Thymoglobulin^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Genzyme Europe B.V. (Netherlands)

Manufactured By

Genzyme Polyclonals S.A.S. (France)

Primary Packaging

GENZYME IRELAND Limited (Ireland)

Secondary Packaging

GENZYME, Ltd. (United Kingdom)

Contact Information

SANOFI

ATC Code

L04AA04 (Antithymocyte immunoglobulin (rabbit))

Active Substance

Anti-T lymphocyte immunoglobulin for human use, animal (Ph.Eur. European Pharmacopoeia)

Dosage Form

Thymoglobulin®

Lyophilisate for the preparation of solution for infusion 25 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for the preparation of solution for infusion in the form of a creamy-white powder.

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

Glass vials (1) – cardboard packs.

Lyophilisate for the preparation of solution for infusion in the form of a creamy-white powder.

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

25 mg – glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antithymocyte immunoglobulin

Pharmacotherapeutic Group

Immunosuppressive agent – immunoglobulin

Pharmacological Action

Rabbit antithymocyte immunoglobulin is a selective immunosuppressive drug that acts on T-lymphocytes.

Mechanism of action

The reduction in the number of lymphocytes is probably the main mechanism of immunosuppression induced by rabbit antithymocyte immunoglobulin, which recognizes most of the molecules involved in the T-cell activation cascade in graft rejection reactions, such as: CD2, CD3, CD4, CD8, CD11a, CD18, CD25, HLA-DR and HLA class I.

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

In addition to reducing the number of T-lymphocytes, rabbit antithymocyte immunoglobulin causes activation of other lymphocyte functions associated with their immunosuppressive activity.

In vitro, at a concentration of about 0.1 mg/ml, Thymoglobulin^® activates T-lymphocytes and stimulates their proliferation (in the same way for CD4+ and CD8+ subpopulations) with the synthesis of interleukin-2 and interferon-γ, and expression of CD25. This mitogenic activity is realized mainly through the CD2-mediated pathway. At higher concentrations, rabbit antithymocyte immunoglobulin suppresses the proliferative lymphocyte response to other mitogens, while causing post-transcriptional blockade of interferon-γ and CD25 synthesis, but not reducing the secretion of interleukin-2. In vitro, Thymoglobulin^® does not activate B-lymphocytes.

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

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

• antiproliferative activity against B-lymphocytes and some lymphoblastic cell lines.

When conducting a course of immunosuppression after transplantation in patients treated with Thymoglobulin^®, profound lymphopenia (a decrease in the number of lymphocytes by more than 50% compared to the baseline) develops as early as 1 day after the start of treatment. Lymphopenia persists throughout the treatment period and after the end of the therapy course. On average, in about 40% of patients by the end of the 3rd month, the number of lymphocytes recovers by more than 50% of the initial level, but the decrease in the number of CD4 lymphocytes persists for a long time and is still observed after 6 months, resulting in an inversion of the CD4/CD8 ratio. Monitoring of lymphocyte subpopulations (CD2, CD3, CD4, CD8, CD14, CD19 and CD25) confirmed the wide range of specific binding of Thymoglobulin^® to T-lymphocytes. During the first 2 weeks of treatment, a pronounced decrease in the absolute number of all lymphocyte subpopulations is observed, except for B-lymphocytes and monocytes (by more than 85% for CD2, CD3, CD4, CD8, CD25, CD56 and CD57).

Pharmacokinetics

After the first infusion of Thymoglobulin^® at a dose of 1.25 mg/kg to renal transplant recipients, the concentration of rabbit IgG in the blood serum ranges from 10 to 40 µg/ml, constantly decreasing by the time of the next infusion (the half-life is 2-3 days). By the end of the 11-day treatment course, the minimum concentration of rabbit IgG gradually increases and reaches 20-170 µg/ml. After the cessation 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.

In approximately 40% of patients, within the first 15 days after the start of treatment with Thymoglobulin^®, intensive formation of antibodies to rabbit immunoglobulin occurs, leading to a more rapid decrease in its minimum concentrations in the blood serum.

Indications

• Immunosuppression in organ transplantation: prevention and treatment of graft rejection reactions;
• Prevention of acute and chronic graft-versus-host disease after hematopoietic stem cell transplantation;
• Treatment of acute graft-versus-host disease resistant to corticosteroid therapy;
• Treatment of aplastic anemia.

ICD codes

Dosage Regimen

Method of administration

The drug is intended for intravenous infusion.

Preparation of the infusion solution

The contents of the vial are dissolved in 5 ml of water for injections with gentle shaking (the resulting IgG concentration is 5 mg/ml). The reconstituted solution should be clear or slightly opalescent and free of undissolved particles. If undissolved particles are present, continue to gently shake the vial until they disappear. However, the dissolution time should not exceed 2 minutes. If particles still persist, the contents of the vial should not be used. It is recommended to use the reconstituted solution immediately after its preparation. Each vial of the drug is intended for single use only. Depending on the required daily dose, it may be necessary to reconstitute the lyophilisate in several vials of Thymoglobulin^®.

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

Immediate administration of the diluted drug is recommended. If the diluted drug cannot be used immediately, it can be stored for no more than 24 hours at a temperature of 2 to 8°C (46.4°F) provided that controlled aseptic conditions were observed during the reconstitution and dilution of the drug solution.

Any drug residues and consumables must be disposed of in accordance with current regulations.

The drug should be administered slowly into a large vein through a 0.2 µm systemic filter to ensure the removal of traces of undissolved drug particles. The infusion rate should be adjusted so that the total duration of the infusion is at least 4 hours.

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

Prior to the start of treatment, preliminary intravenous administration of glucocorticosteroids and antihistamines is recommended.

Dosage regimen

The doses of Thymoglobulin^® depend on the indications for use, the administration regimen and the possible combination with other immunosuppressive drugs. The standard recommendations for the drug dosage regimen are presented below. Treatment can be discontinued without gradual dose reduction.

Immunosuppression in organ transplantation

• Prevention of acute 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 heart transplantation and 2-13.5 mg/kg after transplantation of other organs.
• Treatment of acute graft rejection: 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 disease

After bone marrow or hematopoietic stem cell transplantation from related HLA-non-identical donors or from unrelated HLA-identical donors, it is recommended to use Thymoglobulin^® at a dose of 2.5 mg/kg/day for 1-4 days before transplantation in adult patients, which corresponds to a cumulative dose of 7.5 – 10 mg/kg.

Treatment of acute graft-versus-host disease resistant to glucocorticosteroid therapy

The dose is selected individually and is usually 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.

Dose adjustment

If thrombocytopenia and/or leukopenia (including lymphopenia and neutropenia) develop, dose adjustment is required. In cases where thrombocytopenia and/or leukopenia are not a manifestation of the underlying disease or are not associated with the pathology for which Thymoglobulin^® was used, it is recommended:

• To reduce the dose if the platelet count is from 50,000 to 75,000 cells/mm³ or if the leukocyte count is from 2,000 to 3,000 cells/mm³;
• To suspend treatment with Thymoglobulin^® in case of development of persistent severe thrombocytopenia (<50,000 cells/mm³) or leukopenia (<2,000 cells/mm³).

Adverse Reactions

The safety of Thymoglobulin^® has been studied in 240 patients who received the drug to prevent acute graft rejection after kidney transplantation.

The adverse reactions listed below represent pooled data on all adverse events observed during this study, regardless of their relationship to Thymoglobulin^®.

The frequency of occurrence was determined as follows: very common: (>1/10), common: (from > 1/100 to <1/10).

Disorders of the blood and lymphatic system

Very common: lymphopenia, neutropenia, thrombocytopenia.

Disorders of the respiratory system, thoracic and mediastinal organs

Common: dyspnea.

Gastrointestinal disorders

Common: diarrhea, swallowing disorders, nausea, vomiting.

Disorders of the skin and subcutaneous tissues

Common: pruritus, skin rash.

Disorders of the musculoskeletal and connective tissue and systemic reactions

Common: myalgia.

Infectious and parasitic diseases

Very common: infections.

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

Common: malignant tumors.

Vascular disorders

Common: hypotension.

General disorders and administration site conditions

Very common: fever.

Common: chills.

Disorders of the immune system

Common: serum sickness.

Infusion reactions (IR) and disorders of the immune system

IR may occur upon administration of Thymoglobulin^® after the first or second infusion during one course of treatment. Clinical manifestations of IR may be expressed by the following signs and symptoms: fever, chills, shortness of breath, nausea/vomiting, diarrhea, arterial hypotension or hypertension, malaise, skin rash and/or severe headache. IR to Thymoglobulin^® are usually mild and transient, and can be corrected by reducing the infusion rate 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), of anaphylactic reactions with fatal outcome. IRs manifesting as cytokine release syndrome (CRS), associated with the release of cytokines by activated monocytes and lymphocytes, have been reported. Severe and potentially life-threatening CRS has been rarely reported. During post-marketing surveillance, rare cases of severe CRS accompanied by cardio-respiratory dysfunction (including hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, tachycardia and/or death) have been noted.

Post-marketing surveillance of the drug has recorded reports of reactions such as fever, skin rash, arthralgia and/or myalgia, indicating the possible development of serum sickness. Serum sickness may occur between 5 and 15 days after the start of therapy with Thymoglobulin^®. Symptoms usually resolve on their own or are quickly eliminated by the administration of glucocorticosteroids.

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

Adverse reactions due to immunosuppression

Infections, recurrence of infection and sepsis have been noted in cases of using Thymoglobulin^® in combination with several immunosuppressive drugs. In rare cases, the development of malignant tumors has been noted, including, but not limited to, post-transplant lymphoproliferative disease (PTLD), as well as other lymphomas and solid tumors.

Contraindications

• Acute or chronic infections;
• Hypersensitivity to rabbit proteins or any other component of the drug;
• Development of allergic reactions to previous administration of Thymoglobulin^®.

With caution

• In patients who have previously received rabbit immunoglobulins, as there is a risk of developing serum sickness-like reactions.

Use in Pregnancy and Lactation

Since the conducted animal studies are insufficient and it is impossible to draw a conclusion about the potential risk to humans, Thymoglobulin^® during pregnancy should be used only if the benefit to the mother outweighs the risk of using this drug to the fetus.

It is not known whether rabbit antithymocyte immunoglobulin is excreted in breast milk. Since other immunoglobulins are excreted in breast milk, breastfeeding should be discontinued during the use of Thymoglobulin^®.

Special Precautions

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

If an anaphylactic reaction occurs, the infusion should be stopped immediately and appropriate therapy should be started. Any subsequent administration of Thymoglobulin^® should be carried out only after a careful assessment of the ratio of possible risks and potential benefits.

Dose selection for Thymoglobulin^® containing rabbit antithymocyte immunoglobulin differs from that for other antithymocyte immunoglobulins (ATG), as the protein composition and concentrations vary depending on the type of ATG used. Therefore, it should be verified that the prescribed dose is applicable for the drug being administered.

Strict adherence to the recommended dosage and infusion duration may reduce the likelihood and severity of IR. Moreover, reducing the infusion rate may also minimize many of the listed IR. Pre-administration of antipyretic drugs, glucocorticosteroids and/or antihistamines may reduce both the frequency and severity of these side reactions.

Monitoring of the number of lymphocytes and platelets should be carried out during therapy with Thymoglobulin^® and after it. The severity of lymphopenia and thrombocytopenia may decrease with a reduction in the drug dose.

Careful monitoring of the patient, as well as anti-infective prophylaxis, is recommended when Thymoglobulin^® is administered together with other immunosuppressive drugs.

Components of human origin (formaldehyde-treated erythrocytes and thymus cells) are used in the production of rabbit immunoglobulins. Standard measures to prevent the transmission of infectious agents when using medicinal products obtained using human biological material include careful selection of biological material, as well as the use of effective measures for virus deactivation/elimination during the production process. However, the possibility of transmission of infectious agents cannot be completely excluded. This risk also applies to unknown viruses or other types of infectious agents. The measures taken have been recognized as effective against enveloped 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 against non-enveloped viruses, for example parvovirus B19. Parvovirus B19 infection can be dangerous for the fetus and for persons with certain types of immunodeficiency and anemia. The safety of using live attenuated vaccines in patients during therapy with Thymoglobulin^® has not been studied; thus, immunization with live attenuated vaccines is not recommended for patients who have recently received Thymoglobulin^®.

Special recommendations for the administration of Thymoglobulin^® infusions As with any infusion, the administration of Thymoglobulin^® may cause pain, swelling, and redness at the injection site. The recommended method of administration for Thymoglobulin^® is infusion into central veins; however, administration into peripheral veins is also possible.

Effect on the ability to drive vehicles and operate machinery

Based on potential adverse reactions that may occur during Thymoglobulin^® infusions, in particular – CVS, patients are advised not to drive vehicles or engage in other potentially hazardous activities.

Overdose

Accidental overdose may lead to leukopenia (including lymphopenia and neutropenia) and thrombocytopenia. These manifestations are reversible and can be managed by dose adjustment or discontinuation of therapy. There is no antidote for antithymocyte immunoglobulin.

Drug Interactions

Adverse reactions should be considered when using the following combinations of Thymoglobulin^® with the listed medications.

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

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

Rabbit antithymocyte immunoglobulin may induce the formation of antibodies that react with other rabbit immunoglobulins. Thymoglobulin^® is unlikely to affect the results of routine clinical laboratory tests that use immunoglobulins.

However, the effect of Thymoglobulin^® may be evident in immunological tests based on the use of rabbit antibodies, cross-match studies, or panel reactive antibody cytotoxicity tests.

Incompatibilities

Based on a single compatibility study, it was noted that the combination of Thymoglobulin^®, heparin, and hydrocortisone with a glucose infusion solution leads to precipitate formation and should therefore be avoided. Due to the lack of other compatibility studies, Thymoglobulin^® should not be mixed in the same container with other medicinal products, except for those indicated in the ‘Dosage and Administration’ section.

Storage Conditions

Store at a temperature between 2°C and 8°C (46.4°F). Do not freeze. Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.