Mesna

Mesna Injection is a sterile, nonpyrogenic, aqueous solution of 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, sodium hydroxide for pH adjustment and q.s with Water for Injection. Mesna injection multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. The solution has a pH range of 6.5 to 7.4.

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 to 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.

IV-Oral-Oral Regimen

The half-life of mesna ranged from 1.2 to 8.3 hours after administration of intravenous plus oral doses of mesna. The urinary bioavailability of oral mesna ranged from 45 to 79% of intravenously administered mesna. Food does not affect the urinary availability of orally administered mesna. Approximately 18 to 26% of the combined intravenous and oral mesna dose appears as free mesna in the urine. When compared to intravenously administered mesna, the intravenous plus oral dosing regimen increases systemic exposures (150%) and provides more sustained excretion of mesna in the urine over a 24-hour period. Approximately 5% of the mesna dose is excreted during the 12 to 24 hour interval, as compared to negligible amounts in patients given the IV regimen. The fraction of the administered dose of mesna excreted in the urine is independent of dose. Protein binding of mesna is in a moderate range (69 to 75%).

Special Populations

Gender Effect

An analysis was conducted in four male 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.

Clinical Studies

IV Mesna

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/hpf or macrohematuria) (Morgan, Einhorn^a, Costanzi). In contrast, none of the patients who received mesna injection together with this dose of ifosfamide developed hematuria (Einhorn^a,b). In two randomized studies, (Fukuoka, Scheef), higher doses of ifosfamide, from 2 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%.

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.

PRECAUTIONS

Information for Patients

Healthcare providers should advise patients taking mesna to drink at least a quart of liquid a day. Patients should be informed to report if their urine has turned a pink or red color.

Laboratory Tests

A false positive test for urinary ketones may arise in patients treated with mesna. In this test, a red-violet color develops which, with the addition of glacial acetic acid, will return to violet.

Drug Interactions

No clinical drug studies have been conducted.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

No long-term studies in animals have been performed to evaluate the carcinogenic potential of mesna.

Mutagenesis

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.

Impairment of Fertility

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 (at doses up to 2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day; both studies approximately 10-fold higher than the maximum recommended human dose on a body surface area basis).

Pregnancy

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at oral doses of 1000 mg/kg in rabbits and 2000 mg/kg in rats (approximately 10 times the maximum recommended total daily IV-oral-oral human dose on a body surface area basis) and have revealed no evidence of harm to the fetus due to mesna. There are however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether mesna or dimesna is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from mesna, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

Geriatric Use

Clinical studies of mesna 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. However, the ratio of ifosfamide to mesna should remain unchanged.

ADVERSE REACTIONS

Mesna adverse reaction data are available from four phase I studies in which single IV bolus doses of 600 to 1200 mg mesna injection without concurrent chemotherapy were administered to a total of 53 subjects.

The most frequently reported side effects (observed in two or more patients) for patients receiving single doses of mesna IV were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperaesthesia, influenza-like symptoms, and coughing.

In two phase I multiple-dose studies where patients received mesna tablets alone or IV mesna followed by repeated doses of mesna tablets, flatulence and rhinitis were reported. In addition, constipation was reported by patients who had received repeated doses of IV mesna.

Because mesna is used in combination with ifosfamide or ifosfamide-containing chemotherapy regimens, it is difficult to distinguish the adverse reactions which may be due to mesna from those caused by the concomitantly administered cytotoxic agents.

Adverse reactions reasonably associated with mesna administered IV and orally in four controlled studies in which patients received ifosfamide or ifosfamide-containing regimens are presented in Table 3.

Postmarketing Surveillance

Allergic reactions, decreased platelet counts associated with allergic reactions, hypertension, hypotension, increased heart rate, increased liver enzymes, injection site reactions (including pain and erythema), limb pain, malaise, myalgia, ST-segment elevation, tachycardia, and tachypnea have been reported as part of postmarketing surveillance.

To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

OVERDOSAGE

There is no known antidote for mesna. Oral doses of 6.1 and 4.3 g/kg were lethal to mice and rats, respectively. These doses are approximately 15 and 22 times the maximum recommended human dose on a body surface area basis. Death was preceded by diarrhea, tremor, convulsions, dyspnea, and cyanosis.

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:

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.

HOW SUPPLIED

Mesna Injection is supplied as follows:

Storage Conditions

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.]

LATEX-FREE
Sterile, Nonpyrogenic.

SAGENT™

Mfd. for SAGENT Pharmaceuticals
Schaumburg, IL 60195 (USA)
Made in India
©2012 Sagent Pharmaceuticals, Inc.

Revised: September 2012

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-201-10

Rx only

Mesna Injection

1 g per 10 mL

(100 mg per mL)

For IV Use

10 mL Multi-Dose Vial