Return the other trays to the refrigerator. The remaining tray should contain all the items required for one injection. The list of these items is below. Use only the listed items. Do not use any other syringes.

• 1 vial containing Enbrel lyophilisate;
• 1 syringe filled with a clear, colorless solvent;
• 2 empty syringes;
• 5 needles;
• 6 alcohol wipes.

If any of the listed items are missing from the tray, do not use this tray.

Make sure a cotton ball is prepared for use after the injection. Check the expiration dates on the vial and syringe labels. They should not be used after the month and year indicated in the “Expiration Date” section.

Preparing the dose of Enbrel for injection

Take the Enbrel vial from the tray. Remove the plastic cap from the Enbrel vial. Do not remove the aluminum ring around the vial neck or the rubber stopper. Wipe the rubber stopper on the vial with a new alcohol wipe. After wiping with alcohol, do not touch the stopper with your hands or allow it to come into contact with any surface.

Place the vial in an upright position on a clean, flat surface.

Unscrew the cap from the solvent syringe, without touching the tip of the syringe or allowing it to come into contact with any surface.

Attaching the needle to the syringe

To maintain its sterility, the needle is placed in a plastic package. Take one of the needles from the tray. Break the seal on the needle package by bending its longer end up and down until it breaks. Remove the short, wide end of the plastic package. Holding the needle and the package in one hand, insert the top of the syringe into the needle hub and attach it to the needle by turning the syringe clockwise until the needle is fully secured.

Carefully remove the plastic cap from the needle. To avoid damaging the needle, do not bend or twist the cap when removing it.

Adding solvent to the powder

Into the vial standing upright on a flat surface, insert the syringe needle straight down through the center circle of the rubber stopper on the vial. If the needle is inserted correctly, you will feel slight resistance and then a “give” as the needle passes through the center of the stopper. Do not insert the needle into the vial at an angle, as this may cause the needle to bend and/or incorrect addition of solvent to the vial.

Push the syringe plunger very slowly until all the solvent is in the vial. This will help prevent foam formation (many bubbles). After the solvent has been added to Enbrel, the plunger may move up spontaneously.

Remove the syringe that contained the solvent and the needle from the vial and dispose of them.

Gently swirl the vial to dissolve the powder. Do not shake the vial. Wait until the powder is completely dissolved (usually less than 10 minutes). The solution should be clear or slightly opalescent, it may be colorless or pale yellow, without lumps, flakes, or particles. Some foam may remain in the vial – this is acceptable.

Do not inject Enbrel if all the powder in the vial has not dissolved within 10 minutes. Start over with another tray.

Drawing the Enbrel solution from the vial

The amount of solution to be drawn from the vial is determined by the treating physician.

Take one of the empty syringes from the tray and remove its plastic packaging.

Attach a new needle from the tray to the empty syringe exactly as for the solvent syringe (see Attaching the needle to the syringe).

Into the Enbrel vial standing on a flat surface, insert the syringe needle straight down through the center circle of the rubber stopper on the vial. Do not insert the needle into the vial at an angle, as this may cause the needle to bend and/or incorrect drawing of the solution from the vial.

Without removing the needle, turn the vial upside down and hold it at eye level. Slowly pull back on the syringe plunger and draw the required amount of liquid into the syringe.

As the liquid level in the syringe drops, it may be necessary to partially withdraw the needle from the vial so that the tip of the needle remains in the liquid.

Without removing the needle, check for air bubbles in the syringe. Gently tap the syringe to move the air bubbles to the top of the syringe closer to the needle. Slowly push the plunger to expel the air bubbles from the syringe into the vial. If some liquid is accidentally pushed into the vial during this time, slowly pull the plunger back and draw the liquid back into the syringe. Draw the entire contents of the vial into the syringe, unless otherwise instructed. For children, draw only a portion of the vial contents as directed by the pediatrician. After drawing Enbrel from the vial, some air may remain in the syringe.

Remove the needle from the syringe. If an excess of solution has been drawn, do not reinsert the needle that was removed from the vial. If there is an excess of solution in the syringe, holding the syringe vertically with the needle up at eye level, push the plunger and expel the excess amount of solution until the required volume is obtained. Remove and dispose of the needle.

Take a new needle from the tray and attach it to the syringe as indicated above (see Attaching the needle to the syringe). Use this needle to inject Enbrel.

Choosing the injection site

There are three areas recommended for Enbrel injection: the front of the middle third of the thigh; the anterior abdominal wall, excluding the area within a 5 cm diameter from the navel; the outer surface of the upper arm. When self-injecting, the outer surface of the upper arm should not be used.

Each subsequent administration of the drug should be performed in different areas. The distance between injection sites should be at least 3 cm. Do not inject the drug into areas where the skin is painful, damaged, hardened, or reddened. Avoid areas with scars or stretch marks. (It is convenient to record the sites of already performed injections). Do not inject the drug directly into areas that are raised above the skin surface, thickened, reddened, or into flaky lesions (“psoriatic plaques”).

Preparing the injection site and administering the Enbrel solution

Holding the syringe with the needle up, remove air bubbles from it by slowly pushing the plunger to expel them.

Clean the Enbrel injection site with an alcohol wipe. Do not touch the cleaned area of skin until the moment of injection.

After the cleaned skin surface has dried, pinch the skin with one hand. With the other hand, hold the syringe like a pencil.

With a quick, short movement, insert the needle completely into the skin at an angle from 45°C (113°F) to 90°. Do not insert the needle too slowly or with excessive force.

After the needle is fully inserted into the skin, release the skin fold. Use the freed hand to support the base of the syringe to prevent it from moving. Then, pushing the plunger, slowly and evenly inject the entire solution.

After the syringe is empty, remove the needle from the skin. Remove the needle at the same angle at which it was inserted.

Do not wipe the injection site. If necessary, a bandage can be applied to the injection site.

Storing the Enbrel solution between injections

When using two doses from one vial of Enbrel, the drug solution between the first and second administration should be stored in the refrigerator (2°-8°C (17.6°F)). The vial must be stored upright between injections.

Each vial of Enbrel after dissolving 25 mg of lyophilisate in 1 ml of solvent should be used for a maximum of two injections to the same patient.

Re-drawing the prepared Enbrel solution from the vial

Remove the Enbrel solution from the refrigerator. Wait for 15-30 minutes for the Enbrel solution in the vial to reach room temperature. Do not warm Enbrel in any other way (e.g., do not heat it in a microwave or hot water).

With a new alcohol wipe, wipe the stopper on the Enbrel vial. After wiping with alcohol, do not touch the stopper with your hands or allow it to come into contact with any surface.

To prepare the second dose of Enbrel from the vial, follow the instructions in the section “Drawing the Enbrel solution from the vial” using a new empty syringe, needles, and wipes from the tray.

If there is not enough solution in the vial for another dose of the drug, dispose of the vial and start over with a new tray.

After drawing the second dose of Enbrel from the vial, dispose of the vial (even if some solution remains).

Waste Disposal

Reuse of the syringe and needle is not permitted! Never recap the needle. Dispose of the needle and syringe according to instructions.

Solution

Administered subcutaneously. The single dose for adults is 50 mg, for children aged 2 to 17 years – 800 mcg/kg (but not more than 50 mg/week). The frequency of administration and duration of use depend on the indications and treatment tolerance.

Adverse Reactions

Adverse reactions, depending on the frequency of occurrence, were grouped 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), isolated cases (frequency cannot be determined).

Infections and infestations very common – infections (including upper respiratory tract infections, cystitis, skin infections); uncommon – serious infections (including pneumonia, cellulitis, septic arthritis, sepsis); rare – tuberculosis, opportunistic infections (including invasive fungal, protozoal, bacterial, and atypical mycobacterial infections).

Blood and lymphatic system disorders uncommon – thrombocytopenia; rare – anemia, leukopenia, neutropenia, pancytopenia; very rare – aplastic anemia.

Immune system disorders: common – autoantibody formation; rare – allergic/anaphylactic reactions (including angioedema, bronchospasm); in isolated cases – macrophage activation syndrome.

Nervous system disorders rare – seizures, symptoms of demyelination in the CNS, similar to those observed in multiple sclerosis or a condition of local demyelination, such as optic neuritis and transverse myelitis.

Respiratory, thoracic and mediastinal disorders: uncommon – interstitial lung diseases (including pneumonitis and pulmonary fibrosis).

Gastrointestinal disorders rare – increased liver enzyme activity, autoimmune hepatitis.

Cardiac disorders rare – worsening of congestive heart failure.

Skin and subcutaneous tissue disorders common – pruritus; uncommon – non-melanoma skin cancer, urticaria, rash, psoriasis (including onset of the disease and pustular lesions, mainly on the soles and palms); rare – cutaneous forms of vasculitis (including leukocytoclastic vasculitis), Stevens-Johnson syndrome, erythema multiforme; very rare – toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders cutaneous manifestations of subacute cutaneous lupus erythematosus, discoid lupus erythematosus, lupus-like syndrome.

General disorders and administration site conditions: very common – injection site reactions (including bleeding, subcutaneous hematoma formation, erythema, itching, pain, swelling); common – fever.

Additional Information

Adverse reactions in adults

The frequency of drug discontinuation due to adverse reactions in controlled clinical studies in patients with rheumatoid arthritis was comparable between patients receiving Enbrel and placebo. During treatment with Enbrel, the most common were injection site reactions.

Adverse reactions in children

The frequency and types of adverse reactions in children with juvenile idiopathic polyarthritis were similar to those observed in adult patients with rheumatoid arthritis. Differences from adults and additional data are provided below.

Infections observed in clinical studies in patients with juvenile idiopathic arthritis were mild to moderate in severity, and their types were consistent with those commonly encountered among outpatients. Reports of serious adverse events included varicella with symptoms of aseptic meningitis, which resolved without complications, appendicitis, gastroenteritis, depression/personality disorder, skin ulcers, esophagitis/gastritis, aseptic shock caused by group A streptococci, type 1 diabetes mellitus, and soft tissue and postoperative wound infections. Four reports of macrophage activation syndrome were registered in these patients.

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

Contraindications

• Sepsis or risk of sepsis;
• Active infection, including chronic or localized infections (including tuberculosis);
• Pregnancy;
• Lactation period;
• Children under 3 years of age (the solution contains benzyl alcohol);
• Hypersensitivity to etanercept or any other component of the dosage form.

Use with caution in patients with demyelinating diseases, congestive heart failure, immunodeficiency states, blood dyscrasias, diseases predisposing to the development or activation of infections (diabetes mellitus, hepatitis).

Use in Pregnancy and Lactation

Therapy with Enbrel is not recommended for pregnant women, as there is no experience with this drug in this category of patients.

Women of childbearing potential should not plan pregnancy during treatment with Enbrel.

It is unknown whether Etanercept is excreted in breast milk. Since immunoglobulins, like many other drugs, can be excreted in human milk, either breastfeeding should be discontinued or Enbrel should be discontinued during breastfeeding.

Use in Hepatic Impairment

In hepatic impairment, no dose adjustment is necessary.

Use in Renal Impairment

In renal impairment, no dose adjustment is necessary.

Pediatric Use

There is insufficient experience with Enbrel in children under 4 years of age.

The solvent for Enbrel contains benzyl alcohol, which can cause toxic and anaphylactic reactions in children under 3 years of age. Therefore, Enbrel should not be prescribed to this category under any circumstances.

Geriatric Use

In elderly patients (65 years and older), there is no need to adjust the dose or method of administration.

Special Precautions

Infections

Patients should be examined for infections before prescribing Enbrel, during treatment, and after completion of the course of therapy with Enbrel, taking into account the average half-life of etanercept, which is approximately 80 hours (7-300 hours).

Sepsis, tuberculosis, and serious infections, including opportunistic infections, including invasive fungal infections, have been reported with the use of Enbrel. When examining patients, the possibility of them developing opportunistic infections, such as endemic mycoses, should be taken into account.

Patients who develop new infections during treatment with Enbrel should be closely monitored. Enbrel should be interrupted if a patient develops a severe infection. Enbrel should be prescribed with caution to patients with a history of frequent or chronic infections or those with an underlying condition, such as progressive or poorly controlled diabetes, that may predispose to infections.

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

Tuberculosis

Cases of active tuberculosis included miliary tuberculosis and extrapulmonary tuberculosis.

Before prescribing Enbrel, all patients should be examined for active or latent tuberculosis. The examination should include a detailed medical history regarding tuberculosis disease or past contact with tuberculosis patients, and data on previous or current immunosuppressive therapy. All patients should undergo appropriate screening procedures (according to local requirements), namely, a tuberculin skin test and chest X-ray. The possibility of a false-negative tuberculin test should be kept in mind, especially in severely ill patients or patients with immunocompromised status.

If active tuberculosis is diagnosed, Enbrel should not be prescribed. The diagnosis of inactive tuberculosis suggests the prescription of standard anti-tuberculosis therapy before starting treatment with Enbrel. In this case, the benefit-risk ratio of treatment with Enbrel should be carefully analyzed.

All patients should be informed about the advisability of consulting a doctor if complaints or symptoms characteristic of tuberculosis (for example, persistent cough, weight loss, low-grade fever) appear during or after treatment with Enbrel.

Hepatitis B virus reactivation

Cases of hepatitis B virus reactivation have been reported in carrier patients who received TNF inhibitors, including Enbrel. Before prescribing Enbrel to patients at high risk for hepatitis B, appropriate diagnostic tests should be performed. Particular caution should be exercised when prescribing Enbrel to patients who are carriers of the hepatitis B virus. If they develop symptoms of this disease, discuss the possibility of specific therapy.

Exacerbation of hepatitis C

Cases of exacerbation of hepatitis C during treatment with Enbrel have been registered, although a clear causal relationship has not been established.

Allergic reactions

Allergic reactions often accompany the use of Enbrel. Allergic reactions, including severe ones, included angioedema and urticaria. In case of any severe allergic or anaphylactic reactions, Enbrel should be discontinued immediately and appropriate treatment initiated.

Immunosuppression

With anti-TNF therapy, including Enbrel, there is a possibility of suppression of the body’s defense mechanisms against infections and malignancies, since TNF is involved in inflammatory processes and modulates cellular immune responses. However, in adult patients with rheumatoid arthritis treated with Enbrel, no cases of suppressed delayed hypersensitivity, decreased immunoglobulin levels, or changes in effector cell populations were identified. In children with juvenile idiopathic arthritis, rare cases of varicella and symptoms of aseptic meningitis occurred, which resolved without complications. Patients who have been in contact with patients with varicella should temporarily discontinue Enbrel and be prescribed prophylactic treatment with immunoglobulin against the Varicella zoster virus.

Malignant and lymphoproliferative disorders

Post-marketing reports have been received of various malignancies (including breast and lung carcinoma, as well as lymphoma).

Lymphoma was diagnosed more often in patients taking TNF inhibitors than in patients who did not receive them. On the other hand, these cases were rare, and the follow-up period for patients in the placebo group was shorter than for patients receiving TNF inhibitor therapy. Furthermore, there is a high risk of lymphoma in patients with rheumatoid arthritis – a prolonged, highly active inflammatory disease, which complicates risk assessment. According to current knowledge, a possible risk of developing lymphomas or other malignancies in patients receiving TNF inhibitors cannot be excluded.

Non-melanoma skin cancer (NMSC)

NMSC has been reported in patients treated with TNF inhibitors, including Enbrel. NMSC is most often diagnosed in patients with psoriasis. For all patients at risk, periodic skin examinations are recommended.

Autoantibody formation

Treatment with Enbrel may be accompanied by the formation of autoantibodies. These antibodies are not neutralizing and usually disappear quickly. No correlation has been noted between antibody formation and the clinical efficacy of the drug, or the frequency of adverse reactions. Isolated cases of the formation of additional autoantibodies in combination with a lupus-like syndrome or a rash similar to subacute cutaneous lupus erythematosus or discoid lupus erythematosus (based on clinical examination and biopsy) have been observed in patients, including patients with rheumatoid arthritis with positive rheumatoid factor.

Hematological reactions

Rare cases of pancytopenia and very rare cases of aplastic anemia, including fatal ones, have been reported in patients receiving Enbrel. Caution should be exercised when prescribing Enbrel to patients with a history of blood dyscrasia. All patients, their relatives/caregivers should be informed that if the patient develops signs and symptoms characteristic of infection or hematological disorders (e.g., persistent fever, sore throat, bruising, bleeding, pallor) during Enbrel use, they should seek immediate medical attention. In such patients, an examination, including a complete blood count, is recommended. If a dyscrasia is confirmed, treatment with Enbrel should be discontinued.

CNS disorders

Several cases of CNS disorders caused by demyelination have been reported in adult patients receiving Enbrel. Although Enbrel has not been studied in patients with multiple sclerosis, studies of other TNF inhibitors in this comorbidity have shown the possibility of its exacerbation.

It is recommended to carefully assess the risk/benefit before prescribing Enbrel, including neurological status, in patients with a previous or recent episode of demyelinating disease or in those who have an increased risk of developing demyelinating disease.

Combination therapy

The combination of Enbrel and methotrexate did not yield unexpected results in safety studies. Long-term study of this indicator continues. Safety data for Enbrel administered concomitantly with methotrexate were similar to data from periodic safety reports for Enbrel and methotrexate separately. The long-term safety of Enbrel with other basic anti-inflammatory drugs has not been studied.

Congestive heart failure

Caution should be exercised regarding the prescription of Enbrel to patients with congestive heart failure. Data from a number of studies suggest the possibility of worsening congestive heart failure in patients receiving Enbrel.

Alcoholic hepatitis

Particular caution should be exercised when prescribing Enbrel to patients with moderate to severe alcoholic hepatitis.

Wegener’s granulomatosis

The frequency of development of malignant tumors of various types of non-cutaneous localization was significantly higher in patients receiving Enbrel than in the control group. Therefore, Enbrel is not recommended for the treatment of patients with Wegener’s granulomatosis.

Use in pediatrics

There is insufficient experience with Enbrel in children under 4 years of age.

The solvent for Enbrel contains benzyl alcohol, which can cause toxic and anaphylactic reactions in children under 3 years of age. Therefore, Enbrel should not be prescribed to this category under any circumstances.

Effect on ability to drive and operate machinery

Studies on the effect on the ability to drive a car and operate complex machinery have not been conducted.

Overdose

No cases of exceeding the maximum toxic dose have been recorded in the treatment of patients with rheumatoid arthritis. The highest dose administered intravenously was 32 mg/m² followed by subcutaneous administration of 16 mg/m² twice a week. One patient with rheumatoid arthritis mistakenly self-administered 62 mg of Enbrel subcutaneously twice a week for 3 weeks without adverse effects. A specific antidote for Enbrel is unknown.

Drug Interactions

In adult patients on combination therapy with Enbrel and anakinra, a significant increase in the frequency of serious infections and neutropenia was observed compared to patients receiving Enbrel alone. Concomitant use of Enbrel and anakinra showed no clinical benefit and is therefore not recommended.

Concomitant administration of abatacept and Enbrel was accompanied by an increase in the frequency of serious adverse events. This combination of drugs did not demonstrate clinical benefits and is therefore not recommended.

In patients who received Enbrel while being treated with sulfasalazine, a significant decrease in the average number of leukocytes was described compared to those patients who took only Enbrel or only sulfasalazine.

No undesirable interactions were observed with the concomitant administration of Enbrel with corticosteroids, salicylates (except sulfasalazine), NSAIDs, analgesics.

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

No clinically significant mutual influence on pharmacokinetics was found with the simultaneous use of digoxin and Enbrel.

No clinically significant mutual influence on pharmacokinetics was found with the simultaneous use of warfarin and Enbrel.

Live vaccines should not be administered during treatment with Enbrel. There are no data on the secondary transmission of infection through a live vaccine to patients receiving Enbrel. It is recommended that, before starting treatment with Enbrel, patients receive all vaccinations in accordance with the current national vaccination schedule, if possible.

Storage Conditions

The drug should be stored out of the reach of children at a temperature of 2°C (35.6°F) to 8°C (46.4°F); do not freeze.

Shelf Life

Shelf life – 3 years.

The reconstituted solution should be stored in vials at a temperature of 2°C (35.6°F) to 8°C (46.4°F) for no more than 14 days.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.