MESNA Ampoules of aqueous solution Ref.[9335] Active ingredients: Mesna

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.

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)

Blood and lymphatic system dirorders

Common: Lymphadenopathy

Immune system disorders

Unknown: Anaphylaxis, Hypersensitivity

Metabolism and nutrition disorders

Common: Decreased appetite, Feeling of dehydration

Psychiatric disorders

Common: Insomnia, Nightmare

Nervous system disorders

Very common: Headache, Light-headedness, Lethargy/Drowsiness

Common: Dizziness, Paresthesia, Hyperesthesia, Syncope, Hypoesthesia, Disturbance in attention

Eye disorders

Common: Conjunctivitis, Photophobia, Vision blurred

Cardiac disorders

Common: Palpitations

Unknown: Tachycardia

Vascular disorders

Very common: Flushing

Unknown: Hypotension

Respiratory, thoracic, and mediastinal disorders

Common: Nasal congestion, Cough, Pleuritic pain, Dry mouth, Bronchospasm, Dyspnea, Laryngeal discomfort, Epistaxis

Unknown: Respiratory distress, Hypoxia

Gastrointestinal disorders

Very common: Abdominal pain/colic, Nausea, Diarrhoea

Common: Mucosal irritation¹, Flatulence, Vomiting, Burning pain (substernal/epigastric), Constipation, Gingival bleeding

Hepatobiliary disorders

Common: Transaminases increased

Skin and subcutaneous tissue disorders

Very common: Rash²

Common: Pruritus, Hyperhidrosis

Unknown: Erythema multiforme, Drug rash³, Ulcerations and/or bullae/blistering⁴, Angioedema, Urticaria, Burning sensation, Erythema

Musculoskeletal and connective tissue disorders

Common: Arthralgia, Back pain, Myalgia, Pain in extremity, Pain in jaw

Renal and urinary disorders

Common: Dysuria

Unknown: Acute renal failure

General disorders and administrative site conditions

Very common: Infusion site reactions, Infusion site pruritus, Infusion site rash, Pyrexia, Influenza-like illness³

Common: Infusion site pain, Infusion site erythema, Infusion site urticaria, Infusion site swelling, Rigors, Fatigue, Chest pain, Malaise

Unknown: Face oedema, Oedema peripheral, Asthenia

Investigations

Unknown: Activated partial thromboplastin time prolonged

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 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.

Mesna is incompatible with platinum derivatives (e.g. Cisplatin, carboplatin and nitrogen mustard) and must not be mixed in the same infusion solution.

Mixing mesna and epirubicin leads to inactivation of epirubicin and should be avoided.