Prospect: information for the patient

Tronoxal 1.000 mg powder for solution for infusion

Ifosfamide

Read this prospect carefully before starting to use this medicine,because it contains important information for you.

• Keep this prospect, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medicine has been prescribedonlyto you, and you must not give it to other people althoughtheymay havethe same symptomsas you,as it may harm them.
• If you experience adverse effects, consult your doctor or pharmacist,even if they are not listed in this prospect. See section 4.

1.What Tronoxal is and for what it is used.

2.What you need to know before Tronoxal is administered to you.

3.How Tronoxal will be administered to you

4.Possible adverse effects

5.Storage of Tronoxal

6.Contents of the package and additional information

Tronoxalcontains Ifosfamida as its active substance.It belongs to the group of medications known as “cytotoxic or antineoplastic drugs”, which act by stopping the growth of cancer cells.

Important things you should know about ifosfamida

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

Ifosfamida is a medication that destroys cancer cells but, as a consequence, also attacks normal cells. Therefore, it may have side effects.

Your doctor will not administer ifosfamida unless your cancer poses a greater risk to you than the possible side effects. Your doctor will monitor you regularly and treat any side effects as soon as possible.

Ifosfamida:

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

Tronoxalis usually used in monotherapy or in combination with other antineoplastic medications or radiation therapy for the treatment of various types of cancer. This includes:

-different forms of lymphomas that affect the immune system (Hodgkin's lymphoma and non-Hodgkin's lymphoma),

-ovarian cancer and testicular cancer,

-specific sarcomas, such as Ewing's sarcoma and other types of bone cancer,

Do not useTronoxal:

• If you are allergic to ifosfamide, any of its metabolites, or any of the other components of this medication (listed in section 6).A hypersensitivity reaction may include difficulty breathing, wheezing, hives, itching, or inflammation of the face and lips.
• If your bone marrow does not function properly (especially if you have previously undergone chemotherapy or radiation therapy). Blood tests will be performed to check the function of your bone marrow,
• If you have a urinary tract infection that can be recognized by pain while 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 extra careful with Tronoxal

Consult your doctorbefore starting to useTronoxalif:

• 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 radiation or chemotherapy,
• You have heart problems or have received radiation therapy in the heart area,
• You have a poor overall health or are a fragile or elderly person,
• If you are receiving or have received cisplatino treatment before or during treatment with ifosfamide.

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

Tronoxalmay affect your blood and immune system.

Cells in the blood are produced in the bone marrow. These cells are of three types:

- Red blood cells, which transport oxygen in the body,

- White blood cells, which fight infections, and

- Platelets, which allow blood to clot.

After receivingifosfamide, the count of blood cells for the three types of cells will decrease. This is an inevitable side effect of the medication.Your blood count will reach its lowest level approximately between 5 and 10 days after starting to receiveTronoxaland will remain low for a few days after completing the treatment cycle. Most people recover normal blood cell counts within 21 to 28 days. If you have previously received a large amount of chemotherapy, it may take a bit longer to return to normal.

You are more likely to contract infections if your blood cell count decreases. Try not to come close to people who have a cough, cold, and other infections. Your doctor will treat you with the appropriate medication if they think you have an infection or are at risk of getting one.

Your doctor will ensure that the count of erythrocytes, leucocytes, and platelets is high enough before starting treatment with ifosfamide and during treatment.

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

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

Most people who receiveTronoxalwith Mesna do not develop bladder problems, but your doctor may want to analyze your urine to detect the presence of blood using a dipstick or microscope. If you observe blood in your urine, you must inform your doctor immediately.

While receiving Tronoxal, you must ensure that you drink enough fluids.

Tronoxalmay damage your kidneys and make them not function correctly. 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 treatment with Tronoxal is suspended. Occasionally, the damage is permanent and more severe. Your doctor will check your laboratory 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). Inform 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, slowness of movement, irregular movements), loss of control over urination, and seizures.

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

Cancer medications and radiation therapy may increase the risk of developing other types of cancer; this can occur several years after the completion of your treatment.

Tronoxalmay cause cardiac damage or affect the rhythm at which the heart beats. This effect is greater at higher doses ofTronoxal, if you are being treated with radiation therapy or other chemotherapy medications, or if you are an elderly person. Your doctor will closely monitor your heart during treatment.

Tronoxalmay cause lung problems such as inflammation or pulmonary fibrosis. This can occur more than six months after treatment completion. If you start having difficulty breathing, inform your doctor immediately.

Tronoxalmay have potentially fatal effects on your liver.

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

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

Tronoxalmay cause nausea and vomiting. This can last approximately 24 hours after taking the medication. You may need to take medication to stop nausea and vomiting. Consult your doctor about this.

Children and adolescents

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

Use of Tronoxal with other medications:

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication, including those purchased without a prescription.In particular, inform them of the following medications or treatments because they may be incompatible with the use ofTronoxal.

The following medications may increase the toxicity of Tronoxal on blood cells and the immune system:

• ACE inhibitors (used to treat hypertension),
• carboplatin (used to treat cancer)
• cisplatin (used to treat cancer)
• natalizumab (used to treat multiple sclerosis),

Medications that may increase the toxic effects ofTronoxalon the heart:

• Anthracyclines such as bleomycin, doxorubicin, epirubicin (used to treat cancer)
• Radiation therapy in the heart area.

Medications that may increase the toxic effects ofTronoxalon the lungs:

• Amiodarone (used to treat irregular heartbeat),
• G-CSF, GM-CSF hormones (used to increase leucocyte counts after chemotherapy).

Medications that may increase the toxic effects ofTronoxalon the kidneys:

• Acyclovir (used to treat viruses),
• Aminoglycosides (used to treat fungal infections),
• Anidulafungin (used to treat fungal infections),
• Carboplatin and cisplatin (used to treat cancer).

Medications that may increase the toxic effects on your bladder:

• Busulfan(used to treat cancer),
• Bladder irradiation.

Medications with effects on the brain, such as those used to treat vomiting and nausea, sleeping pills, certain painkillers (opioids), or allergy medications.

The following medications may increase the toxicity of Tronoxal:

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

The following medications may reduce the effectiveness of Tronoxal:

• Ketokonazole, fluconazole, itraconazole (used to treat fungal infections),
• Sorafenib (used to treat cancer).

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

• Docetaxel(used to treat cancer),
• Coumarins such as warfarin (used as an anticoagulant),
• Vaccines,
• Tamoxifen (used to treat breast cancer),
• Cisplatin (used to treat cancer),
• Irinotecan (used to treat cancer).

Use of Tronoxal with food and drinks

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

Pregnancy, lactation, and fertility

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor or pharmacist before usingthis medication.

Pregnancy

If you are a woman, you should not become pregnant during treatment with Tronoxal, as it may cause miscarriage or fetal damage.

Both men and womenshould not attempt to have children during treatment with ifosfamide or for 12 months after treatment completion, and should use effective contraceptive methods during treatment and for 6 months after completing treatment.If you become pregnant during treatment, you may receive genetic counseling (medical advice to assess the risk of congenital malformations in the fetus).

Lactation

You should not breastfeed while being treated with ifosfamide. Consult your doctor.

Fertility

Tronoxalmay cause sterility in both sexes. Consult your doctor about cryopreservation (freezing) of sperm or eggs before treatment, as treatment with ifosfamide may cause irreversible sterility. If you are considering having children after treatment, you should discuss this with your doctor.

Driving and operating machines

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

Patients should exercise caution when performing tasks such as driving cars and operating machines until they confirm that treatment with the medication does not affect their ability to perform these activities.

Tronoxal will be administered by an experienced doctor in the use of antineoplastic chemotherapy (for cancer treatment).

Administration form

By intravenous route.

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

The infusion usually takes several hours, but may be administered over several days.

Tronoxal is usually administered in combination with other antineoplastic medications or radiation therapy.

The recommended dose is:

Your doctor will decide how much medication you need and when you should receive it. This will depend on the type of disease you have, your body size and weight, your overall health, and if you are receiving other antineoplastic medications or radiation therapy.

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

It is essential that you receive adequate amounts of fluid before, during, and after administration to prevent possible adverse effects on the urinary tract.

If you notice that Tronoxal is too strong or weak, consult your doctor or pharmacist.

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

- you have problems with your liver or kidneys,

- 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 administered more Tronoxal than you should

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

You may require urgent medical attention.

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

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service at 915.620.420, indicating the medication and the amount ingested.

Like all medications,this medicationcanproduce side effects, although not all people will experience them.

Inform your doctor immediately if you experience:

• Bleeding or bruising easily, or bleeding in the gums or nose. This could be a sign that your blood platelet levels are too low.
• Severe infection or fever, cough, shortness of breath, signs of septicemia such as fever, rapid breathing, elevated heart rate, confusion, and swelling. This could be a sign of a low white blood cell count and you may need antibiotics to fight off infections.
• Pale skin, feeling tired and lethargic. This could be indicative of low red blood cell levels (anemia). Normally, no treatment is required, as your body will replenish red blood cells over time. In cases of severe anemia, you may need a blood transfusion.
• Blood in the urine, pain while urinating, or reduced urine volume.
• Mental state changes. 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 stop your ifosfamide treatment.

- Confusion

- Drowsiness

- Unconsciousness/coma

- Disorientation

- Restlessness

- Depression

- Hallucinations

- Delusions (false beliefs)

- Blurred vision

- Perceptual disturbances

- Extrapyramidal symptoms (such as continuous spasms, muscle contractions, motor restlessness, slowness of movement, irregular movements)

- Rapid speech

- Repeating words

- Being fixated on a task

- Aggression

- Loss of bladder control

- Seizures

These side effects may be accompanied by fever or tachycardia

The following adverse effects may also occur during treatment withTronoxal.

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

• Reduced white blood cell count, which is important in fighting infections (leucopenia, neutropenia),
• Anemia
• Mental state changes, which can lead to encephalopathy
• Nausea and vomiting,
• Loss of hair (alopecia),
• Blood in the urine (microhematuria),
• Sensation of burning while urinating and frequent need to urinate (cystitis).
• Potentially fatal reduction in kidney function to eliminate toxins and waste products from the blood (renal dysfunction, renal insufficiency),
• Changes in kidney structure that prevent them from functioning correctly (structural renal damage)

Common(may affect up to 1 in 10 patients)

• Reduced white blood cell count and fever (neutropenic fever),
• Infections,
• Loss of appetite,
• Liver toxicity (elevated liver enzymes, also with increased bilirubin, jaundice, and hepatorenal syndrome)
• Vein wall inflammation,
• Neutropenic fever

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 pins and needles in the feet or hands, which may 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 under a blanket; lack of coordination and falls, among others
• Low blood pressure
• Diarrhea,
• Mouth pain or ulcers (stomatitis),
• Fatigue.

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

• Skin rash,
• Dermatitis,

Frequency not known(cannot be estimated from 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 theSpanish System for the Pharmacovigilance of Medicinal Products for Human Use:www.notificaRAM.es.

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

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

Do not store at a temperature above 25°C. Store in the original packaging to protect it 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 usethis medicationafter the expiration date that appears on the boxafter Lot/EXP. The expiration date is the last day of the month indicated.

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

Composition ofTronoxal

The active ingredient isIfosfamide.

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

Appearance of the product and contents of the container

Tronoxalis a white crystalline powder.

Tronoxal1,000 mg powder for solution for infusionis presented in a container containing 1vial.

Marketing Authorization Holder:

Baxter S.L.

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

Responsible for manufacturing:

Baxter Oncology GmbH

Kantstrasse 2, 33790 Halle/Westfalen

Germany

Last review date of this leaflet: March 2023

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

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This information is intended solely for healthcare professionals

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

Tronoxalmust be administered onlywhere there are facilitiesfor the periodic monitoring ofclinical, biochemicaland hematological parametersbefore, during andafter administrationand under the directionof aspecialized oncology service.

Dosage

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

When administered with other cytotoxic agents as part of chemotherapy combinations, follow the dosage instructions for the appropriate treatment scheme.

Intermittent administration:1–3 g/m2of 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/m2of body surface area.

Continuous administration5 g/m2of body surface area (maximum 8 g/m2of body surface area (200 mg/kg of body weight)) in a single dose, administered normally in 24 hours of continuous infusion every 3 or 4 weeks.

Patients with advanced age and debilitated patients

In general, the dose in patients with advanced age and in debilitated patients will be selected with caution, taking into account the higher frequency of deterioration of liver, renal or cardiac function and concomitant diseases or treatments with other medications (See section 4.4 of the Technical Dossier).

Patients with renal insufficiency

It may lead to an increase in toxicity (e.g. neurotoxicity, nephrotoxicity, hematotoxicity), so it should be taken into account when establishing the dose in these patients, see section 4.4 of the Technical Dossier.

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

It is recommended to administer 75% of the dose in patients with a creatinine clearance equal to or less than 10 ml/min.

Use in patients with liver insufficiency

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

Dose adjustment in patients with myelosuppression:

Administration form

Intravenous route.

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

The administration is made by intravenous infusion of short duration during a period of time ranging from 30 minutes to four hours, depending on the volume to be infused and the treatment schedule. It can also be administered in continuous infusion of 24 hours.

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

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

During or immediately after administration, adequate amounts of liquids should be ingested or infused to force diuresis to reduce the risk of urothelial toxicity. See section 4.4 of the Technical Dossier.

Ifosfamide at high doses should be used in combination with mesna as a prophylactic measure against 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 increase in urinary excretion.

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

For instructions on reconstitution and dilution of the medication before administration, see section 6.6 of the Technical Dossier.

Special precautions for disposal and other manipulations

In the preparation of Tronoxal, follow the safety standards for handling cytotoxic agents.

May produce skin reactions associated with accidental exposure to ifosfamide.To minimize the risk of dermal exposure, always use 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 membranes with abundant water.

Preparation of the infusion solution

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

To prepare a concentration of 40 mg/ml ready for use, dissolve the lyophilized in 25 ml of injectable water.

The substance dissolves easily when the vials are shaken vigorously for 30 seconds-1 minute after adding the solvent. If complete dissolution does not occur immediately, it is advisable to allow the solution to stand 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 with 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 in 500 ml for infusion administered over one to two hours. For continuous infusion of 24 hours 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 elimination of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations for cytotoxics.