Enbrel, lyophilizate 25 mg 4 pcs

Pharmgroup:

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

Pharm Action:

The enbrel tumor necrosis factor (TNF-α, TNF-α) is a major cytokine that supports the inflammatory process in rheumatoid arthritis. Increased levels of TNF are also 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 receptors on the cell surface and, thus, inhibits TNF biological activity.

TNF and lymphotoxin are pro-inflammatory cytokines that bind to two clearly distinguishable tumor necrosis factor receptors (TNF) on the cell surface: 55-kilodaltone (p55) and 75-kilodaltone (p75). Both TNFRs are present in the body in membrane-bound and free forms. Soluble TNFRs regulate the biological activity of TNFRs.
TNFRs and lymphotoxin exist primarily as homotrimers; their biological activity depends on cross-linking of TNFRs on the cell surface. Dimeric soluble receptors, such as etanercept, have a higher 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 immunoglobulin Fc region as a binding element in the dimeric receptor structure lengthens the serum half-life.

A large proportion of the pathological changes in the joints in rheumatoid arthritis and ankylosing spondylitis, as well as skin changes in the form of psoriatic plaques, arise from the effects of proinflammatory molecules involved in the TNF-controlled system. The mechanism of action of etanercept seems to lie in the 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 (e.g., cytokines, adhesion 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:

Intake
Etanercept is slowly absorbed from the site of p/k injection, reaching Cmax approximately 48 h after a single dose of Enbrel. Absolute bioavailability is 76%. When Enbrel is administered twice a week, equilibrium concentrations are twice as high as after a single dose. After a single oral administration of 25 mg of Enbrel, the average Cmax in plasma is 1.65±0.66 mcg/ml, AUC is 235±96.6 mcg×h/ml. No apparent saturation of clearance was observed in the dose range.

Distribution
The dependence of etanercept concentration on time is described by a biexponential curve. The average Vd value is 7.6 L, while Vd at equilibrium is 10.4 L.

Elimination
Etanercept is slowly excreted from the body. T1/2 is about 80 h. In patients with rheumatoid arthritis 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 50 mg dose of Enbrel once weekly is bioequivalent to the 25 mg dose administered twice weekly.

Pharmacokinetics in special clinical cases
In patients with acute renal or hepatic impairment no increase in concentrations of etanercept has been 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 is similar to that of 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 older children (10-17 years) and adult patients will have approximately the same serum levels of etanercept, while younger children will have significantly lower levels.

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 a dose of 0.8 mg/kg once weekly (maximum dose 50 mg weekly) and 0.4 mg/kg twice weekly (maximum dose 50 mg weekly) for 12-48 weeks were similar (1.6-2.1 μg/mL). The value was consistent with that of adult psoriasis patients in whom Enbrel was administered at a dose of 25 mg twice weekly.

Indications

Rheumatoid arthritis

In combination with methotrexate, Enbrel is indicated in adults for the treatment of moderate to severe active rheumatoid arthritis when the response to baseline anti-inflammatory drugs (BART), including methotrexate, has been inadequate.
Enbrel may be prescribed 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

The treatment of active juvenile idiopathic polyarthritis in children and adolescents aged 4-17 years who have had insufficient efficacy or intolerance to methotrexate.

Psoriatic arthritis

The treatment of active and progressive psoriatic arthritis in adults when response to DAA therapy has been inadequate.

Ankylosing spondylitis

The treatment of adults with severe active ankylosing spondylitis in whom conventional therapy has not resulted in significant improvement.

Psoriasis

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

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

Active ingredient

Composition

1 vial contains:

Ethanercept 25 mg.

Auxiliary substances:

mannitol,

sucrose,

tromethamol,

tromethamol hydrochloride (to pH).

Solvent:

benzyl alcohol,

d/i water (up to 1 ml).

How to take, the dosage

Enbrel is administered by injection by injection. The 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 of age and older, the dose is determined at the rate of 400 mcg/kg body weight (maximum single dose is 25 mg). The drug is administered twice a week with intervals of 3-4 days between doses.

The frequency of administration and the duration of use depend on the indication and tolerability of the treatment.

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

Interaction

A significant increase in the incidence of serious infections and neutropenia has been observed in adult patients on combined Enbrel and anakinra therapy compared to patients administered Enbrel alone. Co-administration of Enbrel and anakinra showed no clinical benefit and, therefore, is not recommended.

The concomitant administration of abatacept and Enbrel was accompanied by an increased incidence of serious adverse events. This drug combination has not demonstrated any clinical benefit and is therefore not recommended.
A significant decrease in mean white blood cell count has been described in patients who received Enbrel alone or sulfasalazine alone during treatment with sulfasalazine compared to those patients who received Enbrel alone or sulfasalazine alone.

No undesirable interactions have been observed when Enbrel is coadministered with GKS, salicylates (except sulfasalazine), NSAIDs, analgesics.

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

There have been no clinically significant reciprocal effects on pharmacokinetics with concomitant use of digoxin and Enbrel.

No clinically significant reciprocal effects on pharmacokinetics have been found with concomitant use of warfarin and Enbrel.
Live vaccines should not be administered with Enbrel treatment. There are no data on secondary transmission of infection through live vaccine to patients receiving Enbrel. It is recommended that before treatment with Enbrel, patients should, if possible, receive all vaccinations in accordance with the current national vaccination calendar.

Special Instructions

Infections

Patients should be screened for infections before, during and after administration of Enbrel, taking into account the average elimination half-life of etanercept of approximately 80 h (7-300 h).
Sepsis, tuberculosis and severe infections, including opportunistic infections, including invasive fungal infections, have been reported when using Enbrel. The possibility of opportunistic infections, such as endemic mycoses, should be taken into account when screening patients.

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 who have an underlying disease, such as advanced or poorly controlled diabetes, which may contribute to the development of infections.

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

Tuberculosis

Cases of active tuberculosis included miliary tuberculosis and tuberculosis extrapulmonary localization.

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

In case of a diagnosis of active tuberculosis, Enbrel should not be prescribed. A diagnosis of inactive tuberculosis suggests prescribing standard antituberculosis therapy before starting Enbrel treatment. In this case, the benefit-risk ratio of Enbrel treatment should be carefully analyzed.

All patients should be informed to seek medical attention if, during or after treatment with Enbrel, they have complaints or symptoms characteristic of tuberculosis (e.g., persistent cough, weight loss, subfebrile).

Hepatitis B virus activation

Hepatitis B virus activation has been reported in carrier patients who received TNF inhibitors, including Enbrel. Before prescribing Enbrel to patients at high risk for hepatitis B, an appropriate diagnostic search should be performed. Particular caution should be observed when prescribing Enbrel to patients who are carriers of hepatitis B virus. If they have symptoms of the disease, discuss the possibility of specific therapy.

Hepatitis C exacerbations

Hepatitis C exacerbations have been reported with Enbrel treatment, although a clear causal relationship has not been established.

Allergic reactions

Allergic reactions often accompany the administration of Enbrel. Allergic reactions, including severe ones, have included angioedema and urticaria. If any severe allergic or anaphylactic reactions occur, Enbrel should be stopped immediately and appropriate treatment should be initiated.

Immunosuppression

In anti-TNF therapy, including Enbrel, there is a possibility of suppression of the human body’s defense mechanisms against infections and malignancies, since TNF is involved in inflammatory processes and modulates the cellular immune response. However, in adult patients with rheumatoid arthritis, no cases of inhibition of delayed hypersensitivity, drop in immunoglobulin levels or changes in the number of effector cells were detected during Enbrel treatment. Children with juvenile idiopathic arthritis rarely developed chickenpox and symptoms of aseptic meningitis, which resolved without complications. Patients who have been in contact with patients with chickenpox should temporarily discontinue Enbrel and prescribe prophylactic treatment with immunoglobulin against Varicella zoster virus.

Malignant and lymphoproliferative diseases

A variety of malignant neoplasms (including breast and lung carcinoma and lymphoma) have been reported in the post-marketing period.
Lymphoma was diagnosed more frequently 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 lymphoma in patients with rheumatoid arthritis, a protracted, highly active inflammatory disease that complicates risk assessment. According to current knowledge, the possible risk of lymphoma or other malignancies cannot be excluded in patients receiving TNF inhibitors.

The non-melanoma skin cancer (NSCLC)

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

The formation of autoimmune antibodies

The Enbrel treatment may be accompanied by the formation of autoimmune antibodies. These antibodies are not neutralizing antibodies and usually disappear quickly. No correlation between the formation of antibodies and the clinical efficacy of the drug, as well as the frequency of adverse reactions, has been noted. Single cases of additional autoantibodies formation in combination with lupus-like syndrome or rash similar to subacute form of lupus erythematosus or discoid lupus (data from clinical examination and biopsy) were noted in patients, including rheumatoid arthritis patients with rheumatoid factor positive.

Hematologic reactions

Rare cases of pancytopenia and very rare cases of aplastic anemia, including fatal, 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 made aware that if a patient develops signs and symptoms characteristic of infection or hematologic disorders (e.g., prolonged fever, sore throat, bruising, bleeding, pallor) while taking Enbrel, they should seek medical attention immediately. In such patients, an examination, including a complete blood count, is recommended. If the diagnosis of dyscrasias is confirmed, treatment with Enbrel should be discontinued.

CNS damage

A few cases of CNS abnormalities 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 comorbid disease have shown the possibility of exacerbation.

We recommend a careful risk/benefit assessment, including neurologic status, before prescribing Enbrel in patients with a previous or recent attack of demyelinating disease or in those for whom there is an increased risk of developing demyelinating disease.

Combination therapy

The combination of Enbrel and methotrexate produced no unexpected results in the safety study. Long-term studies of this indication are ongoing. The safety data for Enbrel, which was prescribed together with methotrexate, were similar to data from periodic reports on the safety of Enbrel and methotrexate alone. The long-term safety when Enbrel is taken with other basal anti-inflammatory drugs has not been investigated.

Congestive heart failure

Caution should be exercised when prescribing Enbrel to patients with congestive heart failure. Data from several studies suggest the possibility of worsening the course of 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 incidence of malignant tumors of various types of extracutaneous 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.

Pediatric use

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

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

The effect on the ability to drive and operate machinery

There have been no studies of the effect on the ability to drive and operate complex machinery.

Contraindications

Sepsis or conditions with 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.

The drug should be used with caution in demyelinating diseases, congestive heart failure, immunodeficiency states, blood dyscrasias, diseases predisposing to the development or activation of infections (diabetes mellitus, hepatitis).

Side effects

Infections: possibly – infections of the upper respiratory tract. In treatment of rheumatoid arthritis – pyelonephritis, bronchitis, septic arthritis, abdominal abscess, cellulitis, osteomyelitis, wound infection, pneumonia, foot abscess, ulcers on lower extremities, diarrhea, sinusitis, sepsis; infections were caused by viruses, bacteria, fungi, protozoa. In the treatment of psoriasis – cellulitis, gastroenteritis, pneumonia, osteomyelitis. In some cases – pulmonary and extrapulmonary tuberculosis.

CNS and peripheral nervous system disorders: headache, dizziness, brain ischemia, depression, multiple sclerosis.

Digestive system disorders: abdominal pain, dyspepsia, vomiting, cholecystitis, pancreatitis, gastrointestinal bleeding, appendicitis.

Respiratory system: pharyngitis, cough, sinusitis.

Muscular system disorders: bursitis, polymositis.

Dermatological reactions: rash, worsening of the course of psoriasis.

Cardiovascular system: heart failure, myocardial infarction, myocardial ischemia, arterial hypertension, arterial hypotension, deep vein thrombosis, thrombophlebitis.

Urinary system disorders: membranous glomerulonephropathy, kidney stones.

Local reactions: pain, swelling, redness.

Others: asthenia, peripheral edema, lymphoadenopathy. We can not exclude the risk of malignization: cases of lymphoma, cancer of the colon, breast, lung, prostate, extracutaneous solid cancer, skin cancer (nonmelanoma) are described.

Sometimes the formation of autoimmune antibodies that did not have neutralizing properties was observed.

Overdose

No exceeding of the toxic dose limit has been reported in the treatment of patients with rheumatoid arthritis. The highest dose administered w/v was 32 mg/m2 followed by 16 mg/m2 p/c twice weekly.

One patient with rheumatoid arthritis mistakenly self-administered 62 mg of Enbrel b/c 2 times per week for 3 weeks with no adverse effects. A specific antidote for Enbrel is not known.

Pregnancy use

Pregnant women should not be treated with Enbrel as there is no experience with this drug in this patient population.
Women of childbearing age should not plan a pregnancy during treatment with Enbrel.
It is unknown whether Etanercept can be excreted with breast milk. Because immunoglobulins, like many other drugs, can be excreted with human milk, you should either stop breastfeeding or stop taking Enbrel while breastfeeding.