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Composition:


active ingredient: mesna;


1 ml of the solution contains mesni 100 mg;


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



 


Dosage form. Solution for injection.


Basic physical and chemical properties: transparent, colorless solution in ampoules of transparent colorless glass with a volume of 5 ml with a break point and two color coding rings (upper-blue, lower – green).



 


Pharmacotherapeutic group.


Drugs used to eliminate the toxic effects of antitumor therapy.


ATX code V03A F01.



 


Pharmacological properties.


Pharmacodynamics.


The mechanism of action of Uromitexan® 400 mg is aimed at reducing the urotoxic effects of oxazaphosphorin hydroxymetabolites, as well as the formation of non-toxic additive compounds with acrolein. These reactions promote regional detoxification in the kidneys and efferent urinary tract.


Pharmacokinetics.


In the blood serum, mesna, which is used as a free thiol compound, is rapidly converted to a metabolite – mesna disulfide, a significant part of which is reduced to a free thiol compound after glomerular filtration. Almost all excretion of the drug is carried out by the kidneys. Excretion of the drug by the kidneys begins immediately after its use. During the first 4 hours after a single dose, the drug is mainly excreted as a free SH compound, and then almost exclusively as a disulfide. The drug is almost completely excreted by the kidneys in about 8 hours.


Given the need to protect the bladder during treatment with oxazaphosphorins, it should be taken into account that urine is a suitable environment where approximately 30% of the intravenous dose of the drug is biologically available as a free sh-mesna.


Effect of the drug in vivo on the number of lymphocytes


In pharmacokinetic studies involving healthy volunteers, the use of single doses of mesna was usually accompanied by a rapid (within 24 hours) and in some cases a significant decrease in the number of lymphocytes, which was generally reversible within the 1st week of drug use. The data obtained in studies using repeated doses of the drug for several days are insufficient to characterize the dynamics of changes in the number of lymphocytes under such conditions.


Effect of the drug in vivo on serum phosphorus levels


In pharmacokinetic studies involving healthy volunteers, the use of mesna for one or more days was in some cases associated with a moderate transient increase in serum phosphorus concentrations.


In addition, serum creatine phosphokinase (CPK) levels were lower in samples taken 24 hours after mesna administration than in samples taken before Drug Administration. This may be due to the fact that there is significant interference when using thiol (e.g., N-acetylcysteine)-dependent enzyme tests to determine CPK levels.



 


Clinical characteristics.


Indications.


Prevention of toxic effects of oxazaphosphorins (ifosfamide, cyclophosphamide, trophosphamide) on the urinary tract, in particular in patients of the high – risk group-after radiation therapy of the pelvic organs, with cystitis after previous treatment with oxazaphosphorins or a history of urinary tract disorders.



 


Contraindications.


Hypersensitivity to the active substance or to any excipient of the drug.



 


Interactions with other drugs and other types of interactions.


No interaction studies have been conducted.



 


Application features.


Hypersensitivity


Hypersensitivity reactions to mesna have been reported after the use of mesna as a uroprotector. These include various reactions from the skin and subcutaneous tissue.


In addition, cases of severe bullous reactions and ulcerative lesions of the skin and mucous membrane have been reported. Some reactions were considered consistent with Stevens – Johnson syndrome.


In some cases, skin reactions were accompanied by one or more other symptoms, such as:


* fever;


* cardiovascular symptoms;


* signs that were consistent with acute renal failure;


* pulmonary symptoms;


* hematological disorders;


* increased levels of liver enzymes;


* nausea, vomiting;


* pain in the extremities, arthralgia, myalgia, malaise;


* stomatitis;


* conjunctivitis.


Some reactions were manifested as anaphylaxis.


Fever was accompanied, for example, by hypotension, but no skin manifestations were registered.


Autoimmune diseases are associated with an increased risk of allergic and/or anaphylactoid reactions (see the section "adverse reactions"). For this reason, urinary tract protection with Uromitexan® 400 mg in such patients is recommended after careful assessment of the risk/benefit ratio and under medical supervision.


In the case of mesna use in the treatment regimens of severe systemic autoimmune disorders and malignant neoplasms, cases of severe reactions, as well as mild reactions, have been reported.


In most cases, adverse reactions were observed during or after the first administration or after several weeks of using mesna. In other cases, an undesirable reaction developed only after several months of using the drug.


With repeated use, there is a tendency to shorten the interval until symptoms of hypersensitivity appear. The frequency and / or severity of reactions vary depending on the dose administered. In some patients, reactions developed after repeated administration of the drug, sometimes with increased severity.


Some patients with a history of adverse reactions showed positive test results for a delayed skin reaction. However, a negative result for delayed reactions does not exclude the presence of hypersensitivity to mesna. Positive immediate skin reactions were observed in patients regardless of previous mesna exposure or a history of hypersensitivity reactions, and may also be associated with the concentration of mesna solution used in skin tests.


Doctors who prescribe the drug:


- be informed about the possibility of developing such adverse reactions, as well as that these adverse reactions may worsen after repeated use of the drug, and in some cases – be life-threatening;


- you should be aware that hypersensitivity reactions to the use of mesna were interpreted as resembling the clinical picture of sepsis, and in patients with autoimmune disorders resemble an exacerbation of the underlying disease.


Thiol compounds


Mesna is a thiol compound, i.e. it is a sulfhydryl (SH) group containing an organic compound. Thiol compounds show some similarities in their adverse reaction profile, including in terms of their potential to cause severe skin reactions. Examples of medications that are thiol compounds include amifostin, penicillamine, and captopril.


It has not yet been clarified whether patients who have experienced adverse reactions to the use of such a drug have an increased risk of developing any reactions or similar reactions to another thiol compound. However, when considering further use of another thiol compound in such patients, the possibility of an increased risk of adverse reactions should be taken into account.


Mesna cannot prevent the development of hemorrhagic cystitis in all patients. Patients ' condition should be monitored accordingly.


During the use of the drug, it is necessary to maintain the amount of urine released at a sufficient level, as is required for treatment with oxazaphosphorin.


Interactions during laboratory tests


When using mesna, false positive results of tests based on sodium nitroprusside (including tests using indicator strips) for detecting ketone bodies in the urine are possible. The addition of glacial acetic acid helps to distinguish false positive results (cloudy cherry-red color) from really positive results (reddish-purple color, which becomes more intense).


When using mesna, false positive results of screening tests based on Tillman reagent for detecting ascorbic acid in the urine are possible.


Use in geriatric patients


In general, the choice of dosage for elderly patients requires caution, given the increased frequency of deterioration of liver, kidney or heart function, as well as the presence of concomitant diseases or the simultaneous use of other medications. However, the ratio of oxazaphosphorins to mesna should remain unchanged (see the section "dosage and administration").


Uromitexan ® 400 mg contains sodium, but in an amount less than 1 mmol (23 mg) of sodium per 10 ml of the drug.


Use during pregnancy or lactation.


Since Uromitexan 400 mg is used as a uroprotector in cytostatic therapy with oxazaphosphorins, the possibility of its use during pregnancy or lactation is regulated by the criteria for this type of cytostatic therapy. The period of pregnancy or lactation is a contraindication for cytostatic treatment, so the use of mesna during this period is undesirable.


Pregnancy


There are no adequate data on the use of mesna in pregnant women. Animal studies have found no evidence of embryotoxic or teratogenic effects of mesna.

Overdose.


Reports of unintentional overdose, as well as observational data obtained during studies of the tolerability of high doses of the drug in healthy volunteers, showed that in adults, single doses of mesna in the range of approximately 4 g to 7 g can cause the development of symptoms such as nausea, vomiting, abdominal pain/colic, diarrhea, headache, fatigue, pain in the extremities and joints, rash, hyperemia, hypotension, bradycardia, tachycardia, paresthesia, fever and bronchospasm.


Patients treated with oxazaphosphorins also showed a significantly increased incidence of nausea, vomiting, and diarrhea with intravenous mesna administration at a dose of ≥ 80 mg/kg of body weight per day compared to patients treated with lower doses of the drug or hydration therapy alone.


Mesna's specific antidote is unknown. Due to the possibility of developing anaphylactoid reactions described in the sections "application features" and "adverse reactions", conditions should be provided for emergency medical care for patients with autoimmune disorders, if necessary.



 


Adverse reactions.


Due to the fact that Uromitexan® is intended for use in chemotherapy in combination with oxazaphosphorins or oxazaphosphorin-containing combinations, it is often difficult to distinguish adverse reactions that may result from uromitexan® therapy from those caused by cytotoxic substances that are administered simultaneously.


The most frequently reported side effects (> 10 %) with mesna are nausea, diarrhea, abdominal pain/colic, flu – like reactions, fever, hot flashes, dizziness, drowsiness, lethargy, headache, rash, and infusion site reactions.


The most severe adverse reactions associated with the use of mesna are toxic epidermal necrolysis, Stevens – Johnson syndrome, anaphylactic reaction and drug-induced rash, which is accompanied by eosinophilia and systemic symptoms (DRESS).


Frequency of adverse reactions


Very often (≥1/10)


Often (≥1/100 to < 1/10)


Infrequently (≥1/1000 to < 1/100)


Rare (≥1/10000 to < 1/1000)


Very rare (<1/10000)


The frequency is unknown (cannot be estimated from the available data).


Infections and infestations: very rarely – pharyngitis.


From the blood and lymphatic system: often – lymphadenopathy; frequency unknown – pancytopenia, leukopenia, lymphopenia, thrombocytopenia, eosinophilia.


Immune system disorders: frequency unknown-anaphylaxis, hypersensitivity reactions.


From the side of metabolism and nutrition: often – decreased appetite, feeling dehydrated.


Mental disorders: often-insomnia, nightmares.


From the nervous system: very often – dizziness, drowsiness, headache, lethargy; often – dizziness, paresthesia, hyperesthesia, syncope, hypoesthesia, impaired mindfulness; frequency unknown – convulsions.


From the side of the visual organs: often – conjunctivitis, photophobia, blurred vision; frequency unknown – periorbital edema.


From the heart: often-palpitations; frequency unknown-ECG changes, tachycardia.


Vascular disorders: very often – hot flashes; frequency unknown-hypotension or hypertension.


Respiratory, thoracic and mediastinal disorders: often-cough, nasal congestion, pleural pain, dry mouth, bronchospasm, dyspnoea, laryngeal discomfort, nosebleeds; frequency unknown – respiratory distress, hypoxia, decreased oxygen saturation, tachypnea, hemoptysis.


From the digestive system: very often – nausea, diarrhea, colic, abdominal pain; often – irritation of the mucous membranes 1, bloating, constipation, burning pain (behind the sternum, in the epigastrium), bleeding gums; frequency unknown – stomatitis, deterioration of taste sensations.


From the hepatobiliary system: often – increased levels of transaminases; frequency unknown – hepatitis, increased levels of gamma-glutamyltransferase and alkaline phosphatase in the blood.


From the skin and subcutaneous tissues: very often – rash2; often-pruritus, hyperhidrosis; frequency unknown-urticaria, Stevens – Johnson syndrome, erythema multiforme, drug-induced rash3, ulceration and/or bullous rash/blistering 4, angioedema, rash, burning sensation, toxic epidermal necrolysis, photosensitivity, erythema.


Musculoskeletal and connective tissue disorders: often-arthralgia, back pain, myalgia, pain in the extremities, pain in the jaw.


From the side of the kidneys and urinary system: often – dysuria; frequency unknown – acute renal failure.


General disorders and condition of the injection site: very often – local infusion reactions (rash and pruritus), fever, flu – like reactions; often – local infusion reactions (pain, redness, urticaria, edema), chills, loss of strength, chest pain, exhaustion; frequency unknown-facial edema, peripheral edema, asthenia, local infusion reactions (thrombophlebitis, skin irritation).


Laboratory parameters: frequency unknown-laboratory signs of disseminated intravascular coagulation, prolongation of prothrombin time, prolongation of activated partial thromboplastin time.


1 oral, rectal.


2 including erythemic/erythematous, eczematous, papular and/or macular rashes with or without pruritus.


3 with eosinophilia and systemic symptoms.


4 skin and mucous membranes, mucous, oral, vulvovaginal, anorectal.



 


Time to occurrence of adverse events and experience of repeated use of the drug


In studies, some individuals developed adverse events after the first use of mesna; in other individuals, adverse events occurred after the second or third use of the drug. In general, the full range of symptoms observed in the patient appeared within a few hours. In some patients, adverse reactions after their initial appearance were not observed in the future, while in other patients, an exacerbation of adverse events was observed during repeated use of the drug.


Infusion site reactions


In some patients who experienced local skin reactions at the infusion site, further use of mesna led to the development of skin adverse events in places other than the infusion site.


Skin/ mucosal reactions


Adverse skin and mucosal reactions have been reported to develop after intravenous and oral administration of mesna. Approximately one-quarter of patients experienced other adverse symptoms along with any skin/ mucosal phenomenon, including shortness of breath, fever, headache, gastrointestinal symptoms, drowsiness, malaise, myalgia, and flu-like symptoms.

Tags: Uromitexan® [Mesna]