Uromitexan^® (Solution) Instructions for Use

Marketing Authorization Holder

Baxter Oncology, GmbH (Germany)

ATC Code

V03AF01 (Mesna)

Active Substance

Mesna (Rec.INN registered by WHO)

Dosage Form

Uromitexan®

Solution for intravenous administration 100 mg/1 ml: amp. 4 ml 15 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous administration transparent, colorless.

Excipients: disodium edetate, sodium hydroxide, water for injection.

4 ml – glass ampoules (5) – contour cell packs (3) – cardboard boxes.

Clinical-Pharmacological Group

Acrolein antidote

Pharmacotherapeutic Group

Antidote

Pharmacological Action

Mesna is an antidote for acrolein, a metabolite of antineoplastic agents from the oxazaphosphorine group (ifosfamide, cyclophosphamide), which has an irritating effect on the bladder mucosa.

The protective properties of mesna are due to its interaction with the double bond of the acrolein molecule, leading to the formation of a stable non-toxic thioether. By reducing the urotoxic effects of oxazaphosphorines, Mesna does not weaken their antineoplastic action.

Pharmacokinetics

After intravenous administration, the active substance is rapidly oxidized to a disulfide (dimesna). In the epithelium of the renal tubules, dimesna is reduced to a free thiol compound, which irreversibly binds to the metabolites of oxazaphosphorines, forming non-toxic stable thioethers.

Plasma protein binding is 69-75%. Systemic clearance is 1.23 L/h/kg.

After intravenous administration of an 800 mg dose, the T_1/2 of mesna and dimesna in the blood were 0.36 h and 1.17 h, respectively. Approximately 32% and 33% of the administered dose was excreted in the urine within 24 hours as mesna and dimesna, respectively. The majority of the reduced dose was excreted in the urine within 4 hours.

Indications

Local detoxification of the urotoxic effects of cytostatics – derivatives of oxazaphosphorines, including in the following cases

• During ifosfamide administration;
• During administration of oxazaphosphorines in high doses (more than 10 mg/kg);
• In patients at risk – previous radiotherapy to the pelvic area, development of cystitis during previous therapy with oxazaphosphorines, history of diseases of the urinary system.

ICD codes

Dosage Regimen

Uromitexan^® is usually administered intravenously as a bolus (slowly). The single dose for adults is 20% of the single dose of the oxazaphosphorine. The first administration is carried out simultaneously with the first administration of the oxazaphosphorine, the second and third injections are given 4 hours and 8 hours after the oxazaphosphorine administration.

In children, the single dose of Uromitexan^® is 60% of the cytostatic dose, and the drug is administered every 3 hours.

During continuous infusion (24 hours) of ifosfamide or cyclophosphamide, Uromitexan^® should be administered at a dose of 20% of the cytostatic dose at the start of the infusion, then at a dose of 100% of the cytostatic dose as a 24-hour infusion, and after the end of the cytostatic administration, Uromitexan^® administration is continued for another 6-12 hours at the same dose.

When using oxazaphosphorines in very high doses, for example, before bone marrow transplantation, the total dose of Uromitexan^® can be increased to 120-160% of the oxazaphosphorine dose. After administering 20% of Uromitexan^® at the start of cytostatic administration, the remaining calculated dose is recommended to be administered intravenously over a long period, over 24 hours using a perfusor. As an alternative, fractional bolus injection is possible: for adults 3 × 40% (time 0, 4, 8 h) or 4 × 40% (time 0, 3, 6, 9 h). Instead of bolus injections, short infusions lasting 15 minutes each are possible.

Adverse Reactions

Adverse reactions occurring more frequently than in isolated cases are listed according to the following gradation: very common (> 10%); common (> 1%, < 10%); uncommon (> 0.1%, < 1%); rare (> 0.01%, < 0.1%); very rare (< 0.01%).

From the digestive system common – nausea, vomiting, diarrhea, constipation, abdominal pain, flatulence, anorexia.

From the hematopoietic system very rare – thrombocytopenia. Granulocytopenia, leukopenia, anemia have also been observed. A causal relationship of these phenomena with Uromitexan^® has not been established; it could be due to concomitant cytotoxic therapy.

From the CNS: common – dizziness, drowsiness, headache, irritability, depression.

From the cardiovascular system common – flushing.

From the immune system: very rare – hypersensitivity reactions (skin rash, itching, Lyell’s syndrome, Stevens-Johnson syndrome, urticaria, conjunctivitis, decreased BP, tachycardia, tachypnea, anaphylactoid reactions, increased BP, ST segment elevation, myalgia, as well as increased activity of a number of liver function tests).

From the respiratory system common – cough.

Local reactions rare – phlebitis at the injection site, pain and redness.

Other common – arthralgia, back pain, fever, chills, flu-like syndrome, pharyngitis; very rare – limb pain, increased fatigue, weakness. Pneumonia, alopecia were also commonly observed. A causal relationship of these phenomena with Uromitexan^® has not been established; it could be due to concomitant cytotoxic therapy.

Contraindications

• Lactation;
• Pregnancy;
• Hypersensitivity to mesna, any component of the drug, or other thiol compounds.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Pediatric Use

Use is possible according to the dosage regimen.

Special Precautions

Mesna has a protective effect only on the urinary system and does not eliminate other side effects of cytostatics, therefore, when treating with drugs of the oxazaphosphorine group, it is necessary to use a full range of supportive and symptomatic therapy.

Uromitexan^® does not prevent hemorrhagic cystitis in all patients. Therefore, it is necessary to perform a daily analysis of the morning urine sample for the presence of hematuria. If hematuria appears during the use of Uromitexan^® with oxazaphosphorines according to the recommended dosage regimen, it may be necessary to reduce the doses or discontinue oxazaphosphorine therapy.

Due to the possibility of anaphylactic reactions, it is necessary to ensure the availability of appropriate emergency medications.

In patients with autoimmune diseases treated with cyclophosphamide and Uromitexan^®, hypersensitivity reactions are detected with a higher frequency. In such patients, protection of the urinary tract with Uromitexan^® should be carried out only after a thorough risk/benefit analysis and under careful medical supervision.

During treatment, false-positive reactions for the presence of ketone bodies in the urine are noted (when performing a color reaction for ketones, a reddish-purple coloration of the urine is possible, which is unstable and disappears immediately upon adding glacial acetic acid to the urine).

Overdose

A specific antidote for Uromitexan^® is unknown.

Symptoms: nausea, flatulence, diarrhea, headache**,fatigue, pain in limbs and joints, malaise, weakness, depression, irritability, rash, decreased BP, tachycardia.

Treatment is symptomatic.

Drug Interactions

Mesna is compatible with cyclophosphamide and ifosfamide, so it can be administered with them in the same solution, without changing the antineoplastic activity of the latter.

The drug is not compatible with cisplatin (binding and inactivation of the latter), therefore mesna should not be mixed in the same solution with cisplatin.

Mesna does not affect the therapeutic efficacy of doxorubicin, carmustine, cisplatin, methotrexate, vincristine, nor the activity of cardiac glycosides.

Storage Conditions

List B. Store at a temperature below 30°C (86°F). Keep out of reach of children.

Shelf Life

Shelf life – 5 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.