Mesna Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Mesna Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Hemorrhagic Cystitis Prophylaxis
Class: Antineoplastic detoxifying agents
Form: Liquid solution, Intravenous (IV)
Ingredients: Mesna, edetate disodium, benzyl alcohol, sodium hydroxide.

Description

Mesna Injection is a detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide. The active ingredient, mesna, is a synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2 and a molecular weight of 164.18. Its structural formula is as follows:

HS–CH2–CH2SO3–Na+

Mesna injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multiple dose vials for intravenous administration. Mesna injection contains 100 mg/mL mesna, 0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesna injection multiple dose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. The solution has a pH range of 6.5 to 8.5.

Clinical Pharmacology

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.

Pharmacokinetics

Absorption

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 1,200 mg oral or intravenous doses.

Food does not affect the urinary availability of orally administered mesna.

Distribution

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).

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 oral or 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 hours, respectively. Mesna has a plasma clearance of 1.23 L/h/kg.

Nonclinical Toxicology

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 (≤2,000 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.

Clinical Studies

Intravenous Mesna Injection

Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 1). 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 injection was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.

Table 1: Percent of Mes na Injection Patients Developing Hematuria
(≥50 RBC/hpf or macrohematuria)
Study Conventional Uroprophylaxis
(number of patients)
Standard Mesna Injection
Intravenous Regimen
(number of patients)
Uncontrolled Studies *
Study 1 16% (7/44)  -
Study 2 26% (11/43)
Study 3 18% (7/38) 0% (0/21)
Study 4 - 0% (0/32)
Controlled Studies
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

Oral Mesna

Clinical studies comparing recommended intravenous and oral mesna 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 mesna in patients with cancer treated with ifosfamide at a dose of 1.2 g/m2 to 2 g/m2 for 3 to 5 days. Study 8 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2 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 2.

Table 2: Percent of Mes na Patients Developing Grade 3 or 4 Hematuria
  Mesna Dosing Regimen
Study 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)