Orencia® (Orencia®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAbataceptAbatacept
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  • Orencia®
    solution PC 
    Bristol-Myers Squibb Company     USA
  • Orencia®
    lyophilizate d / infusion 
    Bristol-Myers Squibb Company     USA
    • Dosage form: & nbsplyophilizate for solution for infusion
    Composition:

    Each bottle contains *:

    Active substance - Abatacept 262.5 mg (taking into account an excess of 12.5 mg).

    Excipients: maltose monohydrate - 525.0 mg, sodium dihydrogen phosphate monohydrate - 18.1 mg, sodium chloride - 15.3 mg, hydrochloric acid - q.s. to pH 7.5, sodium hydroxide - q.s. to pH 7.5.

    * Packing is done taking into account a 5% rebate, which is necessary to ensure full recovery of the claimed dosage. In this case, the recoverable amount of abatacept in one vial is 250 mg.

    Description:

    Porous mass or powder from white to almost white.

    Pharmacotherapeutic group:Immunosuppressive remedy
    ATX: & nbsp

    L.04.A.A   Selective immunosuppressants

    Pharmacodynamics:

    Abatacept is a soluble protein consisting of the extracellular domain of antigen-4-cytotoxic T-lymphocytes (CTLA-4), associated with a modified Fc-an immunoglobulin fragment G1 (IgG1) rights. Abatacept is a recombinant protein with a molecular weight of about 92 kD, which is produced by genetic engineering on the isolated cell culture of mammals. Abatacept selectively modulates the key co-stimulatory signal necessary for the complete activation of T lymphocytes expressing the differentiation cluster 28 (Cd 28). In patients with rheumatoid arthritis (RA), 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. To fully activate T-lymphocytes, 2 signals from antigen-presenting cells: the first - for recognition of a specific antigen by T-cell receptors (signal 1); second (nonspecific) co-stimulating signal involves the binding of molecules Cd80 and Cd86 on the surface of antigen-presenting cells with a receptor Cd28 on the surface of T-lymphocytes (signal 2). Abatacept specifically binds to Cd80 and Cd86, selectively inhibiting this pathway. Determined that abatacept to a greater extent affects the response of non-activated (naive) T-lymphocytes than T-lymphocytes of memory.

    In studies in vitro on animal models it is shown that abatacept reduces T-lymphocyte-dependent antibody production and inflammation. In vitro abatacept reduces the activation of T-lymphocytes, as evidenced by a decrease in proliferation and production of cytokines in human lymphocytes (F110-alpha,inferferona-γ and interleukin-2). In rats with collagen-induced arthritis abatacept suppresses inflammation, reduces the formation of anti-collagen antibodies and antigen-specific production of inferferone-γ.

    Pharmacokinetics:

    With repeated intravenous administration (days I, 15, 30, then every 4 weeks) there was a proportional increase in the values ​​of CmOh and AUC (area under the concentration-time curve) in the dose range from 2 mg / kg to 10 mg / kg. When a dose of 10 mg / kg is administered, the elimination half-life (T1/2) was 13.1 days, varying from 8 to 25 days, the volume of distribution (Vss) was 0.071 / kg and varied in the range of values ​​from 0.02 / kg to 0.13 / kg. The system clearance value was about 0.22 ml / h / kg, the equilibrium concentration was about 25 μg / ml, and the maximum concentration (CmOh) is about 290 μg / ml. Systemic accumulation of abatacept in the body was not observed in patients with RA with prolonged repeated administration of the drug (at intervals of 1 month) at a dose of 10 mg / kg.

    Population pharmacokinetic analysis revealed a higher clearance of abatacept in patients with increased body weight. Age and sex of patients did not affect the clearance of abatacept. The simultaneous use of methotrexate, non-steroidal anti-inflammatory drugs, glucocorticosteroids and tumor necrosis factor-blockers did not affect abatacept clearance.

    Clinical studies to assess the metabolism and elimination of abatacept were not 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 abatacept not excreted in the urine.

    Pharmacokinetics in specific patient categories

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

    Pharmacokinetics in children

    Population pharmacokinetic analysis of serum abatacept concentration in patients aged 6 to 17 years with juvenile idiopathic arthritis after administration of 10 mg / kg abatacept showed that the clearance of abatacept (in terms of body weight) in children was higher than in adult patients: 0.44 ml / h / kg and 0.3 ml / h / kg, respectively. Age and sex of patients did not affect the clearance of abatacept. The volume of distribution and the half-life of the drug in patients with juvenile idiopathic arthritis was 0.12 l / kg and 11.2 days, respectively. AT As a result of a higher clearance of the drug, the mean serum concentrations of abatacept in the serum (peak and baseline) were lower in children than in adults.

    The simultaneous use of methotrexate, glucocorticosteroids and non-steroidal anti-inflammatory drugs influenced the clearance of abatacept.
    Indications:

    Abatacept is indicated for reducing symptoms, increasing the clinical response, suppressing the progression of structural lesions, and improving the functional activity of adult patients with mild or severe active rheumatoid arthritis with an inadequate response to one or more basic anti-inflammatory (such as methotrexate) or biological antirheumatic drugs.

    Abatacept is indicated for the reduction of symptoms 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.

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

    Contraindications:

    - Hypersensitivity to abatacept and / or any of the auxiliary components of the drug.

    - Joint application with blockers of tumor necrosis factor.

    - Pregnancy (no studies have been performed).

    - Lactation period.

    - Age before 6 years.

    - Severe uncontrolled infections (sepsis, opportunistic infections), active infections (including tuberculosis) until control is established.

    - Joint application with azathioprine, gold preparations and anakinro.

    Carefully:

    Abatacept should be used with caution in patients with recurrent infections; conditions predisposing to infections (diabetes mellitus), hepatitis; in elderly patients. The introduction of abatacept should be discontinued if a new serious infectious disease develops.

    Pregnancy and lactation:

    Due to the lack of clinical studies involving pregnant women, the drug should not be used during pregnancy.

    It is not known whether the drug penetrates into breast milk, so do not breast-feed with the drug.

    Dosing and Administration:

    Abatacept is administered intravenously for 30 minutes at the doses indicated in the table.

    Adults

    After the first administration, the following doses are recommended after 2 and 4 weeks, and then every 4 weeks.

    Patient weight

    Dose

    amount

    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 with a body weight of 75 kg and more

    The drug is administered in the dosing regimen for adults. The maximum dose is 1000 mg.

    Instructions for preparation and administration of the drug

    Abatacept solution should not be used with equipment containing silicone.

    After removing the protective plastic cover, the plug is wiped with sterile cotton wool soaked in alcohol. The contents of one vial are dissolved in 10 ml of water for injection, using a disposable silicone-free syringe (needle size 18-21) and without opening the vial. To reduce foaming, water is added slowly, holding the piston of the syringe with your fingers. The spray of the solvent is directed strictly to the wall of the vial (and not to the lyophilizate). Gently stir in a circular motion. DO NOT BURST.After dissolving the powder from the vial, air must be vented through the needle to remove any bubbles that may have formed. The resulting concentrate should be colorless or pale yellow. Do not use a turbid solution, a solution of a different color or containing foreign particles.

    The resulting concentrate is immediately diluted to 100 ml with a 0.9% solution of sodium chloride for injection to obtain an infusion solution as follows:

    From 100 ml of a bottle of sodium chloride, 10 ml of the solution are taken for each added vial of abatacept. Then, the previously obtained concentrate is slowly added to the remaining solution by means of a disposable non-silicone syringe included in the preparation 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.

    The ready solution is used for administration to the patient, it can also be stored for no more than 24 hours in the refrigerator (2 ° C to 8 ° C) or at room temperature (up to 25 ° C). Immediately before the introduction of the drug, it should be examined to ensure that the color of the solution has not changed, and there are no foreign particles in it.If foreign particles or discoloration are observed in the solution, the solution must be destroyed.

    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 It is not possible to administer simultaneously with other drugs through a single infusion system.

    Side effects:

    The following are undesirable drug reactions (NLR) when using abatacept in clinical trials where the drug or placebo was used with other types of RA therapy. NLR are represented by organs and systems and frequency: very frequent ≥ (0%); frequent (≥1% and <10%); infrequent (≥0.1% and <1%); rare (≥0.01% and <0.1%).

    1. Infections and invasions

    Very Frequent

    Upper respiratory tract infections (including tracheitis and nasopharyngitis)

    Frequent

    Lower respiratory tract infections (including bronchitis), urinary tract infections, herpetic infections (including herpes simplex, oral cavity herpes and shingles), rhinitis, pneumonia, influenza.

    Infrequent

    Infections of the teeth, infected skin ulcers, onychomycosis, sepsis, infectious lesions of the musculoskeletal system, pyelonephritis

    Rare

    Tuberculosis, gastrointestinal infections, bacteremia

    2.Benign and malignant tumors (including cysts and polyps)

    Infrequent

    Thyroid cancer of the skin, papilloma

    Rare

    Basal cell carcinoma of the skin, lung cancer, lymphoma, myelodysplastic syndrome

    3. On the part of the organs of hematopoiesis

    Frequent

    Leukopenia

    Infrequent

    Thrombocytopenia

    4. Mental disorders

    Infrequent

    Depression, anxiety, sleep disorders (including insomnia)

    5. Neurological disorders

    Frequent

    Headache, dizziness, paresthesia

    Infrequent

    Migraine

    6. From the sense organs

    Frequent

    Conjunctivitis

    Infrequent

    Reduction of visual acuity, dry eyes

    7. From the side of the cardiovascular system

    Frequent

    Increased blood pressure, "hot flashes"

    Infrequent

    Tachycardia, aetiology, palpitations, lowering blood pressure, feeling hot, vasculitis

    8. On the part of the respiratory system

    Frequent

    Cough, exacerbation of COPD, dyspnea

    Infrequent

    Bronchospasm, bronchitis

    9. From the gastrointestinal tract

    Frequent

    Abdominal pain, diarrhea, nausea, dyspepsia, ulceration of the oral mucosa, aphthous stomatitis

    Infrequent

    Gastritis

    10. From the skin and subcutaneous tissue

    Frequent

    Rash) including dermatitis), alopecia

    Infrequent

    The formation of bruising, dry skin, hyperhidrosis, erythema

    11. From the side of the musculoskeletal system and connective tissue

    Frequent

    Pain in the extremities

    Infrequent

    Arthralgia

    12. From the genitals and mammary glands

    Infrequent

    Amenorrhea, menorrhagia

    13. General and local

    Frequent

    Fatigue, asthenia

    Infrequent

    The flu-like syndrome

    Rare

    Hypersensitivity reactions (including urticaria, choking, anaphylactic shock)

    14. Laboratory indicators

    Frequent

    Deviations of laboratory parameters of liver function (including increased activity of transaminases)

    Infrequent

    Weight gain

    The following serious adverse reactions were observed in 1.8% of adult patients, the relationship of which with the drug is at least possible: pneumonia,

    inflammation of the subcutaneous tissue, local infections, urinary tract infections, bronchitis, diverticulitis and acute pyelonephritis.

    The profile of adverse reactions in adult patients and in children is the same. In rare cases, the following types of malignant neoplasms were observed in patients treated with Orencia®: non-melanoma neoplasm of the skin, solid tumors (lung cancer), hematologic neoplasms (lymphoma). The incidence of malignant tumors in patients with rheumatoid arthritis was not increased with Orencia®.

    Acute reactions at the site of administration were observed in 9.8% of patients with Orencia® (within 1 hour after the start of infusion) such as headache (1.8%), dizziness (2.1%) and increase in blood pressure (1.2%). Other acute reactions to drug administration were observed in 0.1-1.0 % of patients: fall arterial pressure, dyspnea, nausea, "hot flashes", hives, cough, hypersensitivity reactions, pruritus, rash. Anaphylactic reactions with the administration of Orencia® have been rare, hypersensitivity reactions are infrequent. Other reactions potentially associated with hypersensitivity, such as lowering blood pressure, urticaria, and respiratory failure that occurred within 24 hours after the onset of infusion, were also infrequent.

    4.8% of patients who received Orencia ® before 8 years of age observed the formation of antibodies to abatacept, which persisted even after discontinuation of the drug (> 42 days after the last administration).However, there was no evidence of a pronounced clinical effect and side effects from the presence of antibodies to abatacept in the blood plasma. Post-marketing research data During postmarketing studies it was found that the systemic reactions to the infusion introduction of the drug were similar to the reactions revealed in the clinical trials of Orensia®, with the exception of one case of lethal anaphylaxis. Undesirable drug reactions with subcutaneous administration of Orencia® included itching, a feeling of restraint in the throat, dyspnea.

    Overdose:

    Doses up to 50 mg / kg with intravenous administration 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:

    When using abatacept together with blockers of tumor necrosis factor increases the risk of serious infections, therefore, the use of this combination is not recommended.

    When transferring a patient from treatment with a blocker of tumor necrosis factor to abatacept therapy, the patient's condition should be monitored in connection with the possible development of infection.

    The drug can be used in conjunction with basic anti-inflammatory drugs: methotrexate, glucocorticosteroids, salicylates, NSAIDs, and less commonly used anti-inflammatory drugs - chloroquine / hydroxychloroquine, sulfasalazine and leflunomide. There was no change in the clearance of abatacept when combined with methotrexate, NSAIDs, glucocorticosteroids and TNF-α inhibitors.

    Information about the safety and efficacy of the combination of abatacept with azathioprine, gold preparations and anakinro is not enough, therefore, joint application with these drugs is not recommended.

    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.

    On the day of drug administration, it is possible to obtain false-positive results in the determination of glucose in the blood with the help of tests due to the reaction with maltose contained in the preparation. To determine the concentration of glucose, methods that exclude reaction with maltose should be used.

    Special instructions:

    Hypersensitivity reactions

    Hypersensitivity reactions can be observed in the treatment of any injectable protein preparation. Such reactions were observed with Orensia® in clinical trials. After the first administration of the drug, there is a possibility of anaphylaxis or anaphylactoid reactions, including life-threatening reactions. During post-marketing studies, an anaphylaxis with a fatal outcome was noted after the first infusion of Orensia®. In case of anaphylactic or other serious allergic reaction should stop using the drug Orensia® (both in the form of a lyophilizate for the preparation of a solution for infusion, and in the form of a solution for subcutaneous administration) without further resumption and immediately begin appropriate therapy of adverse reactions.

    Infections

    When using the drug, there were cases of serious infections, including sepsis and pneumonia, including fatal outcome, more often in patients using concomitant therapy with immunosuppressors. If a new infectious disease is detected in the course of treatment, careful monitoring of the patient should be made, and in the case of a new serious infection, discontinue the drug.The safety of the drug in patients with latent tuberculosis has not been studied. Prior to the appointment of abatacept, patients with latent tuberculosis should undergo standard antituberculosis therapy.

    When prescribing anti-rheumatic drugs, reactivation of the hepatitis B virus can be observed, therefore, before the start of treatment with abatacept, carriage of this pathogen should be ruled out. The use of the drug in patients with viral hepatitis has not been studied.

    The effect of neither the development of malignant neoplasm

    The potential role of Orencia® in the development of malignant neoplasms has not been established. The incidence of malignant neoplasms during clinical studies of the infusion form of the drug was similar for patients who received Orencia® and patients who received placebo.

    Influence on the immune system

    Drugs affecting the immune response, including Orencia®. can influence the effectiveness of vaccination, the ability of the body to resist infections and the development of malignant tumors.

    Due to the fact that drugs that affect the immune system, including abatacept, may reduce the effectiveness of vaccination, do not use live vaccines during treatment with abatacept and within 3 months after its withdrawal. It is possible to use inactivated vaccines during drug treatment. When appointing children, it is recommended to complete the mandatory vaccination plan before the drug is started.

    There was no significant effect of the drug on the effectiveness of vaccine prophylaxis with the 23-valent pneumococcal vaccine, most patients had an adequate immune response (a rise in antibody titer) after this vaccination. Also during treatment with Orencia® it is possible to vaccinate trivalent vaccine against seasonal influenza virus - the immune response in most patients was expressed in at least 4-fold increase in tiger antibodies.

    Determination of the concentration of glucose in the blood

    On the day of drug administration, it is possible to obtain false-positive results in the determination of glucose in the blood with the help of tests due to the reaction with maltose contained in the preparation. To determine the concentration of glucose, use methods that exclude reaction with maltose.

    Effect on the ability to drive transp. cf. and fur:

    Avoid driving and other potentially hazardous activities that require increased attention and speed of psychomotor reactions if the drug causes dizziness, visual impairment, and other side effects that may affect these abilities.

    Form release / dosage:

    Lyophilizate for the preparation of a solution for infusions 250 mg.

    Packaging:

    By 262.5 mg of active substance into a glass bottle type I, sealed with a fluororesin stopper and an aluminum cap with a protective plastic cover. 1 bottle of the drug complete with 1 silicone sterile syringe, together with the instruction for use, is placed in a cardboard box.

    Storage conditions:

    At a temperature of 2 to 8 ° C in a dark place.

    Shelf life:

    3 years.

    Do not use the product after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-005404/09
    Date of registration:06.07.2009
    The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company USA
    Manufacturer: & nbsp
    Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia
    Information update date: & nbsp03.02.3015
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