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Mechanism Of Action
Mesna reacts chemically with the urotoxic ifosfamide metabolites, acrolein and 4-hydroxy-ifosfamide, resulting in their detoxification. The first step in the detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a non-urotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites and inhibits their effects on the bladder.
Following oral administration, peak plasma concentrations were reached within 1.5 to 4 hours and 3 to 7 hours for free mesna and total mesna (mesna plus dimesna and mixed disulfides), respectively. Oral bioavailability averaged 58% (range 45 to 71%) for free mesna and 89% (range 74 to 104%) for total mesna based on plasma AUC data from 8 healthy volunteers who received 1200 mg oral or intravenous doses.
Food does not affect the urinary availability of orally administered MESNEX.
Mean apparent volume of distribution (Vd) for mesna is 0.652 ± 0.242 L/kg after intravenous administration which suggests distribution to total body water (plasma, extracellular fluid, and intracellular water).
Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Plasma concentrations of mesna exceed those of dimesna after oral or intravenous administration.
Following intravenous administration of a single 800 mg dose, approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. Mean plasma elimination half-lives of mesna and dimesna are 0.36 hours and 1.17 hours, respectively. Mesna has a plasma clearance of 1.23 L/h/kg.
Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At a dose of 1.2 g/m² ifosfamide administered daily for 5 days, 16 to 26% of the patients who received conventional uroprophylaxis (high fluid intake, alkalinization of the urine, and the administration of diuretics) developed hematuria ( > 50 RBC per hpf or macrohematuria) (Studies 1, 2, and 3). In contrast, none of the patients who received mesna injection together with this dose of ifosfamide developed hematuria (Studies 3 and 4). In two randomized studies, (Studies 5 and 6), higher doses of ifosfamide, from 2 g/m² to 4 g/m² administered for 3 to 5 days, produced hematuria in 31 to 100% of the patients. When MESNEX was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.
Table 4: Percent of MESNEX Patients Developing
Hematuria ( ≥ 50 RBC/hpf or macrohematuria)
|Study||Conventional Uroprophylaxis (number of patients)||Standard MESNEX Intravenous Regimen (number of patients)|
|Study 1||16% (7/44)||-|
|Study 2||26% (11/43)||-|
|Study 3||18% (7/38)||0% (0/21)|
|Study 4||-||0% (0/32)|
|Study 5||31% (14/46)||6% (3/46)|
|Study 6||100% (7/7)||0% (0/8)|
|*Ifosfamide dose 1.2 g/m² d x 5
†Ifosfamide dose 2 g/m² to 4 g/m² d x 3 to 5
Clinical studies comparing recommended intravenous and oral MESNEX dosing regimens demonstrated incidences of grade 3 to 4 hematuria of < 5%. Study 7 was an open label, randomized, two-way crossover study comparing three intravenous doses with an initial intravenous dose followed by two oral doses of MESNEX in patients with cancer treated with ifosfamide at a dose of 1.2 g/m² to 2.0 g/m² for 3 to 5 days. Study 8 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m² for 5 days. In both studies, development of grade 3 or 4 hematuria was the primary efficacy endpoint. The percent of patients developing hematuria in each of these studies is presented in Table 5.
Table 5: Percent of MESNEX Patients Developing Grade 3
or 4 Hematuria
|Study||MESNEX Dosing Regimen|
|Standard Intravenous Regimen (number of patients)||Intravenous + Oral Regimen (number of patients)|
|Study 7||0% (0/30)||3.6% (1/28)|
|Study 8||3.7% (1/27)||4.3% (1/23)|
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of mesna.
Mesna was not genotoxic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte chromosomal aberration assay or the in vivo mouse micronucleus assay.
No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity were seen in 6-month oral rat studies ( ≤ 2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day) at doses approximately 10-fold higher than the maximum recommended human dose on a body surface area basis.
Use In Specific Populations
Pregnancy Category B.
There are no studies of MESNEX in pregnant women. Reproduction studies performed in rats and rabbits at oral doses approximately 10 times the maximum recommended total daily intravenous-oral-oral human dose on a body surface area basis (1000 mg/kg in rabbits and 2000 mg/kg in rats) revealed no evidence of harm to the fetus due to mesna. The incidence of malformations in human pregnancies has not been established for mesna. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations and 15 to 20% for pregnancy loss. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether mesna or dimesna is excreted in human milk. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from MESNEX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of MESNEX in pediatric patients have not been established. MESNEX contains benzyl alcohol (10.4 mg benzyl alcohol per mL) which has been associated with serious adverse reactions and death in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis and gasping respirations) has been associated with benzyl alcohol dosages > 99 mg/kg/day in neonates, premature and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Neonates, premature, and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources [see WARNINGS AND PRECAUTIONS].
Clinical studies of MESNEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The ratio of ifosfamide to MESNEX should remain unchanged.
Use In Patients With Renal Impairment
No clinical studies were conducted to evaluate the effect of renal impairment on the pharmacokinetics of MESNEX.
Use In Patients With Hepatic Impairment
No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of MESNEX.
Last reviewed on RxList: 3/7/2017
This monograph has been modified to include the generic and brand name in many instances.
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