TIMOGLOBULIN 5mg/ml POWDER FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

TIMOGLOBULIN 5mg/ml, powder for solution for infusion.

Rabbit antihuman thymocyte immunoglobulin.

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• This medicine will be administered to you by a doctor or nurse in the hospital.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the package leaflet:

1. What is Timoglobulin and what is it used for
2. What you need to know before using Timoglobulin
3. How to use Timoglobulin
4. Possible side effects
5. Storage of Timoglobulin
6. Contents of the pack and further information

1. What is Timoglobulin and what is it used for

Timoglobulin belongs to a group of medicines called immunosuppressants (anti-rejection medicines).

Timoglobulin is obtained from the blood of rabbits that have been injected with cells from the human thymus gland. The immunoglobulins it contains bind to and destroy certain types of cells in your immune system. These cells play a role in organ transplant rejection processes, such as kidney transplants, or are involved in other undesirable immune reactions.

It is used in:

Kidney transplant.

To prevent and treat transplant rejection.

Haematology.

Immunosuppressive treatment of severe aplastic anaemia in patients who have not responded to previous immunosuppressive treatment with equine antithymocyte immunoglobulin.

Aplastic anaemia is a type of blood disorder in which the body does not produce enough blood cells.

Haematopoietic progenitor cell transplantation.

Prophylaxis of rejection episodes in haematopoietic progenitor cell transplantation from unrelated donors.

Timoglobulin is used in patients who have undergone haematopoietic progenitor cell transplantation to prevent rejection of the transplanted cells.

2. What you need to know before using Timoglobulin

Do not use Timoglobulin

• If you are allergic to the active substance of Timoglobulin (rabbit antihuman thymocyte immunoglobulin) or to any of the other components of this medicine (listed in section 6).
• If you have an infection because Timoglobulin reduces the body's ability to fight infections.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting treatment with Timoglobulin if:

• You have ever had an allergic reaction to animals or other medicines. Your doctor will monitor you closely during administration and interrupt treatment if there are signs of an allergic reaction to Timoglobulin. The use of this medicine can cause a severe allergic reaction (anaphylaxis) or cytokine release syndrome.
• You have a blood disorder, such as a low platelet count (thrombocytopenia) or a low white blood cell count (leucopenia). Your dose will depend on the number of white blood cells or platelets you have in your blood, which will be checked before, during, and after treatment.

During treatment with Timoglobulin, your doctor may regularly perform blood tests or other tests to monitor your condition. Due to the way this medicine works, it may affect your blood or other organs.

The use of Timoglobulin in combination with several immunosuppressants has been associated with infections (bacterial, mycotic, viral, and protozoal) and reactivation of infections (especially cytomegalovirus [CMV]), septicemia (blood infection), and febrile neutropenia (fever associated with a lower than normal number of certain white blood cells).

To control some adverse reactions, your doctor may administer other medicines, such as antipyretics (medicines to prevent fever), corticosteroids, and/or antihistamines, before administering Timoglobulin.

Your blood will be tested to check your blood counts (white blood cell and platelet counts) during treatment with Timoglobulin and after treatment.

The use of immunosuppressants, including Timoglobulin, may increase the incidence of malignant neoplasms, such as lymphoma or lymphoproliferative disorders.

Risk of transmission of infectious agents

In the manufacturing process of Timoglobulin, components of human blood (formaldehyde-treated red blood cells) and thymic cells are used. When medicines derived from human plasma or blood are administered, certain measures must be taken to prevent infections from being transmitted to patients. These measures include careful selection of donors to exclude those at risk of carrying infectious diseases, testing for specific infection markers in individual donations and plasma pools, as well as inclusion of stages in the manufacturing process to eliminate/inactivate viruses. Despite this, when medicines derived from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be entirely excluded. This also applies to emerging or unknown viruses or other types of infections.

The measures taken are considered effective for enveloped viruses such as HIV, HBV, and HCV, and for non-enveloped viruses such as HAV and parvovirus B19.

Using Timoglobulin with other medicines

Tell your doctor if you are taking or have recently taken any other medicines, including those that can be obtained without a prescription. This is especially important if you are taking or have taken:

• Any other anti-rejection medicine (immunosuppressant) such as cyclosporin, azathioprine, or corticosteroids. The reason is that if the body's immune system is severely reduced, serious infections can occur. It may also increase the possibility of developing cancer in the future.
• If you have received blood transfusions or medicines derived from blood.

Vaccinations

Do not receive any vaccinations during or shortly after treatment with Timoglobulin without first talking to your doctor, as they may cause side effects (if it is a live vaccine) or may not work because your immune system cannot respond to it.

The administration of this medicine may interfere with the results of certain tests called immunoassays with rabbit antibodies.

Using Timoglobulin with food and drinks

It is unlikely that consumption of food or drinks will affect the medicine.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine, as it should not be used in pregnant women unless absolutely necessary due to unknown effects.

Do notbreast-feed if you are being treated with Timoglobulin, as it may pass into breast milk and affect the baby.

Driving and using machines

Do notdrive or use tools or machines while being treated with Timoglobulin.

Timoglobulin contains sodium

This medicine contains 4 mg of sodium (main component of cooking/table salt) in each vial. This is equivalent to 0.2% of the maximum daily intake of sodium recommended for an adult.

3. How to use Timoglobulin

Your medicine will be administered to you by a doctor or nurse in the hospital. Timoglobulin is administered through a plastic tube (catheter) directly into the bloodstream (intravenous infusion) over a period of at least 4 hours. The first dose may be administered over a longer period.

The dose administered is variable and depends on your weight, the medical problem being treated, and whether you are taking other medicines at the same time.

Prevention of kidney transplant rejection

1 to 1.5 mg of Timoglobulin per kilogram of body weight, per day, for 3 to 9 days after a kidney transplant.

Treatment of kidney transplant rejection

1.5 mg of Timoglobulin per kilogram of body weight, per day, for 7 to 14 days.

Treatment of aplastic anaemia

3.75 mg of Timoglobulin per kilogram of body weight, per day, for 5 consecutive days.

Prevention of haematopoietic progenitor cell transplant rejection

2.5 mg of Timoglobulin per kilogram of body weight, per day, starting 4 days before transplantation and ending 2 days or 1 day before transplantation.

Your doctor or nurse will monitor you regularly while you are receiving the first dose, as this is when side effects are most likely to occur. They will check for rash, as well as your pulse, blood pressure, and breathing. Occasionally, your doctor may also want to perform a blood test to check your blood cell count.

Your doctor may change your dose of Timoglobulin if you experience any side effects.

Use in children and adolescents

Available information indicates that paediatric patients do not require a different dosage from adult patients.

Other medicines that your doctor may administer

Your doctor may administer other medicines before or at the same time as Timoglobulin. These are used to prevent or treat possible side effects and may include:

• Antipyretics (such as paracetamol) to reduce fever
• Corticosteroids (e.g. hydrocortisone) to prevent organ rejection and side effects
• Antihistamines (e.g. cetirizine) to prevent an allergic reaction
• Heparin to reduce the risk of blood clots

If you use more Timoglobulin than you should

It is unlikely that you will be administered more Timoglobulin than you should, as your doctor or nurse will monitor you closely during treatment. If this happens, you may experience a lower than normal number of platelets (thrombocytopenia) or a lower than normal number of white blood cells (leucopenia). This can cause fever, chills, sore throat, mouth ulcers, and bleeding or bruising more easily than usual. These effects are usually temporary and disappear when the dose is reduced or treatment is discontinued.

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, and others that affect your pulse, blood pressure, and breathing, as well as some allergic reactions, are more likely to occur with the first or second dose of Timoglobulin than with subsequent doses. Serious allergic reactions have been reported, and in very rare cases (at least 1 in 10,000 people), they have been fatal.

Infusion site reactions, including pain, swelling, and erythema, have been reported.

Tell your doctor immediately if you experience any of the following symptoms, as they may be signs of a potentially life-threatening allergic reaction:

• A rash with itching
• Difficulty breathing
• Stomach pain
• Swelling of the face, tongue, or throat

Sometimes, receiving an infusion of Timoglobulin may cause the following additional side effects. You should tell your doctor as soon as possible if you experience any of the following symptoms:

• Difficulty breathing, wheezing, or coughing
• Feeling sick or being sick
• Dizziness or feeling faint
• Tiredness
• Pain in the joints
• Headache
• Bleeding or bruising more easily than usual

• Irregular or rapid heartbeat
• Signs of infection such as fever, chills, sore throat, or mouth ulcers

During or after treatment with Timoglobulin, some patients have developed changes in certain liver function tests. These are usually without symptoms and liver function returns to normal without treatment.

The following side effects were reported during a clinical trial, but this does not necessarily mean that they were all caused by Timoglobulin.

Very common side effects (at least 1 in 10 patients):

• Low white blood cell count; low platelet count
• Fever
• Infection
• Low red blood cell count (anaemia)

Common side effects (at least 1 in 100 but less than 1 in 10 patients):

• Increased liver enzymes in the blood
• Diarrhoea, difficulty swallowing, nausea, vomiting
• Chills
• Serum sickness, which is a condition caused by antibodies to Timoglobulin that causes rash, itching, urticaria (red itchy patches), joint pain, kidney problems, and swelling of the lymph nodes, and which occurs 5 to 15 days after treatment. Serum sickness is usually mild and resolves without treatment or with a short course of steroids
• Muscle pain
• Malignant neoplasms, cysts
• Shortness of breath
• Itching, rash
• Low blood pressure

Uncommon side effects (may affect up to 1 in 1,000 people):

• Liver damage (liver failure)

These side effects may be mild and resolve with treatment with other medicines. They may also be reduced by changing the dose of Timoglobulin or increasing the period over which it is administered.

Frequency not known (cannot be estimated from the available data)

• Increased bilirubin in the blood (elevated laboratory parameter)

Sometimes, side effects may occur several months later. These late effects include an increased risk of infections and certain types of cancer. In some cases, these effects are associated with mortality.

If you receive Timoglobulin with other immunosuppressive medicines, you may be more susceptible to infections.

Other side effects in children and adolescents

Available information indicates that the side effects of Timoglobulin in children and adolescents are not fundamentally different from those observed in adults.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Timoglobulin

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton. The expiry date refers to the last day of the month shown.

Unopened vials of Timoglobulin should be stored in a refrigerator (2-8°C). Do not freeze.

It is recommended to use it immediately after dilution to avoid microbial contamination.

6. Container Contents and Additional Information

Composition of Timoglobulina

Timoglobulina contains 25 mg of the active substance rabbit antihuman thymocyte immunoglobulin. It also contains mannitol, glycine, and sodium chloride (salt).

Appearance of the Product and Container Contents

Timoglobulina is supplied in a glass vial containing a white-cream colored powder. Before use, it is mixed with 5 milliliters (ml) of sterile water to obtain a liquid. Each milliliter (ml) contains 5 mg of rabbit antihuman thymocyte immunoglobulin. This liquid is then mixed with a sodium chloride or glucose solution so that it can be slowly administered (via infusion) into the circulatory system through a plastic tube (catheter) in a large vein.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Sanofi Europe B.V.

Paasheuvelweg 25

1105 BP Amsterdam, Netherlands

Manufacturer:

Genzyme Polyclonals S.A.S

23 boulevard Chambaud de la Bruyère

69007 Lyon, France

Genzyme Ireland Ltd

IDA Industrial Park

Old Kilmeaden Road

Waterford, Ireland

Local Representative:

sanofi-aventis, S.A.

C/ Roselló i Porcel, 21

08016 Barcelona

Spain

Medicine Registration Number: 62650

For any information about Timoglobulina, please contact the Local Representative or the Marketing Authorization Holder.

This leaflet was approved in July 2021

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This information is intended exclusively for doctors or healthcare professionals:

Each vial of Timoglobulina is for single use only.

Depending on the daily dose, it may be necessary to reconstitute several vials of Timoglobulina. Determine the number of vials to be used and round up to the nearest vial.

Using an aseptic technique, reconstitute the powder with 5 ml of sterile water for injection to obtain a solution containing 5 mg of protein per ml. The solution should be transparent or slightly opalescent. The reconstituted product should be visually inspected for particles or a change in color. Do not use vials that have particles or have changed color.

It is recommended to use it immediately after reconstitution.

If not used immediately, the user is responsible for the storage times and conditions before administration and normally should not exceed 24 hours at 2-8°C, unless the reconstitution and dilution have taken place in controlled and validated aseptic conditions.

Preparation of the Timoglobulina Infusion (using an aseptic technique)

Extract the necessary volume of the reconstituted solution from the Timoglobulina vials. Add the daily dose to an infusion solution (0.9% sodium chloride injection solution or 5% glucose solution) to obtain a total infusion volume of between 50 and 500 ml (normally 50 ml/vial).

The product should be administered on the same day. The use of a 0.22 µm in-line filter is recommended.

The disposal of unused medicinal products and all materials that have come into contact with them will be carried out in accordance with local regulations.

Detailed and updated information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es