Orencia^® (Solution, Lyophilisate) Instructions for Use

ATC Code

L04AA24 (Abatacept)

Active Substance

Abatacept

Clinical-Pharmacological Group

Basic antirheumatic drug

Pharmacotherapeutic Group

Immunosuppressive agent

Pharmacological Action

Immunosuppressant. Abatacept is a soluble protein consisting of the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc fragment of human immunoglobulin G1 (IgG1). Abatacept is a recombinant protein produced by genetic engineering in a mammalian cell system.

Abatacept selectively modulates a key co-stimulatory signal necessary for the full activation of T-lymphocytes expressing the CD28 (cluster of differentiation 28) antigen. In patients with rheumatoid arthritis, T-lymphocytes are found in the synovial fluid. Activated T-lymphocytes play an important role in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. Full activation of T-lymphocytes requires two signals from antigen-presenting cells: the first is the recognition of a specific antigen by T-cell receptors (signal 1); the second (major, non-specific) co-stimulatory signal involves the binding of CD80 and CD86 molecules on the surface of antigen-presenting cells to the CD28 receptor on the surface of T-lymphocytes (signal 2). Abatacept specifically binds to CD80 and CD86, selectively inhibiting this pathway. It has been established that Abatacept has a greater effect on the response of unactivated (naive) T-lymphocytes than on memory T-lymphocytes.

In vitro studies and animal models have shown that Abatacept reduces T-cell-dependent antibody formation and inflammation. In vitro, Abatacept reduces T-lymphocyte activation, as evidenced by decreased proliferation and cytokine production in human lymphocytes (TNFα, interferon gamma, and interleukin-2). In rats with collagen-induced arthritis, Abatacept suppresses inflammation, reduces the formation of anti-collagen antibodies, and inhibits antigen-specific interferon gamma production.

Pharmacokinetics

The values of pharmacokinetic parameters are given in Table 1.

Table 1. Pharmacokinetic parameters (mean value and confidence intervals) in healthy subjects and RA patients after intravenous administration of abatacept at a dose of 10 mg/kg.

*IV infusions were administered on days 1, 15, 30, and then monthly.

The pharmacokinetics of abatacept in patients with rheumatoid arthritis and healthy volunteers were comparable.

Distribution

With multiple IV administrations, a proportional increase in C_max and AUC values was observed in the dose range from 2 mg/kg to 10 mg/kg. When administered at a dose of 10 mg/kg, steady-state plasma concentration is reached by day 60, with a mean (range) C_max of 24 (from 1 to 66) µg/ml. Systemic accumulation of abatacept was not observed in patients with rheumatoid arthritis during long-term repeated administration of the drug at a dose of 10 mg/kg at monthly intervals.

Metabolism and Elimination

Studies to assess the metabolism and elimination of abatacept in humans have not been conducted. Due to its spatial structure and hydrophilicity, Abatacept is not metabolized in the liver by cytochrome P450 isoenzymes. Given the high molecular weight of abatacept, it is assumed that Abatacept is not excreted in the urine.

Pharmacokinetics in Special Clinical Cases

Higher clearance of abatacept was found in patients with high body weight.

The age and sex of patients (when corrected for body weight) did not affect the clearance of abatacept.

Concomitant administration of methotrexate, anti-inflammatory drugs, corticosteroids, and tumor necrosis factor blockers did not affect the clearance of abatacept.

Studies to assess the effect of renal and hepatic impairment on the pharmacokinetics of abatacept have not been conducted.

Indications

• For the reduction of symptoms, improvement of clinical response, suppression of the progression of structural damage, and improvement of functional activity in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more basic anti-inflammatory drugs (such as methotrexate) or biological antirheumatic drugs;
• For the reduction of signs and symptoms in children aged 6 years and older with moderately to severely active polyarticular juvenile idiopathic arthritis.

ICD codes

Dosage Regimen

Lyophilisate

Abatacept can be used as monotherapy or in combination with basic anti-inflammatory drugs (e.g., methotrexate).

The drug Orencia^® is administered intravenously as an infusion over 30 minutes at the doses indicated in the table.

For adults, after the first administration, subsequent doses are recommended to be given at 2 and 4 weeks, and then every 4 weeks.

For children aged 6 to 17 years with a body weight of less than 75 kg, the dose of the drug is 10 mg/kg of body weight. The dose should be calculated individually immediately before each administration of the drug. For children with a body weight of 75 kg and more, the dosing regimen is the same as for adults. The maximum dose is 1000 mg.

Rules for preparation of the infusion solution and administration of the drug

The abatacept solution must not be used with equipment containing silicone.

After removing the protective plastic cap, the stopper should be wiped with sterile alcohol-soaked cotton wool. The contents of one vial are dissolved in 10 ml of water for injections using a disposable silicone-free syringe supplied with the drug (the stream of water should be directed at the wall of the vial during dissolution). To reduce foam formation, the vial should be gently rotated until the powder is completely dissolved. Do not shake! After the powder has dissolved, air should be expelled through the needle to remove any bubbles that may have formed. The resulting concentrate should be colorless or pale yellow. Do not use a cloudy solution, a solution of a different color, or one containing foreign particles.

The resulting concentrate is immediately diluted to 100 ml with 0.9% sodium chloride injection to obtain the infusion solution as follows: from a 100 ml vial of sodium chloride, withdraw 10 ml of solution for each vial of abatacept to be added. Then, the previously obtained concentrate is slowly added to the remaining solution using a disposable silicone-free syringe included in the drug kit. The concentration of abatacept in the resulting solution is approximately 5, 7.5, or 10 mg/ml when using 2, 3, or 4 vials of the drug, respectively.

The prepared solution can be stored for 24 hours in a refrigerator at a temperature of 2°C (35.6°F) to 8°C (46.4°F). If foreign particles or discoloration are observed in the solution before administration, the solution must be discarded. The prepared solution must be administered within 24 hours after opening the vial.

The prepared infusion solution is administered over 30 minutes through an infusion system with a sterile, apyrogenic, low protein-binding filter (pore size from 0.2 to 1.2 µm). Abatacept must not be administered simultaneously with other drugs through the same infusion system.

Solution

Administered intravenously as an infusion. Depending on body weight, the single dose for adults is 0.5-1 g. The frequency of administration is determined according to a specific schedule.

For children aged 6 to 17 years with a body weight of less than 75 kg, the dose is 10 mg/kg of body weight. The dose should be calculated individually immediately before each administration of abatacept. For children with a body weight of 75 kg and more, the dosing regimen is the same as for adults. The maximum dose is 1 g.

Adverse Reactions

Adverse reactions observed in clinical studies with the use of abatacept or placebo with other therapies for rheumatoid arthritis. Definition of frequency of adverse reactions: very common (>10%), common (>1% and <10%), uncommon (>0.1% and <1%), rare (>0.01% and <0.1%).

Infections and infestations: common – lower respiratory tract infections (including bronchitis), urinary tract infections, herpes simplex and zoster, upper respiratory tract infections (including tracheitis, nasopharyngitis), rhinitis; uncommon – dental infections, infected skin ulcers, onychomycosis.

Benign and malignant tumors: rare – basal cell skin cancer, lung cancer, lymphoma, myelodysplastic syndrome.

From the hematopoietic system uncommon – thrombocytopenia, leukopenia.

From the central and peripheral nervous system very common – headache; common – dizziness; uncommon – depression, anxiety, paresthesia.

From the organ of vision uncommon – conjunctivitis, blurred vision, dry eye.

From the cardiovascular system common – hypertension, flushing; uncommon – tachycardia, bradycardia, palpitations, feeling hot, decreased blood pressure.

From the respiratory system : common – cough, exacerbation of COPD, dyspnea; uncommon – bronchospasm, sore throat.

From the digestive system common – abdominal pain, diarrhea, nausea, dyspepsia, abnormal liver function tests (including increased transaminase activity); uncommon – gastritis, mouth ulceration, aphthous stomatitis.

Dermatological reactions: common – rash (including dermatitis); uncommon – bruising, alopecia, dry skin, psoriasis.

From the musculoskeletal system uncommon – arthralgia, limb pain.

From the reproductive system uncommon – amenorrhea.

Other common – fatigue, asthenia; uncommon – flu-like syndrome, weight gain.

In placebo-controlled clinical studies, the following serious infections, for which a relationship to the drug was at least possible, were observed in 0.05% of patients: bronchitis, pneumonia, acute pyelonephritis, diverticulitis, intestinal abscess, local infections, skin abscess, muscle and bone infections, sepsis, bacteremia, empyema, hepatitis E, tuberculosis.

Contraindications

• Concomitant use with TNF blockers;
• Severe uncontrolled infections (sepsis, opportunistic infections), active infections (including tuberculosis) until control is established;
• Pregnancy;
• Lactation (breastfeeding);
• Children under 6 years of age;
• Hypersensitivity to the components of the drug.

Use with caution in patients with recurrent infections; conditions predisposing to infections (diabetes mellitus), hepatitis; in elderly patients. Administration of abatacept should be discontinued if an infectious disease develops.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Pediatric Use

Contraindicated for use in children under 6 years of age.

Special Precautions

When prescribing immunomodulatory drugs, a tuberculin skin test should be performed to detect the presence of tuberculosis infection. Abatacept has not been used in patients with a positive tuberculin test, so the safety of the drug in patients with latent tuberculosis is unknown. If the reaction is positive, standard anti-tuberculosis therapy should be administered before prescribing abatacept.

Live vaccines should not be used during treatment with abatacept and for 3 months after its discontinuation. Drugs affecting the immune system, including Abatacept, may reduce the effectiveness of vaccination.

False-positive results may be obtained when determining blood glucose levels on the day of drug administration using glucose dehydrogenase pyrroloquinolinequinone-based tests due to a reaction with maltose contained in the drug. If glucose level determination is required, methods that exclude reaction with maltose should be used.

Overdose

The drug Orencia^® is administered as an intravenous infusion under medical supervision. At doses up to 50 mg/kg, no obvious toxic effects were observed. Symptoms of overdose have not been described.

Treatment in case of overdose, medical supervision and, if necessary, symptomatic therapy are recommended.

Drug Interactions

In patients receiving Abatacept with TNF blockers, serious infections occurred more frequently than in those receiving TNF blockers alone. The combination of abatacept with TNF blockers is not recommended.

There is insufficient information on the safety and efficacy of the combination of abatacept with anakinra or rituximab, so such combinations are not recommended.

Abatacept has not been studied in combination with drugs that cause a reduction in lymphocyte count. With such a combination, potentiation of the effect of abatacept on the immune system is possible.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature of 2°C (35.6°F) to 8°C (46.4°F).

Shelf Life

Shelf life – 3 years.

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.