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

Clinical and pharmacological group: & nbsp

Immunosuppressive drugs

Included in the formulation

Orencia®

solution PC

Bristol-Myers Squibb Company USA

Orencia®

lyophilizate d / infusion

Bristol-Myers Squibb Company USA

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

L.04.A.A Selective immunosuppressants

Pharmacodynamics:

Abatacept is a soluble protein consisting of the extracellular domain of the antigen 4 of cytotoxic T-lymphocytes (CTLA-4) bound to a modified human immunoglobulin G1 (IgG1) Fc fragment. Abatacept is a recombinant protein that is produced by genetic engineering based on mammalian cells. Abatacept selectively modulates the key co-stimulatory signal necessary for the complete activation of T-lymphocytes expressing the differentiation cluster 28 (CD28).

To activate T-lymphocytes and then form an immune response, it is necessary that the antigen-presenting cell (APC) transmits two signals to T-lymphocytes. One of these signals is exposure of a foreign antigen in complex with the molecules of the main histocompatibility complex on the surface, and another signal is CD80 or CD86 molecule. Abatacept specifically binds CD80 and CD86, selectively inhibiting the second route. Without this signal, T-lymphocytes can not be activated.Determined that abatacept to a greater extent affects the response of non-activated (naive) T-lymphocytes than T-lymphocytes of memory.

In in vitro studies and animal models, it has been shown that abatacept reduces T-lymphocyte-dependent antibody production and inflammation, as well as activation of T-lymphocytes, as evidenced by a decrease in proliferation and production of cytokines in human lymphocytes (TNF-alpha, interferon-gamma and interleukin-2). In rats with collagen-induced arthritis abatacept suppresses inflammation, reduces the formation of anti-collagen antibodies and antigen-specific production of interferon-gamma.

Pharmacokinetics:

With repeated intravenous administration, the values of Cmax and AUC (the area under the concentration-time curve) are proportionally increased in the dose range from 2 mg / kg to 10 mg / kg. When a dose of 10 mg / kg is administered, the serum concentration reaches the equilibrium state by the 60th day, with the mean value (interval) of the minimum concentration being 24 (1 to 66) μg / ml. With prolonged repeated administration of the drug at a dose of 10 mg / kg at intervals of 1 month, systemic accumulation of the drug in the body is not observed.

It was revealed that a higher clearance of abatacept is observed in patients with a high body weight. Age and sex of patients (with correction for body weight) do not affect the clearance of the drug.

Studies to assess the metabolism and elimination of abatacept in humans have not been conducted. In connection with the spatial structure and hydrophilicity abatacept It is not metabolized in the liver by enzymes of the cytochrome P450 system. Given the large molecular weight of abatacept, it is assumed that the drug is not excreted in the urine.

Indications:

Abatacept can be used in the form of monotherapy or in combination with basic anti-inflammatory drugs (for example, methotrexate):

- to reduce symptoms, increase the clinical response, suppress the progression of structural damage, and improve functional activity in adult patients with mild or severe active rheumatoid arthritis with insufficient response to one or more basic anti-inflammatory (such as methotrexate) or biological antirheumatic drugs;

- to reduce the manifestations and symptoms in children 6 years of age and older with a mild or severe course of active juvenile idiopathic arthritis with multiple joint damage.

ICD-10

XIII.M05-M14.M05 Seropositive rheumatoid arthritis

XIII.M05-M14.M08 Juvenile [juvenile] arthritis

Contraindications:

- severe infections (including sepsis, abscesses, tuberculosis, opportunistic infections);

- active infections (including tuberculosis) until control is established;

- hypersensitivity to abatacept;

- simultaneous use with other biological agents for the treatment of rheumatoid arthritis (such as TNF blockers, rituximab, anakinra);

- pregnancy and lactation;

- age up to 6 years.

Carefully:

In patients with recurrent infections; conditions predisposing to infections (diabetes mellitus), hepatitis; in elderly patients (since the incidence of side effects in people older than 65 years is higher than in younger patients). The introduction of abatacept should be discontinued in the event of an infectious disease.

Pregnancy and lactation:

FDA Action Category - C.

It should not be used during pregnancy and lactation (breastfeeding).

Dosing and Administration:

Administer IV in the form of an infusion or subcutaneously. Depending on the body weight, a single dose is 0.5-1 g.The frequency of administration is determined by a special scheme.

Adults

After the first administration, the following doses are recommended after 2 and 4 weeks, and then every 4 weeks. Besides, adults can get 125 mg in the form of subcutaneous injections the day after initial dose depending on the mass, and then 125 mg in the form of subcutaneous injections once a week.

Body mass	Dose	Number of vials
<60 kg	500 mg	2
60-100 kg	750 mg	3
> 100 kg	1 g	4

Children aged 6 to 17 years

- Children weighing less than 75 kg. The administered dose of abatacept - 10 mg / kg body weight - should be calculated individually, immediately before each administration of the drug.

- Children weighing 75 kg or more. The drug is administered in the dosing regimen for adults. The maximum dose is 1000 mg.

The prepared infusion solution is injected for 30 minutes through an infusion system with a sterile, apyrogenic filter with a low ability to bind proteins (pore size from 0.2 to 1.2 μm).

Abatacept can not be administered concomitantly with other drugs through a single infusion system.

Side effects:

Most often: headache, upper respiratory tract infection, nasopharyngitis, nausea.

Infectious complications: lower respiratory tract infections, urinary tract infections, herpes simplex virus infections, upper respiratory tract infections (including tracheitis, nasopharyngitis), dental infections, infected skin ulcers, and onychomycosis.

From the side of the central nervous system: headache, depression, anxiety, dizziness, paresthesia.

On the part of the hematopoiesis system: thrombocytopenia, and leukopenia.

From the sense organs: conjunctivitis, decreased visual acuity, vertigo.

From the cardiovascular system: tachycardia, bradycardia, palpitation, arterial hypertension, hot flushes, hypotension, fever.

From the respiratory system: cough; in patients with COPD - exacerbation of COPD, dyspnea, bronchitis.

From the digestive system: abdominal pain, diarrhea, nausea, dyspepsia, gastritis, ulcerative lesions of the oral cavity, aphthous stomatitis, deviations in liver function tests (including increased activity of transaminases).

Dermatological reactions: rash (including dermatitis), a tendency to bruising, alopecia, dry skin, psoriasis.

From the musculoskeletal system: arthralgia, pain in the extremities.

On the part of the reproductive system: amenorrhea.

Allergic reactions: Arterial hypotension, urticaria, dyspnea, anaphylactic reactions.

Benign and malignant tumors: rarely - basal cell carcinoma of the skin, lung cancer, lymphoma, myelodysplastic syndrome.

Other: weakness, asthenia, flu-like reactions, weight gain.

In clinical placebo-controlled trials, 0.05% of patients experienced the following serious infections, whose association with the drug was at least possible: bronchitis, pneumonia, acute pyelonephritis, diverticulitis, intestinal abscess, local infections, skin abscess, muscle infections and bones, sepsis, bacteremia, empyema, hepatitis E, tuberculosis.

Overdose:

Doses up to 50 mg / kg did not cause obvious toxic effects. In case of an overdose, it is recommended that the doctor be observed and, if necessary, symptomatic treatment. Symptoms of overdose are not described.

Interaction:

With the simultaneous use of abatacept and TNF blockers (tumor necrosis factor), the risk of severe infectious diseases increases (the combination is contraindicated).

Population analysis of pharmacokinetic parameters showed that methotrexate, NSAIDs, corticosteroids, TNF antagonists do not affect the abatacept clearance.

It is not recommended simultaneous use of abatacept with azathioprine, anakin, etanercept and rituximab because of the increased incidence of serious adverse events and the lack of clinical benefits.

Abatacept has not been studied in combination with drugs that cause a decrease in the number of lymphocytes. With such a combination, potentiation of the action of abatacept on the immune system is possible.

Special instructions:

It is not recommended for patients with impaired liver and / or kidney function (efficacy and safety not established).

It is not recommended for use in children and adolescents under the age of 18 years (efficacy and safety not established).

Before starting treatment, patients should be examined to exclude the presence of latent tuberculosis, viral hepatitis.

Caution should be exercised when it is necessary to use abatacept in patients prone to recurrent infections, with chronic, latent or local infections.

With the development of an infectious disease on the background of treatment, abatacept should be canceled.

Abatacept is a protein compound, therefore it is capable of causing allergic reactions, which were observed in rare cases and occurred within 24 hours after administration.

During the period of treatment with abatacept, vaccination is not recommended. possibly a violation of the immune response. It should not be immunized with live vaccines during treatment with abatacept and within 3 months after its abolition.

When using abatacept in patients with COPD, strict clinical control is necessary to detect side effects.

When switching to abatacept therapy after treatment with TNF blockers, the patient should be monitored for infection.

It is possible to obtain false-positive results in determining the blood glucose level on the day of drug administration using glucose-dehydrogenase-pyrroloquinolinequinone tests due to the reaction with the maltose contained in the preparation. If glucose testing is required, methods that exclude reaction with maltose should be used.

Instructions

Abatacept (Abataceptum)