Package Insert: information for the user

Uromitexan 100 mg/ml injectable solution and for perfusion

mesna

Read this package insert carefully beforestarting to usethis medication,because it contains important information for you.

• Keep this package insert, as you may need to read it again.
• If you have any questions, consult your doctor,pharmacistor nurse.
• Ifyou experienceadverse effects,consult yourdoctor,pharmacistor nurse,evenifthey do not appearin this package insert. See section 4

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

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

3.How to use Uromitexan 100 mg/ml

4.Possible adverse effects

5.Storage of Uromitexan 100 mg/ml

6.Contents of the package and additional information

Uromitexan contains mesna as its active substance. 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) at doses considered urototoxic.

Urinary tract irritant corrector in chemotherapy with cytostatics (drugs used in cancer treatment).

Ifosfamide and cyclophosphamide can cause damage to the lining of the bladder. 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 "stick" or a microscope to check for blood. If a significant amount of blood appears in the urine (macrohematuria), it will be noticeable because it will be red and you may occasionally see blood clots in it.

Uromitexan 100 mg/mlprotects the lining of the bladder from the damage caused by ifosfamide and cyclophosphamide.

No use Uromitexan 100 mg/ml:

• If you are allergic to the active ingredientor to any of the other components of this medication(see section6).A hypersensitivity reaction may include difficulty breathing, wheezing, skin rash, itching, or swelling of the face and lips.
• If you have ever had a hypersensitivity reaction to a similar medication.

You will not be administeredUromitexanif any of the above circumstances apply to you. If you are unsure, consult your doctor, nurse, or pharmacist beforereceivingthis medication.

Warnings and precautions

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

• Rheumatoid arthritis
• Systemic lupus erythematosus (also known as lupus or SLE)
• Any other autoimmune disease, where the body's immune system attacks itself.

If you have an autoimmune disease, you have a higher risk of experiencing hypersensitivity reactions such as skin and mucous membrane reactions of varying extent and severity, local tissue inflammation, conjunctivitis, hypotension (decreased 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 increases in certain liver function tests. Therefore, bladder protection with mesna should only be carried out in these patients after a risk-benefit analysis and under close medical supervision.

If you are unsure whether any of the above circumstances apply to you, consult your doctor, nurse, or pharmacist.

Uromitexandoes not prevent hemorrhagic cystitis in all patients, soappropriate controls should be performed.

You should maintain a urine production of at least 100 ml per hour,as required for treatmentwithoxazaphosphorines(ifosfamide, cyclophosphamide) (see section 3. How to use Uromitexan 100 mg/ml).

Older patients (over 65 years)

The dose for an elderly patient should be chosen taking into account possible liver, kidney, or heart impairments, and concomitant diseases or other medication therapy.

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

Children and adolescents

The safety and efficacy ofUromitexanin pediatric patients (under 16 years) have not been established in clinical studies. However, in medical literature, the use of mesna in pediatric patients is mentioned.

Use of Uromitexan 100 mg/ml with other medications

Inform your doctor or nurse if you are using, have used recently, ormay have to use any other medication.

Uromitexan 100 mg/mlis administered with ifosfamide and cyclophosphamide. It does not react with these medications, and no reaction with other medications is known.

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

Use ofUromitexan 100 mg/mlwith food and beverages

Food does not affect the absorption and urinary elimination ofUromitexan 100 mg/ml.

Pregnancy, lactation, and fertility

If you are pregnant or breastfeeding, or think you may be pregnant or intend to become pregnant,consult your doctor, pharmacist, or nurse before using this medication.

Uromitexan 100 mg/mlis not recommended during pregnancy or lactation. Your doctor should carefully consider the potential risks and benefits for each patient individually before prescribingUromitexan 100 mg/ml.

Pregnancy, fertility, and lactation are usually contraindications for treatment with cytostatics (cancer medications), so it is unlikely thatUromitexan 100 mg/mlwill be used in these circumstances.If a patient is individually 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 undergoing treatment with these medications.

Laboratory tests

Ifosfamide and cyclophosphamide can cause damage to the bladder lining. This damage may 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 strip or observe it under a microscope, looking for the presence of blood.

Inform your doctor or nurse if you have any other test with a "reactive strip," as this medication may affect the results obtained. These "reactive strip" tests can be used in blood or urine and detect certain chemical substances present in the blood called "ketones," or red blood cells in the urine.

Treatment withUromitexanmay give false positives in certain laboratory tests.

Driving and operating machinery

Some of the side effects of treatment withUromitexan 100 mg/mlmay affect your ability to drive and operate machinery. Your doctor will decide if it is safe for you to do so.

Uromitexan 100 mg/mlcontainssodium

This medication contains less than 1 mmol (23 mg) of sodium per ml. You should be aware of this in the treatment of patients with low-sodium diets.

Follow exactly the administration instructions for this medication as indicated by your doctor or pharmacist. In case of doubt, 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 a nurse.

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

While using this medication, you must 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 on the amount of medication 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 it in the form of tablets or injection
• whether you suffer from urinary tract infections
• whether you have ever had signs of bladder damage before using ifosfamide or cyclophosphamide
• whether 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 needed 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 oxazaphosphorine (ifosfamide or cyclophosphamide) dosing schedule.

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 (protein in urine) throughout the treatment period.

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

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

Example of dosing:

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

Example of dosing

Repeat this dosing schedule 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 moreUromitexan 100 mg/mlthan 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 medication and the amount administered.

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

There is no known antidote for mesna overdose.

If this 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, as it will be administered by a trained and qualified person.

If you forget to receiveUromitexan 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 your bladder is completely protected against damage.

If you think you have not received a dose, inform your doctor or nurse.

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

If you interrupt treatment withUromitexan 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 other questions about the use of this medication, ask your doctor, pharmacist, or nurse.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

The following side 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 common adverse reactions associated with the use of Uromitexan 100 mg/ml are: headache, injection site reactions, abdominal pain/colic, dizziness, lethargy/somnolence, fever, rash, diarrhea, nausea, flushing, and flu-like symptoms.
• The most severe 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 (a severe allergic reaction to medications characterized by skin rash, fever, and organ damage, 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, blisters in the mouth or skin, sudden drop in blood pressure (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 rather than Uromitexan 100 mg/ml, as 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 blood cells:
• • decrease in all types of blood cells (pancytopenia),
  • reduction in the number of white blood cells (which fight infections, leucopenia, lymphopenia),
  • abnormally high levels of eosinophils (a type of white blood cell produced in the bone marrow) either in the blood or tissues (eosinophilia); and platelets (which help blood to clot, thrombocytopenia)

Metabolism and Nutrition

• decreased appetite

Psychiatric

• insomnia, nightmares

Immune system

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

Nervous system

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

Eye

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

Heart and Circulation

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

Lungs

• difficulty breathing or wheezing (bronchospasm)
• congested nose
• cough
• sharp, severe pain when inhaling (pleuritic pain)
• dry mouth
• difficulty breathing (dyspnea)
• throat irritation
• nasal bleeding (epistaxis)
• respiratory difficulty
• decreased oxygen levels in the body (hypoxia, decreased oxygen saturation)
• rapid breathing (tachypnea)
• coughing up blood or bloody sputum from the lungs or respiratory tract (hemoptysis)

Digestive system

• abdominal pain/colic
• nausea
• vomiting
• diarrhea
• mucosal irritation
• burning pain
• constipation
• gingival bleeding (bleeding gums)
• inflammation of the mucous membranes of the mouth, including ulcers (stomatitis)
• bad taste

Liver

• conditions that cause inflammation of the liver, which can cause yellowing of the skin or eyes (jaundice), weight loss, and general malaise (hepatitis)
• increase in 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
• abnormal increase in sweating or perspiration, exceeding the required for temperature regulation (hyperhidrosis)
• conditions that pose a risk to life, causing rashes, ulcers, sore throat, fever, conjunctivitis, separation of skin layers (toxic epidermal necrolysis, Stevens-Johnson syndrome)
• itching, red rash that can develop in blisters (erythema multiforme, erythema)
• allergic reaction to medications, characterized by skin rash, fever, lymph node inflammation, and organ damage(erythema with eosinophilia and systemic symptoms)
• ulcers and/or blisters (mucocutaneous, oral mucosa, vulvovaginal, anorectal)
• swelling of the deeper layers of the skin caused by fluid accumulation (angioedema)
• recurring lesions in the same area, when the same medication is given(fixed eruption)
• rash
• photodistributed rash
• rash in the skin with a pale red color, hives, and itching(urticaria)
• burning sensation

Musculoskeletal and connective tissue

• muscle pain (myalgia), or joint pain (arthralgia).
• back pain
• unpleasant sensation in the upper or lower extremities (pain in the extremities)
• jaw pain

Renal and urinary

• painful urination (dysuria)
• acute renal insufficiency

General disorders and administration site conditions

• change in appearance of the skin 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 the tissues, usually in the lower extremities, due to fluid accumulation (peripheral edema)
• inflammation of the face (facial edema)
• fatigue
• reactions at the infusion site (thrombophlebitis, irritation)

Reporting of side effects:

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

Keepthis medicationout of the sight and reach of children.

Do not usethis medicationafter the expiration date that appears on the box afterCAD. The expiration date is the last day of the month indicated.

Do not store at a temperature above30ºC.

Keep the containerin the outer packaging.

Use only if the solution is transparent, free of visible particles, and if the container is not damaged.

Thesolution must be administered at the time of opening the injectable ampoule.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the medicines you no longer need. In this way, you will help protect the environment.

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, nitrogenand water for injection preparations.

Appearance of the product and contents of the packaging

Uromitexan 100 mg/ml is a sterile, transparent, and colorless solution that is 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 within a cardboard box.

Each box contains 5 or 10 ampoules.

Only some packaging sizes may be marketed

Marketing authorization holder and responsible manufacturer

Marketing authorization holder

Baxter S.L.

Pouet de Camilo 2, 46394 Ribarroja del Turia (Valencia)

Spain

Responsible manufacturer:

Baxter Oncology, GMBH.

Kantstrasse, 2 D-33790 (Halle/Westfalen)

Germany

Last review date of this leaflet: February 2019

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/