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.

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:

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:

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:

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.

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 symptoms, 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.

PRECAUTIONS

Mesna 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.

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.

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.

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.

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)

¹ Oral, rectal

² Including nonpruritic, pruritic, erythema/erythematous, eczematous, papular, and/or macular rashes.

³ mucocutaneous, mucosal, oral, vulvovaginal, anorectal

⁴ vesicular, exfoliative, maculo-papular, morbilliform

• Time to onset and experience with re-exposure

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.

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, dyspnea, 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of Holoxan is important. It allows continued monitoring of the benefit/risk balance of Holoxan. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system as per following contact details:

• Saudi Arabia:

• Other GCC States:

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.

Mesna is an antidote, and offers the possibility of reliably preventing urotoxic side-effects associated with aggressive cancer chemotherapy using oxazaphosphorine cytostatics. Extensive and wide-ranging pharmacological and toxicological investigations have shown that Mesna has no intrinsic pharmacodynamics and low toxicity. The pharmacological and toxicological inertness of Mesna administered systemically and its excellent detoxifying effect in the efferent urinary tract and bladder, are due to the nature of its pharmacokinetics.

Mesna is easily and rapidly transformed by auto-oxidation into its only metabolite mesna-disulphide (dimesna). Dimesna remains in the intravascular compartment and is quickly transported to the kidneys. In the epithelium of renal tubuli, dimesna is reduced to the free thiol compound, which is then able to react chemically in the urine with toxic oxazaphosphorine metabolites.

Following oral administration, absorption occurs in the small intestine. Mean peak concentrations of free thiols in the urine occur between 2-4 hours after dosing. Approximately 25 ± 10% of the given dose appears as free Mesna in the urine in the first 4 hours.

Nothing relevant.

Core: Lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate dihydrate, corn starch, povidone K25, magnesium stearate.

Film-coating (Pharma coat): Hydroxypropylmethylcellulose, polyethylene glycol 6000, titanium dioxide E 171, simethicone.

None.

Do not store above 30ºC.

Protected from light.

Folding box containing blister packs consisting of: aluminium 20 µm (top layer),polyamide 25 µm, aluminium 45 µm, PVC 60 µm (bottom layer).

One blister strip contains 10 tablets. Pack sizes: 10 tablets, 20 tablets, 50 tablets

No special instructions necessary.