Thymoglobuline即复寧

Thymoglobuline

Manufacturer:

Sanofi

Distributor:

DCH Auriga - Healthcare
Full Prescribing Info
Contents
Rabbit anti-human thymocyte immunoglobulin.
Description
Thymoglobuline also contains the following excipients: Glycine, sodium chloride and mannitol.
Action
Immunosuppressive agent.
Pharmacology: Rabbit anti-human thymocyte immunoglobulin is a selective immunosuppressive agent (acting on T lymphocytes).
The mechanism of action of rabbit anti-human thymocyte immunoglobulin is as follows:
Lymphocyte depletion probably constitutes the primary mechanism of the immunosuppression induced by rabbit anti-human thymocyte immunoglobulin.
Thymoglobuline recognizes most of the molecules involved in the T-cell activation cascade during graft rejection eg, CD2, CD3, CD4, CD8, CD11a, CD18, CD25, HLA-DR and HLA class I.
T-cells are eliminated from the circulation by complement-dependent lysis and, by an Fc-dependent opsonization mechanism mediated by the monocyte and phagocyte system.
Rabbit anti-human thymocyte immunoglobulin, in addition to its effect of depleting T-cells, triggers other lymphocyte functions related to its immunosuppressive activity.
In vitro, at concentrations of 0.1 mg/mL, Thymoglobuline activates T-cells and stimulates their proliferation (in the same manner for the CD4+ and CD8+ subsets) with synthesis of IL-2 and IFN-γ and expression of CD25. This mitogenic activity primarily involves the CD2 pathway. At higher concentrations, rabbit anti-human thymocyte immunoglobulin inhibits the proliferative responses of lymphocytes to other mitogens with post-transcriptional blockade of INF-γ and CD25 synthesis but no decrease in IL-2 secretion.
In vitro, Thymoglobuline does not activate B-cells.
The low risk of B-cell lymphoma observed in patients treated with Thymoglobuline may be explained by the following mechanisms: No activation of B-cells with, as a result, non-differentiation of plasmocytes; antiproliferative activity against B-cells and certain lymphoblastoid cell lines.
In the course of immunosuppression in the context of organ transplantation, patients treated with rabbit anti-human thymocyte immunoglobulin experience profound lymphopenia (defined as a >50% depletion compared to the baseline value) as early as 1 day post-treatment initiation. The lymphopenia persists throughout treatment and after the course. On average, about 40% of patients recover >50% of the initial lymphocyte count at 3 months.
Monitoring of lymphocyte subsets (CD2, CD3, CD4, CD8, CD14, CD19 and CD25) has confirmed the broad range of T-cell specificities of Thymoglobuline. Over the first 2 weeks of treatment, the absolute count for all subsets except B-lymphocytes and monocytes shows marked depletion (>85% for CD2, CD3, CD4, CD8, CD25, CD56 and CD57).
At the beginning of treatment, monocytes undergo less marked depletion. B-lymphocytes are almost unaffected. Most of the subsets have recovered >50% of their initial value before the end of the 2nd month. CD4-cell depletion is very long-lasting and persists at 6 months with, as a result, an inversion of the CD4/CD8 ratio.

Retrospective clinical studies have provided evidence strongly in favour of reducing the risk of acute GvHD disease. However, no beneficial effects on patient survival have been demonstrated.
Pharmacokinetics: Following the 1st infusion of 1.25 mg/kg of Thymoglobuline (in kidney transplant recipients), serum rabbit IgG levels of between 10 and 40 mcg/mL are obtained. The serum levels decline steadily until the following infusion with an estimated elimination half-life of 2-3 days.
The trough rabbit IgG levels increase progressively reaching 20-170 mcg/mL at the end of an 11-day course of treatment. A gradual decline is subsequently observed following discontinuation of treatment with rabbit anti-human thymocyte immunoglobulin. However, rabbit IgG remains detectable in 80% of patients at 2 months.
Significant immunization against rabbit IgG is observed in about 40% of patients. In most cases, immunization develops within the first 15 days of treatment initiation. Patients presenting with immunization show a faster decline in trough rabbit IgG levels.
Toxicology: Preclinical Safety Data: The single and repeated-dose toxicity studies did not demonstrate any specific toxicity of Thymoglobuline.
No mutagenicity, reproduction or genotoxicity study has been conducted with Thymoglobuline.
Indications/Uses
Immunosuppression in Transplantation: Prevention and treatment of graft rejection. Prophylaxis of acute and chronic graft versus host disease, after hematopoietic stem cell transplantation. Treatment of steroid-resistant acute graft versus host disease (GvHD).
Hematology: Treatment of aplastic anemia.
Dosage/Direction for Use
Dosage: The dosage regimen depends on the indication, the administration regimen and combination with other immunosuppressive agents. Treatment can be discontinued without gradual tapering of the dose. The following dosage recommendations may be used as a reference:
Immunosuppression in Transplantation: Prophylaxis of Acute Graft Rejection: 1-1.5 mg/kg/day for 2-9 days after transplantation of a kidney, pancreas or liver and for 2-5 days after heart transplantation, corresponding to a cumulative dose of 2-7.5 mg/kg in heart transplantation and 2-13.5 mg/kg for other organs.
Treatment of Acute Graft Rejection: 1.5 mg/kg/day for 3-14 days, corresponding to a cumulative dose of 4.5-21 mg/kg.
Aplastic Anemia: 2.5-3.5 mg/kg/day for 5 consecutive days, corresponding to a cumulative dose of 12.5-17.5 mg/kg.
The use of Thymoglobuline in the treatment of aplastic anemia has not been established by controlled clinical trials.
Prophylaxis of Acute and Chronic Graft versus Host Disease: In transplantation of grafts (bone marrow or hematopoietic stem cells from peripheral blood) from mismatched related or matched unrelated donors, it is recommended in adult patients that Thymoglobuline be administered, as a preliminary therapy, at a dose of 2.5 mg/kg/day from day -4 to day -2 or -1, corresponding to a cumulative dose of 7.5-10 mg/kg. Treatment of Steroid-Resistant, Acute Graft versus Host Disease: The dosage must be determined on an individual basis. It is usually between 2-5 mg/kg/day for 5 days.
Administration: Rabbit anti-human thymocyte immunoglobulin is usually administered in the context of a therapeutic regimen combining several immunosuppressive agents.
Administer the daily doses of IV corticosteroids and antihistamines required prior to infusion of rabbit anti-human thymocyte immunoglobulin.
Rabbit anti-human thymocyte immunoglobulin is infused after dilution in isotonic solution of 0.9% sodium chloride or 5% dextrose.
Infuse slowly into a large vein. Adjust the infusion rate so that the total duration of infusion takes at least 4 hrs.
Instructions for Use and Handling: Reconstitute the powder using 5 mL of water for injections.
Dilute the daily dose in an isotonic diluent medium (0.9% sodium chloride or 5% dextrose solution) so as to obtain a total infusion volume of 50-500 mL (usually 50 mL/vial).
Overdosage
Inadvertent overdose (>5 mg/kg/day) may induce leukopenia and thrombocytopenia. Prolonged use longer than 3 weeks of rabbit anti-human thymocyte immunoglobulin may induce severe infections and increase the risk of lymphoma.
Contraindications
Acute infections contraindicating any further immunosuppression. Known allergy to rabbit proteins or one of the constituents of Thymoglobuline.
Special Precautions
Rabbit anti-human thymocyte immunoglobulin must always be used under strict medical supervision in a hospital setting.
Some severe adverse reactions may be related to the infusion rate. The recommended infusion rate given under Dosage & Administration must be complied with. Patients must be carefully monitored during the infusion.
Due to the risk of serum sickness-type reactions, special precautions should be taken in patients who have already received rabbit immunoglobulins.
In the event of an adverse reaction, the infusion rate can be reduced or the infusion discontinued until the symptoms have resolved.
Administration must be immediately discontinued and permanently withdrawn if an anaphylactic reaction occurs. If shock occurs, usual emergency treatment should be instituted promptly.
Blood cell count must be monitored for 2 weeks following the end of treatment. In patients presenting with initial relative thrombocytopenia (<150 x 109 platelet/L), and particularly in heart transplant recipients, the platelet count should also be monitored.
In Organ Transplantation: A reduction of dosage must be considered if the platelet count is <80 x 109/L or if the leukocyte count is <2.5 x 109cells/L; the treatment must be discontinued if persistent and severe thrombocytopenia (<50 x 109cells/L) or leukopenia (<1.5 x 109cells/L) develops.
In conditioning protocols, the risk of infection is markedly increased. The risk of a recurrence of the initial malignant disease is increased. These factors must therefore be taken into account.
In aplastic anemia, the immunosuppressive treatment contributes to the risk of infection (in particular fungal infection) associated with the aplastic anemia itself. The increased risk of lymphoproliferative disorders is to be taken into account.
Use in pregnancy & lactation: The safety of rabbit anti-human thymocyte immunoglobulins during pregnancy and lactation has not been established.
In consequence, Thymoglobuline must not be prescribed during lactation or pregnancy unless absolutely required.
Use In Pregnancy & Lactation
The safety of rabbit anti-human thymocyte immunoglobulins during pregnancy and lactation has not been established.
In consequence, Thymoglobuline must not be prescribed during lactation or pregnancy unless absolutely required.
Adverse Reactions
The adverse reactions reported during and subsequent to Thymoglobuline infusion are as follows:
Systemic adverse reactions which may present as chills, fever, hypotension, tachycardia, vomiting and dyspnea. Local adverse reactions eg, pain at the infusion site and peripheral thrombophlebitis have also been reported.
Delayed allergic reactions eg, serum sickness (fever, pruritus, rash combined with joint and muscle pain) may occur 7-15 days post-treatment initiation. Immediate serious allergic reactions are exceptional.
The most frequent and most serious adverse reactions occur after the 1st infusion. The mechanism of some of those adverse reactions is probably related to cytokine release. Premedication with corticosteroids and antihistamines and a decrease in the infusion rate or use of a higher volume of solvent (isotonic 0.9% sodium chloride or 5% dextrose solution) may enable the incidence and severity of certain adverse reactions to be reduced.
Adverse reactions associated with the presence of antibodies inducing cross-reactions eg, neutropenia and thrombocytopenia have been reported during and following treatment with rabbit anti-human thymocyte immunoglobulin. These reactions may occur during the first 2 days of treatment or after the end of treatment. The mechanism of those effects involves the presence of antibodies inducing cross-reactions with neutrophils or platelets. Monitoring of the white blood cell and platelet counts enables the severity and frequency of such reactions to be reduced.
Adverse effects associated with over-immunosuppression including infectious complications (bacterial, fungal, viral and parasitic) and rare neoplastic malignancies (particularly lymphoproliferative syndrome) have been reported during and after rabbit anti-human thymocyte immunoglobulin treatment. It is important to note that concomitant or previous immunosuppressive treatments may contribute to the over-immunosuppression observed.
The risk of lymphoproliferative disorders is enhanced by concomitant treatment with other immunosuppressive agents.
In conditioning protocols, the risk of infection linked to the administration of Thymoglobuline is markedly increased.
Drug Interactions
Combinations to be taken into account: Cyclosporine, tacrolimus, mycophenolate mofetil: Risk of over-immunosuppression with a risk of lymphoproliferation. Live attenuated vaccines: Risk of systemic infection which may potentially be fatal. This risk is enhanced in subjects who are immunocompromised due to the underlying disease (aplastic anemia).
Rabbit anti-human thymocyte immunoglobulin may induce formation of antibodies which react with other rabbit immunoglobulins. It may interfere with ELISA tests involving rabbit antibodies over a period of 2 months.
Incompatibilities: Thymoglobuline must not be mixed with other products and/or drugs.
Storage
Store at a temperature between 2°C and 8°C. Do not freeze.
Immediate use of reconstituted Thymoglobuline is recommended. However, reconstituted product has been shown to remain stable at a temperature of 20°C for 24 hrs.
Shelf-Life: 3 years.
MIMS Class
ATC Classification
L04AA04 - antithymocyte immunoglobulin (rabbit) ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
Presentation/Packing
Vial 25 mg/5 mL x 1's.
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