Consumer medicine information

UROMITEXAN Tablets

Mesna

BRAND INFORMATION

Brand name

Uromitexan Tablets

Active ingredient

Mesna

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using UROMITEXAN Tablets.

What is in this leaflet

This leaflet answers some common questions about UROMITEXAN Tablets.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking UROMITEXAN Tablets against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What UROMITEXAN Tablets is used for

UROMITEXAN Tablets is a protective agent which is used to prevent damage to your bladder and urinary system, that may be caused by some drugs used to treat cancer or auto-immune diseases. These drugs can cause a condition of the bladder, with pain in the bladder or back and blood in the urine. UROMITEXAN Tablets can help prevent this.

Your doctor may have prescribed UROMITEXAN Tablets for another reason. Ask your doctor if you have any questions about why UROMITEXAN Tablets has been prescribed for you.

Your doctor may decide to give you some of your doses in the form of UROMITEXAN Injection instead of UROMITEXAN Tablets. Both work just as well.

UROMITEXAN Tablets is not addictive.

This medicine is available only with a doctor's prescription.

Before you take UROMITEXAN Tablets

When you must not take it

Do not take UROMITEXAN Tablets if you have an allergy to UROMITEXAN Tablets or any related products (thiols), or to any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to UROMITEXAN Tablets may include:

  • shortness of breath, wheezing, difficulty breathing or a tight feeling in your chest
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching, hives or flushed, red skin
  • dizziness or lightheadedness
  • fast heart beat

Do not take UROMITEXAN Tablets after the expiry date printed on the pack.

If you take this medicine after the expiry date has passed, it may not work as well.

Do not take UROMITEXAN Tablets if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking UROMITEXAN Tablets, talk to your doctor or pharmacist.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

Tell your doctor if you have or have had any medical conditions, especially the following:

  • bladder problems
  • auto-immune disease

Tell your doctor if you have had radiation therapy to the area of the pelvis.

This could mean you need a higher dose of UROMITEXAN Tablets.

Tell your doctor about any other treatments that you have had for cancer, or are planned to have, such as other medicines, or radiation therapy.

The doctor may need to alter the dose of UROMITEXAN Tablets or change to UROMITEXAN Injection.

Tell your doctor if you are pregnant or intend to become pregnant.

Your doctor will discuss the risks and benefits of having your medicines during pregnancy.

Tell your doctor if you are breast-feeding or plan to breast-feed.

It is not known whether UROMITEXAN passes into breast milk. There is also the possibility that the breast-fed baby may be affected by the anti-cancer medicines you are receiving.

If you have not told your doctor about any of the above, tell them before you start taking UROMITEXAN Tablets.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

It is possible that some medicines and UROMITEXAN Tablets may interfere with each other.

How to take UROMITEXAN Tablets

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

How much to take

Your doctor or pharmacist will tell you how many tablets you will need to take, the time between doses and the length of time to take UROMITEXAN Tablets. This depends mainly on the dose of the anti-cancer medicines you are receiving, and other factors such as other treatments you have been given and any bladder.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How to take it

Swallow UROMITEXAN Tablets with a glass of water.

When to take it

UROMITEXAN Tablets is given before, during and for a few hours after each dose of your anti-cancer medicine.

Take UROMITEXAN Tablets at the exact times told to you by the doctor or pharmacist.

If you do not take UROMITEXAN Tablets at the right times, it may not work.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Your doctor will tell you when your treatment should be stopped.

If you forget to take it

If you have forgotten to take a dose of UROMITEXAN Tablets, take it as soon as you remember, and then go back to taking your medicine as scheduled. Contact your doctor or pharmacist immediately.

If you take too much (overdose)

Telephone your doctor or pharmacist if you think that you or anyone else may have taken too many UROMITEXAN Tablets. Do this even if there are no signs of discomfort or poisoning.

Symptoms of a UROMITEXAN Tablets overdose include the side effects listed below in the 'Side Effects' section, but are usually of a more severe nature.

While you are taking UROMITEXAN Tablets

Things you must do

Tell your doctor or nurse as soon as possible if you vomit while you are taking UROMITEXAN Tablets.

You may need to change to UROMITEXAN Injection.

Be sure to keep all your doctor's appointments so your progress can be checked.

Your doctor may want to check your urine and do some other tests from time to time to check on your progress and detect any unwanted side effects.

Be sure to follow your doctor's instructions about other medicines you should take, and other things you should do.

The protective effect of UROMITEXAN Tablets applies only to the bladder and urinary system. You may still need to take additional medicines to protect other body systems.

Your doctor may also advise you to drink extra fluid while you are taking UROMITEXAN Tablets. This will help to prevent damage to your bladder and urinary system.

Ask your doctor or pharmacist if you have any questions.

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking UROMITEXAN Tablets.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking UROMITEXAN Tablets.

If you become pregnant while taking UROMITEXAN Tablets, tell your doctor.

If you are having any tests on your urine such as for diabetic acidosis, tell your doctor or pharmacist that you are taking UROMITEXAN Tablets.

UROMITEXAN Tablets can interfere with some urine tests.

Things you must not do

Do not give UROMITEXAN Tablets to anyone else, even if they have the same condition as you.

Do not have UROMITEXAN Tablets to treat any other complaints unless your doctor or pharmacist tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how UROMITEXAN Tablets affects you.

As with many other medicines, UROMITEXAN Tablets may cause dizziness, light-headedness, and tiredness in some people. Make sure you know how you react to UROMITEXAN Tablets before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are taking UROMITEXAN Tablets.

UROMITEXAN Tablets may have unwanted side effects. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor, nurse or pharmacist if you notice any of the following and they worry you:

  • headache
  • tiredness, sleepiness
  • nausea, vomiting
  • diarrhoea, soft stools
  • wind
  • constipation
  • abdominal pain
  • loss of appetite
  • bad taste in the mouth
  • fever
  • chills, shivering
  • flushing
  • cough
  • sore throat
  • dizziness
  • pain in the arms or legs
  • pain in the back or joints

These are the more common or less serious side effects of UROMITEXAN Tablets.

If any of the following happen, tell your doctor or nurse immediately, or go to Accident and Emergency at your nearest hospital:

  • Sudden life-threatening allergic reaction, with symptoms such as:
  • shortness of breath, wheezing, fast breathing, difficulty breathing or a tight feeling in your chest
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching, hives or flushed, red skin
  • conjunctivitis
  • dizziness or light-headedness
  • fast heart beat
  • muscle pain
  • bleeding or bruising more easily than normal

These allergic reactions occur more often in patients being treated for auto-immune diseases than in patients being treated for cancer.

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may occur in some patients. Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

The benefits and side effects of UROMITEXAN Tablets may take some time to occur. Therefore even after you have finished your treatment with UROMITEXAN Tablets you should tell your doctor immediately if you notice any of the side effects listed in this section.

After taking UROMITEXAN Tablets

Storage

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of the pack they will not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30 deg C.

Do not store UROMITEXAN Tablets or any other medicine in the bathroom or near a sink.

Do not leave it on a window sill or in the car on hot days.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop taking UROMITEXAN Tablets, ask your pharmacist what to do with any that is left over.

Product description

What it looks like

UROMITEXAN Tablets are white, oblong, with rounded sides and a notch on one side. The 400mg tablet is marked "M4" and the 600mg tablet is marked "M6".

Ingredients

Active ingredients:

  • mesna

Other ingredients

  • lactose
  • cellulose - microcrystalline
  • calcium hydrogen phosphate
  • starch - maize
  • povidone
  • magnesium stearate
  • hypromellose
  • macrogol 6000
  • titanium dioxide E171
  • simethicone

UROMITEXAN Tablets does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Baxter Healthcare Pty Limited
(ABN 43 000 392 781)
1 Baxter Drive
Old Toongabbie NSW 2146

UROMITEXAN Tablets is available in the following sizes:

400mg AUST R 56481
600mg AUST R 56482

Date of Preparation of this leaflet:
5 April 2006

UROMITEXAN is a trademark of Baxter Healthcare S.A.

BRAND INFORMATION

Brand name

Uromitexan Tablets

Active ingredient

Mesna

Schedule

S4

 

1 Name of Medicine

Mesna.

6.7 Physicochemical Properties

Molecular weight: 164.18.

Chemical structure.


CAS number.

19767-45-4.

2 Qualitative and Quantitative Composition

The active ingredient, mesna, is a synthetic sulphydryl compound designated as sodium 2-mercapto-ethane sulphonate.
Excipients: calcium hydrogen phosphate, cellulose microcrystalline, hypromellose, lactose, macrogol 6000, magnesium stearate, povidone, simethicone, starch-maize and titanium dioxide.

3 Pharmaceutical Form

Uromitexan tablets are white, oblong, biconvex film-coated tablets, scored on one side and marked "M 4" or "M 6", containing 400 mg or 600 mg (respectively) of mesna.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Uromitexan was developed as a prophylactic agent, used to prevent and reduce the urothelial toxicity (haemorrhagic cystitis) induced by oxazaphosphorine alkylating agents such as ifosfamide or cyclophosphamide.

Clinical trials.

Evidence of the efficacy of oral mesna is based on studies with the drinking ampoule which was administered either following an initial dose of intravenous mesna or as the only form of mesna therapy. In 18 studies involving 320 patients and 700 courses of treatment, macroscopic haematuria was observed in 1.6% of courses. This may be compared with results from two other studies in which patients were hydrated instead of receiving mesna therapy. In these studies, the incidence of macroscopic haematuria after 65 courses of treatment was 45%.

5.2 Pharmacokinetic Properties

Two bioavailability studies have been undertaken comparing mesna tablets with mesna injection. In one study, the urinary recovery of mesna 24 hours after 2 x 600 mg tablets was 48% of that after 1200 mg mesna given intravenously. In the second study, the corrected urinary recovery of mesna 24 hours after 2 x 600 mg tablets was 80% of that after 600 mg mesna given intravenously. The reason for the higher recovery of mesna in this study is not clear.
Dosing regimens are based on the observation that the urinary excretion of mesna after tablet administration begins two hours later than after intravenous administration, and on the assumption that the bioavailability of the tablets is 50%, based on the two studies summarised above. Hence the recommended dosing (see Section 4.2 Dose and Method of Administration) is that, when oral mesna is administered, tablets should be taken two hours before oxazaphosphorine therapy and then at 2 and 6 hours later. If an initial intravenous dose of mesna is given with cytotoxic therapy, tablets should be taken 2 and 6 hours later. The dose of oral mesna should be double that of intravenous mesna (i.e. 40% of the oxazaphosphorine dose).

Metabolism.

Analogous to the physiological cysteine-cystine system, mesna is rapidly and easily converted by autoxidation to its only metabolite, disodium 2,2'-dithio-bisethane sulphonate (mesna disulfide, dimesna) forming a disulfide link. Following intravenous injection, only a small portion of the administered dose is detected in the blood as a reduced thiol compound (mesna). Mesna disulfide remains in the intravascular space and is rapidly delivered to the kidney. In the renal tubular epithelium a considerable proportion of mesna disulfide is again reduced to a free thiol compound, presumably mediated by glutathione reductase. Acrolein or other urotoxic oxazaphosphorine metabolites are detoxified by chemical reaction with the free thiol compound, i.e. mesna.

Excretion.

The first and most important step towards detoxification is the reaction of mesna with the double bond of acrolein, resulting in the formation of a stable thioether which can be detected in the urine by chromatography. In the second step, mesna reduces the speed of degradation of the 4-hydroxy metabolite in the urine. A relatively stable, nonurotoxic condensation product from 4-hydroxy cyclophosphamide or 4-hydroxy ifosfamide and mesna is formed. As a result of this chemical interaction, mesna inhibits the degradation of 4-hydroxy cyclophosphamide or 4-hydroxy ifosfamide and hence the formation of acrolein. The presence of this intermediate chemical species can be detected by chromatographic urinalysis.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No long-term animal studies have been performed to evaluate the carcinogenic potential of mesna.

4 Clinical Particulars

4.1 Therapeutic Indications

For the reduction and prevention of urinary tract toxicity (haemorrhagic cystitis) of oxazaphosphorines (see Section 4.8 Adverse Effects (Undesirable Effects) sections of the cyclophosphamide and ifosfamide product information).

4.3 Contraindications

Uromitexan is contraindicated in individuals with a known hypersensitivity to mesna or any of the excipients (see Section 6.1 List of Excipients) and other thiols.

4.4 Special Warnings and Precautions for Use

The protective effect of mesna applies only to the urothelial toxic effect of oxazaphosphorines (viz. ifosfamide or cyclophosphamide) and not to their renal and other toxic effects. Additional prophylactic or accompanying measures recommended during treatment with oxazaphosphorines are thus not affected and should not be discontinued.
Severe allergic symptoms, such as systemic anaphylactic reactions, have occurred with mesna, especially in patients suffering from autoimmune diseases.
Due to the possibility of anaphylactoid reactions, it should be ensured that adequate emergency medication is available.
Patients with autoimmune diseases who were treated with cyclophosphamide and Uromitexan appeared to have a higher incidence of hypersensitivity reactions: skin and mucosal reactions of varying extent and severity (rash, itching, redness, severe bullous and ulcerative skin, vesiculation, Lyell syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema exudative multiforme), localised or generalised urticarial or other forms of exanthema, pruritus, burning, local tissue swelling (urticarial oedema), angioedema and/or flushing. Some reactions appeared to be consistent with a diagnosis of fixed drug eruption. Skin reactions were accompanied by one or more other symptoms (see Section 4.8 Adverse Effects (Undesirable Effects)) such as:
fever;
conjunctivitis;
cardiovascular symptoms (hypotension, in some cases reported as fluid refractory, associated with circulatory reactions and increased pulse rate above 100/min (tachycardia), hypertension, ST segment elevation, ECG signs consistent with perimyocarditis);
signs consistent with acute renal failure;
pulmonary symptoms (hypoxia, respiratory distress, bronchospasm, cough, bloody sputum and increased respiration rate (tachypnoea) due to severe acute hypersensitivity reactions;
prolonged prothrombin time and partial prothrombin time, laboratory signs of disseminated intravascular coagulopathy;
haematological abnormalities (leukopaenia, eosinophilia, lymphopaenia, thrombocytopaenia, pancytopaenia);
pain in the extremities, arthralgia, myalgia, malaise;
transient rise in certain liver function tests (e.g. transaminases);
nausea, vomiting, stomatitis.
Photodistribution of a rash has also been reported. Some reactions have presented as anaphylaxis. Fever accompanied by, e.g. hypotension but no skin manifestations has also been reported.
Severe as well as minor reactions were reported with the use of mesna in regimens to treat both severe systemic autoimmune disorders and malignancy. In most cases, reactions occurred during or after a first treatment occasion or after several weeks of mesna exposure. In other cases, the initial reaction was observed only after several months of exposure. In many cases, symptoms appeared on the day of exposure, with a tendency to shorter intervals following subsequent exposures.
In some patients, the occurrence and/or severity of reaction appeared to vary with the dose administered. Recurrence of reactions, in some cases with increasing severity, has been reported with re-exposure. However, in some cases, a reaction did not recur with re-exposure.
Some patients with a history of a reaction have shown positive delayed type skin test results. However, a negative delayed reaction does not exclude hypersensitivity to mesna. Positive immediate type skin test reactions have occurred in patients regardless of previous mesna exposure or history of hypersensitivity reactions, and may be related to the concentration of the mesna solution used for testing.
Protection of the urinary tract with mesna should therefore only be undertaken in such patients with autoimmune diseases following careful risk-benefit analysis and under medical supervision. Prescribers should:
be aware of the potential for such reactions and that reactions may worsen with re-exposure and may in some cases be life threatening;
be aware that hypersensitivity reactions to mesna were interpreted to resemble 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. a sulfhydryl group containing organic compound. Thiol compounds show some similarities in their adverse reaction profile, including a potential to elicit severe skin reactions. Examples of drugs that are thiol compounds include amifostine, penicillamine, and captopril.
It is not clear whether patients who experienced an adverse reaction to such a drug are at increased risk for any reactions, or similar reactions, to another thiol compound. However, when considering subsequent use of another thiol compound in such patients, the possibility of an increased risk should be taken into account.
Uromitexan does not prevent haemorrhagic cystitis in all patients. As a result, a morning specimen of urine should be examined for the presence of haematuria (microscopic evidence of red blood cells) and proteinuria each day prior to oxazaphosphorine therapy. If haematuria develops when Uromitexan is given with oxazaphosphorines according to the recommended dosage schedule, depending on the severity of the haematuria, dosage reduction or discontinuation of oxazaphosphorine therapy may be indicated.
Urinary output should be maintained at 100 mL/hr (as required for oxazaphosphorine treatment). The urine should be monitored for haematuria and proteinuria throughout the treatment period.

Use in the elderly.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The ratio of oxazaphosphorines to mesna should remain unchanged.

Paediatric use.

Safety and effectiveness of Mesna in paediatric patients (< 16 years of age) have not been established in formal clinical studies, but its use in paediatric patients is referenced in the medical literature.

Effects on laboratory tests.

A false positive test in nitroprusside sodium based urine tests (including dipstick tests) for urinary ketones may arise in patients treated with Uromitexan. In this test, a red-violet (rather than purple) colour develops which is less stable, e.g. with the addition of glacial acetic acid, will return to violet.
Mesna treatment may cause false positive reactions in Tillman's reagent based urine screening tests for ascorbic acid.
Mesna may also cause false positive or false negative reactions in the dipstick test for erythrocytes in urine. To exactly determine erythrocytes in the urine, urinary microscopy is recommended.
In pharmacokinetics studies in healthy volunteers, serum creatine phosphokinase (CPK) values were lower in samples taken 24 hours after mesna dosing than in predosing samples. While available data are insufficient to determine the cause of this phenomenon, it might be considered to represent a significant interference with thiol (e.g. N-acetylcysteine) dependent enzymatic CPK tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro and in vivo animal tumour models have shown that mesna does not have any effect on the antitumour efficacy of concomitantly administered cytotoxic agents.
It may be necessary to replace oral mesna with iv mesna in patients treated with total body irradiation in combination with high dose cyclophosphamide.
Oral mesna should be replaced by intravenous mesna in patients experiencing vomiting.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Animal studies of potential toxicity in a fertility and general reproductive screen have not been carried out. It is not known whether Uromitexan can affect reproductive capacity.
(Category B1)
Teratology studies with oral doses of mesna given to rabbits at up to 1000 mg/kg/day and to rats at up to 2000 mg/kg/day have revealed no harm to the foetus. Animal studies of potential toxicity in a peri-/post-natal screen has not been carried out. It is not known whether Uromitexan can cause foetal harm when administered to a pregnant woman. Uromitexan should be given to a pregnant woman only if the benefits clearly outweigh any possible risks.
It is not known whether mesna or dimesna are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

4.8 Adverse Effects (Undesirable Effects)

As Uromitexan is used in combination with oxazaphosphorine alkylating agents and other chemotherapeutic agents with documented toxicities, it is difficult to distinguish the adverse reactions which may be due to Uromitexan from those caused by the concomitantly administered cytotoxic agents. Consequently, the side effect profile of mesna has been assessed from studies in which oral mesna was given alone.
In an early dose ranging study, 6 patients were given an oral solution of mesna at doses of 60-70 mg/kg without concurrent chemotherapy. Diarrhoea (83%), headache (67%), fatigue (50%), nausea (33%), limb pain (50%), cardiovascular collapse (17%) and allergy (17%) were reported.
In 4 pharmacokinetic studies involving 72 subjects given mesna tablets (0.6 to 2.4 g) on up to 10 occasions, the most common adverse events were diarrhoea (6%), headache (12%), nausea (5%), vomiting (2%) and fatigue (1%).
Frequently reported side effects from clinical studies and/or spontaneous reporting are nausea, vomiting, flatulence, diarrhoea, constipation, colic (e.g. abdominal pain), anorexia, influenza-like reactions, fever, rigors, flushing, cough, pharyngitis, lightheadedness/ dizziness, lethargy/ somnolence, headache, back pain and arthralgia.
Isolated cases of partially organ related hypersensitivity reactions have been reported, e.g. in some cases associated with decreased platelet counts (thrombocytopenia), skin and mucosal reactions of varying extent and severity (rash, itching, redness, vesiculation, Lyell syndrome, Stevens-Johnson syndrome), local tissue swelling (urticarial oedema), conjunctivitis. Very rare cases of hypotension associated with circulatory reactions and increased pulse rate above 100/min (tachycardia), as well as increased respiration rate (tachypnoea) due to severe acute hypersensitivity reactions (anaphylactoid reactions), hypertension, ST segment elevation, myalgia, and also a transient rise in certain liver function tests (e.g. transaminases) have been reported.
The most severe adverse reactions associated with use of mesna are: toxic epidermal necrolysis, Stevens-Johnson syndrome, anaphylaxis, and drug rash with eosinophilia and systemic symptoms (DRESS). The occurrence of hypersensitivity reactions (hyperergic reactions) following Uromitexan has been reported more frequently in patients with autoimmune disorders than in tumour patients (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). See Table 2.

Time to onset.

In these studies, some subjects experienced their events on first exposure to mesna and others after the second or third exposure. In general, the complete spectrum of symptoms experienced by a subject developed over a period of several hours.

Experience with re-exposure.

Some subjects experienced no further reactions after their initial event while others experienced an exacerbation of events upon repeated dosing.

Cutaneous/ mucosal reactions.

Cutaneous and mucosal reactions were reported to occur after both intravenous and oral mesna. These reactions included rashes, pruritus, flushing, mucosal irritation, pleuritic pain, and conjunctivitis. Approximately one-quarter of subjects with any event experienced cutaneous/ mucosal reactions in conjunction with other adverse symptoms, which included, dyspnoea, fever, headache, gastrointestinal symptoms, drowsiness, malaise, myalgia, and influenza-like symptoms.

Gastrointestinal reactions.

Gastrointestinal reactions reported in healthy subjects included nausea, vomiting, diarrhoea, abdominal pain/ colic, epigastric pain/ burning, constipation, and flatulence and were reported to occur after intravenous and oral mesna administration.

In vivo effect on lymphocyte counts.

In pharmacokinetics studies in healthy volunteers, administration of single doses of mesna was commonly associated with a rapid (within 24 hours) and in some cases marked decrease in lymphocyte count, which was generally reversible within 1 week of administration. Data from studies with repeated dosing over several days are insufficient to characterize the time course of lymphocyte count changes under such conditions.

In vivo effect on serum phosphorus levels.

In pharmacokinetics studies in healthy volunteers, administration of mesna on single or multiple days was in some cases associated with moderate transient increases in serum phosphorus concentration. These phenomena should be considered when interpreting laboratory results.

Postmarketing adverse reactions.

The following adverse reactions have been identified from postmarketing reports of patients receiving mesna in combination with oxazaphosphorine cytostatics and other medications.
Many of the adverse reactions listed occurred as part of a syndrome suggestive of hypersensitivity reactions (see Section 4.4 Special Warnings and Precautions for Use).

Blood and lymphatic system disorders.

Pancytopaenia, leukopaenia, lymphopaenia, thrombocytopaenia, eosinophilia.

Immune system disorders.

Anaphylaxis, hypersensitivity.

Nervous system disorders.

Convulsion.

Eye disorders.

Periorbital oedema.

Cardiac disorders.

Electrocardiogram abnormal (consistent with perimyocarditis), tachycardia.

Vascular disorders.

Hypotension (in some cases fluid refractory), hypertension.

Respiratory, thoracic, mediastinal disorders.

Respiratory distress, hypoxia, oxygen saturation decreased, tachypnoea, haemoptysis.

Gastrointestinal disorders.

Stomatitis, bad taste.

Hepatobiliary disorders.

Hepatitis, gamma-glutamyl transferase increased, blood alkaline phosphatase increased.

Skin and subcutaneous tissue disorders.

Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, drug rash with eosinophilia and systemic symptoms, ulcerations and/or bullae/ blistering (mucocutaneous, mucosal, oral, vulvovaginal, anorectal), angioedema, fixed drug eruption, rash (vesicular, exfoliative, maculopapular, morbilliform), photodistributed rash, urticaria, burning sensation, erythema.

Renal and urinary disorders.

Acute renal failure.

General disorders and administration site conditions.

Face oedema, oedema peripheral, asthenia, infusion site reactions (thrombophlebitis, irritation).

Investigations.

Laboratory signs of disseminated intravascular coagulation, prothrombin time prolonged, activated partial thromboplastin time prolonged.

Injury, poisoning and procedural complications.

Occupational sensitization to other mesna formulations used for inhalation (manifested as eczema, papulovesicular rash, erythema, pruritus).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Sufficient mesna must be given to protect the patient adequately from the urotoxic effects of the oxazaphosphorine. The duration of mesna treatment should equal that of the oxazaphosphorine treatment plus the time taken for the urinary concentration of oxazaphosphorine metabolites to fall to nontoxic levels. This usually occurs within 8-12 hours after the end of oxazaphosphorine treatment but may vary depending on the scheduling of oxazaphosphorine. When calculating the dose of mesna, the quantity should be rounded down to the nearest whole tablet. Urinary output should be maintained at 100 mL/hr (as required for oxazaphosphorine treatment) and the urine monitored for haematuria and proteinuria throughout the treatment period.

For intermittent oxazaphosphorine therapy.

Oral mesna, 40% (w/w) of the oxazaphosphorine dose, should be given 2 hours prior to the oxazaphosphorine dose, and repeated at 2 and at 6 hours after oxazaphosphorine administration. Alternatively, an initial intravenous dose of mesna (20% (w/w) of the oxazaphosphorine dose) can be given with the cytotoxic dose and additional oral mesna, 40% (w/w) of the oxazaphosphorine dose, given at 2 and 6 hours, see Table 1.

Following 24 hour infusion of ifosfamide and mesna.

The first oral mesna dose of 40% (w/w) of the ifosfamide dose is given as the infusion is stopped, and the same dose is repeated after 2 and 6 hours.
Higher doses of mesna can be given if urothelial toxicity occurs.

Elderly.

No specific information on the use of this product in the elderly is available. Clinical trials have included patients over 65 years and no adverse reactions specific to this age group have been reported.

Children.

Due to increased micturition, children may require shorter intervals between doses and/or an increased number of individual doses.

High risk patients.

Those who have had previous irradiation of the small pelvis, occurrence of cystitis during previous cyclophosphamide or ifosfamide therapy or a history of urinary tract lesions may require shorter intervals between doses and/or an increased number of doses.

4.7 Effects on Ability to Drive and Use Machines

Patients undergoing treatment with mesna may experience undesirable effects (including, e.g. syncope, lightheadedness, lethargy/ drowsiness, dizziness, and blurred vision) which could affect the ability to drive or use machines. The decision to drive or operate machinery should be made on an individual basis.

4.9 Overdose

No specific antidote for mesna is known. Overdosage should be managed with supportive measures to sustain the patient through any period of toxicity. Mesna has been administered at doses from 70 to 100 mg/kg without any toxic effect on haematopoiesis, hepatic or renal function or the CNS.
Overdose may lead to the reactions observed in a tolerability study in healthy volunteers at single doses of 60-70 mg/kg: nausea, vomiting, abdominal pain, colic, diarrhoea, headache, fatigue, paresthesia, fever, limb and joint pains, lack of energy like exhaustion and weakness, depression, irritability, rash, bronchospasm, flushing, hypotension, bradycardia and tachycardia.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

The tablets should be stored below 30°C.

6.5 Nature and Contents of Container

Package size.

Uromitexan (mesna) 400 mg (film coated) tablets in pack sizes of 10, 20 and 50.
Uromitexan (mesna) 600 mg (film coated) tablets in pack sizes of 10, 20 and 50.

6.6 Special Precautions for Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes