UROMITEXAN
Bristol
Mesna
Uroprotector
Action And Clinical Pharmacology: Mesna is rapidly and easily converted by autooxidation to its only metabolite disodium 2,2¢-dithio-bis ethane sulfonate (mesna disulfide, dimesna), forming a disulfide link. Following i.v. injection, only a small portion of the administered dose is detected in the blood as a reactive thiol compound (mesna). Mesna disulfide remains in the intravascular space and is rapidly forwarded to the kidney. In the renal tubular epithelium a considerable proportion of mesna disulfide is again reduced to a free thiol compound, presumably by mediation of glutathione reductase. It is then capable of chemically reacting with acrolein or other urotoxic oxazaphosphorine metabolites in the urine, thereby developing its detoxifying activity.
The first and most important step towards detoxification is the addition of mesna to the double bond of acrolein, resulting in the formation of a stable thio ether which could 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, non-urotoxic condensation product from 4-hydroxy cyclophosphamide or 4-hydroxy ifosfamide and mesna is formed. By such stabilization mesna inhibits the degradation of 4-hydroxy cyclophosphamide or 4-hydroxy ifosfamide and hence the formation of acrolein. This intermediate deactivated product could also be detected by chromatographic urinalysis.
Indications And Clinical Uses: For the reduction and prevention of urinary tract toxicity (hemorrhagic cystitis) of oxazaphosphorines (see Adverse Effects sections of the Cytoxan and Ifex product monographs).
Contra-Indications: In individuals with a known hypersensitivity to it.
Manufacturers’ Warnings In Clinical States: The protective effect of mesna applies only to the urotoxic effects of oxazaphosphorines. Additional prophylactic or accompanying measures recommended during treatment with oxazaphosphorines are thus not affected and should not be discontinued.
In vitro mesna is incompatible with cisplatin. The combination of an oxazaphosphorine cytostatic agent with mesna and cisplatin in the same infusion solution is not stable and is not to be used.
Precautions: Mesna treatment may cause false positive reactions in tests for ketone bodies in the urine. The color reaction is reddish purple rather than purple. The reddish purple color is less stable, and fades immediately by adding glacial acetic acid.
Children: Mesna has been administered to patients as young as 13 years of age.
Pregnancy: Although the use of mesna in pregnant women has not been established, animal studies have not revealed any embryotoxic or mutagenic effects. However, in view of the fact that oxazaphosphorines are not recommended during pregnancy, this would eliminate the need for mesna.
Adverse Reactions: At recommended doses, side effects are not usually observed.
The following adverse reactions have been reported in a phase I trial in healthy volunteers: diarrhea, abdominal pain, headache, pain in limbs and joints, transient drop in blood pressure, increase in pulse rate. These reactions occurred at doses of 60 mg/kg or more, given as a single bolus.
Venous irritation may occur in rare instances. This reaction may be attributed to the physical properties of mesna (i.e., pH 6, and hypertonic solution). No venous complications were observed when the solution was given diluted with Sterile Water for Injection USP (1 part mesna solution to 3 parts water).
Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 hematopoiesis, hepatic and renal function or the CNS.
Dosage And Administration: Mesna should be administered by i.v. injection, usually at 20% of the respective oxazaphosphorine dose at time 0 (=administration of the cytostatic agent), 4 hours and 8 hours. In the case of ifosfamide, the usual dose of mesna is 10 to 12 mg/kg i.v. at 0, 4 and 8 hours after the ifosfamide dose (see Dosage sections of Cytoxan and Ifex product monographs).
In the treatment of children, and particularly when administering very high doses, such as required when conditioning patients for bone-marrow transplantations, the mesna doses should be given at 0, 1, 3, 6, 9 and 12 hours or dosage increased to 30% of the respective oxazaphosphorine dose.
Oral administration of mesna, e.g., in patients with poor veins, is also feasible. Mesna is then given either at doses of 20% of the oxazaphosphorine dose at time 0 hours by the parenteral route, followed by oral doses of 40% of the oxazaphosphorine dose after 4 and 8 hours, taken in juice or cola, or in 3 oral doses of 40% of the oxazaphosphorine dose at time 0, 4 and 8 hours.
Solution for I.V. Infusion: 5% Dextrose Injection USP, 5% Dextrose Injection with 0.45% Sodium Chloride Injection USP, 0.9% Sodium Chloride Injection USP, Lactated Ringer’s Injection USP. Solutions for infusion should be made up at a concentration of 1 mg/mL or greater.
Stability of Solution: Solutions for infusion should be used within 24 hours from the time of preparation.
Availability And Storage: Each mL of solution contains: mesna 100 mg. Nonmedicinal ingredients: disodium edetate, sodium hydroxide (for pH adjustments) and water for injection. Ampuls of 4 and 10 mL.
UROMITEXAN Bristol Mesna Uroprotector
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