olume 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).
Metabolism
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 intravenous administration.
Excretion
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.
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo long-term studies in animals have been performed to eva luate 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.
14. CLINICAL STUDIES
14.1 Intravenous MesnaHemorrhagic 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 mesna was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.
Table 4. Percent of Mesna Patients Developing Hematuria (≥50 RBC/hpf or macrohematuria) 1Ifosfamide dose 1.2 g/m2d x 5
2Ifosfamide dose 2 g/m2 to 4 g/m2 d x 3 to
Study
Conventional Uroprophylaxis (number of patients)
Standard Mesna Intravenous Regimen (number of patients)
Uncontrolled Studies1
Study 1
16% (7/44)
-
Study 2
26% (11/43)
-
Study 3
18% (7/38)
0% (0/21)
Study 4
-
0% (0/32)
Controlled Studies2
Study 5
31% (14/46)
6% (3/46)
Study 6
100% (7/7)
0% (0/8)
16. HOW SUPPLIED/STORAGE AND HANDLING
Mesna injection 1 g per 10 mL (100 mg/mL) is supplied as:
NDC
Vial
Pack
76126-075-01
10 mL multi-dose-vial
1 vial per carton
Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]
17. PATIENT COUNSELING INFORMATION
Advise the patient to discontinue mesna and seek immediate medical atten |
