Mesna

Mesna (sodium 2-mercaptoethanesulfonate, molecular weight 164.18) is a synthetic sulfhydryl compound used as a detoxifying agent in cytotoxic therapy. Extensive pharmacological and toxicological studies showed that it has no pharmacodynamic activity of its own and low toxicity. Its inertness when given systemically and its detoxifying effect in the urinary tract both follow from its pharmacokinetics.

Mechanism of Action

• Redox cycle: like the physiological cysteine–cystine system, mesna is oxidised rapidly to its main metabolite, the disulfide dimesna. Dimesna stays in the bloodstream and is cleared quickly by the kidneys.
• Reactivation in the kidney: in the renal tubules dimesna is reduced back to free mesna.
• Detoxification in the urine: free mesna reacts chemically with the urotoxic metabolites of the oxazaphosphorines (acrolein and 4-hydroxy-ifosfamide or 4-hydroxy-cyclophosphamide). It first binds the 4-hydroxy metabolite, forming a non-urotoxic 4-sulfoethylthio compound, and it also binds the double bonds of acrolein and other urotoxic metabolites.
• No loss of cytostatic activity: in several human xenograft and rodent tumour models, mesna given with ifosfamide (at dose ratios of up to 20 times, single or multiple) did not interfere with the antitumour efficacy.

Pharmacokinetics

• Oxidation: mesna, with its free thiol group, auto-oxidises easily and rapidly to its only metabolite, dimesna.
• Distribution: dimesna remains in the intravascular compartment and is transported rapidly to the kidneys. Protein binding of mesna is moderate (69–75%).
• Renal reduction: in the renal tubular epithelium dimesna is reduced to free thiol, which then reacts in the urine with toxic oxazaphosphorine metabolites. About 30% of an intravenous dose becomes available in the urine as free thiol (mesna).
• Elimination: almost exclusively renal, starting immediately after administration and almost complete after about 8 hours. After an intravenous dose of 800 mg, the blood half-lives of mesna and dimesna were 0.36 hours and 1.17 hours, and plasma clearance of mesna was 1.23 L/hour/kg. About 32% and 33% of the dose appeared in the urine within 24 hours as mesna and dimesna, mostly within 4 hours.
• Why repeat doses: at ifosfamide doses of 2–4 g/m² the terminal half-life of ifosfamide is 4–8 hours, so repeated mesna doses are needed to keep adequate levels in the bladder while the toxic metabolites are being eliminated.

• Prevention of urothelial toxicity, including haemorrhagic cystitis, microhaematuria and macrohaematuria, in patients treated with oxazaphosphorines (ifosfamide, cyclophosphamide, trofosfamide) at doses considered urotoxic. The SmPC also describes it as a cystitis corrector in cytostatic therapy.

• Known hypersensitivity to mesna, to any compound containing a thiol group, or to any of the excipients.

The most frequent reactions (more than 10%) are headache, infusion-site reactions, abdominal pain or colic, light-headedness, lethargy or drowsiness, fever, rash, diarrhoea, nausea, flushing and flu-like symptoms. The most serious are toxic epidermal necrolysis, Stevens-Johnson syndrome, anaphylaxis and drug rash with eosinophilia and systemic symptoms (DRESS). Mesna is used with oxazaphosphorines or combination chemotherapy, so it is often hard to tell its reactions from those of the cytotoxic medicines. Frequencies below follow the Spanish SmPC; the Not known group lists reactions reported after marketing.

Very common (≥1/10): headache, light-headedness, lethargy or drowsiness, flushing, abdominal pain or colic, nausea, diarrhoea, rash, infusion-site reactions (including itching and rash at the site), pyrexia, flu-like symptoms.

Common (≥1/100 to <1/10): lymphadenopathy; decreased appetite, feeling of dehydration; insomnia, nightmares; dizziness, paraesthesia, hyperaesthesia, syncope, hypoaesthesia, disturbance in attention; conjunctivitis, photophobia, blurred vision; palpitations; nasal congestion, cough, pleuritic pain, dry mouth, bronchospasm, dyspnoea, laryngeal discomfort, epistaxis; mucosal irritation, flatulence, vomiting, burning substernal or epigastric pain, constipation, gingival bleeding; increased transaminases; pruritus, hyperhidrosis; arthralgia, back pain, myalgia, pain in extremity, jaw pain; dysuria; infusion-site pain, erythema, urticaria and swelling; chills, fatigue, chest pain, malaise.

Uncommon and rare: no reactions are listed in these categories.

Not known: pancytopenia, leucopenia, lymphopenia, thrombocytopenia, eosinophilia; anaphylaxis, hypersensitivity; convulsion; periorbital oedema; abnormal electrocardiogram, tachycardia; hypotension, hypertension; hypoxia, respiratory distress, decreased oxygen saturation, tachypnoea, haemoptysis; stomatitis, bad taste; hepatitis, raised gamma-glutamyl transferase and alkaline phosphatase; toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, drug rash with eosinophilia and systemic symptoms, ulcers or blisters of skin and mucous membranes, angioedema, fixed drug eruption, photodistributed eruption, urticaria, burning sensation, erythema; acute renal failure; facial and peripheral oedema, asthenia, infusion-site reactions such as thrombophlebitis and irritation; laboratory signs of disseminated intravascular coagulation, prolonged prothrombin time and activated partial thromboplastin time.

Some patients react at the first exposure and others after the second or third, and the full picture usually develops over several hours. Some have no further reactions after the first episode, while others get worse with repeated doses.

• Oxazaphosphorines (ifosfamide, cyclophosphamide, trofosfamide): mesna does not affect their systemic effects. In clinical trials, mesna overdoses did not reduce their acute or subacute toxicity, leucocyte activity or immunosuppressive efficacy, and animal studies in various tumours showed no interference with their antineoplastic activity.
• Other cytostatics: mesna does not affect the antineoplastic efficacy of doxorubicin, carmustine (BCNU), methotrexate or vincristine.
• Digitalis glycosides: their therapeutic effect is not affected.
• Laboratory tests: mesna can interfere with some urine and enzyme assays (see Special Instructions).

Mesna is given intravenously alongside the oxazaphosphorine. The dose depends on the dose of the oxazaphosphorine the patient receives, and enough mesna must be given to protect the patient adequately from its urotoxic effects. The solution should be inspected before use: parenteral medicines are checked for particles and discolouration, and a solution that is discoloured, turbid or contains visible particles must not be used.

Recommended Dose

• Schedule for a bolus of ifosfamide or cyclophosphamide: mesna is given at the same time by intravenous injection over 15–30 minutes, at 20% (w/w) of the oxazaphosphorine dose. The same dose is repeated 4 and 8 hours later, so the total mesna dose is 60% (w/w) of the oxazaphosphorine dose. The schedule is repeated each time the cytotoxic agent is given.
• Example: for 2 g of ifosfamide or cyclophosphamide, mesna 400 mg is given at 0, 4 and 8 hours.
• Changed oxazaphosphorine dose: the mesna dose is changed too, so that the ratio between the two medicines is kept.
• Duration: as long as the oxazaphosphorine treatment, plus the time needed for urinary levels of its metabolites to fall to non-toxic levels. This usually happens within 8–12 hours after the oxazaphosphorine treatment ends, but depends on its schedule.
• Fluids and monitoring: urine output should be kept at 100 mL/hour, as required for oxazaphosphorine treatment, and urine monitored for haematuria and proteinuria throughout.

Special Populations

• Children: children pass urine more often than adults, so the interval between doses may need to be shorter and/or the number of doses higher. Safety and efficacy in paediatric patients (under 16 years) have not been established in clinical studies, although the medical literature describes use in children.
• Elderly: no specific information. Clinical trials included patients aged 65 with no age-specific adverse reactions. In general, the dose for an older patient is chosen with caution, reflecting more frequent reduced liver, kidney or heart function and concomitant disease or therapy; the oxazaphosphorine-to-mesna ratio stays unchanged.
• Renal and hepatic impairment: the SmPC gives no separate dose recommendation.

Hypersensitivity Reactions

• Patients with autoimmune diseases given cyclophosphamide and mesna seem to have more hypersensitivity reactions (skin and mucosal reactions including Lyell’s and Stevens-Johnson syndromes, local swelling, conjunctivitis, and rarely hypotension with tachycardia and rapid breathing). In them, uroprotection with mesna should be used only after a risk–benefit assessment and with careful medical supervision.
• Hypersensitivity to mesna given as a uroprotector has been reported in patients treated for severe systemic autoimmune disorders and for malignancies. Skin and mucosal reactions can be severe, some compatible with Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiforme. They may come with fever, low blood pressure (sometimes resistant to fluids), signs of acute renal failure, breathing problems, blood count and clotting changes, raised liver enzymes, nausea, vomiting, joint and muscle pain, stomatitis and conjunctivitis. Some were anaphylaxis, and fever with hypotension without skin signs has also been reported.
• Reactions usually occurred during or after the first treatment or after several weeks of exposure, and sometimes only after months. Reactions may recur on re-exposure, sometimes more severely, but not always. A delayed skin test was positive in some patients, but a negative test does not exclude hypersensitivity.
• Doctors should know that such reactions can worsen on re-exposure and may be fatal, and that they can be mistaken for sepsis or, in autoimmune disease, for a flare of the underlying illness.

Other Thiol Compounds

Mesna is a thiol. Thiol medicines share some adverse reaction patterns, including a potential for severe skin reactions; the SmPC names amifostine, penicillamine and captopril. It is unclear whether a reaction to one thiol raises the risk with another, but the possibility should be considered.

Haemorrhagic Cystitis Is Not Always Prevented

Mesna does not prevent haemorrhagic cystitis in every patient, so suitable checks are needed. Urine output must be kept adequate, as required for oxazaphosphorine treatment.

Interference with Laboratory Tests

• Mesna can cause false-positive ketone body results in urine tests based on sodium nitroprusside, including dipsticks. Adding glacial acetic acid separates a false positive (cherry-red colour that fades) from a true positive (red-violet colour that deepens).
• False positives can also occur in urine tests for ascorbic acid with Tillman’s reagent.
• In healthy volunteers, serum creatine phosphokinase was lower 24 hours after a dose than before it, which may point to interference with thiol-dependent enzymatic assays for this enzyme.

Sodium

The solution contains less than 1 mmol (23 mg) of sodium per mL.

Pregnancy, Breastfeeding and Fertility

• There are not enough data on mesna in pregnant or breastfeeding women, and the doctor should weigh the risks and benefits for each patient.
• Pregnancy and breastfeeding are contraindications to cytostatic treatment, so mesna is unlikely to be used in these circumstances. If a patient does receive oxazaphosphorine therapy during pregnancy, she should be given mesna. Mothers should not breastfeed while being treated with these medicines.
• Animal studies showed no evidence of embryotoxic or teratogenic effects of mesna.

Effect on Driving

Reactions such as fainting, light-headedness, lethargy or drowsiness, dizziness and blurred vision may affect the ability to drive or use machines. Each patient should be assessed individually.

Do not store above 30 °C, and keep the ampoules in the outer carton. The solution is packed under a protective atmosphere, so it should be used as soon as the ampoule is opened. No refrigeration or cold-chain handling is required.

3 years unopened. Once an ampoule is opened, administer the solution straight away.

Prescription only (Rx). Mesna is given intravenously with ifosfamide, cyclophosphamide or trofosfamide during cytostatic therapy, so it is supplied to the hospital or clinic that administers it. The Spanish SmPC is for Uromitexan 100 mg/mL (Baxter S.L.), supplied as glass ampoules of 4 mL or 10 mL in cartons of 5 or 10; not all pack sizes may be marketed. Uromitexan is also the brand name on the French and Irish registers, and the national SmPC of the product in use applies.