Product Information for the Patient

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

Human Anti-Thymocyte Globulin from Rabbit.

Read this entire product information carefully before starting to use the medication, as it contains important information for you.

- Keep this product information, as you may need to read it again.

- If you have any questions, consult your doctor, pharmacist, or nurse.

- This medication will be administered by a doctor or nurse in the hospital.

- If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this product information. See section 4.

1. What is Timoglobulina and for what it is used

2. What you need to know before using Timoglobulina

3. How to use Timoglobulina

4. Possible adverse effects

5. Storage of Timoglobulina

6. Contents of the package and additional information

Thymoglobulin belongs to a group of medications called immunosuppressants (anti-rejection medications).

Thymoglobulin is obtained from rabbit blood to which human thymus gland cells have been injected. The immunoglobulins it contains bind to and destroy some types of immune system cells in your body. These cells play a role in transplant rejection processes, such as kidney transplant rejection, or in other unwanted immune reactions.

It is used in:

Kidney transplant.

To prevent and treat transplant rejection.

Hematology.

Immunosuppressive treatment of severe aplastic anemiain patients who have not responded to previous immunosuppressive treatment with equine anti-thymocyte globulin.

Aplastic anemia is a type of blood disorder in which the body does not produce a sufficient amount of blood cells.

Stem cell transplant.

Prophylaxis of rejection episodes in stem cell transplants from unrelated donors.

Thymoglobulin is used in patients who have received hematopoietic stem cell transplants to prevent rejection of these transplanted cells.

No use Timoglobulina

- If you are allergic to the active ingredient of Timoglobulina (Human Antithymocyte Globulin) or to any of the other components of this medication (listed in section 6).

- If you have an infection because Timoglobulina reduces the body's ability to fight infections.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Timoglobulina if:

• You have ever had an allergic reaction to animals or other medications. Your doctor will closely monitor you during the administration of the medication and will interrupt treatment if there are signs of an allergic reaction to Timoglobulina. With the use of this medication, a severe allergic reaction (anaphylaxis) or cytokine release syndrome may occur.
• You have any blood disorders, such as a low platelet count in the blood (thrombocytopenia) or a low white blood cell count in the blood (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 Timoglobulina, your doctor may perform regular blood tests or other tests to monitor your condition. Due to the way this medication works, it may affect your blood or other organs.

With the use of Timoglobulina in combination with several immunosuppressants, infections (bacterial, fungal, viral, and protozoal) and reactivation of infections (especially cytomegalovirus [CMV]) have been reported, septicemia (blood infection), and febrile neutropenia (fever associated with a low count of certain white blood cells).

To control some adverse reactions, it may be possible for your doctor to administer other medications before administering Timoglobulina, such as antipyretics (fever-reducing medications), corticosteroids, and/or antihistamines.

Your blood will be analyzed to control your blood counts (leukocytes and platelets) during treatment with Timoglobulina and after treatment.

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

Risk of transmission of infectious agents

In the manufacturing process of Timoglobulina, components of human blood (formaldehyde-treated erythrocytes) and thymic cells are used. When administering medications derived from plasma or human blood, certain measures must be taken to prevent infections from passing to patients. These measures include a careful selection of donors to exclude those at risk of being carriers of infectious diseases, analysis of specific infection markers in individual donations and plasma mixtures, and inclusion of stages in the manufacturing process to eliminate/inactivate viruses. Despite this, when administering medications derived from human blood or plasma, the possibility of transmission of infectious agents cannot be completely ruled out. 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, HCV, and HBV, and for non-enveloped viruses VHA and parvovirus B19.

Use of Timoglobulina with other medications

Inform your doctor if you are taking or have recently taken any other medication, including medications that can be purchased without a prescription. This is especially important if you are taking or have taken:

• Any other immunosuppressive medication such as cyclosporine, azathioprine, or corticosteroids. The reason is that if the body's immune system is severely reduced, severe infections may occur. It may also increase the likelihood of developing cancer in the future.
• You have received transfusions or medications derived from blood.

Vaccinations

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

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

Use of Timoglobulina with food and beverages

It is unlikely that the consumption of food or beverages will affect the medication.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor or pharmacist before using this medication, as Timoglobulina should not be used in pregnant women unless absolutely necessary, as its effects are unknown.

Do not breastfeed while being treated with Timoglobulina, as it may pass into breast milk and affect the baby.

Driving and operating machinery

Do not drive or use tools or machines while being treated with Timoglobulina.

Timoglobulina contains sodium

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

Your medication will be administered by a doctor or a nurse in the hospital.Timoglobulina is administered through a plastic tube (catheter) directly into the circulatory system (intravenous infusion) for a period of at least 4 hours. The first dose may be administered for a longer period of time.

The dose administered is variable and depends on your weight, the medical condition being treated, and if you are receiving other medications at the same time.

Prevention of kidney transplant rejection

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

Treatment of kidney transplant rejection

1.5 mg of Timoglobulina per kilogram of body weight, once a day for 7 to 14 days.

Treatment of aplastic anemia

3.75 mg of Timoglobulina per kilogram of body weight, once a day for 5 consecutive days.

Prevention of hematopoietic stem cell transplant rejection

2.5 mg of Timoglobulina per kilogram of body weight, once a day starting 4 days before the transplant and ending 2 or 1 day before the transplant.

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

Your doctor may adjust your Timoglobulina dose if you experience any side effects.

Use in children and adolescents

The available information indicates that pediatric patients do not require a different dosage regimen than adult patients.

Other medications that your doctor may administer

Your doctor may administer other medications before or at the same time as Timoglobulina. 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 receive more Timoglobulina than you should

It is unlikely that you will receive more Timoglobulina than you should, as your doctor or nurse will closely monitor you during treatment. If this happens, you may experience a lower than normal platelet count (thrombocytopenia) or a lower than normal white blood cell count (leucopenia). This can cause you to be more susceptible to fever, chills, sore throat, mouth ulcers, and bleeding or bruising more easily than normal. These effects are usually temporary and resolve when the dose is reduced or the treatment is discontinued.

Like all medicines, this medicine can cause side effects, although not everyone will experience 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 Timoglobulina than with subsequent doses. Severe allergic reactions have been reported, and in very rare cases (at least 1 in 10,000 people), they have led to death.

Reactions at the site of infusion, among others, such as pain, swelling, and erythema, have been reported.

Inform your doctor immediately if you experience any of the following symptoms, as they may be potentially fatal signs of an allergic reaction:

• A pruritic rash
• Difficulty breathing
• Abdominal pain
• Swelling of the face, tongue, or throat

At times, receiving a Timoglobulina infusion may cause the following additional side effects.You should inform your doctor as soon as possible if you experience any of the following symptoms:

• Difficulty breathing, wheezing, or coughing
• Sensation of nausea or nausea
• Dizziness or feeling of fainting
• Fatigue
• Joint pain
• Headache
• Bleeding or bruising that occurs more easily than normal

• Irregular or rapid heart rhythm
• Symptoms of infection such as fever, chills, sore throat, or mouth ulcers

During or after treatment with Timoglobulina, some patients experience alterations in certain liver function tests. Generally, there are no symptoms, and liver function returns to normal without the need for treatment.

The following side effects were reported during a clinical trial, butthis does not necessarily mean that all were caused by Timoglobulina.

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

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

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

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

Rare side effects (may affect more than 1 in 1,000 people):

• Liver damage (hepatic insufficiency)

These side effects may be mild and disappear with treatment with other medications.They may also be reduced by changing the dose of Timoglobulina or increasing the period during which it is administered.

Unknown frequency (cannot be estimated from available data)

• Increased bilirubin in the blood (elevated laboratory parameter)

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

If you receive Timoglobulina with other immunosuppressive medications, you may be more vulnerable to infections.

Other side effects in children and adolescents

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

Reporting side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through the Spanish System for the Pharmacovigilance of Medicines for Human Use:https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

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

Do not use this medication after the expiration date that appears on the packaging. The expiration date is the last day of the month indicated.

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

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

Composition of Timoglobulin

Timoglobulin contains 25 mg of the active substance human antithymocyte immunoglobulin from rabbit.It also contains mannitol, glycine, and sodium chloride (salt).

Appearance of the product and contents of the container

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

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization:

Sanofi Europe B.V.

Paasheuvelweg 25

1105 BP Amsterdam,Netherlands

Responsible for manufacturing:

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 Timoglobulin, contact the Local Representative or the Holder of the Marketing Authorization.

This prospectus was approved in July 2021

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This information is intended solely for doctors or healthcare professionals:

Each vial of Timoglobulin is for single use only.

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

Using an aseptic technique, reconstitute the powder with 5 ml of sterile injection water to obtain a solution containing 5 mg of protein per ml.The solution must be transparent or slightly opalescent.The reconstituted product should be visually inspected for particles or color change.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 during use before administration and normally should not exceed 24 hours at 2-8°C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.

Preparation of the Timoglobulin infusion (use of an aseptic technique)

Draw off the required volume from the reconstituted solution from the Timoglobulin vials.Add the daily dose to an infusion solution (0.9% sodium chloride for injection or 5% glucose solution) to obtain a total infusion volume of between 50 and 500 ml (usually 50 ml/vial).

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

The elimination of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.

Detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es