URONEFREX 125 mg CAPSULES

Introduction

Package Leaflet: Information for the User

Uromitexan 100 mg/ml Solution for Injection and Infusion

mesna

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

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

Contents of the Package Leaflet:

1. What is Uromitexan 100 mg/ml and what is it used for
2. What you need to know before you are given Uromitexan 100 mg/ml
3. How to use Uromitexan 100 mg/ml
4. Possible side effects
5. Storage of Uromitexan 100 mg/ml
6. Contents of the pack and further information

1. What is Uromitexan 100 mg/ml and what is it used for

Uromitexan contains the active substance mesna. It is a detoxifying agent for antineoplastic treatment.

Uromitexan is used as a prevention of urothelial toxicity including hemorrhagic cystitis (inflammation of the urinary bladder with blood in the urine), microhematuria, and macrohematuria in patients treated with oxazaphosphorines (ifosfamide, cyclophosphamide) in doses that are considered urotoxic.

Corrector of cystitis in therapies with cytostatics (drugs used in cancer treatment).

Ifosfamide and cyclophosphamide can cause damage to the bladder lining. This damage can appear as blood in the urine. If there are very small amounts of blood (microhematuria), they may not be visible, so your doctor or nurse will perform a urine test with a "dipstick" or a microscope to check for blood. If a significant amount of blood appears in the urine (macrohematuria), you will notice because it will be red and you may occasionally see blood clots in it.

Uromitexan 100 mg/ml protects the bladder lining from damage caused by ifosfamide and cyclophosphamide.

2. What you need to know before you are given Uromitexan 100 mg/ml

Do not use Uromitexan 100 mg/ml:

• If you are allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6). An allergic reaction can include difficulty breathing, wheezing, skin rash, itching, or swelling of the face and lips.
• If you have ever had an allergic reaction to a similar medicine.

Uromitexan will not be given to you if any of the above circumstances apply to you. If you are not sure, consult your doctor, nurse, or pharmacist before receiving this medicine.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Uromitexan if you have any autoimmune disease such as:

• rheumatoid arthritis
• systemic lupus erythematosus (also called lupus or SLE)
• any other autoimmune disease, where the body's immune system attacks itself.

If you have an autoimmune disease, you are at a higher risk of suffering from hypersensitivity reactions such as skin and mucous membrane reactions of varying extent and severity, local tissue inflammation, conjunctivitis, hypotension (decrease in blood pressure) associated with circulatory reactions, and increased heart rate (more than 100 beats per minute), increased respiratory rate, increased blood pressure, muscle pain, and transient increase in certain liver function tests. Therefore, protection of the urinary tract with mesna should only be carried out in these patients after a risk-benefit analysis and under careful medical supervision.

If you are not sure if any of the above circumstances apply to you, consult your doctor, nurse, or pharmacist.

Uromitexan does not prevent hemorrhagic cystitis in all patients, so appropriate checks should be performed.

A sufficient urine production of 100 ml per hour should be maintained, as required for treatment with oxazaphosphorines (ifosfamide, cyclophosphamide) (see section 3. How to use Uromitexan 100 mg/ml).

Elderly patients(over 65 years old)

The dose for an elderly patient should be chosen taking into account possible hepatic, renal, or cardiac disorders, and concomitant diseases or other therapy with medicines.

The ratio of oxazaphosphorine to mesna should remain unchanged (see section 3. How to use Uromitexan 100 mg/ml).

Children and adolescents

The safety and efficacy of Uromitexan in pediatric patients (under 16 years old) have not been established in clinical studies. However, medical literature refers to the use of mesna in pediatric patients.

Using Uromitexan 100 mg/ml with other medicines

Tell your doctor or nurse if you are using, have recently used, or might use any other medicine.

Uromitexan 100 mg/ml is administered with ifosfamide and cyclophosphamide. It does not react with these medicines, and it is not known to react with others.

Uromitexan 100 mg/ml also does not affect the antineoplastic efficacy of other cytostatics (cancer medicines, such as adriamycin, BCNU (carmustine), methotrexate, vincristine) or the therapeutic effect of other medicines such as digitalis glycosides (like digoxin) used to treat heart failure.

Using Uromitexan 100 mg/ml with food and drinks

Food does not influence the absorption and urinary elimination of Uromitexan 100 mg/ml.

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, pharmacist, or nurse for advice before using this medicine.

Uromitexan 100 mg/ml should not be administered during pregnancy or breastfeeding. The doctor must carefully weigh the potential risks and benefits for each patient before prescribing Uromitexan 100 mg/ml.

Pregnancy, fertility, and breastfeeding are usually contraindications for treatment with cytostatics (cancer medicines), so it is unlikely that Uromitexan 100 mg/ml will be used in these circumstances. If a patient is undergoing therapy with oxazaphosphorines (ifosfamide and cyclophosphamide) during pregnancy, Uromitexan 100 mg/ml should be administered to the patient.

Animal studies have not shown evidence of embryotoxic or teratogenic effects of mesna.

Do not breastfeed while being treated with these medicines.

Laboratory tests

Ifosfamide and cyclophosphamide can cause damage to the bladder lining. This damage can appear as blood in the urine. If there are very small amounts of blood, they may not be visible, so your doctor or nurse will regularly analyze your urine with a special "dipstick" or observe it under a microscope, looking for blood.

Tell your doctor or nurse if you have any other test with a "dipstick", because this medicine can affect the results obtained. These "dipstick" tests can be used in blood or urine and detect certain chemicals called "ketones" or red blood cells in the urine.

Treatment with Uromitexan may give false positives in certain laboratory tests.

Driving and using machines

Some of the side effects of treatment with Uromitexan 100 mg/ml may affect your ability to drive and use machines. Your doctor will decide if it is safe for you to do so.

Uromitexan 100 mg/ml contains sodium

This medicine contains less than 1 mmol (23 mg) of sodium per ml. This should be taken into account in the treatment of patients with low-sodium diets.

3. How to use Uromitexan 100 mg/ml

Follow exactly the administration instructions of this medicine given by your doctor or pharmacist. If you are unsure, consult your doctor or pharmacist again.

Uromitexan 100 mg/ml is used in the form of an injection, which will be administered by a doctor or nurse.

Sufficient amounts of Uromitexan 100 mg/ml should be administered to adequately protect the patient from the urotoxic effects of ifosfamide or cyclophosphamide. Your doctor will decide the amount and frequency of administration needed based on the dose of ifosfamide or cyclophosphamide you receive.

While using this medicine, you should drink enough liquid every day to maintain a urine production (diuresis) of 100 ml per hour, which will help protect your bladder. You should urinate normally when you need to. Do not try to change your usual pattern.

Your doctor will decide the amount of medicine needed and when it is needed. Follow their instructions exactly.

The dose will depend on:

• the dose and timing of your treatment with ifosfamide or cyclophosphamide, and whether you are receiving them in the form of tablets or injection
• if you have urinary tract infections (urinary tract infections)
• if you have ever had signs of bladder damage before using ifosfamide or cyclophosphamide
• if you have received radiation therapy near the bladder.

The duration of treatment should be equal to the duration of treatment with ifosfamide or cyclophosphamide, plus the time necessary for the urinary concentration of ifosfamide or cyclophosphamide metabolites to decrease to non-toxic levels, which usually occurs within 8-12 hours after the end of treatment with ifosfamide or cyclophosphamide, but may vary depending on the scheduling of the oxazaphosphorine (ifosfamide or cyclophosphamide).

Urine production should be maintained at a rate of 100 ml/h (as required for treatment with ifosfamide or cyclophosphamide) and should be monitored for hematuria (blood in urine) and proteinuria (proteins in urine) throughout the treatment period.

The dosing schedule of mesna should be repeated every day that the oxazaphosphorine is received.

If the dose of ifosfamide or cyclophosphamide is modified, the dose of mesna should also be modified to maintain the ratio between the two drugs.

Dosing example:

When the oxazaphosphorine is administered as an IV bolus:Uromitexan 100 mg/ml will be administered simultaneously by intravenous injection over 15-30 minutes at 20% w/w (weight/weight) of the oxazaphosphorine. Repeat the same dose of Uromitexan 100 mg/ml after 4 and 8 hours. The total dose of mesna is 60% w/w (weight/weight) of the oxazaphosphorine dose.

Dosing example

Repeat this dosing regimen every time the cytotoxic agents are used.

Use in children and adolescents

Children usually urinate more frequently than adults, and therefore, it may be necessary to shorten the interval between doses and/or increase the number of individual doses.

If you receive more Uromitexan 100 mg/ml than you should

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 administered.

In case of overdose, you may develop symptoms such as nausea, vomiting, abdominal pain/cramps, diarrhea, headache, fatigue, joint and limb pain, skin rash, redness, hypotension, slow heart rate (bradycardia), fast heart rate (tachycardia), tingling (paresthesia), fever, and wheezing (bronchospasm).

There is no known antidote for mesna overdose.

If it occurs, the injection will be stopped immediately, and you will receive treatment for your symptoms.

It is unlikely that you will receive more Uromitexan 100 mg/ml than you should, since it will be administered by a trained and qualified person.

If you miss a dose of Uromitexan 100 mg/ml

It is very important to use Uromitexan 100 mg/ml exactly as your doctor has told you. These times have been carefully calculated to ensure that the bladder is fully protected against damage.

If you think you have missed a dose, inform your doctor or nurse.

You will not be given a double dose to make up for missed doses.

If you stop treatment with Uromitexan 100 mg/ml

Your doctor will decide when to stop treatment with Uromitexan.

Do not stop treatment with Uromitexan without consulting your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible Adverse Effects

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

The following adverse effects have been reported with Uromitexan 100 mg/ml:

Tell your doctor immediately if you notice any of the following side effects, as you may need urgent medical attention:

• The most frequent adverse reactions associated with the use of Uromitexan 100 mg/ml are: headache, reactions at the injection site, abdominal pain/cramps, dizziness, lethargy/drowsiness, fever, rash, diarrhea, nausea, flushing, and flu-like symptoms.
• The most serious adverse reactions associated with the use of Uromitexan 100 mg/ml are: Stevens-Johnson syndrome and toxic epidermal necrolysis (skin diseases), anaphylaxis, and DRESS syndrome (drug allergic reaction characterized by skin rash, fever, and involvement of various organs, such as the kidneys and liver).
• Rarely, it can also cause something similar to an allergic reaction. The signs may include skin rashes and hives, itching of the skin, blisters in the mouth or skin, sudden drop in blood pressure (feeling of dizziness), faster heart rate, and changes in blood test results used to check that your liver is functioning properly.

Some of these side effects may be caused by ifosfamide or cyclophosphamide instead of Uromitexan 100 mg/ml, since they are always taken together.

Other possible side effects include:

Blood and lymphatic system

• swelling of the lymph nodes (lymphadenopathy)
• decrease in the number of cells in the blood:
• • decrease in all types of blood cells (pancytopenia),
  • reduction in the number of white blood cells (which fight infections (leukopenia, lymphopenia)),
  • abnormally high levels of eosinophils (a type of white blood cell produced in the bone marrow) either in the blood or in body tissues (eosinophilia); and of platelets (which help blood clotting (thrombocytopenia))

Metabolism and nutrition

• decreased appetite

Psychiatric

• insomnia, nightmares

Immune system

• allergic reactions (hypersensitivity) or severe allergic reactions with rapid onset (anaphylaxis)

Nervous system

• headache
• dullness
• lethargy/drowsiness
• tingling, numbness, burning, stabbing (paresthesia)
• unusual or pathological sensitivity of the skin or a particular sense to stimulation (hyperesthesia)
• temporary loss of consciousness and postural tone (syncope)
• decrease in touch or sensation, or partial loss of sensitivity to sensory stimuli (hypoesthesia)
• alteration of attention
• seizures (convulsions)

Eyes

• blurred vision, reduced or lost vision
• eye inflammation (conjunctivitis)
• swelling around the eyes (periorbital edema)

Heart and circulation

• flushing
• abnormal heart graph (abnormal electrocardiogram)
• abnormal heartbeat (palpitations)
• rapid heart rate (tachycardia)
• high blood pressure (hypertension) or low blood pressure (hypotension)

Lungs

• difficulty breathing or wheezing (bronchospasm)
• nasal congestion
• cough
• sharp severe pain when inhaling (pleuritic pain)
• dry mouth
• difficulty breathing (dyspnea)
• laryngeal discomfort
• nasal bleeding (epistaxis)
• breathing difficulties
• decrease in oxygen levels in your body (hypoxia, decrease in oxygen saturation)
• rapid breathing (tachypnea)
• coughing up blood or bloody sputum from the lungs or airways (hemoptysis)

Digestive system

• abdominal pain/cramps
• nausea
• vomiting
• diarrhea
• irritation of the mucosa
• burning pain
• constipation
• gum bleeding (gum bleeding)
• inflammation of the mouth mucosa, including ulcers (stomatitis)
• bad taste

Liver

• conditions that cause liver inflammation, which can cause yellowing of the skin or the whites of the eyes (jaundice), weight loss, and general malaise (hepatitis)
• increase in the levels of certain proteins produced by the liver called enzymes. Your doctor will perform blood tests to check for their presence.

Skin and subcutaneous tissue

• rash
• itching
• abnormally high sweating or transpiration, exceeding that required for body temperature regulation (hyperhidrosis)
• life-threatening conditions causing rashes, ulcers, sore throat, fever, conjunctivitis, separation of skin layers (toxic epidermal necrolysis, Stevens-Johnson syndrome)
• itching, red-colored rash that can develop in the mouth (erythema multiforme, erythema)
• drug hypersensitivity reaction, characterized by skin rash, fever, lymph node inflammation, and involvement of internal organs (drug rash with eosinophilia and systemic symptoms)
• ulcerations and/or blisters (mucocutaneous, oral mucosa, vulvovaginal, anorectal)
• swelling of the deeper layers of the skin caused by fluid accumulation (angioedema)
• lesions that recur in the same area when the same medicine is given (fixed exanthem)
• rash
• photodistributed rash
• rash with a notable pale red color, hives, and itching (urticaria)
• burning sensation

Musculoskeletal and connective tissue

• muscle pain (myalgia), or joint pain (arthralgia).
• back pain
• feeling of discomfort in the upper or lower limbs (limb pain)
• jaw pain

Renal and urinary

• pain when urinating (dysuria)
• acute kidney failure

General disorders and administration site conditions

• change in skin appearance and irritation at the injection or infusion site
• chest pain
• fever, chills
• flu-like symptoms, such as headache, fever, chills, joint and muscle pain, weakness, fatigue
• swelling of tissues, usually in the lower limbs, due to fluid accumulation (peripheral edema)
• facial swelling (facial edema)
• fatigue
• reactions at the infusion site (thrombophlebitis, irritation)

Reporting of adverse effects:

If you experience any type of adverse effect, consult your doctor 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: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Conservation of Uromitexan 100 mg/ml

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

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

Do not store at a temperature above 30°C.

Keep the container in the outer packaging.

Use only if the solution is transparent, without visible particles, and if the container is not damaged.

The solution must be administered at the moment of opening the injectable ampoule.

Medicines should not be thrown down the drain or into the trash. Ask your pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Package contents and additional information

Composition ofUromitexan 100 mg/ml

The active ingredient is mesna. Each 4 ml ampoule contains 400 mg of mesna, and each 10 ml ampoule contains 1000 mg of mesna.

The other components are: sodium edetate, sodium hydroxide, nitrogen, and water for injectable preparations.

Product appearance and package contents

Uromitexan 100 mg/ml is a sterile, transparent, and colorless solution supplied in transparent glass ampoules of 5 ml (containing 4 ml of solution) or 10 ml (containing 10 ml of solution) capacity.

The ampoules are packaged in a plastic tray inside a cardboard box.

Each box contains 5 or 10 ampoules.

Only some package sizes may be marketed

Marketing authorization holder and manufacturer

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

Prasfarma SL

c/Sant Joan, 11-15

08560 Manlleu (Barcelona)

Spain

Date of the last revision of this prospectus: February 2019

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/