INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Tymoglobulin® (Thymoglobulin®)

Composition:

Active substance: rabbit antithymocyte immunoglobulin;

One vial contains 25 mg of rabbit antithymocyte immunoglobulin. After reconstitution with 5 ml of water for injections, 1 ml of concentrate contains 5 mg/ml of rabbit antithymocyte immunoglobulin, corresponding to 25 mg/5 ml per vial;

Excipients: glycine, sodium chloride, mannitol (E 421).

Pharmaceutical form. Lyophilized powder for preparation of a concentrate for solution for infusion.

Main physicochemical properties: cream-white lyophilized powder for preparation of a concentrate for solution for infusion.

Pharmacotherapeutic group. L - Antineoplastic and immunomodulating agents. Immunosuppressants. Selective immunosuppressants. Antithymocyte immunoglobulin (rabbit). ATC code L04A A04.

Pharmacological Properties

Pharmacodynamics

Rabbit anti-human thymocyte immunoglobulin is a selective immunosuppressive agent (acts on T-lymphocytes).

Mechanism of action of rabbit anti-human thymocyte immunoglobulin

T-cells are removed from circulation via complement-dependent lysis and subsequently by Fc-dependent opsonization mediated by the monocyte and phagocyte system. Thymoglobulin® recognizes most molecules involved in the T-cell activation cascade during transplant rejection, such as CD2, CD3, CD4, CD8, CD11a, CD18, CD25, HLA-DR, and HLA class I.

Lymphocyte depletion likely represents the primary mechanism of immunosuppression caused by rabbit anti-human thymocyte immunoglobulin.

In addition to T-cell depletion, rabbit anti-human thymocyte immunoglobulin triggers other lymphocyte functions associated with its immunosuppressive activity.

In vitro, at a concentration of approximately 0.1 mg/mL, Thymoglobulin® activates T-cells and stimulates their proliferation (similarly in both CD4+ and CD8+ subpopulations), along with synthesis of interleukin IL-2 and interferon IFN-γ and expression of CD25. This mitogenic activity is initially mediated via CD2. At higher concentrations, rabbit anti-human thymocyte immunoglobulin inhibits lymphocyte proliferative responses to other mitogens, with post-transcriptional blockade of INF-γ and CD25 synthesis, but without reducing IL-2 secretion.

In vitro, Thymoglobulin® does not activate B-cells.

In patients receiving Thymoglobulin® , a slightly increased risk of B-cell lymphoma has been observed, which may be explained by the following mechanisms:

lack of B-cell activation and, consequently, absence of plasma cell differentiation;
antiproliferative activity against B-cells and certain lymphoblastoid cell lines.

During immunosuppression related to organ transplantation in patients treated with rabbit anti-human thymocyte immunoglobulin, marked lymphopenia is observed as early as day 1 after initiation of treatment (reflecting more than 50% depletion compared to baseline). Lymphopenia persists throughout treatment and after completion of the therapy course. On average, approximately 40% of patients recover more than 50% of their initial lymphocyte count within 3 months.

Monitoring of lymphocyte subpopulations (CD2, CD3, CD4, CD8, CD14, CD19, and CD25) has confirmed the broad specificity of Thymoglobulin® for T-cells. After the first 2 weeks of treatment, the absolute count of all subpopulations—except B-lymphocytes and monocytes—shows significant depletion (over 85% for CD2, CD3, CD4, CD8, CD25, CD56, and CD57).

At the beginning of treatment, monocytes show less pronounced depletion. Minimal effect is observed on B-lymphocytes. In most subpopulations, more than 50% of the initial levels are restored by the end of the second month. Depletion of CD4+ cells is very prolonged and continues beyond 6 months, resulting in altered CD4/CD8 ratio.

Pediatric Population

Several reports on the use of Thymoglobulin® in children have been published. These reports reflect extensive clinical experience with this agent in pediatric patients and indicate that its safety and efficacy in children are fundamentally not different from those in adults.

However, there is no clearly defined dosing regimen for pediatric patients. As in adults, the dose in children depends on the indication, route of administration, and whether the drug is used in combination with other immunosuppressive agents. Physicians should consider these factors when selecting an appropriate dose for pediatric patients.

Preclinical Data

Preclinical data based on standard toxicity studies following single or repeated doses of Thymoglobulin® do not indicate a specific risk for humans. No mutagenicity, reproductive toxicity, or genotoxicity studies have been conducted with Thymoglobulin®.

Pharmacokinetics

After the first infusion of Thymoglobulin® at a dose of 1.25 mg/kg in kidney transplant recipients, serum levels of rabbit immunoglobulin IgG ranged from 10 to 40 µg/mL. Serum levels gradually decrease before the next infusion, with a half-life of 2–3 days.

Trough levels of rabbit immunoglobulin IgG gradually increase and reach 20–170 µg/mL by the end of the 11-day treatment course. Subsequently, a gradual decline is observed after discontinuation of rabbit anti-human thymocyte immunoglobulin therapy. However, rabbit immunoglobulin remains detectable in 80% of patients up to 2 months after completion of treatment.

Significant (notable) immunization against rabbit immunoglobulin was observed in approximately 40% of patients. In most cases, immunization developed within the first 15 days of treatment initiation. Patients who developed immunization showed a faster decline in rabbit IgG immunoglobulin levels.

Clinical Characteristics.

Indications.

Immunosuppression in transplantation: prevention and treatment of transplant rejection. Prevention of acute and chronic graft-versus-host reaction following hematopoietic stem cell transplantation.

Treatment of steroid-resistant acute graft-versus-host disease.

Treatment of aplastic anemia (hematology).

Contraindications.

Acute or chronic infections, which are contraindications for any additional immunosuppression.
Hypersensitivity to rabbit proteins or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Combinations to be considered:

Cyclosporine, tacrolimus, mycophenolate mofetil: risk of excessive immunosuppression with potential risk of lymphoproliferative disorders.
Live attenuated vaccines: risk of developing systemic infection following vaccination, which may potentially lead to fatal outcome. This risk is increased in patients with impaired immunity due to underlying disease (aplastic anemia).

Human anti-rabbit thymocyte immunoglobulin may induce formation of antibodies reacting with other rabbit immunoglobulins.

Thymoglobulin**®** has not demonstrated any effect on any standard clinical laboratory tests using immunoglobulins. However, Thymoglobulin**®** may interfere with immunological tests based on rabbit antibodies, cross-matching compatibility tests, or cytotoxicity assays using test antigen antibodies.

Special precautions for use.

Thymoglobulin® must always be administered under strict medical supervision in a hospital setting. Thymoglobulin® should only be administered by physicians experienced in immunosuppressive therapy in the context of transplantation. Patients must be carefully monitored during infusion. Particular attention should be paid to observing the patient for any symptoms of anaphylactic shock.

Close monitoring of the patient should continue throughout the infusion and for a period of time after the infusion has ended, until the patient becomes stable.

Prior to administration of Thymoglobulin® it is advisable to determine whether the patient has any allergy to rabbit proteins. Medical personnel and emergency equipment should be readily available during the initial days of therapy to provide emergency treatment if necessary.

Warnings

Immune-mediated reactions

Severe immune-mediated reactions have rarely been observed with Thymoglobulin® administration, including anaphylaxis or severe cytokine release syndrome (CRS). Very rare cases of fatal anaphylactic reactions have been reported (see section "Adverse reactions"). If an anaphylactic reaction occurs, infusion of Thymoglobulin® must be stopped immediately and appropriate emergency treatment initiated. Any further administration of Thymoglobulin® to a patient with a history of anaphylaxis during prior Thymoglobulin® therapy should only be considered after careful risk-benefit assessment.

Severe acute infusion-related reactions are consistent with cytokine release syndrome, caused by cytokine release from activated monocytes and lymphocytes. Rarely, these reported reactions have been associated with severe cardiopulmonary complications and/or fatal outcomes (see section "Adverse reactions" and subsection "Precautions for use" below).

Infectious diseases

Thymoglobulin® is generally used in combination with other immunosuppressive agents. Infectious diseases (bacterial, fungal, viral, and protozoal), reactivation of infections (particularly cytomegalovirus [CMV]), and sepsis have been reported after administration of Thymoglobulin® in combination with various immunosuppressive agents. Rarely, these infections may be fatal.

Hepatic disease

Extreme caution should be exercised when administering Thymoglobulin® to patients with liver disease, as pre-existing coagulation disorders may worsen. Platelet counts and coagulation factors should be monitored closely.

Precautions for use

General

The required dosage of Thymoglobulin® differs from that of other anti-thymocyte globulin (ATG) preparations due to differences in protein composition and concentration depending on the source of ATG used. Therefore, the physician must carefully determine the dose according to the specific ATG preparation being administered.

Strict adherence to the recommended dose and infusion duration may reduce the frequency and severity of infusion-related reactions. Furthermore, reducing the infusion rate may minimize many of these reactions. Premedication with antipyretics, corticosteroids, and/or antihistamines may reduce the frequency and severity of these adverse reactions.

High infusion rates have been associated with reports of CRS. Rarely, severe CRS may lead to fatal outcomes.

Effects on blood parameters

Thrombocytopenia and/or leukopenia (including lymphopenia and neutropenia), which are reversible upon dose adjustment, have been observed. If thrombocytopenia and/or leukopenia are not part of the underlying disease or related to the condition being treated with Thymoglobulin®, dose reduction is recommended (see section "Dosage and administration").

White blood cell and platelet counts should be monitored during and after Thymoglobulin® therapy.

Infections

Following administration of Thymoglobulin® in combination with various immunosuppressive agents, development of infections, reactivation of infections, and sepsis have been reported. Close monitoring of the patient and implementation of anti-infective prophylaxis are recommended.

Malignant neoplasms

The use of immunosuppressive agents, including Thymoglobulin®, may increase the incidence of malignancies, including lymphoma or post-transplant lymphoproliferative disorder (PTLD) (which may be of viral origin). These events have sometimes been associated with fatal outcomes (see section "Adverse reactions").

Risk of transmission of infectious agents

Human-derived materials are used in the production of rabbit immunoglobulin. Standard measures to prevent infections arising from products manufactured with human blood components include careful selection of raw materials and inclusion of effective manufacturing steps to inactivate/eliminate viruses. Despite these measures, the possibility of transmitting infectious agents cannot be completely excluded. This risk also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective against enveloped viruses such as HIV, hepatitis B virus, hepatitis C virus, and non-enveloped hepatitis A virus.

The measures may have limited effectiveness against non-enveloped viruses such as parvovirus B19.

Parvovirus B19 infection may be dangerous for pregnant women (fetal infection) and for individuals with compromised immune systems or certain types of anemia.

It is strongly recommended that the patient's name and the batch number of the product be documented with each administration of Thymoglobulin® to ensure traceability.

Infusion-related considerations for Thymoglobulin®

As with any infusion, local reactions at the infusion site may occur, including pain, swelling, and redness.

Vaccination

The safety of vaccination with live attenuated vaccines after treatment with Thymoglobulin® has not been studied; therefore, prophylactic vaccination with live attenuated vaccines is not recommended for patients who have recently received Thymoglobulin® (see section "Interaction with other medicinal products and other forms of interaction").

Information on excipients

Each 10 ml vial of this medicinal product contains 0.171 mmol of sodium, equivalent to 4 mg of sodium, i.e., 0.2% of the WHO recommended maximum daily dietary intake of 2 g sodium for an adult.

Traceability

To improve traceability of biological medicines, the name and batch number of the administered product should be clearly documented.

Use during pregnancy or breastfeeding

Fertility

Studies on the effect of Thymoglobulin® on reproductive function in animals have not been conducted. It is unknown whether Thymoglobulin® may cause harm to the fetus or affect reproductive function.

Pregnancy

Studies on the effect of Thymoglobulin® on reproductive function in animals have not been conducted. It is unknown whether Thymoglobulin® may cause harm to the fetus. Thymoglobulin® should not be used during pregnancy unless absolutely necessary.

Studies on Thymoglobulin® during labor and delivery have not been conducted.

Breastfeeding

It is unknown whether rabbit anti-human thymocyte immunoglobulin is excreted in human milk. Since other immunoglobulins are excreted in breast milk, breastfeeding should be discontinued during treatment with Thymoglobulin®.

Ability to affect reaction speed when driving or operating machinery

Given the possible adverse effects that may occur during Thymoglobulin® infusion, particularly cytokine release syndrome (CRS), driving a vehicle or operating complex machinery is not recommended during Thymoglobulin® treatment.

Administration and Dosage

Dosage

Dosage depends on the indication, route of administration, and possible combination with other immunosuppressive agents. The following dosage recommendations may be used as a standard. Treatment may be discontinued without tapering the dose.

Immunosuppression in transplantation

Prophylaxis of acute transplant rejection

1–1.5 mg/kg body weight per day for 2–9 days following kidney, pancreas, or liver transplantation, and for 2–5 days following heart transplantation, corresponding to a total dose of 2–7.5 mg/kg in heart transplantation and 2–13.5 mg/kg in transplantation of other organs.

Treatment of acute transplant rejection

1.5 mg/kg/day for 3–14 days, corresponding to a total dose of 4.5–21 mg/kg.

Prophylaxis of acute and chronic graft-versus-host disease (GvHD)

For transplantation (bone marrow or peripheral blood hematopoietic stem cells) from related non-HLA-identical donors or unrelated HLA-identical donors, Thymoglobulin**®** is recommended as pre-treatment in adult patients at a dose of 2.5 mg/kg/day, starting from day -4 to day -2 or -1, corresponding to a total dose of 7.5–10 mg/kg.

Treatment of steroid-resistant acute graft-versus-host disease (GvHD)

Dosage is individually determined. Typically, the dose is 2–5 mg/kg/day for 5 consecutive days.

Treatment of aplastic anemia

2.5–3.5 mg/kg/day for 5 consecutive days, corresponding to a total dose of 12.5–17.5 mg/kg. The use of this medicinal product for the treatment of aplastic anemia has not been studied in controlled clinical trials.

Dose adjustment

Thrombocytopenia and/or leukopenia (including lymphopenia and neutropenia) have been reported, which are reversible upon dose adjustment. If thrombocytopenia and/or leukopenia are not part of the underlying disease or related to the condition being treated with Thymoglobulin**®**, the following options for dose reduction should be considered:

Dose reduction should be considered if platelet count is 50,000–75,000 cells/mm³ or if white blood cell count is 2,000–3,000 cells/mm³;
Discontinuation of Thymoglobulin**®** treatment should be considered if persistent and severe thrombocytopenia (<50,000 cells/mm³) or leukopenia (<2,000 cells/mm³) develops.

Route of administration

Rabbit antithymocyte immunoglobulin is usually administered according to a therapeutic regimen combining several immunosuppressive agents.

Prior to infusion of rabbit antithymocyte immunoglobulin, a dose of corticosteroids and antihistamines should be administered intravenously.

Administer by slow intravenous infusion into a large-bore vein. Adjust the infusion rate so that the total duration is at least 4 hours.

Instructions for solution preparation and disposal

Reconstitute the powder with 5 mL of sterile water for injection to obtain a solution containing 5 mg of protein per 1 mL. Reconstitution must be performed in accordance with good practice, particularly with regard to aseptic technique.

The reconstituted solution is clear and slightly opalescent. The solution should be inspected visually for particulate matter and discoloration. If some solid particles are present, gently invert the vial until they completely disappear. If solid particles remain, do not use the vial.

The prepared solution should be used immediately. Each vial is for single use only. Depending on the daily dose, it may be necessary to prepare the solution from several vials of Thymoglobulin**®. In this case, determine the number of vials required by rounding up the calculated value to the next higher number of vials. To avoid inadvertent infusion of solid particles, it is recommended to administer Thymoglobulin®** through a 0.2 µm in-line filter. Dilute the daily dose in an infusion solution (9 mg/mL (0.9%) sodium chloride solution for injection or 5% glucose) to achieve a total infusion volume of 50 to 500 mL (typically 50 mL per vial). The product should be administered on the same day. Any unused product or waste material must be disposed of properly.

Children. Available data are described in the sections "Pharmacological properties" and "Undesirable effects", however, no dosage recommendations can be given for this patient group. Available data suggest that there is no need to modify the dosage for pediatric patients compared to adult dosage.

Overdose.

Accidental overdose may cause leukopenia (including lymphopenia and neutropenia) and thrombocytopenia. These adverse effects are reversible upon dose adjustment or discontinuation of treatment (see section "Administration and dosage"). There is no specific antidote.

Adverse Reactions

Adverse reactions observed during clinical trials and post-marketing use are listed below.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Adverse reactions reported from the results of the French multicenter post-marketing study are also listed below.

From June 1997 to March 1998, 18 French transplant centers participated in the French Multicenter Post-marketing Surveillance Study-00PTF0.

A total of 240 patients were included in this prospective, observational, single-group cohort study. All patients received Thymoglobulin**®** for prophylaxis of acute kidney transplant rejection.

The safety data presented below reflect all adverse events reported during the study, regardless of the established relationship to Thymoglobulin**®** administration.

Blood and lymphatic system disorders

Very common: lymphopenia, neutropenia, thrombocytopenia, anemia.

Common: febrile neutropenia.

Respiratory system disorders

Common: dyspnea (shortness of breath).

Gastrointestinal disorders

Common: diarrhea, dysphagia, nausea, vomiting.

Skin and subcutaneous tissue disorders

Common: pruritus, rash.

Musculoskeletal and connective tissue disorders

Common: myalgia.

Infections and infestations

Very common: infections (including reactivation of infections).

Common: sepsis.

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

Common: malignancy, lymphoma (possibly of viral origin), malignant neoplasms (solid tumors).

Uncommon: lymphoproliferative disorders.

Vascular disorders

Common: arterial hypotension.

General disorders and administration site conditions

Very common: fever.

Common: chills.

Uncommon: infusion-related reactions.

Hepatobiliary disorders

Common: increased transaminase levels.

Uncommon: hepatocellular injury, hepatotoxic effects, liver failure.

Frequency not known: hyperbilirubinemia.

Immune system disorders

Common: serum sickness, cytokine release syndrome (CRS), anaphylactic reaction.

Description of selected adverse reactions

Infusion-related reactions may occur after administration of Thymoglobulin**®** and typically develop immediately after the first or second infusion during a single course of Thymoglobulin**®** therapy. Clinical manifestations of infusion-related reactions may include some of the following signs and symptoms: flushing, chills/shivering, dyspnea, nausea/vomiting, diarrhea, hypotension or hypertension, malaise, rash, urticaria, and/or headache. Infusion-related reactions associated with Thymoglobulin**®** are usually mild and transient in nature and can be managed by reducing the infusion rate and/or pharmacological treatment (see section "Special precautions"). Severe and, in isolated cases, fatal anaphylactic reactions have been reported (see section "Special precautions"). Fatal outcomes occurred in patients who did not receive adrenaline during the reaction.

Infusion-related reactions resembling cytokine release syndrome (CRS) have been reported (see section "Special precautions"). Severe and potentially life-threatening CRS has been rarely observed. Post-marketing reports of severe CRS have been associated with cardiopulmonary dysfunction (including hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, tachycardia, and/or fatal outcome). During the post-marketing study, reactions such as flushing, rash, urticaria, arthralgia, and/or myalgia were reported, suggesting possible serum sickness. Serum sickness tends to develop between 5 and 15 days after initiation of Thymoglobulin**®** therapy. Symptoms are usually transient or rapidly resolve with corticosteroid treatment.

Local adverse reactions such as pain at the infusion site and peripheral thrombophlebitis have also been reported.

Hepatobiliary disorders

Transient, reversible increases in transaminase levels, without any clinical symptoms, have been reported during Thymoglobulin**®** use.

Cases of liver failure have been reported following allergic hepatitis and hepatitis reactivation in patients with underlying complicating factors such as hematological disorders and/or stem cell transplantation.

Adverse effects due to immunosuppression

Infectious diseases, reactivation of infections, febrile neutropenia, and sepsis have been reported after administration of Thymoglobulin**®** in combination with various immunosuppressive agents (see section "Special precautions"). In rare cases, these infections were fatal. Malignant neoplasms, including post-transplant lymphoproliferative disorders (PTLD), other lymphomas (which may be of viral origin), and solid tumors, have been reported rarely (see section "Special precautions"). These adverse effects were always observed in patients receiving combination therapy with multiple immunosuppressants and were sometimes fatal.

For information on the risks of transmission of infectious agents, see section "Special precautions".

Pediatric population

Available data are limited. They show no significant difference in the safety profile of Thymoglobulin**®** between pediatric and adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

The reconstituted and diluted solution should be used immediately to prevent microbial contamination. Chemical and physical stability has been demonstrated for 24 hours at 2 to 8°C. The storage time of the ready-to-use solution should not exceed 24 hours at 2 to 8°C.

Storage conditions.

Keep out of the reach of children. Store at 2 to 8°C (in a refrigerator), protected from light. Do not freeze.

Incompatibilities.

Based on a single compatibility study, precipitation occurs when Thymoglobulin**®, heparin, and hydrocortisone are combined in glucose infusion solution, and such combination is not recommended. In the absence of other compatibility studies, Thymoglobulin®** should not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Packaging.

No. 1: 1 vial in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Sanofi Winthrop Industrie, France / Sanofi Winthrop Industrie, France.

Genzyme Ireland Limited, Ireland / Genzyme Ireland Limited, Ireland.

Manufacturer's address and location of operations.

23, boulevard Chambaud de la Bruyere, 69007 Lyon, France / 23 boulevard Chambaud de la Bruyere, 69007 Lyon, France.

IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland / IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland.

Marketing authorization holder.

Sanofi B.V., The Netherlands / Sanofi B.V., The Netherlands.