Enbrel solution for subcutaneous injection 50mg/ml 1ml syringes + wipes, 4pcs

Composition

Etanercept 50 mg;

Auxiliary substances:

arginine hydrochloride,

sodium chloride,

sucrose,

sodium hydrophosphate dihydrate,

sodium dihydrogen phosphate dihydrate,

d/i water.

Pharmacological action

of the pharmaceutical group:

A drug with an anti-inflammatory effect. Inhibitor of tumor necrosis factor alpha (TNF-alpha).

Pharmaceutical action:  

Enbrel-tumor necrosis factor (TNF-α, TNF) is the main cytokine supporting the inflammatory process in rheumatoid arthritis. Elevated TNF levels were also found in synovial membranes and psoriatic plaques in patients with psoriatic arthritis, as well as in plasma and synovial tissues of patients with ankylosing spondylitis. Etanercept is a competitive inhibitor of the binding of TNF with its receptors on the cell surface, and thus inhibits the biological activity of TNF.

TNF and lymphotoxin refer to the Pro-inflammatory cytokines, which are associated with two distinct receptors for tumor necrosis factor (FNAR) on the cell surface: 55 kilodalton (p 55) and 75 kilodalton (p 75). Both TNFs are present in the body in membrane-bound and free forms. Soluble TNF-ros regulate the biological activity of TNF.

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

A significant part 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 TNF-controlled system. The mechanism of action of etanercept appears to be competitive inhibition of TNF binding to TNF receptors on the cell surface. Thus, etanercept prevents the TNF-mediated cellular response by promoting the biological inactivation of TNF. Etanercept can also modulate biological responses controlled by additional downstream signaling molecules (such as cytokines, adhesive molecules, or proteinases). And these responses can either stimulate or control TNF.

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

Pharmacokinetics:  

Absorption Ethanercept is slowly absorbed from the subcutaneous injection site, reaching Cmax approximately 48 hours after a single dose of Enbrel. Absolute bioavailability is 76%. With the introduction of a dose of Enbrel 2 times a week,2 times higher equilibrium concentrations are achieved than after a single dose. After a single subcutaneous injection of 25 mg of Enbrel, the mean plasma Cmax was 1.65±0.66 mcg / ml, and AUC was 235±96.6 mcg × h / ml. There was no apparent saturation of clearance within the dose range.

Distribution The time dependence of the etanercept concentration is described by a biexponential curve. The average Vd is 7.6 l, while the Vd at steady state is 10.4 l.

Excretion etanercept is slowly excreted from the body. T1 / 2 is about 80 hours. In patients with rheumatoid arthritis, the clearance is approximately 0.066 l / h, which is slightly 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 once a week is bioequivalent to the dose of 25 mg administered 2 times a week.

Pharmacokinetics in special clinical cases 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.

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

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

Mean serum concentrations of etanercept in 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 12-48 weeks were similar (1.6-2.1 mcg/ml). The value of this indicator coincided with that in adult patients with psoriasis, who received Enbrel at a dose of 25 mg 2 times a week.

Indications

Rheumatoid arthritis

In combination with methotrexate, Enbrel is prescribed for adults in the treatment of active rheumatoid arthritis of moderate to high severity, when the response to basic anti-inflammatory drugs (DMARDs), including methotrexate, was inadequate. Enbrel may be given as monotherapy if methotrexate is ineffective or intolerant. 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 in children and adolescents aged 4-17 years who have experienced insufficient efficacy or intolerance to methotrexate.

Psoriatic arthritis

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

Ankylosing spondylitis

Treatment of adults with severe active ankylosing spondylitis in whom conventional therapy has not significantly improved.

Psoriasis

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

Treatment of children aged 8 years and older with severe chronic psoriasis who have experienced intolerance or insufficient response to other systemic or phototherapy.

Contraindications

Sepsis or conditions with an increased risk of its development; severe active infections, including chronic or localized infections; concomitant use with interleukin 1 inhibitors (including anakinra); pregnancy and lactation; children under 3 years of age; hypersensitivity to etanercept. With caution, the drug should be prescribed for demyelinating diseases, congestive heart failure, conditions of immunodeficiency, blood dyscrasia, diseases predisposing to the development or activation of infections (diabetes mellitus, hepatitis).

Side effects

Adverse reactions, depending on the frequency of occurrence, were grouped as follows: very common (>1/10), often (>> 1/100, >>< 1/10), infrequently (>1/1000,1/10 000, < 1/10), infrequently (>

From the hematopoietic system: infrequently-thrombocytopenia; rarely-anemia, leukopenia, neutropenia, pancytopenia; very rarely-aplastic anemia.

From the immune system: often-formation of autoantibodies; rarely-allergic/anaphylactic reactions (including angioedema, bronchospasm); in isolated cases – macrophage activation syndrome.

From the central nervous system: rarely-convulsions, symptoms of demyelination in the central nervous system, similar to those observed in multiple sclerosis or a state of local demyelination, such as optic neuritis and transverse myelitis.

From the respiratory system: infrequently-interstitial lung diseases (including pneumonitis and pulmonary fibrosis).

From the digestive system: rarely-increased activity of liver enzymes, autoimmune hepatitis.

From the cardiovascular system: rarely-worsening of the course of congestive heart failure.

From the skin: often-pruritus; infrequently-non-melanoma skin cancer, urticaria, rash, psoriasis (including the onset of the disease and pustular lesions, mainly of the soles and palms); rarely-cutaneous forms of vasculitis (including leukocytoclastic vasculitis), Stevens-Johnson syndrome, erythema multiforme; very rarely-toxic epidermal necrolysis.

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

General disorders and reactions at the injection site: very often – local reactions after injection (including bleeding, subcutaneous hematoma, erythema, itching, pain, swelling); often – fever.

Additional information

Adverse reactions in adults

The frequency of drug withdrawal due to the development of adverse reactions in controlled clinical trials in patients with rheumatoid arthritis was comparable in patients receiving Enbrel and placebo. When treated with Enbrel, the most common reactions were at the injection site.

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 given below.

Infections that were observed in clinical studies in patients with juvenile idiopathic arthritis were mild to moderate in severity, and their types did not contradict those that are usually found among outpatient patients. Reports of severe adverse events included chickenpox with symptoms of aseptic meningitis that resolved without complications, appendicitis, gastroenteritis, depression/personality disorders, skin ulcers, esophagitis/gastritis, aseptic shock caused by Group A streptococci, type 1 diabetes mellitus, and soft tissue and postoperative wound infections. There were 4 reports of macrophage activation syndrome in these patients. The frequency and types of adverse reactions in children with psoriasis were similar to those observed in adult patients.

Interaction

In adult patients treated with Enbrel and anakinra combined, there was a significant increase in the incidence of serious infections and neutropenia compared to patients treated with Enbrel alone. Co-use of Enbrel and anakinra has not shown any clinical benefit and is therefore not recommended.

Concomitant use of abatacept and Enbrel was associated with an increased incidence of serious adverse events. This combination of medications has not demonstrated clinical benefits and is therefore not recommended.

Patients who received Enbrel during treatment with sulfasalazine showed a significant decrease in the average white blood cell count compared to those who received Enbrel alone or sulfasalazine alone.

No undesirable interactions were observed when Enbrel was co-administered with corticosteroids, salicylates (except for sulfasalazine), NSAIDs, and analgesics.

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

There was no clinically significant mutual effect on pharmacokinetics when digoxin and Enbrel were co-administered.

There was no clinically significant mutual effect on pharmacokinetics when warfarin and Enbrel were co-administered.

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

How to take, course of use and dosage

Enbrel is administered subcutaneously. A single dose for adults is 50 mg, for children aged 8 to 17 years – 800 mcg/kg (but not more than 50 mg per week). For children 4 years and older, the dose is determined at the rate of 400 mcg/kg of body weight (the maximum single dose is 25 mg). The drug is administered 2 times a week with intervals of 3-4 days between doses. The frequency of use and duration of use depend on the indications and tolerability of treatment. Treatment should be prescribed and supervised by a physician experienced in the diagnosis and treatment of rheumatoid arthritis, juvenile idiopathic polyarthritis, psoriatic arthritis, ankylosing spondylitis, or psoriasis.

Overdose

In the treatment of patients with rheumatoid arthritis, no excess of the toxic dose limit was recorded. The highest dose administered intravenously was 32 mg / m2, followed by subcutaneous use of 16 mg / m2 2 times a week.

One patient with rheumatoid arthritis mistakenly self-administered 62 mg of Enbrel subcutaneously 2 times a week for 3 weeks without the appearance of undesirable effects. The specific antidote for Enbrel is unknown.

Special instructions

Infections

Patients should be screened for infections prior to Enbrel use, during treatment, and after the end of Enbrel therapy, taking into account the average etanercept half-life of approximately 80 hours (7-300 hours). Sepsis, tuberculosis, and severe infections, including opportunistic ones, including invasive fungal infections, have been reported with Enbrel. When examining patients, it is necessary to take into account the possibility of developing opportunistic infections, for example, endemic mycoses.

Patients who develop new infections during treatment with Enbrel should be closely monitored. Enbrel should be discontinued if the patient develops a severe infection. Caution should be exercised when prescribing Enbrel to patients with a history of frequent or chronic infections or an underlying medical condition, such as advanced or poorly controlled diabetes, that may contribute to the development of 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 screened for active or latent tuberculosis. The examination should include a detailed examination of the medical history of tuberculosis or previous contact with tuberculosis patients, as well as data on previous or ongoing immunosuppressive therapy. All patients should undergo appropriate screening procedures (according to local requirements), namely, a tuberculin skin test and a lung X-ray. It is necessary to keep in mind the possibility of a false-negative tuberculin test, especially in seriously ill or immunocompromised patients.

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

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

Hepatitis B virus activation

Cases of hepatitis B virus activation have been reported in carrier patients treated with TNF inhibitors, including Enbrel. Before prescribing Enbrel to patients who are at high risk for hepatitis B, it is necessary to conduct an appropriate diagnostic search. Special care should be taken when prescribing Enbrel to patients with hepatitis B virus carriers. If they develop symptoms of this disease, discuss the possibility of specific therapy.

Hepatitis C exacerbation

Cases of hepatitis C exacerbation have been reported with Enbrel treatment, although no clear causal relationship has 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, you should immediately stop taking Enbrel and start appropriate treatment.

Immunosuppression

With anti-TNF therapy, including Enbrel, there is a possibility of inhibiting the protective mechanisms of the human body against infections and malignancies, since TNF is involved in inflammatory processes and modulates the cellular immune response. However, in adult patients with rheumatoid arthritis treated with Enbrel, there were no cases of inhibition of delayed hypersensitivity, a drop in the level of immunoglobulin, or changes in the population of effector cells. Children with juvenile idiopathic arthritis rarely developed chickenpox and symptoms of aseptic meningitis, which resolved without complications. Patients who have been in contact with chickenpox patients should temporarily stop taking Enbrel and prescribe preventive treatment with immunoglobulin against Varicella zoster virus.

Malignant and lymphoproliferative diseases

In the post-marketing period, various malignancies (including breast and lung carcinoma, as well as lymphoma) were reported.

More often, lymphoma was diagnosed 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 treated with TNF inhibitors. In addition, there is a high risk of developing lymphoma in patients with rheumatoid arthritis, a long – term, highly active inflammatory disease that complicates risk assessment. In accordance with current knowledge, it is impossible to exclude the possible risk of developing lymphomas or other malignancies in patients receiving TNF inhibitors.

Non-melanoma skin cancer (NSCLC)

PCNM has been reported in patients treated with TNF inhibitors, including Enbrel. Most often, PCNM is diagnosed in patients with psoriasis. Periodic skin examinations are recommended for all patients at risk.

Formation of autoimmune antibodies

Treatment with Enbrel may be accompanied by the formation of autoimmune antibodies. These antibodies are not neutralizing and usually disappear quickly. There was no correlation between the formation of antibodies and the clinical efficacy of the drug, as well as the frequency of adverse reactions.Isolated cases of formation of additional autoantibodies in combination with lupus-like syndrome or rash similar to subacute lupus erythematosus or discoid lupus erythematosus (data from clinical examination and biopsy) They were observed in patients, including patients with rheumatoid arthritis with a positive rheumatoid factor.

Hematological reactions

Rare cases of pancytopenia and very rare cases of aplastic anemia, including fatal cases, have been reported in patients receiving Enbrel. Caution should be exercised when prescribing Enbrel to patients with a history of blood dyscrasia. All patients and their relatives/caregivers should be informed that if a patient develops signs and symptoms that are characteristic of infection or hematological disorders (for example, prolonged fever, sore throat, bruising, bleeding, pallor) while taking Enbrel, they should immediately seek medical attention. In such patients, it is recommended to conduct an examination, including a complete blood test. If the diagnosis of dyscrasia is confirmed, treatment with Enbrel should be discontinued.

CNS

damage Several cases of demyelination-induced CNS disorders 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 concomitant disease have shown the possibility of its exacerbation.

Before prescribing Enbrel, it is recommended to carefully assess the risk / benefit, including neurological status, in patients with a previous or recent attack 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 produce unexpected results in the safety study. A long-term study of this indicator is ongoing. Data on the safety of Enbrel, which was administered together with methotrexate, were similar to data from periodic reports on the safety of 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 when prescribing Enbrel to patients with congestive heart failure. Data from a number of studies suggest the possibility of worsening the course of congestive heart failure in patients receiving Enbrel.

Alcoholic hepatitis

Special care should be taken when prescribing Enbrel to patients with moderate to severe alcoholic hepatitis.

Wegener’s granulomatosis

The incidence of various types of extracutaneous malignancies was significantly higher in patients treated with 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 no sufficient experience of using Enbrel in children under 4 years of age.

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

Influence on the ability to drive motor vehicles and manage mechanisms

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

Form of production

Solution for subcutaneous use.

Storage conditions

At a temperature of 2-8 °C (do not freeze)

Shelf life

2 years

Active ingredient

Etanercept

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

For adults as prescribed by a doctor, for children as prescribed by a doctor

Indications

Cancer