4.1. Therapeutic indications

For the prevention of urothelial toxicity including haemorrhagic cystitis, microhaematuria and macrohaematuria in patients treated with ifosfamide and cyclophosphamide, in doses considered to be urotoxic.

4.2. Posology and method of administration

Sufficient Mesna must be given to adequately protect the patient 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 non-toxic 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.Compared with intravenous administration, overall availability of Mesna in urine after oral administration is approximately 50%; and the onset of urinary excretion is delayed by up to 2 hours and is more prolonged than following intravenous dosing. For intermittent oxazaphosphorine therapy

Oral administration of 40% of the dosage of the oxazaphosphorine on a weight for weight basis rounded down to the nearest whole tablet. The oral dose of Mesna should be taken 2 hours before and at 2 hours and 6 hours after oxazaphosphorine dosing.If the Mesna is to be administered intravenously in the first instance, the oral administration at -2 hours should be replaced by the i.v. at 0 hours.Example dosage schedule: -2 hrs 0 hrs 2 hrs 6 hrs

Cyclophosphamide/ Ifosfamide - 1 g iv - -

Mesna 400 mg po - 400 mg po 400 mg po

200 mg iv 400 mg po 400 mg po

Where ifosfamide is used as a 24 hour infusion

Oral Mesna should be taken as the combined infusion of ifosfamide and Mesna finishes. Then at 2 hours and 6 hours after the time at the finish of the infusion. All doses are 40% (w/w) of the ifosfamide dose rounded down to the nearest whole tablet.Example dosage schedule: 0 hrs 0-24 hrs 24 hrs 26 hrs 30 hrs

Ifosfamide - 5g/m2 infusion - - -

Mesna 1 g/m2 iv 5g/m2 infusion 2g/m2 po 2g/m2 po 2g/m2 po

Where ifosfamide is used as a long-term continuous infusion

Oral Mesna should be taken as the combined infusion of ifosfamide and Mesna finishes, then at 2 hours and 6 hours after the time at the finish of the infusion. All oral Mesna doses should be 40% (w/w) of the final 24 hour ifosfamide dose rounded down to the nearest whole tablet.Example dosage schedule: Day 1 Day 2 Day 3 Day 4

0 hrs 0-24 hrs 0-24 hrs 0-24 hrs 24 hrs 26 hrs 30 hrs

Ifosfamide - 2g/m2 infusion 2g/m2 infusion 2g/m2 infusion - - -

Mesna 0.4g/m2 iv 2g/m2 infusion 2g/m2 infusion 2g/m2 infusion 0.8g/m2 po 0.8g/m2 po 0.8g/m2 po

Children

In children it may be necessary to shorten the interval between doses and/or to increase the number of individual doses. This regime protects children who generally have increased micturition. Elderly

No specific information is available. Clinical trials have included patients over 65 and no adverse reactions specific to this age group have been reported. High risk patients

Patients who have damaged urothelium from previous treatment with oxazaphosphorines or pelvic irradiation, or who are not adequately protected by Mesna at the standard dose, e.g. patients with case history of urinary tract disease:the dose of 40% of oxazaphosphorine dose should be given at intervals shorter than 4 hours and/or the number of doses increased.

4.3. Contraindications

Known hypersensitivity to Mesna or any of the excipients.

4.4. Special warnings and precautions for use

WARNINGS Hypersensitivity

Hypersensitivity reactions to mesna have been reported following administration of mesna as an uroprotectant. These include various skin and subcutaneous tissue symptoms (see Section 4.8).In addition, cases of severe bullous and ulcerative skin and mucosal reactions were reported.In some cases, skin reactions were accompanied by one or more other symptoms, such as fever, cardiovascular, pulmonary symptoms, haematological abnormalities, nausea, vomiting, pain in the extremities, arthralgia, myalgia, malaise and conjunctivitis (see section 4.8).Some reactions have presented as anaphylaxis.Fever accompanied by, e.g., hypotension but no skin manifestations has also been reported.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.Prescribers should be aware that:- severe as well as minor reactions were reported with the use of mesna in regimens to treat both severe systemic autoimmune disease and malignancy and that mesna should be suspected in any hypersensitivity reaction,- these reactions may occur with first exposure or after several months of exposure and in some cases can be life threatening,- the occurrence and severity of reactions appeared to vary with the dose administered with a tendency to shorter intervals following subsequent exposures,- 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 (SH) 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.PRECAUTIONSMesna does not prevent hemorrhagic cystitis in all patients. Patients should be monitored accordingly.Sufficient urinary output should be maintained, as required for oxazaphosphorine treatment. Lactose Content

Mesna tablets contain lactose. This should be taken into account when using the tablets in patients with lactose intolerance, glucose-galactose malabsorption, or galactose intolerance. Lab test interferences

Mesna treatment may cause false positive reactions in nitroprusside sodium-based urine tests (including dipstick tests) for ketone bodies. The addition of glacial acetic acid can be used to differentiate between a false positive result (cherry-red color that fades) and a true positive result (red-violet color that intensifies).Mesna treatment may cause false positive reactions in Tillman's reagent-based urine screening tests for ascorbic acid.In pharmacokinetics studies in healthy volunteers, serum creatine phosphokinase (CPK) values were lower in samples taken 24 hours after mesna dosing than in pre- dosing 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.See also Section 4.8 for information on laboratory test abnormalities observed in pharmacokinetic studies.

4.5. Interaction with other medicinal products and other forms of interaction

The systemic effects of oxazaphosphorines are not affected by Mesna. In clinical trials it was shown that overdoses of Mesna did not diminish the acute toxicity, subacute toxicity, leucocytic activity, and immunosuppressive efficacy of oxazaphosphorines. Animal studies with ifosfamide and cyclophosphamide on a variety of tumours, have also demonstrated that Mesna does not interfere with their antineoplastic activity.Mesna also does not affect the antineoplastic efficacy of other cytostatics (e.g. adriamycin, BCNU, methotrexate, vincristine), nor the therapeutic effect of other drugs such as digitalis glucosides.Food does not influence the absorption and urinary elimination of Mesna.

4.6. Fertility, pregnancy and lactation

There are no adequate data from the use of mesna in pregnant or lactating women. Physicians should carefully consider the potential risks and benefits for each specific patient before prescribing mesna.Pregnancy and lactation are contraindications for cytostatic treatment, and consequently Mesna is not likely to be used under these circumstances.Should an individual patient be undergoing oxazaphosphorine therapy during pregnancy then Mesna should be administered to this patient.Mothers should not breast-feed whilst being treated with these drugs.Animal studies have shown no evidence of embryotoxic or teratogenic effects of Mesna.

4.7. Effects on ability to drive and use machines

Patients undergoing treatment with mesna may experience undesirable effects (including, e.g., syncope, light-headedness, 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.

4.8. Undesirable effects

The most frequently occurring adverse reactions (> 10%) associated with use of mesna are: headache, abdominal pain/colic, light headedness, lethargy/drowsiness, pyrexia, rash, diarrhoea, nausea, flushing, and influenza-like illness.The most severe adverse reactions associated with use of mesna are: bullous skin reactions, anaphylaxis, and drug rash with eosinophilia and systemic symptoms (DRESS).Because mesna is used in combination with oxazaphosphorines or oxazaphosphorine- containing combination chemotherapy, it is often difficult to distinguish adverse reactions that may be due to mesna from those caused by concomitantly administered cytotoxic agents.ADR frequency is based upon 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), Unknown (adverse reactions reported in the post-marketing experience) System Organ Class (SOC) Adverse Reaction Frequency

BLOOD AND LYMPHATIC SYSTEM DISORDERS Lymphadenopathy Common

IMMUNE SYSTEM DISORDERS Anaphylaxis Hypersensitivity Unknown Unknown

METABOLISM AND NUTRITION DISORDERS Decreased appetite Feeling of dehydration Common Common

PSYCHIATRIC DISORDERS Insomnia Nightmare Common Common

NERVOUS SYSTEM DISORDERS Headache Light-headedness Lethargy/Drowsiness Dizziness Paresthesia Hyperesthesia Syncope Hypoesthesia Disturbance in attention Very common Very common Very common Common Common Common Common Common Common

EYE DISORDERS Conjunctivitis Photophobia Vision blurred Common Common Common

CARDIAC DISORDERS Palpitations Tachycardia Common Unknown

VASCULAR DISORDERS Flushing Hypotension Very common Unknown

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Nasal congestion Cough Pleuritic pain Dry mouth Bronchospasm Dyspnea Laryngeal discomfort Epistaxis Respiratory distress Hypoxia Common Common Common Common Common Common Common Common Unknown Unknown

GASTROINTESTINAL DISORDERS Abdominal pain/colic Nausea Diarrhoea Mucosal irritation1 Flatulence Vomiting Burning pain (substernal / epigastric) Constipation Gingival bleeding Very common Very common Very common Common Common Common Common Common Common

HEPATOBILIARY DISORDERS Transaminases increased Common

SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash2 Pruritus Hyperhidrosis Erythema multiforme Drug rash 3 Ulcerations and/or bullae/blistering 4 Angioedema Urticaria Burning sensation Erythema Very common Common Common Unknown Unknown Unknown Unknown Unknown Unknown Unknown

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Back pain Myalgia Pain in extremity Pain in jaw Common Common Common Common Common

RENAL AND URINARY DISORDERS Dysuria Acute renal failure Common Unknown

GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Pyrexia Influenza-like illness3 Rigors Fatigue Chest pain Malaise Face oedema Oedema peripheral Asthenia Very common Very common Common Common Common Common Unknown Unknown Unknown

INVESTIGATIONS Activated partial thromboplastin time prolonged Unknown

1Oral, rectal2Including nonpruritic, pruritic, erythema/erythematous, eczematous, papular, and/or macular rashes.3mucocutaneous, mucosal, oral, vulvovaginal, anorectal4vesicular, exfoliative, maculo-papular, morbilliform• Time to onset and experience with re-exposureIn 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.Some subjects experienced no further reactions after their initial event while others experienced an exacerbation of events upon repeated dosing.• Cutaneous/mucosal reactionsCutaneous 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, dyspnea, fever, headache, gastrointestinal symptoms, drowsiness, malaise, myalgia, and influenza-like symptoms.• Gastrointestinal reactionsGastrointestinal 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 countsIn 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 levelsIn 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. Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme.Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

Reports of inadvertent overdose and observations from a high-dose tolerability study in healthy volunteers showed that, in adults, single doses in the range of approximately 4g to 7g of mesna can cause symptoms such as nausea, vomiting, abdominal pain/colic, diarrhoea, headache, fatigue, limb and joint pains, rash, flushing, hypotension, bradycardia, tachycardia, paresthesia, fever, and bronchospasm.A markedly increased rate of nausea, vomiting and diarrhoea has also been found in oxazaphosphorine-treated patients receiving ≥ 80 mg mesna per kg per day intravenously compared with patients receiving lower doses or hydration treatment only.A specific antidote to Mesna is not known.