Tronoxal 1,000 mg powder for solution for infusion

Package leaflet: Information for the user

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, as you may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only, and you should not give it to other people, even if they have the same symptoms as you, because it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are adverse effects not listed in this leaflet. See section 4.

Leaflet contents:

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 administered to you.
4. Possible side effects.
5. How to store 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 consequence, it also attacks normal cells. Therefore, it may have side effects.

Your doctor will not administer ifosfamide unless the risk posed by your cancer is greater than the potential side effects. Your doctor will monitor you regularly and will treat any side effects whenever possible.

Ifosfamide:

• 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 medicine 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. If you experience these symptoms, inform your doctor immediately.

Tronoxal is usually used as monotherapy or in combination with other antineoplastic medicines or radiotherapy, for the treatment of various types of cancer. This includes:

• various forms of lymphomas affecting 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 starting to use Tronoxal.

Do not use Tronoxal:

• If you are allergic to ifosfamide, to any of its metabolites, or to 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 functioning properly (especially if you have previously received chemotherapy or radiotherapy). Blood tests will be performed to check your bone marrow function.
• If you have a urinary tract infection that may cause pain when urinating (cystitis).
• If you have a disease that reduces your ability to urinate (urinary flow obstruction).
• If you currently have an infection.
• If you are pregnant or breastfeeding.

Exercise special caution with Tronoxal

Consult your doctor before starting to use 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 to the area of the heart,
• you are in poor general health or are frail or elderly,
• you are receiving or have received treatment with cisplatin before or during ifosfamide treatment.

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

Tronoxal can affect your blood and immune system.

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

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

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

You are more likely to develop infections if your blood cell count is reduced. Try to avoid contact with people who have coughs, colds, or other infections. Your doctor will treat you with appropriate medication if they suspect you have an infection or are at risk of developing one.

Your doctor will ensure that your red blood cell, white blood cell, and platelet counts are sufficiently high before and during ifosfamide treatment.

Tronoxal may affect normal wound healing. Keep cuts clean and dry and check that they are healing properly. It is important to maintain good gum health, as infections and mouth ulcers may occur. Consult your doctor if you have any doubts.

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

Most people receiving Tronoxal with Mesna do not develop bladder problems, but your doctor may wish to test your urine for blood using a test strip or microscope. If you notice blood in your urine, you must inform your doctor immediately.

While receiving Tronoxal, you should ensure you drink enough fluids.

Tronoxal can damage your kidneys and cause them to function improperly. This is more likely if you have only 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 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, perceptual disturbances, 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 for signs and symptoms of central nervous system toxicity.

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

Tronoxal may cause heart damage or affect your heart rhythm. This effect is greater at higher doses of Tronoxal, if you are receiving radiotherapy or other chemotherapy drugs, or if you are elderly. 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 treatment ends. If you develop breathing difficulties, inform your doctor immediately.

Tronoxal may have potentially life-threatening effects on your liver.

If you experience a sudden weight gain, liver pain, or yellowing of the skin or whites of the eyes (jaundice), inform your doctor immediately.

Hair loss or baldness may occur. Your hair should regrow normally, although its texture and color may be different.

Tronoxal may cause nausea and vomiting. This may last approximately 24 hours after taking the medicine. You may need to take medications to prevent nausea and vomiting. Consult your doctor about this.

Children and adolescents

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

Use of Tronoxal with other medicines:

Inform your doctor or pharmacist if you are taking, have recently taken, or might need to take any other medicines, including those obtained without a prescription. In particular, tell them about the following medicines or treatments, as they could be incompatible with the use of Tronoxal.

The following medicines 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).

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 area of the heart.

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 viral infections),
• aminoglycosides (used to treat fungal infections),
• amphotericin B (used to treat fungal infections),
• carboplatin and cisplatin (used to treat cancer).

Medicines that may increase toxic effects on your bladder:

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

Medicines with effects on the brain, such as those used for nausea and vomiting, 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 medicinal product for mild depression), corticosteroids (used to treat inflammation).

The following medicines may decrease the efficacy of Tronoxal:

• ketoconazole, fluconazole, itraconazole (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),
• 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 beverages

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

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist 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 fetal harm.

Both men and women must not attempt to have children during treatment with ifosfamide or for up to 12 months after treatment has ended. Effective contraceptive methods must therefore be used during treatment and for at least 6 months after its completion. If pregnancy occurs during treatment, genetic counselling should be considered (medical advice to assess the potential risk of congenital malformations in the fetus).

Breastfeeding

You must not breastfeed while being treated with ifosfamide. Please seek advice from your doctor.

Fertility

Tronoxal may cause infertility in both sexes. Consult your doctor about sperm or oocyte cryopreservation (freezing) prior to treatment due to the possibility of irreversible infertility caused by ifosfamide therapy. If you are considering becoming a parent after treatment, you should discuss this with your doctor.

Driving and operating machinery

Some of the adverse effects of ifosfamide treatment may affect your ability to drive and operate machinery safely. Your doctor will decide whether you can do so safely.

Patients should exercise caution when performing tasks such as driving cars or operating machinery until they have determined that the treatment with this medicine does not impair their ability to carry out these activities.

3. How to use Tronoxal

Tronoxal will be administered by a physician experienced in the use of antineoplastic chemotherapeutic agents (for cancer treatment).

Method of administration

By intravenous route.

Tronoxal is given as an injection and is usually added to a large bag of fluid, which is then slowly infused (perfusion) directly into a vein. The vein may be located in the arm, the back of the hand, or a large vein beneath the clavicle.

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

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

Recommended dose:

Your doctor will determine how much medication you need and when you should receive it. This will depend on the type of disease you have, your body composition (a combination of your height and weight), your general health status, and whether you are receiving other antineoplastic medicines or radiotherapy.

Ifosfamide is generally administered as a series of treatments. After one cycle, a rest period (a period during which no injections are given) is provided before the next cycle begins.

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

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

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

• you have problems with your liver or kidneys,
• you are an elderly person (over 65 years of age).

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 more Tronoxal than you should

Since Tronoxal is administered under the supervision of your doctor, it is highly unlikely that you could 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.

Symptoms of an ifosfamide overdose include the adverse effects listed in the section "Side effects", but they are usually more severe in nature.

In case of overdose or accidental ingestion, contact your doctor or pharmacist immediately or call the Toxicology Information Service at 915 620 420, indicating the medication and the amount ingested.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone experiences them.

Tell your doctor immediately if you experience:

• Appearance of bruises without having suffered an injury, or bleeding gums or nosebleeds. This could be a sign that your blood platelet levels are too low.

• Severe infection or fever, cough, shortness of breath, signs of sepsis such as fever, rapid breathing, increased heart rate, confusion, and edema. This could indicate a reduction in your white blood cell count, and antibiotics may be needed to fight infections.

• Paleness, feeling lethargic and tired. This could indicate low red blood cell levels (anemia). Treatment is usually not required, as your body will eventually replenish the red blood cells. In cases of severe anemia, a blood transfusion may be necessary.

• Blood in the urine, pain when urinating, or reduced urine volume.

• Changes in mental state. In some people, ifosfamide can affect the brain. Sometimes individuals 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 treatment with ifosfamide.

• 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

• lack 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 in white blood cells, which are important in fighting infections (leukopenia, neutropenia),
• anemia,
• disturbances in mental state, which may progress to encephalopathy,
• nausea and vomiting,
• hair loss (alopecia),
• presence of blood in the urine (microhematuria),
• burning sensations when urinating and frequent need to urinate (cystitis),
• potentially life-threatening reduction in the kidney's ability to properly eliminate toxins and waste products from the blood (renal dysfunction, renal failure),
• changes in kidney structure that prevent proper function (structural kidney damage).

Common (may affect up to 1 in 10 patients)

• reduction in 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)

• heart problems (congestive heart failure, tachycardia, pulmonary edema),
• peripheral neuropathy which may include the following signs: gradual onset of numbness, tingling, or prickling sensations in the feet or hands, which may spread upward into the legs and arms; extreme sensitivity to touch; pain during activities that should not cause pain, such as foot pain when bearing weight or 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)

• malaise.

Reporting of adverse effects

If you experience any kind of adverse effect, consult your doctor, pharmacist, or nurse, even if they are possible adverse effects not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicinal Products: www.notificaRAM.es.

By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Tronoxal

Keep this medicine out of sight and reach of children.

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

The reconstituted and diluted solution may be used up to 24 hours after reconstitution (do not store above 8°C).

Do not use this medicine after the expiry date stated on the carton after Lot/CAD. The expiry date refers to the last day of the month indicated.

Disposal of unused medicine and of all materials that have been in contact with it must be carried out in accordance with local regulations for cytotoxic agents.

6. Contents of the pack and other information

Composition of Tronoxal

The active substance is Ifosfamide.

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

Appearance of the product and contents of the package

Tronoxal is a white crystalline powder.

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

Marketing Authorization Holder:

Baxter S.L.

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

Manufacturer:

Simtra Deutschland GmbH

Kantstrasse 2

33790 Halle/Westfalen

Germany

Date of the most recent review of this leaflet: March 2023

Detailed and up-to-date 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/

---

This information is intended for healthcare professionals only

Tronoxal must be administered exclusively by physicians experienced in antineoplastic chemotherapy.

Tronoxal must only be administered where facilities are available for regular monitoring of clinical, biochemical, and haematological parameters before, during, and after administration, and under the supervision of a specialist oncology department.

Dosage

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

When administered together with other cytostatic agents as part of a chemotherapy combination, the dosage instructions for the appropriate treatment regimen must 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 administration: 5 g/m² of body surface area (maximum 8 g/m² of body surface area (200 mg/kg body weight)) as a single dose, normally administered as a continuous infusion over 24 hours 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 higher frequency of impaired hepatic, renal, or cardiac function, as well as concomitant diseases or concomitant use of other medicinal products (See section 4.4. of the Summary of Product Characteristics).

Patients with renal impairment

This may lead to increased toxicity (e.g., neurotoxicity, nephrotoxicity, hematotoxicity), which should be taken into consideration when determining the dose in these patients; see section 4.4 of the Summary of Product Characteristics.

Ifosfamide and its metabolites are dialyzable. In patients requiring dialysis, administration intervals between ifosfamide and dialysis should be consistently scheduled.

A dose reduction to 75% is recommended in patients with a creatinine clearance of ≤10 ml/min.

Use in patients with hepatic impairment

Hepatic impairment may be associated with a reduced 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 Summary of Product Characteristics.

Dose adjustment in patients with myelosuppression:

Leukocyte count/?l	Platelet count/?l
> 4,000	> 100,000	100% of planned dose
4,000 – 2,500	100,000 – 50,000	50% of planned dose
< 2,500	< 50,000	postpone until normalization is achieved or make an individualized decision

Administration Method

Intravenous route.

Care must be taken to ensure that the diluted ifosfamide solution does not exceed a concentration of 4%.

Administration is performed by intravenous infusion over a short duration, lasting between 30 minutes and four hours, depending on the volume to be infused and the treatment regimen. It may also be administered as a continuous 24-hour infusion.

When used in combination with other chemotherapeutic agents with similar toxicity, dose reduction and/or extension of treatment-free intervals may be necessary.

When appropriate, hematopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or to help facilitate the delivery of the intended dose. For information on potential interactions with G-CSF and GM-CSF (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor), see section 4.5 of the Summary of Product Characteristics.

During or immediately after administration, an adequate amount of fluids should be ingested or infused to promote forced diuresis, in order to reduce the risk of urothelial toxicity. See section 4.4 of the Summary of Product Characteristics.

High-dose ifosfamide should be used in combination with mesna as a prophylactic measure against hemorrhagic cystitis. The usual dose of mesna should reach or exceed 60% of the daily dose of ifosfamide, divided into three doses administered at 0 h, 4 h, and 8 h after ifosfamide. In the case of combination therapy with cisplatin, which requires daily hyperhydration, the dose of mesna should be increased to compensate for its enhanced urinary excretion.

Parenteral medications should be visually inspected for particulate matter and discoloration prior to administration. Prior to parenteral administration, the substance must be completely dissolved.

For instructions on reconstitution and dilution of the medication prior to administration, see section 6.6 of the Summary of Product Characteristics.

Special Precautions for Disposal and Other Handling

When preparing Tronoxal, safety procedures for handling cytotoxic agents must be followed.

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

Preparation of the infusion solution

Care must be taken to ensure that the diluted ifosfamide solution does not exceed a concentration of 40 mg/ml.

To prepare a ready-to-use concentration of 40 mg/ml, dissolve the lyophilisate in 25 ml of water for injections.

The substance dissolves readily when the vials are shaken vigorously for 30 seconds to 1 minute after addition of 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 with 5% glucose solution, 0.9% sodium chloride solution, or Ringer's solution. The following may be used as a guide: dilution in 250 ml for infusion over a period of 30 to 60 minutes, or dilution in 500 ml for infusion administered over one to two hours. For continuous 24-hour infusion with high doses of Tronoxal, it is recommended to dilute the total dose (e.g., 5 g/m²) in three liters of 5% glucose solution or 0.9% sodium chloride solution.

Disposal of unused medicinal product and of all materials that have come into contact with it must be carried out in accordance with local regulations for cytotoxic agents.