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Drug: Mesna - Mesnex®

Usual Diluents

D5W, LR, NS, D51/3NS, D51/2NS

Dilution Data

DILUTION SUMMARY

[Amount of drug] [Infusion volume] [Infusion rate]

[Usual dose] [50-100 ml] [15-30min]
(Concentration range: 1-20 mg/ml)

Intravenous Schedule ¹
Mesna is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide. The total daily dose of mesna is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below:

	0 Hours	4 Hours	8 Hours
Ifosfamide	1.2 g/m2	—	—
Mesna	240 mg/m2	240 mg/m2	240 mg/m2

Preparation of Intravenous Solutions/Stability ¹
The mesna multidose vials may be stored and used for up to 8 days.

For IV administration the drug can be diluted by adding the Mesna Injection solution to any of the following fluids obtaining final concentrations of 20 mg mesna/mL.

5% Dextrose Injection, USP
5% Dextrose and 0.2% Sodium Chloride Injection, USP
5% Dextrose and 0.33% Sodium Chloride Injection, USP
5% Dextrose and 0.45% Sodium Chloride Injection, USP
0.92% Sodium Chloride Injection, USP
Lactated Ringer's Injection, USP

For example ¹:
One mL of Mesna Injection multidose vial 100 mg/mL may be added to 4 mL of any of the solutions listed above to create a final concentration of 20 mg mesna/mL.

Diluted solutions are chemically and physically stable for 24 hours at 25°C (77°F).
Mesna is not compatible with cisplatin or carboplatin.

Alternative source ²:
Administer by short (15-30 minutes) infusion or continuous infusion (maintain continuous infusion for 12-24 after completion of ifosfamide infusion) . Dilute in 50-1000 mL.

Stability / Miscellaneous

WARNINGS	CLINICAL PHARMACOLOGY	INDICATIONS
CONTRAINDICATIONS	DOSAGE AND ADMINISTRATION	RECONSTITUTION / DILUTION
	HOW SUPPLIED
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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 to light pink appearance in clear glass multidose vials for intravenous administration. Mesna Injection contains 100 mg/mL mesna, 0.25 mg/mL edetate disodium and sodium hydroxide and/or hydrochloric acid for pH adjustment. Mesna Injection multidose vials also contain 10.4 mg of benzyl alcohol as a preservative. The solution has a pH range of 6.5 to 7.3.

CLINICAL PHARMACOLOGY

Mechanism of Action
Mesna was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis induced by ifosfamide.

Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Mesna disulfide remains in the intravascular compartment and is rapidly eliminated by the kidneys.

In the kidney, the mesna disulfide is reduced to the free thiol compound, mesna, which 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 nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and other urotoxic metabolites.

In multiple human xenograft or rodent tumor model studies of limited scope, using IV or IP routes of administration, mesna in combination with ifosfamide (at dose ratios of up to 20-fold as single or multiple courses) failed to demonstrate interference with antitumor efficacy.

Pharmacokinetics
At doses of 2 to 4 g/m2, the terminal elimination half-life of ifosfamide is about 4 to 8 hours. As a result, in order to maintain adequate levels of mesna in the urinary bladder during the course of elimination of the urotoxic ifosfamide metabolites, repeated doses of mesna are required.

IV-IV-IV Regimen
After intravenous administration of an 800 mg dose, the half-lives of mesna and dimesna in the blood are 0.36 hours and 1.17 hours, respectively. Approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered was eliminated within 4 hours. Mesna has a plasma clearance of 1.23 L/h/kg.

Special Populations

Gender Effect
An analysis was conducted in four males and four female volunteers; no differences in plasma pharmacokinetics were detected.

Pediatrics and Geriatrics
Pharmacokinetic data of mesna in pediatric and geriatric patients are not available.

Hepatic and Renal Insufficiency
No clinical studies were conducted to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of mesna.

Drug-Drug Interaction
No clinical drug interaction studies have been conducted with mesna

INDICATIONS AND USAGE
Mesna is indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.

CONTRAINDICATIONS
Mesna is contraindicated in patients known to be hypersensitive to mesna or other thiol compounds.

WARNINGS
Allergic reactions to mesna ranging from mild hypersensitivity to systemic anaphylactic reactions have been reported. Patients with autoimmune disorders who were treated with cyclophosphamide and mesna appeared to have a higher incidence of allergic reactions. The majority of these patients received mesna orally.

Mesna has been developed as an agent to reduce the risk of ifosfamide-induced hemorrhagic cystitis. It will not prevent or alleviate any of the other adverse reactions or toxicities associated with ifosfamide therapy.

Mesna does not prevent hemorrhagic cystitis in all patients. Up to 6% of patients treated with mesna have developed hematuria (>50 RBC/hpf or WHO grade 2 and above). As a result, a morning specimen of urine should be examined for the presence of hematuria (microscopic evidence of red blood cells) each day prior to ifosfamide therapy. If hematuria develops when mesna is given with ifosfamide according to the recommended dosage schedule, depending on the severity of the hematuria, dosage reductions or discontinuation of ifosfamide therapy may be initiated.

In order to reduce the risk of hematuria, mesna must be administered with each dose of ifosfamide as outlined in the DOSAGE AND ADMINISTRATION section. Mesna is not effective in reducing the risk of hematuria due to other pathological conditions such as thrombocytopenia.

Because of the benzyl alcohol content, the multidose vial should not be used in neonates or infants and should be used with caution in older pediatric patients.

DOSAGE AND ADMINISTRATION
For the prophylaxis of ifosfamide induced hemorrhagic cystitis, mesna may be given on a fractionated dosing schedule of three bolus intravenous injections as outlined below.

Intravenous Schedule
Mesna is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide. The total daily dose of mesna is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below:

	0 Hours	4 Hours	8 Hours
Ifosfamide	1.2 g/m2	—	—
Mesna	240 mg/m2	240 mg/m2	240 mg/m2

Preparation of Intravenous Solutions/Stability
The mesna multidose vials may be stored and used for up to 8 days.

For IV administration the drug can be diluted by adding the Mesna Injection solution to any of the following fluids obtaining final concentrations of 20 mg mesna/mL.

5% Dextrose Injection, USP
5% Dextrose and 0.2% Sodium Chloride Injection, USP
5% Dextrose and 0.33% Sodium Chloride Injection, USP
5% Dextrose and 0.45% Sodium Chloride Injection, USP
0.92% Sodium Chloride Injection, USP
Lactated Ringer's Injection, USP

For example:

One mL of Mesna Injection multidose vial 100 mg/mL may be added to 4 mL of any of the solutions listed above to create a final concentration of 20 mg mesna/mL.

Diluted solutions are chemically and physically stable for 24 hours at 25°C (77°F).

Mesna is not compatible with cisplatin or carboplatin.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED
Mesna Injection is available as follows:

NDC 55390-347-01 1 gram; 10 mL Multidose Vial, individually boxed.

Store at 20° to 25°C (68° to 77°F). See USP for controlled room temperature

Novation, the supply company of VHA and UHC, and NOVAPLUS are trademarks of Novation, LLC
Bedford Laboratories

Reference(s)

PRIMARY:
1) [PACKAGE INSERT DATA] : MESNA injection, solution. [Bedford Laboratories] Bedford, OH 44146 Bedford, OH 44146. Revised: 12/2009.

2) Solimando, Dominic A. Drug Information Handbook for Oncology: A Complete Guide to Combination Chemotherapy Regimens, 8th ed. Hudson, OH: Lexi-Comp, Inc.; 2010.