MESNEX (mesna 400 mg) Dailymed

10 Overdosage

There is no known antidote for MESNEX.

In a clinical trial, 11 patients received intravenous MESNEX 10 mg/kg to 66 mg/kg per day for 3 to 5 days. Patients also received ifosfamide or cyclophosphamide. Adverse reactions included nausea, vomiting, diarrhea and fever. An increased rate of these adverse reactions has also been found in oxazaphosphorine-treated patients receiving ≥80 mg MESNEX per kg per day intravenously compared with patients receiving lower doses or hydration treatment only.

Postmarketing, administration of 4.5 g to 6.9 g of MESNEX resulted in hypersensitivity reactions including mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.

11 Description

MESNEX (mesna) 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⁺

MESNEX injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multidose vials for intravenous administration. MESNEX injection contains 100 mg/mL mesna, 0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. MESNEX injection multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. The solution has a pH range of 7.5-8.5.

MESNEX tablets are white, oblong, scored biconvex film-coated tablets with the imprint M4. They contain 400 mg mesna. The excipients are calcium phosphate, cornstarch, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and titanium dioxide.

12 Clinical Pharmacology

12.1 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.

12.3 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 1200 mg oral or intravenous doses.

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

Distribution

Mean apparent volume of distribution (V_d) 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 1.17 hours, respectively. Mesna has a plasma clearance of 1.23 L/h/kg.

13 Nonclinical Toxicology

13.1 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.

14 Clinical Studies

14.1 Intravenous MESNEX

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 (mesna) Intravenous Regimen (number of patients)
Uncontrolled Studies Ifosfamide dose 1.2 g/m2 d x 5
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 Ifosfamide dose 2 g/m2 to 4 g/m2 d x 3 to 5
Study 5	31% (14/46)	6% (3/46)
Study 6	100% (7/7)	0% (0/8)

14.2 Oral MESNEX

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

	MESNEX 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)

16 How Supplied/storage And Handling

MESNEX (mesna) injection 100 mg/mL

• •NDC 0338-1305-01 1 g Multidose Vial, Box of 1 vial of 10 mL
• •NDC 0338-1305-03 1 g Multidose Vial, Box of 10 vials of 10 mL
•  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]

If MESNEX is co-administered with ifosfamide, refer to the ifosfamide prescribing information for safe handling instructions.

MESNEX (mesna) tablets

• •NDC 67108-3565-9 400 mg scored tablets packaged in box of 10 tablets
•  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

See FDA-approved patient labeling (Patient Information).

Hypersensitivity

• •Advise the patient to discontinue MESNEX and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction, including systemic anaphylactic reactions occur [see Warnings and Precautions (5.1)].

Dosing Instructions

• •Advise the patient to take MESNEX at the exact time and in the exact amount as prescribed. Advise the patient to contact their healthcare provider if they vomit within 2 hours of taking oral MESNEX, or if they miss a dose of oral MESNEX [see Dosage and Administration (2.2)].

Hemorrhagic Cystitis

• •MESNEX does not prevent hemorrhagic cystitis in all patients nor does it prevent or alleviate any of the other adverse reactions or toxicities associated with ifosfamide. Advise the patient to report to their healthcare provider if his/her urine has turned a pink or red color [see Dosage and Administration (2.3)].
• •Advise the patient to drink 1 to 2 liters of fluid each day during MESNEX therapy [see Dosage and Administration (2.3)].

Dermatologic Toxicity

• •Advise the patient that Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions have occurred with MESNEX. Advise the patient to report to their healthcare provider if signs and symptoms of these syndromes occur [see Warnings and Precautions (5.2)].

Benzyl Alcohol Toxicity

• •Advise patients that serious adverse reactions are associated with the benzyl alcohol found in MESNEX and other medications in premature neonates and low-birth weight infants [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].

Embryo-Fetal Toxicity

• •MESNEX is used in combination with ifosfamide. Ifosfamide or other cytotoxic agents can cause fetal harm when administered to a pregnant woman. Inform female patients of the risk to a fetus and potential loss of the pregnancy. Advise females to inform their healthcare provider if they are pregnant or become pregnant [see Use in Specific Populations (8.1)].

Contraception

• •Advise females of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosamide and for 6 months after the last dose [see Use in Specific Populations (8.3)].
• •Advise male patients with female partners of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosamide and for 3 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

• •Advise lactating women not to breastfeed during treatment with MESNEX or ifosfamide and for 1 week after the last dose [see Use in Specific Populations (8.2)].

Baxter Logo MESNEX (mesna) injection manufactured by:

MESNEX (mesna) tablets manufactured for:

•   Baxter Healthcare Corporation Deerfield, IL 60015 USAFor Product Inquiry 1800 ANA DRUG (1-800-262-3784)

Made in Germany

Baxter and Mesnex are registered trademarks of Baxter International Inc.

Material No. HA-30-01-811