Timoglobulin® (Thymoglobuline®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceImmunoglobulin antithymocyteImmunoglobulin antithymocyte
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  • Timoglobulin®
    lyophilizate d / infusion 
    Genzyme Europe BV     Netherlands
    • Dosage form: & nbsplyophilizate for solution for infusion
    Composition:

    1 bottle contains:

    active substance: immunoglobulin antimitocyte (rabbit) 25 mg;

    Excipients: glycine 50 mg, sodium chloride 10 mg, mannitol 50 mg.

    Description:

    Cream white powder.

    Pharmacotherapeutic group:immunosuppressive agent - immunoglobulin
    ATX: & nbsp

    L.04.A.A.04   Immunoglobulin antitimotsitarny (rabbit)

    Pharmacodynamics:

    Rabbit antitumocyte immunoglobulin is a selective immunosuppressive drug that affects T-lymphocytes.

    Mechanism of action

    Reducing the number of lymphocytes is probably the main mechanism immunosuppression caused by rabbit anti-thymocyte immunoglobulin, which recognizes most of the molecules involved in the T cell activation cascade in the transplant rejection reaction, such as: Cd2, Cd3, Cd4, Cd8, Cd1la, Cd18, Cd25, HLA-DR and HLA I class.

    T-lymphocytes are eliminated from the bloodstream by complement-dependent lysis and, more likely, due to opsonization of T lymphocytes, with their subsequent elimination by a monocyte-phagocytic system.

    Rabbit antitimotsitarny immunoglobulin, in addition to reducing the number of T-lymphocytes, causes the activation of other functions of lymphocytes associated with their immunosuppressive activity.

    In vitro, at a concentration of about 0.1 mg / ml, Timoglobulin® activates T-lymphocytes and stimulates their proliferation (in the same way for subpopulations Cd4+ and Cd8+) with the synthesis of interleukin-2 and interferon-γ, and expression Cd25. This mitogenic activity is realized mainly by means of CD2-mediated pathway. In higher rabbit concentrations, the antitumocyte immunoglobulin inhibits the proliferative lymphocyte response to other mitogens, causing a post-transcriptional blockade of interferon-γ synthesis and Cd25, but without reducing the secretion of interleukin-2.

    In vitro Timoglobulin® does not activate B-lymphocytes.

    The low risk of developing B-cell lymphoma in patients treated with Tymoglobulin® can be explained by the following reasons:

    - absence of activation of B-lymphocytes and, as a result, the absence of their differentiation into plasma cells;

    - anti-proliferative activity against B-lymphocytes and some lymphoblastic cell lines.

    During the course of immunosuppression after transplantation in patients receiving treatment with Tymoglobulin®, deep lymphopenia develops as early as 1 day after the initiation of treatment (a decrease in the number of lymphocytes by more than 50% compared to the baseline value). Lymphopenia persists throughout the treatment period and after the termination of the course of therapy. On average, about 40% of patients at the end of the 3rd month there is a recovery of more than 50% of the lymphocytes from the baseline, but a decrease in the number Cd4 lymphocytes persists for a long time and is still observed after 6 months, resulting in an inversion of the ratio Cd4/Cd8.

    Monitoring of lymphocyte subpopulations (Cd2, Cd3, Cd4, Cd8, Cd14, Cd19 and Cd25) confirmed a wide range of specific binding of the preparation of Tymoglobulin® to T-lymphocytes. During the first 2 weeks of treatment, there is a marked decrease in the absolute number of all subpopulations of lymphocytes with the exception of B-lymphocytes and monocytes (more than 85% for: Cd2, Cd3, Cd4, Cd8, Cd25, Cd56 and Cd57).

    Pharmacokinetics:

    After the first infusion to the recipients of the kidney graft of the drug Timoglobulin® at a dose of 1.25 mg / kg, the concentration of rabbit IgG in the blood serum ranges from 10 to 40 mcg / ml, constantly decreasing by the time of the next infusion (the half-life period is 2-3 days). By the end of the 11-day course of treatment, the minimum concentration of rabbit IgG gradually increases and reaches 20-170 μg / ml. After discontinuation of treatment, a gradual decrease in the content of this immunoglobulin in the blood is observed. Nevertheless, in 80% of patients rabbit IgG can be detected in the blood serum even 2 months after the end of therapy.

    Approximately 40% of patients within the first 15 days after the start of treatment with Tymoglobulin ®, there is an intensive formation of antibodies to rabbit immunoglobulin, which leads to a faster reduction of its minimum concentrations in the blood serum.

    Indications:

    - Immunosuppression in organ transplantation: prevention and treatment of transplant rejection reactions;

    - prevention of acute and chronic "graft versus host" reaction after hematopoietic stem cell transplantation;

    - treatment of an acute "graft versus host" reaction, resistant to glucocorticosteroid therapy;

    - treatment of aplastic anemia.

    Contraindications:

    - Acute or chronic infections;

    - hypersensitivity to rabbit proteins or any other component of the drug;

    - the development of allergic reactions to the previous administration of the drug Timoglobulin®.

    Carefully:

    In patients who previously received rabbit immunoglobulins, since there is a risk of developing reactions by type of serum sickness.

    Pregnancy and lactation:

    Since animal studies are inadequate and it is impossible to conclude a potential risk for humans, the preparation of Timoglobulin® in pregnancy should be used only if the benefit to the mother exceeds the risk of using this medication for the fetus.

    It is not known whether a rabbit anti-thymocyte immunoglobulin with breast milk stands out. Since other immunoglobulins are excreted in breast milk, breastfeeding should be discontinued for the duration of the Timoglobulin® preparation.

    Dosing and Administration:

    The drug is intended for intravenous infusion.

    Preparation of the infusion solution

    The contents of the vial with gentle shaking are dissolved in 5 ml of water for injection (the concentration obtained IgG is 5 mg / ml). The reconstituted solution must be clear or slightly opalescent, not containing undissolved particles. In the case of the presence of undissolved particles, you should continue to shake the bottle gently until they disappear. However, the dissolution time should not exceed 2 minutes. If the particles are still stored, the contents of the vial can not be used. It is recommended to use reconstituted solution immediately after its preparation. Each vial is only for single use. Depending on the required daily dose, it may be necessary to reconstruct the lyophilizate in several vials of the Tymoglobulin® preparation.

    After reconstitution of the lyophilizate in each of the vials, the resulting solutions are combined and the collected, thus daily dose of the drug, diluted in one of the infusion solutions (sodium chloride isotonic solution for injection 0.9% or glucose 5% solution for injection) until the final infusion volume is from 50 to 500 ml (usually 50 ml / bottle).

    It is recommended that the diluted product be administered immediately.

    If the diluted product can not be used immediately, it is allowed to store it for no more than 24 hours at a temperature of 2 to 8 ° C, provided that when the reconstitution and dilution of the drug solution are carried out, the conditions of the controlled aseptic are met.

    Any residues and consumables must be disposed of in accordance with the regulations in force.

    The drug should be injected slowly into a large vein through a 0.2 μm system filter to ensure clearance from the traces of insoluble particles of the drug. The rate of administration should be adjusted so that the total duration of the infusion is at least 4 hours.

    Rabbit antitumocyte immunoglobulin is usually used in combination with several immunosuppressive drugs.

    Prior to the start of treatment, it is recommended to perform a preliminary intravenous injection of glucocorticosteroids and antihistamines.

    Dosing regimen

    Doses of the drug Timoglobulin ® depend on the indications for use, the scheme of administration and possible combination with other immunosuppressive drugs. Below are the standard recommendations for the dosing regimen.Treatment can be stopped without a gradual dose reduction.

    Immunosuppression in organ transplantation

    - Prevention of acute rejection of graft rejection: 1-1.5 mg / kg / day for 2-9 days after kidney, pancreas or liver transplantation and for 2-5 days after heart transplantation, which corresponds to a cumulative dose of 2-7.5 mg / kg after cardiac transplantation and 2-13.5 mg / kg after transplantation of other organs.

    - Treatment of an acute transplant rejection reaction: 1.5 mg / kg / day for 3-14 days, which corresponds to a cumulative dose of 4.5-21 mg / kg.

    Prevention of acute and chronic "graft versus host"

    After bone marrow transplantation or hematopoietic stem cells from related HLAnonidentical donors or from unrelated HLA-identical donors, in adults it is recommended to use Timoglobulin® at a dose of 2.5 mg / kg / day 1-4 days before transplantation, which corresponds to a cumulative dose of 7.5-10 mg / kg.

    Treatment of acute "graft-versus-host" reaction, resistant to glucocorticosteroid therapy

    The dose is selected individually and usually ranges from 2 to 5 mg / kg / day for 5 days.

    Treatment of aplastic anemia

    2.5-3.5 mg / kg / day for 5 days, which corresponds to a cumulative dose of 12.5-17.5 mg / kg.

    Correction of dose

    When developing thrombocytopenia and / or leukopenia (including lymphopenia and neutropenia), dose adjustment is required. In those cases where thrombocytopenia and / or leukopenia are not manifestations of the underlying disease or are not associated with the pathology for which Timoglobulin® has been used, it is recommended that:

    - dose reduction if the platelet count is between 50,000 and 75,000 cells / mm3 or, if the number of leukocytes is from 2000 to 3000 cells / mm3;

    - suspension of treatment with the drug Timoglobulin® in the case of development of persistent severe thrombocytopenia (<50000 cells / mm3) or leukopenia (<2000 cells / mm3).

    Side effects:

    The safety of the drug Timoglobulin® was studied in 240 patients who received the drug to prevent the reaction of acute graft rejection after a kidney transplantation operation.

    The adverse reactions listed below are generalized data for all adverse events noted in this study, regardless of their association with the Tymoglobulin® preparation.

    Frequency of occurrence was determined as follows: very often: (≥1 / 10), often: (from ≥1 / 100 to <1/10).

    Violations of the blood and lymphatic system

    Very often: lymphopenia, neutropenia, thrombocytopenia.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: dyspnoea.

    Disorders from the gastrointestinal tract

    Often: diarrhea, swallowing disorders, nausea, vomiting.

    Disturbances from the skin and subcutaneous tissues

    Often: itching, skin rash.

    Disturbances from musculoskeletal and connective tissue and systemic reactions

    Often: myalgia.

    Infectious and parasitic diseases

    Very often: infection.

    Benign, malignant and unspecified neoplasms (including cysts and polyps)

    Often: malignant tumors.

    Vascular disorders

    Often: hypotension.

    General disorders and disorders at the site of administration

    Very often: fever.

    Often: chills.

    Immune system disorders

    Often: serum sickness.

    Reactions to infusion (RI) and disorders of the immune system

    RIs may occur on the administration of the drug Timoglobulin® after the first or second infusion during one course of treatment.Clinical manifestations of RI can be expressed by the following signs and symptoms: fever, chills, dyspnea, nausea / vomiting, diarrhea, hypotension or hypertension, discomfort, skin rash and / or severe headache. The RI of the drug Timoglobulin® is usually easily expressed and passes quickly, and is amenable to correction by decreasing the rate of infusion and / or appropriate drug therapy. However, there are reports of the development of serious anaphylactic reactions and in very rare cases, in the absence of emergency therapy of such patients with epinephrine (adrenaline) about the development of anaphylactic reactions with a fatal outcome.

    RI has been reported as a cytokine release syndrome (SIC) associated with the release of cytokines by activated monocytes and lymphocytes. Severe and potentially life-threatening SICs were reported rarely. During the postmarketing period, rare cases of severe cardiovascular disease accompanied by cardiorespiratory dysfunction (including hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, tachycardia and / or death) were noted.

    Postmarketing surveillance of the drug recorded reports of reactions such as fever, skin rash, arthralgia and / or myalgia, indicating a possible development of serum sickness. Serum sickness can occur in the period from 5 to 15 days after the start of therapy with the drug Timoglobulin®. Symptoms usually go away or are quickly eliminated by the administration of glucocorticosteroids.

    Also reported were local adverse reactions, such as: pain at the injection site and peripheral thrombophlebitis.

    Undesirable reactions due to immunosuppression

    Infections, relapse of infection and sepsis were noted in cases of use of the drug Timoglobulin® in combination with several immunosuppressive drugs.

    In rare cases, development of malignant tumors has been noted, including but not limited to post-transplant lymphoproliferative disease (PTLB), as well as other lymphomas and solid tumors.

    Overdose:

    In case of an accidental overdose, leukopenia (including lymphopenia and neutropenia) and thrombocytopenia can develop. These manifestations are reversible and eliminated by dose adjustment or discontinuation of therapy.Antidote to antitimotsitarnomu immunoglobulin does not exist.

    Interaction:

    It is necessary to take into account undesirable reactions using the following combinations of the drug Timoglobulin® with the medicines listed below.

    - Cyclosporine, tacrolimus, mycophenolate mofetil: risk of excessive immunosuppression with risk of lymphoproliferation.

    - Live attenuated vaccines: risk of developing severe forms of vaccine infection with possible fatal outcome. This risk increases if the patient already had a decrease in immunity caused by the underlying disease (bone marrow aplasia).

    Rabbit antitumocyte immunoglobulin can induce the formation of antibodies that react with other rabbit immunoglobulins. Timoglobulin® probably does not affect the results of routine clinical laboratory studies in which immunoglobulins are used.

    However, the effect of the drug Tymoglobulin® can affect immunological tests based on the use of rabbit antibodies, cross-compatibility studies, or in cytotoxicity tests with paneled antibodies.

    Incompatibilities

    Based on a single study of compatibility, it was noted that the combination of the drug Timoglobulin®, heparin and Hydrocortisone with an infusion solution of glucose leads to the formation of sediment, and therefore it should be avoided.

    Due to the lack of other compatibility studies, the preparation of Timoglobulin® should not be mixed in the same container with other medicinal products, except as indicated in the section "Method of administration and dose".

    Special instructions:

    Timoglobulin® should only be used in a hospital setting under strict medical supervision.

    If an anaphylactic reaction occurs, the infusion should be stopped immediately and appropriate therapy initiated. Any subsequent administration of Tymoglobulin® should only be carried out after a thorough assessment of the relationship between the potential risks and potential benefits.

    The dose selection for the preparation of Tymoglobulin® containing rabbit antitimocyte immunoglobulin differs from that for other antimitocyte immunoglobulins (ATIG), as the protein composition and concentrations vary depending on the type of ATIG used.Therefore, it should be ensured that the prescribed dose is applicable for the drug being administered.

    Accurate compliance with the recommended dosage and duration of infusion may reduce the likelihood and severity of RI. In addition, a decrease in the rate of infusion can also minimize many of the listed RIs. Preliminary administration of antipyretic drugs, glucocorticosteroids and / or antihistamines may reduce both the incidence and severity of these adverse reactions.

    In the course of therapy with the drug Tymoglobulin® and after it, the number of lymphocytes and platelets must be monitored. The severity of lymphopenia and thrombocytopenia may decrease with a decrease in the dose of the drug.

    It is recommended to closely monitor the patient, as well as anti-infectious prophylaxis with the simultaneous administration of the drug Timoglobulin® with other immunosuppressive drugs.

    In the process of production of rabbit immunoglobulins, components of human origin (formaldehyde treated erythrocytes and thymus cells) are used. Standard measures to prevent the transfer of infectious agents when using medicines,obtained using human biological material, include careful selection of biological material, as well as the use of effective measures for decontamination / elimination of viruses in the production process. However, the possibility of transmission of infectious agents can not be completely ruled out. This risk also applies to unknown viruses or other types of infectious agents. The measures taken have been recognized as effective against envelope viruses such as: HIV, hepatitis B and hepatitis C viruses, and the non-enveloped hepatitis A virus.

    However, the measures taken may have limited effectiveness with respect to non-enveloped viruses, for example parvovirus B19. Infection with parvovirus B19 can be dangerous for the fetus and for individuals with certain types of immunodeficiency and anemia. The safety of the use of live attenuated vaccines in patients during therapy with the drug Timoglobulin® has not been studied; Thus, immunization with live attenuated vaccines is not recommended for patients recently receiving Tymoglobulin®.

    Special recommendations for the infusion of the drug Timoglobulin®

    As with any infusion, the administration of the drug Timoglobulin® can cause pain, swelling and redness at the injection site. The recommended method of administration of the drug Timoglobulin® is infusion into the main veins; at the same time, it is possible to introduce into the peripheral veins.

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

    Based on possible undesirable reactions that may occur during the infusion of the drug Timoglobulin®, in particular RVC, patients are not recommended to drive vehicles or engage in other potentially hazardous activities.

    Form release / dosage:

    Lyophilizate for the preparation of a solution for infusions, 25 mg.

    Packaging:

    Lyophilizate in an amount equivalent to 25 mg of active ingredient in a bottle of Type I glass capped with a chlorobutyl stopper with a fluoropolymer coating and an aluminum cap with a plastic lid of the "FLIP-OFF".

    One bottle with instructions for use in a cardboard pack.

    Storage conditions:

    Store at a temperature of 2 to 8 ° C. Do not freeze.

    Keep out of the reach of children.

    Transporting is carried out at the same temperature.It is allowed to transport the preparation of Tymoglobulin® at a temperature of 9 to 25 ° C for 72 hours.

    Shelf life:

    3 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:П N012718 / 01
    Date of registration:07.08.2008
    The owner of the registration certificate:Genzyme Europe BVGenzyme Europe BV Netherlands
    Manufacturer: & nbsp
    Representation: & nbspJENZAIM RUS LLCJENZAIM RUS LLCRussia
    Information update date: & nbsp12.10.2015
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