TRONOXAL 1000 mg POWDER FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Tronoxal 1,000 mg powder for solution for infusion

Ifosfamide

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 or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack and other information:

1. What Tronoxal is and what it is used for.
2. What you need to know before you are given Tronoxal.
3. How Tronoxal will be given to you.
4. Possible side effects.
5. Storing Tronoxal.
6. Contents of the pack and other information.

1. What Tronoxal is and what it is used for

Tronoxal contains the active substance Ifosfamide. It belongs to a group of medicines known as “cytotoxic or antineoplastic medicines”, which work by stopping the growth of cancer cells.

Important things you should know about ifosfamide

Your doctor has prescribed Ifosfamide because you have a cancer that can be treated.

Ifosfamide is a medicine that destroys cancer cells, but as a result, it also attacks normal cells. Therefore, it can have side effects.

Your doctor will only give you ifosfamide if your cancer poses a greater risk to you than the possible side effects. Your doctor will regularly check you and treat any side effects as much as possible.

Ifosfamide:

• will reduce your blood cell count, which can make you feel tired and more prone to infections.
• may affect your kidneys and bladder. You may be given another medicine called Mesna to help prevent any damage. If you see blood in your urine, tell your doctor immediately.
• may cause mental problems, such as confusion, unusual sleepiness, and, more seriously, seizures and loss of consciousness. If you have these symptoms, tell your doctor immediately.

Tronoxal is usually used alone or in combination with other antineoplastic medicines or radiotherapy, in the treatment of different types of cancer. This includes:

• various forms of lymphomas that affect the immune system (Hodgkin's lymphoma and non-Hodgkin's lymphoma),
• ovarian cancer and testicular cancer,
• certain sarcomas, such as Ewing's sarcoma and other types of bone cancer,

2. What you need to know before you are given Tronoxal

Do not useTronoxal

• If you are allergic to ifosfamide, any of its metabolites, or any of the other ingredients of this medicine (listed in section 6). An allergic reaction may include difficulty breathing, wheezing, rash, itching, or swelling of the face and lips.
• If your bone marrow is not working properly (especially if you have previously undergone chemotherapy or radiotherapy). You will have blood tests to check your bone marrow function,
• If you have a urinary tract infection that can be recognized by pain when urinating (cystitis).
• If you have a disease that reduces your ability to urinate (obstruction of urine flow).
• If you currently have an infection.
• If you are pregnant or breastfeeding.

Be cautious with Tronoxal

Talk to your doctor before starting Tronoxal if:

• you have low blood cell counts,
• you have diabetes
• you have severe infections,
• you have liver or kidney problems,
• you are receiving or have recently received radiotherapy or chemotherapy,
• you have heart problems or have received radiotherapy in the heart area,
• you are in poor general health or are a fragile or elderly person,
• if you are receiving or have received treatment with cisplatin before or during treatment with ifosfamide.

If you are in any of the above situations, your doctor may need to perform additional blood or urine tests and may decide to change your treatment.

Tronoxal may have effects on your blood and immune system.

Blood cells are produced in your bone marrow. These cells are of three types:

• red cells, which carry oxygen in the body,
• white cells, which fight infections, and
• platelets, which allow blood to clot.

After receiving ifosfamide, the value of your blood cell count for all three types of cells will decrease. This is an inevitable side effect of the medicine. Your blood count will reach its lowest level about 5 to 10 days after starting Tronoxal and will remain low for some days after the treatment cycle ends. Most people recover normal blood cell counts within 21 to 28 days. If you have received a large amount of chemotherapy in the past, it may take a little longer to return to normal.

You are more likely to get infections if your blood count is low. Try to avoid people who have coughs, colds, and other infections. Your doctor will treat you with the appropriate medicine if they think you have an infection or are at risk of getting one.

Your doctor will make sure that your red blood cell, white blood cell, and platelet counts are high enough before and during treatment with ifosfamide.

Tronoxal may affect the normal healing of wounds. Keep cuts clean and dry and check that they are healing normally. It is important to maintain good oral health, as infections and mouth ulcers can occur. Consult your doctor if you are unsure.

Tronoxal may damage the lining of your urinary bladder and cause bleeding in the urine or pain when urinating. Your doctor knows that this can happen and, if necessary, will give you a medicine called Mesna (Uromitexan) to protect your bladder. Mesna can be given as a short injection or mixed with ifosfamide in the infusion solution. You can find more information about Mesna in the package leaflet that comes with Uromitexan.

Most people who receive Tronoxal with Mesna do not develop bladder problems, but your doctor may want to test your urine for blood using a dipstick or microscope. If you see blood in your urine, you must tell your doctor immediately.

While you are receiving Tronoxal, you should make sure to drink plenty of fluids.

Tronoxal may damage your kidneys and prevent them from working properly. This is more likely to happen if you only have one kidney or if your kidneys are already damaged, and it is usually temporary, returning to normal once Tronoxal therapy is stopped. Occasionally, the damage is permanent and more severe. Your doctor will check your test results for signs of kidney damage.

Tronoxal may have a toxic effect on the brain and spinal cord and cause encephalopathy (non-inflammatory brain disease). Tell your doctor immediately if you experience any of the following symptoms, which may be signs of brain and spinal cord toxicity:

• confusion, drowsiness, unconsciousness/coma, hallucinations/delirium, blurred vision, perception disorders, extrapyramidal symptoms (such as continuous spasms, muscle contractions, motor restlessness, slow movement, irregular movements), loss of control over urination, and seizures.

Your doctor may monitor you for signs and symptoms of brain and spinal cord toxicity.

Cancer medicines and radiotherapy may increase the risk of developing other types of cancer; this may occur several years after the end of your treatment.

Tronoxal may cause heart damage or affect the rhythm of your heartbeat. This effect is greater at higher doses of Tronoxal, if you are being treated with radiotherapy or other chemotherapeutic medicines, or if you are an elderly person. Your doctor will closely monitor your heart during treatment.

Tronoxal may cause lung problems such as inflammation or pulmonary fibrosis. This may occur more than six months after the end of treatment. If you start to have difficulty breathing, tell your doctor immediately.

Tronoxal may have potentially fatal effects on your liver.

If you experience a sudden increase in weight, liver pain, and your skin or the white of your eyes turn yellow (jaundice), tell your doctor immediately.

You may experience hair loss or baldness. Your hair should grow back normally, although its texture and color may be different.

Tronoxal may cause you to feel nauseous and vomit. This may last for about 24 hours after taking the medicine. You may need to take medicines to stop feeling nauseous and vomiting. Talk to your doctor about this.

Children and adolescents

Based on established treatment regimens, similar doses to those recommended for adults should be used in children and adolescents.

Using Tronoxal with other medicines

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines, including those bought without a prescription. In particular, tell them about the following medicines or treatments because they may be incompatible with the use of Tronoxal.

The following medicines may increase the toxicity of Tronoxal on blood cells and immunity:

• ACE inhibitors (used to treat high blood pressure),
• carboplatin (used to treat cancer)
• cisplatin (used to treat cancer)
• natalizumab (used to treat multiple sclerosis),

Medicines that may increase the toxic effects of Tronoxal on the heart:

• anthracyclines such as bleomycin, doxorubicin, epirubicin (used to treat cancer)
• radiotherapy in the heart area.

Medicines that may increase the toxic effects of Tronoxal on the lungs:

• amiodarone (used to treat irregular heartbeat),
• G-CSF, GM-CSF hormones (used to increase white blood cell counts after chemotherapy).

Medicines that may increase the toxic effects of Tronoxal on the kidneys:

• acyclovir (used to treat viruses),
• aminoglycosides (used to treat fungal infections),
• amphotericin B (used to treat fungal infections),
• Carboplatin and cisplatin (used to treat cancer).

Medicines that may increase the toxic effects on your bladder:

• Busulfan(used to treat cancer),
• irradiation of the bladder.

Medicines with an effect on the brain, such as those used against vomiting and nausea, sleeping pills, certain painkillers (opioids), or medicines for allergies.

The following medicines may increase the toxicity of Tronoxal:

• medicines that increase liver enzymes such as: rifampicin (used to treat bacterial infections), carbamazepine, phenobarbital, phenytoin (used to treat epilepsy), St. John's Wort (a herbal medicine for mild depression), corticosteroids (used to treat inflammation).

The following medicines may decrease the effectiveness of Tronoxal:

• ketokonazol, fluconazol, itraconazol (used to treat fungal infections),
• sorafenib (used to treat cancer).

Other medicines that may affect Tronoxal or be affected by it include:

• docetaxel (used to treat cancer),
• cumarins such as warfarin (used as an anticoagulant),
• vaccines,
• tamoxifen (used to treat breast cancer),
• cisplatin (used to treat cancer),
• irinotecan (used to treat cancer).

Using Tronoxal with food and drinks

Alcohol consumption should be avoided, as it may increase the nausea and vomiting caused by ifosfamide.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, or think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy

If you are a woman, you must not become pregnant during treatment with Tronoxal, as it may cause miscarriage or harm to the fetus.

Both men and women must not try to have children during treatment with ifosfamide or up to 12 months after the end of treatment, and must use effective contraceptive methods during treatment and up to 6 months after the end of treatment. If you become pregnant during treatment, there is a possibility of receiving genetic counseling (medical advice to assess the possible risk of congenital malformations in the fetus).

Breastfeeding

You must not breastfeed while being treated with ifosfamide. Ask your doctor for advice.

Fertility

Tronoxal may cause infertility in both sexes. Talk to your doctor about the cryopreservation (freezing) of sperm or eggs before treatment, as there is a possibility of irreversible infertility due to treatment with ifosfamide. If you are considering becoming a parent after treatment, you should discuss this with your doctor.

Driving and using machines

Some of the side effects of treatment with ifosfamide may affect your ability to drive or use machines safely. Your doctor will decide whether you can do so safely.

Patients should be cautious when performing tasks such as driving cars and operating machines until they have verified that treatment with the medicine does not affect their ability to perform these activities.

3. How to use Tronoxal

Tronoxal will be given to you by a doctor with experience in the use of antineoplastic chemotherapy.

Method of administration

By intravenous route.

Tronoxal is administered in an injection and is usually added to a large bag of fluid and injected slowly (infusion) directly into a vein. The vein may be in your arm, the back of your hand, or a large vein under your collarbone.

Depending on the dose, the infusion usually takes several hours, but can be administered over several days.

Tronoxal is usually given in combination with other antineoplastic medicines or radiotherapy.

The recommended dose is:

Your doctor will decide how much medicine you need and when you should receive it. This will depend on the type of disease you have, your build (a combination of your height and weight), your overall health, and whether you are receiving other antineoplastic medicines or radiotherapy.

Ifosfamide is usually given as a series of treatments. After a course, there is a break (a period during which no injections are given) before the next course.

Before, during, and after administration, it is essential that you receive adequate amounts of fluid to avoid possible side effects on the urinary tract.

If you think that Tronoxal is too strong or too weak, talk to your doctor or pharmacist.

Your doctor may need to change the amount of medicine you take and may need to monitor you more closely if:

• you have liver or kidney problems,
• you are an elderly person (over 65 years old)

Use in children and adolescents

Tronoxal is also indicated in children. The safety profile of Tronoxal in children is similar to that in adults.

If you are given too much Tronoxal

Since Tronoxal is administered under the supervision of your doctor, it is very unlikely that you can receive too much. However, if you experience side effects after receiving the medicine, tell your doctor immediately or go to the emergency department of the nearest hospital.

You may need urgent medical attention.

The symptoms of an overdose with ifosfamide include the side effects listed in the "Side effects" section, but they are usually more severe.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone 915.620.420, indicating the medicine and the amount taken.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Inform your doctor immediately if you experience:

• Appearance of bruises without being hit, or bleeding in the gums or nose. This could be a sign that the levels of platelets in your blood are too low.
• Severe infection or fever, cough, shortness of breath, signs of septicemia such as fever, rapid breathing, increased heart rate, confusion, and edema. This could be a sign of a reduction in your white blood cell count and antibiotics may be needed to fight infections.
• Pallor, feeling of lethargy and fatigue. This could be indicative of a low level of red blood cells (anemia). Normally, no treatment is required, as your body will replace the red blood cells over time. In case of pronounced anemia, a blood transfusion may be needed.
• Blood in the urine, pain when urinating, or reduced urine volume.
• Changes in mental state. In some people, ifosfamide can affect the brain. Sometimes, people taking ifosfamide may not realize they have been affected, but friends and family may notice a change in them. If you observe any of the following side effects, your doctor will interrupt your treatment with ifosfamide.

• confusion
• drowsiness
• unconsciousness/coma
• disorientation
• restlessness
• depression
• hallucinations
• delirium (false beliefs)
• blurred vision
• perception disorders
• extrapyramidal symptoms (such as continuous spasms, muscle contractions, motor restlessness, slow movement, irregular movements)
• rapid speech
• repeating words
• being fixed on a task
• aggression
• loss of control over urination
• seizures

These side effects may be accompanied by fever or tachycardia.

The following adverse effects may also occur during treatment with Tronoxal.

Very Common(may affect more than 1 in 10 patients)

• reduction of white blood cells, which are important in fighting infections (leukopenia, neutropenia),
• anemia
• alterations of mental state, which can lead to encephalopathy
• nausea and vomiting,
• hair loss (alopecia),
• presence of blood in the urine (microhematuria),
• burning sensations when urinating and frequent need to do so (cystitis).
• potentially fatal decrease in the ability of the kidneys to properly eliminate toxins and waste products from the blood (renal dysfunction, renal failure),
• changes in the structure of the kidneys that prevent them from functioning properly (structural kidney damage)

Common(may affect up to 1 in 10 patients)

• Reduction of white blood cell count and fever (febrile neutropenia),
• infections,
• anorexia,
• liver toxicity (increased liver enzymes, also with increased bilirubin, jaundice, and hepatorenal syndrome)
• inflammation of the venous walls,
• febrile neutropenia

Uncommon(may affect up to 1 in 100 patients)

• cardiac problems (congestive heart failure, tachycardia, pulmonary edema)
• peripheral neuropathy that may include the following signs: gradual onset of numbness, tingling, or prickling in the feet or hands, which can extend upwards to the legs and arms; extreme sensitivity to touch; pain during activities that should not cause pain, such as pain in the feet when putting weight on them or when they are under a blanket; lack of coordination and falls, among others
• low blood pressure
• diarrhea,
• pain or ulcers in the mouth (stomatitis),
• fatigue.

Rare(may affect up to 1 in 1,000 patients)

• skin rash,
• dermatitis,

Frequency Not Known(cannot be estimated from the available data)

• discomfort

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es.

By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Tronoxal

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

Do not store above 25°C. Store in the original package to protect from light.

Both the reconstituted and diluted solutions can be used up to 24 hours after reconstitution (do not store above 8°C).

Do not use this medicine after the expiration date that appears on the box after Lot/EXP. The expiration date is the last day of the month indicated.

The disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations for cytotoxics.

6. Package Contents and Additional Information

Composition ofTronoxal

The active ingredient is Ifosfamide.

A vial of Tronoxal contains 1,000 mg of Ifosfamide.

Appearance of the Product and Package Contents

Tronoxal is a white crystalline powder.

Tronoxal 1,000 mg powder for solution for infusion is presented in a package containing 1 vial.

Marketing Authorization Holder:

Baxter S.L.

Pouet de Camilo 2, 46394 Ribarroja del Turia, Valencia, Spain

Manufacturer:

Baxter Oncology GmbH

Kantstrasse 2, 33790 Halle/Westfalen

Germany

Date of the Last Revision of this Prospectus: March 2023

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

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This information is intended only for healthcare professionals

Tronoxal should be administered exclusively by doctors who have experience in antineoplastic chemotherapy.

Tronoxal should be administered only where there are facilities for periodic monitoring of clinical, biochemical, and hematological parameters before, during, and after administration and under the direction of a specialist oncology service.

Dosage

The dosage, duration, and/or intervals of treatment with ifosfamide depend on the therapeutic indication, the scheme of combined therapy, the patient's general state of health, laboratory parameters, as well as the recovery of analytical values.

When administered together with other cytostatic agents as a combination of chemotherapy, the dosage instructions of the appropriate treatment scheme should be followed.

Intermittent administration:1–3 g/m² of body surface area administered daily in cycles of 2 to 5 consecutive days every 2, 3, or 4 weeks. The maximum dose per cycle is 12 g/m² of body surface area.

Continuous administration5 g/m² of body surface area (maximum 8 g/m² of body surface area or 200 mg/kg of body weight) in a single dose, usually administered in 24 hours of continuous infusion every 3 or 4 weeks.

Elderly Patients and Debilitated Patients

In general, the dose in elderly patients and debilitated patients should be selected with caution, taking into account the greater frequency of deterioration of hepatic, renal, or cardiac function and concomitant diseases or treatments with other medicines (see section 4.4 of the Technical Sheet).

Patients with Renal Insufficiency

May lead to increased toxicity (e.g., neurotoxicity, nephrotoxicity, hematotoxicity), so it should be taken into consideration when establishing the dose in these patients, see section 4.4 of the Technical Sheet.

Ifosfamide and its metabolites are dialyzable. In patients who require dialysis, the use of consistent intervals between ifosfamide administration and dialysis should be considered.

A dose of 75% is recommended in patients with a creatinine clearance of 10 ml/minute or less.

Use in Patients with Hepatic Insufficiency

Hepatic insufficiency may be associated with a decrease in the activation of ifosfamide, which may alter the efficacy of ifosfamide treatment. This should be taken into consideration when selecting the dose and interpreting the response to the selected dose, see section 4.4 of the Technical Sheet.

Dose Adjustment in Patients with Myelosuppression:

Method of Administration

Intravenous route.

Attention should be paid to ensure that the diluted ifosfamide solution does not exceed a concentration of 4%

Administration is by short-term intravenous infusion over a period of time that ranges between 30 minutes and four hours, depending on the volume to be infused and the treatment scheme. It can also be administered in continuous infusion over 24 hours.

When used in combination with other cytostatic agents of similar toxicity, it may be necessary to reduce the dose and/or extend the treatment-free intervals.

When appropriate, the use of hematopoietic stimulants (colony-stimulating factors and erythropoiesis-stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or help facilitate the administration of the planned dose. For information on possible interactions with G-CSF and GM-CSF (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor), see section 4.5 of the Technical Sheet.

During or immediately after administration, an adequate amount of fluids should be ingested or infused to force diuresis in order to reduce the risk of urothelial toxicity. See section 4.4 of the Technical Sheet.

Ifosfamide at high doses should be used in combination with mesna as a prophylactic measure for hemorrhagic cystitis. The usual dose of mesna reaches or exceeds 60% of the daily dose of ifosfamide divided into 3 doses administered at 0h, 4h, and 8h after ifosfamide. In the case of the combination of ifosfamide with cisplatin, whose daily administration requires hyperhydration, it will be necessary to increase the dose of mesna administered to compensate for the increased urinary excretion.

Parenteral medicines should be visually inspected for particles and discoloration before administration. Before parenteral administration, the substance must be completely dissolved.

To consult the instructions for reconstitution and dilution of the medicine before administration, see section 6.6 of the Technical Sheet.

Special Precautions for Disposal and Other Handling

In the preparation of Tronoxal, the safety standards for handling cytostatic agents should be followed.

Skin reactions associated with accidental exposure to ifosfamide may occur. To minimize the risk of skin exposure, always wear impermeable gloves when handling vials and solutions containing ifosfamide. If ifosfamide comes into contact with the skin or mucous membranes, wash the skin immediately with water and soap or rinse the mucous membrane with a large amount of water.

Preparation of the Infusion Solution

Attention should be paid to ensure that the diluted ifosfamide solution does not exceed a concentration of 40 mg/ml.

In order to prepare a concentration of 40 mg/ml ready for use, dissolve the lyophilized powder in 25 ml of water for injectable preparations.

The substance dissolves easily when the vials are shaken vigorously for 30 seconds to 1 minute after adding the solvent. If complete dissolution does not occur immediately, it is convenient to allow the solution to rest for a few minutes.

For infusion purposes, it is recommended to dilute the reconstituted solution in a 5 mg/ml glucose solution, a 9 mg/ml sodium chloride solution, or a Ringer's solution. As a guide, the following can be used: dilution in 250 ml for infusion over a period of 30 to 60 minutes and dilution to 500 ml for infusion administered over one to two hours. For a 24-hour continuous infusion with high doses of Tronoxal, it is recommended to dilute the total dose (e.g., 5 g/m²) in three liters of 5 mg/ml glucose solution or 9 mg/ml sodium chloride solution.

The disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations for cytotoxics.