UROMITEXAN 400 mg /4 Ml Инъекционный Раствор

Содержание инструкции

1. UROMITEXAN 400 mg/4 ml solution for injection for intravenous use
2. UROMITEXAN and must be considered as adverse reactions due to the simultaneous

UROMITEXAN 400 mg/4 ml solution for injection for intravenous use

Mesna

PHARMACOTHERAPEUTIC CATEGORY
Detoxifying substance for cytotoxic treatments.

THERAPEUTIC INDICATIONS
Prevention of toxic lesions of the urinary tract caused by oxazaphosphorines (cyclophosphamide,
ifosfamide). During cytostatic therapy with ifosfamide, UROMITEXAN should always be administered.
When cyclophosphamide is administered, UROMITEXAN should always be used when the
cytostatic is administered as a bolus (doses greater than 10 mg/kg), and also in patients at high risk.
The main risk factors are: previous radiotherapy of the small pelvis, cystitis phenomena with
previous therapy with ifosfamide and cyclophosphamide or a history of urinary tract disorders.
Principali fattori di rischio sono: precedente radioterapia della piccola pelvi, fenomeni di cistite con
precedente terapia con ifosfamide e ciclofosfamide o anamnesi di affezioni delle vie urinarie.

CONTRAINDICATIONS
Hypersensitivity to the active ingredient, to other thiol compounds or to any of the excipients.

PRECAUTIONS FOR USE
Due to possible anaphylactoid reactions, ensure that emergency medicines are available.
The protective effect of UROMITEXAN is expressed only at the level of the urinary tract, reducing the risk of
hemorrhagic cystitis due to therapy with oxazaphosphorines. All other precautionary measures deemed
necessary are not affected by its use and therefore must be maintained. Protection of the urinary tract with
UROMITEXAN should still be undertaken only after a careful risk-benefit analysis and always under medical
supervision.
UROMITEXAN does not prevent hemorrhagic cystitis in all patients. Therefore, a urine sample must be
examined for the presence of hematuria (microscopic evidence of the presence of red blood cells) every day
before starting treatment with oxazaphosphorines.
Sufficient urinary excretion must be maintained as required for treatment with oxazaphosphorines. In case of
hematuria during administration of UROMITEXAN and oxazaphosphorines in accordance with the dosage
indicated in the table in the section DOSAGE, METHOD AND TIME OF ADMINISTRATION, depending on the
severity of the hematuria, the dosage should be reduced or treatment with oxazaphosphorines should be
interrupted.
Paediatric use
Mesna is used as a protective agent for urotoxicity associated with oxazaphosphorines. Therefore, the only
references relating to the safety and efficacy of mesna in paediatric patients under 16 years of age are found
in the published medical literature on the use of oxazaphosphorine anti-cancer agents. No clinical studies are
dedicated exclusively to the use of mesna in paediatrics.

INTERACTIONS
Inform your doctor or pharmacist if you are taking or have recently taken any other medicines, including those
available without a prescription.
The systemic effects of oxazaphosphorines are not modified by UROMITEXAN. Clinical studies have
shown that an overdose of UROMITEXAN does not decrease acute and subacute toxicity, leucotoxic activity
and immunosuppressive efficacy of oxazaphosphorines. The administration of ifosfamide and
cyclophosphamide to animals affected by various types of tumors has also shown that UROMITEXAN does not
affect the antineoplastic efficacy of these medicines. Furthermore, UROMITEXAN does not affect the
antineoplastic activity of other cytostatics (e.g. doxorubicin, BCNU, methotrexate, vincristine) or the therapeutic
effect of digitalis glycosides.
Interference with diagnostic tests
Treatment with UROMITEXAN may give rise to false positivity to the acetone test (e.g. with the Rothera test,
urine test based on sodium nitroprusside, or N-Multistick reactive strips) and to false positivity or false
negativity to the dipstick test (reactive strips) for hematuria. The chromatic reaction for acetone is
amaranth instead of violet, is less stable and fades immediately upon addition of glacial acetic acid. Microscopic
examination is recommended to determine the presence of hematuria.
Treatment with mesna may cause false positives in the urine screening test for ascorbic acid based on Tillman's
reagent.
In pharmacokinetic studies on healthy volunteers, serum creatine phosphokinase (CPK) values were lower in
samples taken 24 hours after the administration of mesna than in samples taken before administration. Although
the available data are insufficient to determine the cause of this phenomenon, a significant interference with
enzymatic tests for thiol-dependent CPK (e.g. N-acetylcysteine) could be suspected.
See also section ADVERSE EFFECTS for information on abnormalities in diagnostic tests observed in
pharmacokinetic studies.

SPECIAL WARNINGS
Protection of the urinary tract with UROMITEXAN should still be undertaken only after a careful risk-benefit
analysis and always under medical supervision.
Hypersensitivity
In patients with immune system disorders who were receiving cyclophosphamide and UROMITEXAN, reactions due
to hypersensitivity, such as skin and mucous membrane reactions of varying extent and severity (pruritus,
skin rash, redness, blister formation, Lyell's syndrome, Stevens-Johnson syndrome), local edema of the tissues
(urticarial edema), conjunctivitis, rare cases of blood pressure drop associated with circulatory disorders,
increased heart rate above 100 beats/minute (tachycardia) and increased respiratory rate (tachypnea) due to
severe hypersensitivity reactions (anaphylactoid reactions), hypertension, ST segment elevation, myalgia and
even a temporary increase in some parameters of liver function (transaminases) have been reported at a higher
incidence compared to neoplastic patients.
Therefore, the urinary tract of patients with immune system disorders must be protected by administering mesna,
carefully evaluating the risk/benefit ratio and always under medical supervision.
Hypersensitivity reactions to mesna have been reported after the administration of mesna as a uroprotector. These
include:

• Skin reactions characterized by symptoms such as localized or generalized urticaria or other forms of exanthema, pruritus, burning, angioedema and/or flushing.
• In addition, severe cases of blisters and skin ulceration and reactions to the mucous membranes have been reported. Some reactions were considered compatible with Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiforme.
• Other reactions appeared compatible with a diagnosis of drug-induced fixed erythema. Photodistribution of rash has also been reported. In some cases, skin reactions were accompanied by one or more additional symptoms:
• Fever
• Cardiovascular symptoms (hypotension, in some cases reported as refractory to fluids, tachycardia, electrocardiographic signs compatible with perimyocarditis, see section ADVERSE EFFECTS)

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• Signs compatible with acute renal failure
• Pulmonary symptoms (hypoxia, respiratory distress, bronchospasm, tachypnea, cough, expectoration with blood, see section ADVERSE EFFECTS)
• Prolonged prothrombin time (PT) and partial thromboplastin time (PTT), laboratory tests showing signs of disseminated intravascular coagulation (DIC)
• Hematological abnormalities (leukopenia, eosinophilia, lymphopenia, thrombocytopenia, pancytopenia, see section ADVERSE EFFECTS)
• Increased liver enzyme levels
• Nausea, vomiting
• Limb pain, arthralgia, myalgia, malaise
• Stomatitis
• Conjunctivitis Some reactions presented as anaphylaxis. Fever accompanied by, for example, hypotension but not by skin manifestations has also been reported. Serious as well as minor reactions have been reported with the use of mesna in regimens for the treatment of severe systemic autoimmune diseases and tumors. In most cases, the reactions occurred during or after the first treatment or after several weeks of exposure to mesna. In other cases, the initial reaction was observed only after several months of exposure. In many cases, the symptoms appeared on the day of exposure with a tendency to shorter intervals following subsequent exposures. In some patients, the manifestation and/or severity of the reaction appeared to vary depending on the dosage administered. Recurrence of the reactions has been reported, in some cases with greater severity, in case of subsequent exposures. However, in some cases, there was no recurrence of the reaction with re-exposure. Some patients with a history of a reaction showed positive results with delayed-type skin testing. However, a negative delayed reaction does not exclude hypersensitivity to mesna. Some patients showed a positive result with immediate-type skin testing regardless of a previous exposure to mesna or a history of hypersensitivity reactions; this could be related to the concentration of the mesna solution used for the test. The prescribing physician must:
• be aware of the possibility of such reactions, that reactions may worsen with re-exposure and that in some cases they may be life-threatening;
• know that hypersensitivity reactions to mesna resemble the clinical picture of sepsis and, in patients with autoimmune diseases, can mimic an exacerbation of the underlying disease. Thiol compoundsMesna is a thiol compound, i.e. an organic compound containing a sulfhydryl group (SH). Thiol compounds show some similarities in their adverse reaction profile, including the potential to cause severe skin reactions. Examples of medicines that are thiol compounds include amifostine, penicillamine and captopril. It is not clear whether patients who have experienced an adverse reaction to these medicines are at greater risk of developing such reactions or similar reactions with another thiol compound. In any case, when assessing the use of another thiol compound in such patients, the possibility of a greater risk should be considered.

Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Since UROMITEXAN is used as a uroprotector during cytostatic treatment with oxazaphosphorines, its use during
pregnancy and breastfeeding follows the same criteria as those used during cytostatic therapy.
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Pregnancy:
No adequate data are available regarding the use of UROMITEXAN during pregnancy. Animal studies have not
shown embryotoxic or teratogenic effects of UROMITEXAN. Since reproductive studies in animals are not always
able to predict the response in humans, this medicine should be administered during pregnancy only if strictly
necessary.
Breastfeeding:
It is not known whether mesna or dimesna are excreted in breast milk. Since many medicines are excreted in
breast milk and considering the possible occurrence of adverse reactions due to UROMITEXAN in the newborn,
it will be necessary to decide whether to discontinue breastfeeding or the administration of the medicine, based on
the mother's condition.
The doctor must carefully evaluate the potential risks and benefits for each specific patient before prescribing mesna.

Effects on ability to drive and operate machinery
Caution should be exercised when driving vehicles and operating machinery due to the possibility of adverse effects
(including e.g. syncope, dizziness, drowsiness, headache, vertigo and blurred vision) that may impair the ability
to drive vehicles or operate machinery. The decision to drive or use machinery must be made on an individual
basis.

Important information about some excipients:
Sodium content
UROMITEXAN, solution for injection for intravenous use, contains approximately 59 mg of sodium per 400 mg of
mesna.

DOSAGE, METHOD AND TIME OF ADMINISTRATION
Unless otherwise prescribed, UROMITEXAN is normally administered intravenously at a dose equal to 20% of that
of the oxazaphosphorines, at time zero (time of administration of oxazaphosphorines) and subsequently at intervals
of 4 and 8 hours.
Example:

Time8.0012.0016.00
Oxazaphosphorine dose 40 mg/kg - -
UROMITEXAN dose 8 mg/kg 8 mg/kg 8 mg/kg
Therapeutic experience in children shows that it would be more useful, in individual cases, to administer
UROMITEXAN at shorter intervals (e.g. every 3 hours) [total UROMITEXAN dose = 60% of the
dose].
With high-dose cytostatic therapy with oxazaphosphorine (e.g. before bone marrow transplantation)
the total UROMITEXAN dose can be increased by 120 to 160% of the oxazaphosphorine dose.
After administration of 20% of UROMITEXAN (in relation to the total oxazaphosphorine dose) at
time zero, the remaining dose should be administered within a period of 24 hours via continuous venous perfusion. As an alternative, intermittent bolus injection is possible: in adults 3 x 40% (at
times 0, 4 and 8 hours) or 4 x 40% (at times 0, 3, 6 and 9 hours).
In children, given the more frequent urination, bolus injections should always be administered
at intervals of 3 hours (e.g. 20% at times 0, 1, 3, 6, 9 and 12 hours). As an alternative to bolus injection, short infusions lasting 15 minutes are also possible.
With continuous infusion of ifosfamide (Holoxan) it is better to administer UROMITEXAN at time zero
after a first bolus injection (start of infusion, time 0) followed by an infusion with a dose
up to 100% of that of ifosfamide, and continue the uroprotective action in the 6 - 12 hours following
completion of the ifosfamide infusion.
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Example of UROMITEXAN administration with ifosfamide infusion lasting 24 hours:

Parenteral medications must be visually inspected before administration to
check for the presence of particulate matter or discoloration.
If the solution is discolored, cloudy or contains visible particulate matter, it should not be used.
Incompatibilities:
Mesna has been found to be incompatible in vitro with cisplatin, carboplatin and nitrogen mustard and is reactive
with acrolein.
Mixing mesna with epirubicin causes inactivation of epirubicin and should be avoided.

OVERDOSE
A specific antidote for UROMITEXAN is not known.
Due to possible anaphylactoid reactions, ensure that emergency medications are available.
In tolerability studies conducted on healthy volunteers using high doses of mesna intravenously and
orally, single doses of 60-70 mg/kg have shown phenomena such as nausea, vomiting, colic, diarrhea,
headache, joint pain, hypotension, tachycardia, skin reactions, depression, irritability,
fatigue, weakness, hot flashes, bradycardia, paresthesia, fever and bronchospasm.
In patients treated with oxazaphosphorine to whom daily doses of mesna ≥ 80 mg/kg were administered intravenously, a significantly higher rate of nausea, vomiting and diarrhea was found
compared to patients to whom lower doses were administered or only hydration therapy.
In case of accidental ingestion of an excessive dose of the medication, immediately notify the
doctor and go to the nearest hospital.

UNDESIRABLE EFFECTS
Like all medicines, this one can also cause side effects, although not everyone will
experience them.
Hypersensitivity reactions after taking UROMITEXAN have been reported more frequently in
patients with immune system disorders than in patients with cancer.
Some cases of partial organ-related hypersensitivity (hyperergic reactions) have been reported
such as a decrease in platelet count (thrombocytopenia), skin and mucous membrane reactions, of varying
extent and severity (pruritus, erythema, redness, blister formation, Lyell's syndrome, Stevens-Johnson syndrome), local tissue edema (urticarial edema), conjunctivitis, rare cases of blood pressure drop associated with circulatory disturbances, increased heart rate above 100
beats/minute (tachycardia) and increased respiratory rate (tachypnea) due to severe hypersensitivity reactions (anaphylactoid reactions), hypertension, ST segment elevation, myalgia and even a
temporary increase in the values of some liver function parameters (transaminases). Rare cases of venous irritation at the injection site have been reported.
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During treatment it is difficult to clearly differentiate these side effects from those attributable
to oxazaphosphorine as such or to the concurrent use of other drugs.
In clinical studies or spontaneous reports, side effects such as nausea, vomiting, flatulence, diarrhea, constipation, colic (abdominal pain), anorexia, flu-like symptoms, fever, chills, hot flashes, cough, pharyngitis, dizziness, drowsiness, headache, back pain,
arthralgia have been frequently reported. Other side effects such as leukopenia, granulocytopenia,
anemia, alopecia and pneumonia, which cannot be reasonably associated with the administration of

UROMITEXAN and must be considered as adverse reactions due to the simultaneous

administration of cytotoxic drugs.
Clinical studies conducted on patients over 65 years of age have not revealed adverse reactions
specific to this age group.
Undesirable effects: Incidence
The frequency of undesirable effects is based on the following scale: very common (≥ 1/10), common (≥
1/100 - <1/10), uncommon (≥ 1/1,000 - <1/100), rare (≥ 1/10,000 - <1/1,000), very rare (<1/10,000),
not known (the frequency cannot be defined based on available data)

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Time of onset
In these studies some subjects experienced events at the first exposure to mesna and others after the
second or third exposure. In general, the full spectrum of symptoms presented by the subject
develops over several hours.
Experience with re-exposure
Some subjects did not experience further reactions after the initial events while others
experienced an exacerbation of the events following repetition of administration.
Reactions at the infusion site
In some subjects who had experienced local skin reactions at the infusion site, subsequent
exposure to mesna led to skin events in other areas.
Skin/mucosal reactions
Following the administration of mesna, skin and mucosal reactions have been reported. These reactions
include rash, pruritus, hot flushes, mucosal irritation, pleuritic pain, and conjunctivitis. Approximately one
quarter of subjects with events, presented skin and/or mucosal reactions together with other adverse symptoms
including dyspnea, fever, headache, gastrointestinal symptoms, somnolence, malaise,
myalgia and flu-like symptoms.
Gastrointestinal reactions
The gastrointestinal reactions reported in healthy subjects following the administration of mesna
include nausea, vomiting, diarrhea, abdominal pain/colic, epigastric pain/burning, constipation and
flatulence.
In-vivo effect on leukocyte count
In pharmacokinetic studies on healthy volunteers, the administration of single doses of mesna was
commonly associated with a rapid (within 24 hours) and in some cases considerable decrease in leukocyte
count, generally reversible within one week of administration. There is insufficient data
to characterize the evolution over time of the leukocyte count in the case of repeated administrations
for several days.
In-vivo effect on serum phosphorus levels
In pharmacokinetic studies on healthy volunteers, the administration of mesna for one or more days was in
some cases associated with a moderate temporary increase in serum phosphorus concentration.
These phenomena should be taken into consideration when interpreting laboratory results.
If any of these side effects worsen, or if you notice any side

EXPIRY DATE AND STORAGE
Expiry date: see the expiry date indicated on the packaging.
Caution: do not use the medicine after the expiry date which is reported on the vials and the packaging.
The expiry date indicated refers to the product in intact packaging, correctly stored.
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Store at a temperature not exceeding 30 °C

KEEP OUT OF THE REACH AND SIGHT OF CHILDREN.
Medicines should not be disposed of via drains or household waste. Ask your pharmacist
how to dispose of medicines you no longer use. This will help to protect the environment.

COMPOSITION
One 4 ml vial contains:

Active ingredient:
Mesna: 400 mg;

Excipients:
sodium edetate, water for injections.

PHARMACEUTICAL FORM AND CONTENT
Solution for injection for intravenous use.
Pack containing 15 vials of 4 ml.

MARKETING AUTHORISATION HOLDER
Baxter S.p.A. – Piazzale dell’Industria, 20 - 00144 Rome

MANUFACTURER
Baxter Oncology GmbH - Halle - Germany

DRUG:
June 2013
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