Thimoglobuline 5 mg/ml

Leaflet attached to the packaging: patient information

Thymoglobuline 5 mg/ml, 25 mg

Powder for solution for infusion

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, please tell your doctor or pharmacist. See section 4.

Table of contents of the leaflet

• 1. What is Thymoglobuline 5 mg/ml and what is it used for
• 2. Important information before using Thymoglobuline 5 mg/ml
• 3. How to use Thymoglobuline 5 mg/ml
• 4. Possible side effects
• 5. How to store Thymoglobuline 5 mg/ml
• 6. Contents of the pack and other information

1. What is Thymoglobuline 5 mg/ml and what is it used for

Thymoglobuline 5 mg/ml is a medicine in the form of a powder containing 25 mg of rabbit immunoglobulin against human thymocytes. Before administration, the powder should be dissolved in water for injections, and then diluted to prepare an infusion solution (drip). Thymoglobuline 5 mg/ml is an immunosuppressive medicine (ATC: L04AA04, immunoglobulin against human thymocytes).

Indications:

• Immunosuppression in transplantation: prevention and treatment of graft rejection;
• Prevention of acute and chronic graft-versus-host disease after hematopoietic stem cell transplantation in adults;
• Treatment of acute, steroid-resistant graft-versus-host disease (GvHD);
• Treatment of aplastic anemia.

2. Important information before using Thymoglobuline 5 mg/ml

When not to use Thymoglobuline 5 mg/ml:

Warnings and precautions

Before starting treatment with Thymoglobuline 5 mg/ml, discuss it with your doctor. Thymoglobuline 5 mg/ml should only be administered in a hospital under strict medical supervision. During treatment with thymoglobulin, the doctor will regularly perform blood tests and other tests to monitor the patient's health. Due to the mechanism of action of this medicine, it may affect the blood and other organs of the patient. Some severe side effects may be related to the rate of infusion. The recommended infusion rate in section 3 "How to use Thymoglobuline 5 mg/ml" should be followed. During the infusion, patients should be closely monitored. Due to the risk of serum sickness (fever, itching, rash, hives (itching, redness), muscle and joint pain), special precautions should be taken for those patients who have previously received rabbit immunoglobulin. If a side effect occurs, the infusion rate should be reduced or the infusion stopped until the symptoms resolve. If a generalized anaphylactic reaction occurs, the infusion should be stopped immediately. In case of shock (a disease characterized by a sudden drop in blood pressure), immediate symptomatic anti-shock treatment should be initiated. The decision to re-administer Thymoglobuline 5 mg/ml to patients who have previously experienced an anaphylactic reaction to this medicine should be carefully considered. In the case of organ transplantation:

• consider reducing the dose if the platelet count is between 50,000 and 75,000 cells/mm or the white blood cell count is between 2,000 and 3,000 cells/mm;
• consider discontinuing treatment in case of persistent severe thrombocytopenia (below 50,000 cells/mm) or leukopenia (below 2,000 cells/mm). During and after treatment with Thymoglobuline 5 mg/ml, the white blood cell and platelet count should be monitored.

After administration of Thymoglobuline 5 mg/ml in combination with several immunosuppressive drugs, infections, recurrence of infections (especially cytomegalovirus), neutropenia with fever (fever associated with a reduced number of certain white blood cells), and sepsis have been observed. Therefore, careful monitoring of the patient and the use of appropriate infection prophylaxis are recommended. The increased risk of malignant changes, lymphomas, or lymphoproliferative disorders (excessive growth of white blood cells) should be considered. In the production process of this medicine, human blood components (formaldehyde-treated red blood cells) and thymocytes are used. Standard measures to prevent infections caused by the use of medicines produced from human blood components include donor selection, screening of individual donors for infection markers, and the implementation of effective procedures in the production process that allow for inactivation and/or removal of viruses. Nevertheless, it cannot be completely ruled out that the risk of transmitting infectious agents during the administration of medicines prepared using human blood components. This risk also applies to unknown or newly discovered viruses and other pathogens.

Thymoglobuline 5 mg/ml and other medicines

Tell your doctor about all medicines you are taking or have recently taken, as well as any medicines you plan to take. Due to the risk of excessive immunosuppression and the risk of lymphoproliferative disease (excessive growth of white blood cells), the concomitant administration of Thymoglobuline 5 mg/ml with other immunosuppressive medicines such as cyclosporine, tacrolimus, and mycophenolate mofetil should be considered. It has been found that the combination of Thymoglobuline 5 mg/ml with heparin and hydrocortisone in a glucose infusion solution leads to precipitation. Therefore, these medicines should not be mixed.

Vaccinations

During treatment with this medicine, the administration of live, attenuated vaccines is associated with a risk of generalized infection, which can be life-threatening. This risk is increased in patients with impaired immunity due to the underlying disease (aplastic anemia).

Diagnostic tests

This medicine may cause the formation of antibodies that react with other rabbit immunoglobulins. For two months after administration of rabbit immunoglobulin against human thymocytes, the results of serum tests performed using ELISA tests, which include rabbit antibodies, may be abnormal.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a child, ask your doctor for advice before taking this medicine. This is because the medicine should not be used during pregnancy unless it is absolutely necessary. You should not breastfeed while taking Thymoglobuline 5 mg/ml, as the medicine may pass into human milk and affect the baby.

Driving and using machines

Do not drive or operate machines while being treated with Thymoglobuline 5 mg/ml.

Thymoglobuline 5 mg/ml contains sodium

This medicine contains 4 mg of sodium (the main component of common salt) per vial, which is 0.2% of the maximum recommended daily intake of sodium in the diet for adults.

3. How to use Thymoglobuline 5 mg/ml

The dosing of Thymoglobuline 5 mg/ml differs from that of other medicines containing immunoglobulin against thymocytes, as they differ in the type and concentration of protein. The doctor should exercise caution and ensure that the prescribed dose of the medicine is appropriate. The dosing of the medicine depends on the indication, administration schedule, and concomitant use of other immunosuppressive medicines. The presented dosing can be considered as recommended. Treatment can be discontinued without the need for gradual dose reduction.

• Immunosuppression in transplantation:
• Prevention of graft rejection: 1.0 to 1.5 mg/kg body weight/day for 2 to 9 days after kidney, pancreas, or liver transplantation, or for 2 to 5 days after heart transplantation, which corresponds to a total dose of 2.0 to 7.5 mg/kg body weight after heart transplantation and 2.0 to 13.5 mg/kg body weight after transplantation of other organs. Treatment can be discontinued without the need for gradual dose reduction.
• Treatment of acute rejection: 1.5 mg/kg body weight/day for 3 to 14 days, which corresponds to a total dose of 4.5 to 21 mg/kg body weight.
• Prevention of acute and chronic graft-versus-host disease: When transplanting cells (bone marrow or hematopoietic stem cells from peripheral blood) from a mismatched related or matched unrelated donor in adult patients

it is recommended to administer Thymoglobuline 5 mg/ml prophylactically at a dose of 2.5 mg/kg body weight/day from day -4 to day -2 or day -1, which corresponds to a total dose of 7.5 to 10 mg/kg body weight.

• Aplastic anemia: 2.5 to 3.5 mg/kg body weight/day for 5 consecutive days, which corresponds to a total dose of 12.5 to 17.5 mg/kg body weight. The use of the medicine in aplastic anemia has not been established in controlled clinical trials.
• Treatment of acute, steroid-resistant graft-versus-host disease: The dosing should be determined individually for each patient. It is usually 2 to 5 mg/kg body weight/day for 5 days.

The doctor or nurse will regularly monitor the patient's condition during the administration of the first dose of the medicine, due to the increased risk of side effects. They will check for rash and monitor heart rate, blood pressure, and breathing. From time to time, the doctor may also order a blood test to check the patient's blood cell count. If the white blood cell count is low, the doctor may also administer medicines to prevent or treat infections; if the platelet count is low, the doctor may recommend platelet transfusion. The doctor may change the dose of Thymoglobuline 5 mg/ml if the patient experiences side effects.

Other medicines prescribed by the doctor

The doctor may administer other medicines to the patient before starting or during the administration of Thymoglobuline 5 mg/ml. These medicines, listed below, are used to prevent or treat possible side effects:

• antipyretic medicines to reduce fever;
• intravenous corticosteroids to prevent graft rejection and side effects;
• antihistamines to prevent allergic reactions;
• heparin to reduce the risk of blood clots.

Use in children and adolescents

There are no dosing recommendations. Available data indicate that the dosing regimen used in adult patients does not require modification in children and adolescents. As in adult patients, dosing in children and adolescents depends on the indication, administration schedule, and concomitant use of other immunosuppressive medicines. All these factors should be taken into account by the treating doctor when determining the dosing.

Use of a higher than recommended dose of Thymoglobuline 5 mg/ml

It is unlikely that a patient will receive a higher than recommended dose of Thymoglobuline 5 mg/ml, as the patient's condition will be closely monitored by the doctor or nurse throughout the treatment period. In case of administration of a higher than recommended dose of Thymoglobuline 5 mg/ml, thrombocytopenia (low platelet count) or leukopenia (low white blood cell count) may occur. This can cause fever, chills, sore throat, mouth ulcers, and bleeding or easier bruising than usual. The use of this medicine for more than 3 weeks may promote serious infections and increase the risk of lymphomas (a disease characterized by the excessive growth of white blood cells).

Missing a dose of Thymoglobuline 5 mg/ml

Do not take a double dose to make up for a missed dose.

Discontinuation of Thymoglobuline 5 mg/ml

If you have any further questions about the use of this medicine, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some side effects, such as fever, rash, and headache, as well as other side effects affecting heart rate, blood pressure, and breathing, and some allergic reactions, may occur more frequently after the first or second dose of Thymoglobuline 5 mg/ml than after subsequent doses. You should immediately inform your doctor if you experience:

• Itching rash
• Breathing difficulties
• Stomach pain
• Swelling of the face, tongue, or throat

The following side effects have been reported during and after the administration of this medicine:

• very common side effects (may affect more than 1 in 10 people): low red blood cell count (anemia);
• infusion-related reactions after the first or second administration of the medicine, during a single treatment cycle. These reactions are characterized by fever, chills, shortness of breath, nausea or vomiting, diarrhea, low or high blood pressure, general malaise, rash, hives, and/or headache. These reactions are usually mild and transient and can be prevented by reducing the infusion rate and/or using appropriate medicines;
• during treatment or after discontinuation of Thymoglobuline 5 mg/ml, elevated liver enzyme activity in the blood has been commonly (in more than 1 in 100 people) observed in patients. This is usually an asymptomatic condition and liver function test results return to normal without treatment. However, liver damage (liver failure) has been rarely (possibility of occurrence in more than 1 in 1,000 people) reported;
• unknown frequency (frequency cannot be estimated from available data): increased bilirubin levels in the blood (elevated laboratory test result);
• infusion-related reactions as a result of cytokine release syndrome (a condition characterized by the release of immune system-related molecules). Severe and potentially life-threatening cases of this syndrome have been rarely reported. Severe cytokine release syndrome has been reported, which involved cardiovascular and respiratory disorders (hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, tachycardia, and/or death);
• very rare cases of severe anaphylactic reactions have been reported, which involved patients who did not receive epinephrine during the event;
• side effects such as fever, rash, hives, joint and/or muscle pain, which suggested serum sickness. Serum sickness may occur between 5 and 15 days after the start of treatment. These symptoms are transient and resolve after corticosteroid administration;
• side effects at the injection site, such as pain, swelling, and redness at the injection site. After concomitant administration of this medicine, heparin, and hydrocortisone in a 0.9% sodium chloride solution, the risk of superficial thrombophlebitis (inflammation of the vein caused by a blood clot) and deep vein thrombosis can be reduced;

side effects such as neutropenia (reduced granulocyte count - a change in the blood picture) and thrombocytopenia (reduced platelet count), related to the presence of cross-reacting antibodies. These reactions may occur during the first two days of treatment and after its completion. Their mechanism is related to the presence of cross-reacting antibodies with neutrophils and platelets. Monitoring the white blood cell and platelet count helps to reduce the severity and frequency of these reactions;

If you experience any side effects, including any not listed in this leaflet, please inform your doctor or nurse.

Additional side effects in children and adolescents

Available information indicates that the side effects of Thymoglobuline 5 mg/ml observed in children and adolescents do not differ significantly from those observed in adult patients.

Reporting side effects

If you experience any side effects, including any not listed in this leaflet, please inform your doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Adverse Reaction Monitoring of Medicinal Products, Medical Devices, and Biocidal Products, Urząd Rejestracji Produktów Leczniczych, Wyrobów Medycznych i Produktów Biobójczych, Al. Jerozolimskie 181C, 02-222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl. Side effects can also be reported to the marketing authorization holder or its representative in Poland: Sanofi Sp. z o.o., ul. Marcina Kasprzaka 6, 01-211 Warsaw, Tel.: 022 280 00 00. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Thymoglobuline 5 mg/ml

Keep the medicine out of the sight and reach of children. Unopened vials of Thymoglobuline 5 mg/ml should be stored in a refrigerator at 2°C - 8°C. Do not freeze. After reconstitution, the solution should be used immediately; however, it has been shown that the prepared solution remains stable for 24 hours at 20°C. Do not use this medicine after the expiry date stated on the carton after "Expiry date (EXP)". The expiry date refers to the last day of the month stated.

6. Contents of the pack and other information

What Thymoglobuline 5 mg/ml contains

• The active substance is: Rabbit immunoglobulin against human thymocytes - 25 mg.
• The other ingredients are: glycine, sodium chloride, mannitol.

What Thymoglobuline looks like and contents of the pack:

Thymoglobuline 5 mg/ml is supplied in vials of type I glass with a chlorobutyl rubber stopper coated with a fluorobutyl rubber layer, containing 25 mg of powder, in a cardboard box.

Marketing authorization holder and manufacturer

Marketing authorization holder: Sanofi B.V., Paasheuvelweg 25, 1105 BP Amsterdam, Netherlands

Manufacturer:

Sanofi Winthrop Industrie, 23 boulevard Chambaud de la Bruyere, 69007 Lyon, France; Genzyme Ireland Ltd, IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland. For further information, please contact the representative of the marketing authorization holder in Poland: Sanofi Sp. z o.o., ul. Marcina Kasprzaka 6, 01-211 Warsaw, Tel.: 022 280 00 00

Date of last revision of the leaflet:

Information intended for healthcare professionals only:

Each vial of Thymoglobuline 5 mg/ml is intended for single use only. It is recommended that each time Thymoglobuline 5 mg/ml is administered to a patient, the patient's name and the batch number of the product should be recorded to enable the patient to be linked to the batch. Rabbit immunoglobulin against human thymocytes is usually used as one of the medicines in the immunosuppressive treatment regimen. Before administering Thymoglobuline 5 mg/ml, daily doses of antipyretic medicines, intravenous corticosteroids, and/or antihistamines should be used. This medicine is administered intravenously as an infusion after dilution in isotonic (0.9% sodium chloride or 5% glucose) solution. The solution should be clear or slightly opalescent. The reconstituted product should be inspected visually for particulate matter and discoloration. Do not use if the vial contains particulate matter or the solution is discolored. It is recommended to use the reconstituted product immediately. The medicine is administered as a slow infusion into a large vein; however, administration into a peripheral vein is also possible. The infusion rate should be set so that the total infusion time is not less than 4 hours. During administration of the medicine, an in-line filter with a pore size of 0.2 µm and low protein-binding capacity should be used. It has been shown that the use of a 0.2 µm filter removes visible particulate matter and does not result in significant loss of protein or its activity. To reduce the risk of superficial thrombophlebitis and deep vein thrombosis, this medicine can be administered into a peripheral vein with heparin and hydrocortisone in a 0.9% sodium chloride solution. Do not mix Thymoglobuline 5 mg/ml with heparin and hydrocortisone in a glucose infusion solution, as this causes precipitation.

Preparation of the infusion solution of Thymoglobuline 5 mg/ml (using aseptic technique)

Preparation of the solution:

• dissolve the powder using 5 ml of water for injections;
• dilute the daily dose in an isotonic solution (0.9% sodium chloride or 5% glucose) to obtain an infusion solution with a total volume of 50 to 500 ml (usually 50 ml per vial).

The product should be used on the same day.