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: & nbsp

    solution for subcutaneous administration 125 mg / ml

    Composition:

    Each syringe contains active substance - Abatacept 125.875 mg (including an excess of 0.875 mg).

    Excipients: sucrose 171.19 mg, nolokeramer 188 8.056 mg, sodium dihydrogen phosphate monohydrate 0,288 mg, sodium hydrophosphate anhydrous 0.844 mg, water for injection q.s. up to 1.007 ml.

    - Packaging is performed taking into account the re-laying in 0,7% (0,007 ml), which is necessary to ensure full recovery of the declared dosage. In this case, the recoverable amount of abatacept in one syringe is 125 mg.

    Description:

    The clear or slightly opalescent solution from colorless to pale yellow.

    Pharmacotherapeutic group:Immunosuppressive remedy
    ATX: & nbsp

    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), associated with a modified Fc fragment of immunoglobulin (IgGl) 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 are required: the first for the recognition of a specific antigen by T-cell receptors (signal 1); The 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 and animal models show 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 the proliferation and production of cytokines in human lymphocytes (TNF-alpha, interferon-y 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-y.

    Pharmacokinetics:

    The pharmacokinetics of abatacept after subcutaneous administration is subject to linear dependence. Mean minimum and maximum equilibrium concentrations were established 85 days after initiation of treatment and were 32.5 μg / ml (6.6-113.8 μg / ml) and 48.1 μg / ml (9.8-132.4 μg / ml), respectively. Bioavailability of abatacept with subcutaneous injection is 78.6% of its bioavailability when administered intravenously. The mean systemic clearance (0.28 ml / h / kg), the volume of distribution (0.11 d / kg), the terminal half-life (14.3 days) are comparable for subcutaneous and intravenous administration.

    It was found that a higher clearance of abatacept is observed in patients with high body weight. Age and sex of patients (when corrected for body weight) did not affect the clearance of abatacept. Simultaneous administration of methotrexate, anti-inflammatory drugs, glucocorticosteroids and tumor necrosis factor blockers did not affect the abatacept clearance

    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 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.

    Indications:

    Abatacept is indicated for reducing symptoms, enhancing clinical response, suppressing the progression of structural lesions, and improving the functional activity of adult patients with mild or severe active rheumatoid arthritis. Abatacept can be used in the form of monotherapy or in combination with basic anti-inflammatory drugs.

    Contraindications:

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

    Joint application with blockers of tumor necrosis factor.

    Pregnancy and lactation.

    Age under 18 years (effectiveness and safety not studied).

    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 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:The drug is administered once a week subcutaneously in a dose of 125 mg (1 filled syringe) regardless of body weight, after the administration of the loading dose of Orencia®, lyophilizate for the preparation of a solution for infusion or without a pre-loading dose. Administration to patients who have not previously used Orencia®: - No loading dose.The drug is administered once a week subcutaneously in a dose of 125 mg (1 filled syringe) regardless of body weight; - With loading dose. If it is necessary to administer a loading dose of the drug, the patient is given an intravenous Orencia® preparation in accordance with the instructions for the use of Orencia®, a lyophilizate for the preparation of a solution for infusions, and then the first subcutaneous injection of the drug is administered during the day. 2. Transfer of the patient from the intravenous form of Orencia® to the subcutaneous form: - When transferring the patient from intravenous pa subcutaneous administration of Orencia®, the first subcutaneous injection is performed instead of the next planned infusion of Orencia®. The drug for subcutaneous administration is not intended for intravenous injection or infusion. The preparation is administered by medical personnel. If the patient is able to do the injections on his own, the medical staff must ensure that the patient is properly trained in this procedure and clearly follows the instructions for subcutaneous injection of the drug. The drug before the examination is examined. The solution should be clear or slightly opalescent,from colorless to light yellow color; in the presence of particles or a change in the color of the solution, a syringe with a solution ns is to be used. It is necessary to enter the entire volume of the drug in the syringe, changing the injection site at each injection. Do not administer the drug into areas with a tender or chapped skin, if there is damage or redness of the skin. For detailed instructions on how to administer the injection, see the "Pre-filled syringe / pre-filled syringe with retractable needle" manual. Dose skipping If the patient misses the date of the Orenci® subcutaneous injection for a period of up to 3 days, he should be injected immediately and then follow the initial weekly schedule of the drug administration. If a dose is missed more than 3 days from the expected date of administration, the patient should consult a doctor for instructions on the further schedule of the administration, which should be specified depending on the patient's condition and the stage of the disease. Do not need a dose change in elderly patients.
    Side effects:

    The following are undesirable drug reactions (NLR),Identified with the use of abatacept in clinical and postmarketing studies of the drug, where the drug or placebo was used in conjunction with other types of RA therapy. The most frequent adverse effects in the use of the drug were headache, nausea and upper respiratory tract infections.

    NLR are represented by organs and systems and frequency: very frequent (> 1/10); frequent (> 1/100 and <1/10); infrequent (> I / 1000 and <1/100); rare (> 1/10 000 and <1/1000) and very rare (<1/10 000).

    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: dental infections, onychomycosis, sepsis, musculoskeletal infections, cutaneous abscesses, pyelonephritis, pelvic inflammatory disease.

    Rare: Tuberculosis, gastrointestinal infections and bacteremia.

    2.

    Benign and malignant tumors (including cysts and polyps)

    Infrequent: basal cell skin cancer, keratinized skin cancer, skin papilloma

    Rare: lymphoma, malignant neoplasms of the lungs,

    3. From the side

    bodies

    hematopoiesis

    Frequent: leukopenia Infrequent: thrombocytopenia

    4. Immune disorders

    Infrequent: Hypersensitivity reactions

    5. Mental disorders

    Infrequent: depression, anxiety, sleep disorders (including insomnia)

    6. Neurological disorders

    Frequent: headache, dizziness, paresthesia Infrequent: migraine

    7. From the sense organs

    Frequent: conjunctivitis

    Infrequent: dry eye, decreased visual acuity

    8. From the side

    cardiovascular

    systems

    Frequent: increase in blood pressure, "hot flashes" Infrequent: tachycardia, aetiology, palpitation, lowering blood pressure, feeling hot, vasculitis

    9. On the part of the respiratory system

    Frequent: cough, exacerbation of COPD Infrequent: bronchospasm, dyspnea, dyspnea Rare: a spasm in the throat

    10. From the side

    gastro-

    intestinal tract

    Frequent: abdominal pain, diarrhea, nausea, dyspepsia, ulceration of the oral mucosa, aphthous stomatitis

    Infrequent: gastritis

    11. From the skin and subcutaneous fat

    Frequent: rash (including dermatitis), alopecia, itching Infrequent: tendency to bruising, dry skin, psoriasis, erythema, hyperhidrosis

    12. From the musculoskeletal system and connective tissue

    Frequent: pain in the limbs Infrequent: arthralgia

    13. From the genitals and mammary glands

    Infrequent: amenorrhea, menorrhagia

    14. General and local symptoms

    Frequent: fatigue, asthenia, reactions at the site of administration Infrequent: flu-like syndrome, weight gain

    15. Laboratory indicators

    Frequent: deviations in laboratory parameters of liver function (including increased activity of transaminases)

    The most frequent serious infections (frequency 0.1-0.4%) when treated with Orencia® were: pneumonia, inflammation of subcutaneous tissue, local infections, urinary tract infections, bronchitis, diverticulitis and acute pyelonephritis. In rare cases, the following types of malignant tumors were observed in patients treated with Orencia®: non-melanoma skin tumors, solid tumors (lung cancer), hematologic neoplasms (lymphoma). When using Orencia® in patients with rheumatoid arthritis, there was no increase in the incidence of malignant neoplasms.

    In some patients (an average of 2.6%) at the injection site, adverse events in the form of pruritus, hematoma, erythema, mild or moderate severity were observed, not requiring withdrawal of the drug.

    With the use of the drug in patients with chronic obstructive pulmonary disease (COPD), adverse events were observed more often than in the placebo group, incl. serious - exacerbation of COPD and bronchitis. Respiratory disorders (including dyspnea and exacerbation of COPD) were observed in 5.9% of patients.

    In 9.3% of patients, antibodies to abatacept were observed, which were preserved after the drug was discontinued. However, there was no evidence of a pronounced clinical effect and the development of side effects from the presence of antibodies to abatacept in the blood plasma. Data on the formation of antibodies to the drug did not differ between the group of patients receiving abatacept directly in the form of a subcutaneous injection, and a group of patients transferred from an intravenous to a subcutaneous form.

    In a two-year blind for the researcher's first direct comparison, no less effective biological disease-modifying antirheumatic drugs abatacept subcutaneously (without loading intravenous dose) and adalimumab subcutaneously, clinical, functional and radiographic data demonstrate similar efficacy in patients with mild or severe active rheumatoid arthritis receiving methotrexate therapy and who did not respond to neonatal infection. Overall, both groups showed the same incidence of adverse events, but abatacept was numerically less likely to terminate early therapy due to adverse events, serious adverse events and serious infections, and fewer reactions at the injection site.

    Post-marketing research data

    In postmarketing studies, it was found that systemic reactions to infusion administration of the drug were similar to those found in clinical trials of Orencia®, with the exception of one case of anaphylaxis with a fatal outcome. Undesirable drug reactions with subcutaneous administration of Orencia® included itching, a feeling of tightness 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. Because of the lack of sufficient data, it is not recommended to use abatacept together with other biological agents for the treatment of rheumatoid arthritis (for example, anakinro).

    The drug can be used in conjunction with basic anti-inflammatory drugs: methotrexate, glucocorticosteroids, salicylates, NSAIDs. and also less often 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-a 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.

    Special instructions:Hypersensitivity reactions can be observed in the treatment of any injectable protein preparation. Such reactions were observed with Orencia® during clinical trials.

    After the first administration of the drug, there is a possibility of anaphylaxis or anaphylactoid reactions, including life-threatening reactions. In postmarketing studies, an anaphylaxis with a fatal outcome was noted after the first infusion of Orencia®. In clinical studies, cases of anaphylaxis were rare, hypersensitivity reactions were infrequent. In case of anaphylactic or other serious allergic reaction, the drug (both intravenous and subcutaneous form) should be discontinued without the subsequent resumption and immediately begin appropriate therapy of the side reaction.

    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. When prescribing the drug, it is necessary to diagnose for tuberculosis. 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.

    Influence on the development of malignant neoplasm

    The potential role of Orencia® in the development of malignant neoplasms has been established.When using Orencia® in patients with rheumatoid arthritis, there was no increase in the incidence of malignant neoplasms.

    Influence on the immune system

    Drugs that affect the immune response, including Orencia®, can affect 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. There is no evidence of secondary infection of patients on drug therapy abatacept, from patients receiving live vaccines. It is possible to use inactivated vaccines during drug treatment.

    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 the treatment with Orencia®, vaccination with a trivalent vaccine from seasonalinfluenza virus - the immune response in The majority of patients expressed in at least 4-fold increase in antibody titer.

    Due to the fact that the risk of developing serious infections and malignant neoplasms in patients older than 65 years is generally higher than in those of younger age, caution should be exercised in appointing abatacept to elderly patients.

    Patients before starting treatment with Orencia® should read the "manual on the use of a pre-filled syringe / pre-filled syringe with an automatically retractable needle" attached to the drug.

    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:

    Solution for subcutaneous administration 125 mg / ml.

    Packaging:To 1,007 ml of solution in a syringe or syringe with an automatically retractable needle of colorless glass type I.1 syringe, or 1 or 4 syringes with an automatically retractable needle in a plastic pallet along with the instruction for use and guidance on the use of a syringe or syringe with an automatically retractable needle is placed in a cardboard pack.
    Storage conditions:

    At a temperature of 2 to 8 ° C in a dark place. Do not freeze!

    KEEP OUT OF THE REACH OF CHILDREN.

    Shelf life:

    2.5 years.

    Do not apply the drug but the expiration date indicated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002236
    Date of registration:19.09.2013 / 16.01.2017
    Expiration Date:19.09.2018
    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: & nbsp29.01.2015
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