ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following are discussed in more detail in other sections of the labeling.Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Dermatological Toxicity [see Warnings and Precautions (5.2)] Benzyl Alcohol Toxicity [see Warnings and Precautions (5.3)] Laboratory Test Interferences [see Warnings and Precautions (5.4)] Use in Patients with History of Adverse Reactions to Thiol Compounds [see Warnings and Precautions (5.5)] Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Dermatological Toxicity [see Warnings and Precautions (5.2)] Benzyl Alcohol Toxicity [see Warnings and Precautions (5.3)] Laboratory Test Interferences [see Warnings and Precautions (5.4)] Use in Patients with History of Adverse Reactions to Thiol Compounds [see Warnings and Precautions (5.5)] The most common adverse reactions (> 10%) when mesna is given with ifosfamide are nausea, vomiting, constipation, leukopenia, fatigue, fever, anorexia, thrombocytopenia, anemia, granulocytopenia, diarrhea, asthenia, abdominal pain, headache, alopecia, and somnolence. (6.1) 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.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Mesna adverse reaction data are available from four Phase studies in which single intravenous doses of 600 to 1200 mg mesna injection without concurrent chemotherapy were administered to total of 53 healthy volunteers. The most frequently reported side effects (observed in two or more healthy volunteers) for healthy volunteers receiving single doses of mesna injection alone were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperesthesia, influenza-like symptoms, and coughing. In two Phase multiple-dose studies where healthy volunteers received mesna tablets alone or intravenous mesna followed by repeated doses of mesna tablets, flatulence and rhinitis were reported. In addition, constipation was reported by healthy volunteers who had received repeated doses of intravenous mesna.Additional adverse reactions in healthy volunteers receiving mesna alone included injection site reactions, abdominal pain/colic, epigastric pain/burning, mucosal irritation, lightheadedness, back pain, arthralgia, myalgia, conjunctivitis, nasal congestion, rigors, paresthesia, photophobia, fatigue, lymphadenopathy, extremity pain, malaise, chest pain, dysuria, pleuritic pain, dry mouth, dyspnea, and hyperhidrosis. In healthy volunteers, mesna was commonly associated with rapid (within 24 hours) decrease in lymphocyte count, which was generally reversible within one week of administration.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 intravenously and orally in four controlled studies in which patients received ifosfamide or ifosfamide-containing regimens are presented in Table 3.Table 3: Adverse Reactions in >=5% of Patients Receiving Mesna in combination with Ifosfamide-containing Regimens1Intravenous dosing of ifosfamide and mesna followed by either intravenous or oral doses of mesna according to the applicable dosage schedule [see Dosage and Administration (2)].Mesna RegimenIntravenous-Intravenous-Intravenous1Intravenous-Oral-Oral1N exposed119 (100.0%)119 (100%)Incidence of AEs101 (84.9%)106 (89.1%)Nausea65 (54.6)64 (53.8)Vomiting35 (29.4)45 (37.8)Constipation28 (23.5)21 (17.6)Leukopenia25 (21.0)21 (17.6)Fatigue24 (20.2)24 (20.2)Fever24 (20.2)18 (15.1)Anorexia21 (17.6)19 (16.0)Thrombocytopenia21 (17.6)16 (13.4)Anemia20 (16.8)21 (17.6)Granulocytopenia16 (13.4)15 (12.6)Asthenia15 (12.6)21 (17.6)Abdominal Pain14 (11.8)18 (15.1)Alopecia12 (10.1)13 (10.9)Dyspnea11 (9.2)11 (9.2)Chest Pain10 (8.4)11 (9.2)Hypokalemia10 (8.4)11 (9.2)Diarrhea9 (7.6)17 (14.3)Dizziness9 (7.6)5 (4.2)Headache9 (7.6)13 (10.9)Pain9 (7.6)10 (8.4)Sweating Increased9 (7.6)2 (1.7)Back Pain8 (6.7)6 (5.0)Hematuria8 (6.7)7 (5.9)Injection Site Reaction8 (6.7)10 (8.4)Edema8 (6.7)9 (7.6)Edema Peripheral8 (6.7)8 (6.7)Somnolence8 (6.7)12 (10.1)Anxiety7 (5.9)4 (3.4)Confusion7 (5.9)6 (5.0)Face Edema6 (5.0)5 (4.2)Insomnia6 (5.0)11 (9.2)Coughing5 (4.2)10 (8.4)Dyspepsia4 (3.4)6 (5.0)Hypotension4 (3.4)6 (5.0)Pallor4 (3.4)6 (5.0)Dehydration3 (2.5)7 (5.9)Pneumonia2 (1.7)8 (6.7)Tachycardia1 (0.8)7 (5.9)Flushing1 (0.8)6 (5.0). 6.2 Postmarketing Experience. The following adverse reactions have been reported in the postmarketing experience of patients receiving mesna in combination with ifosfamide or similar drugs, making it difficult to distinguish the adverse reactions which may be due to mesna from those caused by the concomitantly administered cytotoxic agents. Because these reactions are reported from population of unknown size, precise estimates of frequency cannot be made.Cardiovascular: Hypertension Gastrointestinal: Dysgeusia Hepatobiliary: Hepatitis Nervous System: Convulsion Respiratory: Hemoptysis.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 body surface area basis.

CLINICAL PHARMACOLOGY SECTION.

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 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. AbsorptionFollowing oral administration, peak plasma concentrations were reached within 1.5 to hours and to 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 healthy volunteers who received 1200 mg oral or intravenous doses.Food does not affect the urinary availability of orally administered mesna.. DistributionMean 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).. MetabolismAnalogous 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.. ExcretionFollowing intravenous administration of 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 plasma clearance of 1.23 L/h/kg.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Intravenous Mesna. Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At dose of 1.2 g/m2 ifosfamide administered daily for 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 and 4). In two randomized studies, (Studies and 6), higher doses of ifosfamide, from g/m2 to g/m2 administered for to 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)Ifosfamide dose 1.2 g/m2 x 5+Ifosfamide dose g/m2 to g/m2 x to 5StudyConventional Uroprophylaxis(number of patients)Standard Mesna IntravenousRegimen (number of patients)Uncontrolled StudiesStudy 116% (7/44)-Study 226% (11/43)-Study 318% (7/38)0% (0/21)Study 4-0% (0/32)Controlled Studies+Study 531% (14/46)6% (3/46)Study 6100% (7/7)0% (0/8).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Mesna is contraindicated in patients known to be hypersensitive to mesna or to any of the excipients [see Warnings and Precautions (5.1)]. Known hypersensitivity to mesna or to any of the excipients in mesna, including benzyl alcohol. (4). Known hypersensitivity to mesna or to any of the excipients in mesna, including benzyl alcohol. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Mesna is sterile, nonpyrogenic, aqueous detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide. The active ingredient, mesna, is synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate with molecular formula of C2H5NaO3S2 and molecular weight of 164.18. Its structural formula is as follows:Mesna Injection is sterile, nonpyrogenic, aqueous solution of colorless to light pink appearance in clear glass multidose vials for intravenous administration. Mesna Injection contains 100 mg per mL mesna, 0.25 mg per mL edetate disodium, sodium hydroxide for pH adjustment and qs with Water for Injection. Mesna Injection multidose vials also contain 10.4 mg per mL of benzyl alcohol as preservative. The solution has pH range of 6.5 to 7.4.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Mesna injection may be given on fractionated dosing schedule of three bolus intravenous injections or single bolus injection followed by two oral administrations of mesna tablets as outlined below. The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is adjusted, the ratio of mesna to ifosfamide should be maintained. (2) Intravenous Dosing Schedule:0 Hours4 Hours8 HoursIfosfamide1.2 g/m2 --Mesna injection240 mg/m2 240 mg/m2 240 mg/m2 Intravenous and Oral Dosing Schedule:0 Hours2 Hours6 HoursIfosfamide1.2 g/m2 --Mesna injection240 mg/m2 --Mesna tablets-480 mg/m2 480 mg/m2 Maintain sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. (2.3). 2.1 Intravenous Dosing. Mesna injection may be given on fractionated dosing schedule of three bolus intravenous injections as outlined below.Mesna injection is given as intravenous bolus injections in dosage equal to 20% of the ifosfamide dosage weight by weight (w/w) at the time of ifosfamide administration and and hours after each dose of ifosfamide. The total daily dose of mesna injection is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below in Table 1.Table 1. Recommended Intravenous Dosing Schedule1The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or decreased, the ratio of mesna to ifosfamide should be maintained.0 Hours4 Hours8 HoursIfosfamide1.2 g/m2 --Mesna injection1240 mg/m2 240 mg/m2 240 mg/m2 2.2 Intravenous and Oral Dosing. Mesna injection may be given on fractionated dosing schedule of single bolus injection followed by two oral administrations of mesna tablets as outlined below.Mesna injection is given as intravenous bolus injections in dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. Mesna tablets are given orally in dosage equal to 40% of the ifosfamide dose and hours after each dose of ifosfamide. The total daily dose of mesna is 100% of the ifosfamide dose. The recommended dosing schedule is outlined in Table 2.Table 2. Recommended Intravenous and Oral Dosing Schedule1The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or decreased, the ratio of mesna to ifosfamide should be maintained.0 Hours2 Hours6 HoursIfosfamide1.2 g/m2 --Mesna injection1240 mg/m2 --Mesna tablets-480 mg/m2 480 mg/m2 The efficacy and safety of this ratio of intravenous and oral mesna has not been established as being effective for daily doses of ifosfamide higher than g/m2.Patients who vomit within two hours of taking oral mesna should repeat the dose or receive intravenous mesna injection.. 2.3 Monitoring for Hematuria. Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. If severe hematuria develops when mesna injection is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.. 2.4 Preparation for Intravenous Administration and Stability. PreparationDetermine the volume of mesna injection for the intended dose.Dilute the volume of mesna injection for the dose in any of the following fluids to obtain final concentration of 20 mg per mL: 5% Dextrose Injection, USP5% Dextrose and 0.2% Sodium Chloride Injection, USP5% Dextrose and 0.33% Sodium Chloride Injection, USP5% Dextrose and 0.45% Sodium Chloride Injection, USP0.9% Sodium Chloride Injection, USPLactated Ringers Injection, USP. 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. 0.9% Sodium Chloride Injection, USP. Lactated Ringers Injection, USP. StabilityThe mesna injection multidose vials may be stored and used for up to days after initial puncture.Store diluted solutions at 25C (77F). Use diluted solutions within 24 hours.Do not mix mesna injection with epirubicin, cyclophosphamide, cisplatin, carboplatin, and nitrogen mustard.The benzyl alcohol contained in mesna injection vials can reduce the stability of ifosfamide. Ifosfamide and mesna injection may be mixed in the same bag provided the final concentration of ifosfamide does not exceed 50 mg per mL. Higher concentrations of ifosfamide may not be compatible with mesna injection and may reduce the stability of ifosfamide.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any solutions which are discolored, hazy, or contain visible particulate matter should not be used.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Mesna Injection: gram Multi-Dose Vial, 100 mg per mL. Mesna Injection: gram Multi-Dose Vial, 100 mg per mL. Mesna Injection: gram (100 mg per mL) Multi-Dose vials (3). Mesna Injection: gram (100 mg per mL) Multi-Dose vials (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. No clinical drug interaction studies have been conducted with mesna.

GERIATRIC USE SECTION.

8.5 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. The ratio of ifosfamide to mesna should remain unchanged.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Mesna Injection is supplied as follows:NDCMesna Injection (100 mg per mL)Package Factor25021-201-101 gram per 10 mL Multi-Dose Vial1 vial per carton25021-201-111 gram per 10 mL Multi-Dose Vial10 vials per carton. Storage ConditionsStore at 20 to 25C (68 to 77F); excursions permitted between 15 and 30C (59 and 86F). [See USP Controlled Room Temperature.]Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex.If Mesna Injection is co-administered with ifosfamide, refer to the ifosfamide prescribing information for safe handling instructions.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Mesna Injection is indicated as prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.. Mesna Injection is cytoprotective agent indicated as prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis. (1) Limitation of Use:Mesna Injection is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia. (1). Limitation of Use:Mesna Injection is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. HypersensitivityAdvise the patient to discontinue mesna and seek immediate medical attention if any signs or symptoms of hypersensitivity reaction, including systemic anaphylactic reactions occur [see Warnings and Precautions (5.1)]. Hemorrhagic CystitisMesna 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 pink or red color [see Dosage and Administration (2.3)]. Advise the patient to drink to liters of fluid each day during mesna therapy [see Dosage and Administration (2.3)]. Advise the patient to discontinue mesna and seek immediate medical attention if any signs or symptoms of hypersensitivity reaction, including systemic anaphylactic reactions occur [see Warnings and Precautions (5.1)]. Mesna 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 pink or red color [see Dosage and Administration (2.3)]. Advise the patient to drink to liters of fluid each day during mesna therapy [see Dosage and Administration (2.3)]. Dermatologic ToxicityAdvise 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 mesna. Advise the patient to report to their healthcare provider if signs and symptoms of these syndromes occur [see Warnings and Precautions (5.2)]. 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 mesna. 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 ToxicityAdvise patients that serious adverse reactions are associated with the benzyl alcohol found in mesna and other medications in premature neonates and low-birth weight infants [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)]. Advise patients that serious adverse reactions are associated with the benzyl alcohol found in mesna 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 ToxicityMesna is used in combination with ifosfamide. Ifosfamide or other cytotoxic agents can cause fetal harm when administered to pregnant woman. Inform female patients of the risk to 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)]. Mesna is used in combination with ifosfamide. Ifosfamide or other cytotoxic agents can cause fetal harm when administered to pregnant woman. Inform female patients of the risk to 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)]. ContraceptionAdvise females of reproductive potential to use effective contraception during treatment with mesna in combination with ifosamide and for 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 mesna in combination with ifosamide and for months after the last dose [see Use in Specific Populations (8.3)]. Advise females of reproductive potential to use effective contraception during treatment with mesna in combination with ifosamide and for 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 mesna in combination with ifosamide and for months after the last dose [see Use in Specific Populations (8.3)]. LactationAdvise lactating women not to breastfeed during treatment with mesna or ifosfamide and for week after the last dose [see Use in Specific Populations (8.2)].SAGENT(R) Mfd. for SAGENT PharmaceuticalsSchaumburg, IL 60195 (USA) Made in India(C)2021 Sagent Pharmaceuticals, Inc.Revised: January 2021SAGENT Pharmaceuticals(R) Advise lactating women not to breastfeed during treatment with mesna or ifosfamide and for week after the last dose [see Use in Specific Populations (8.2)].

LABORATORY TESTS SECTION.

5.4 Laboratory Test Interferences. False-Positive Urine Tests for Ketone BodiesA false positive test for urinary ketones may arise in patients treated with mesna when using nitroprusside sodium-based urine tests (including dipstick tests). The addition of glacial acetic acid can be used to differentiate between false positive result (cherry-red color that fades) and true positive result (red-violet color that intensifies).. False-Negative Tests for Enzymatic CPK ActivityMesna may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use thiol compound (e.g., N-acetylcysteine) for CPK reactivation. This may result in falsely low CPK level.. False-Positive Tests for Ascorbic AcidMesna may cause false-positive reactions in Tillmans reagent-based urine screening tests for ascorbic acid.

LACTATION SECTION.

8.2 Lactation. Risk SummaryMesna is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide is excreted in breast milk. Refer to the ifosfamide prescribing information for more information on use during lactation. There are no data on the presence of mesna in human or animal milk, the effect on the breastfed child, or the effect on milk production.Mesna injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].Because of the potential for serious adverse reactions in breastfed child, advise lactating women not to breastfeed during treatment and for week after the last dose of mesna or ifosfamide.

MECHANISM OF ACTION SECTION.

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 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.

NONCLINICAL TOXICOLOGY SECTION.

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 body surface area basis.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no known antidote for mesna.In clinical trial, 11 patients received intravenous mesna 10 mg/kg to 66 mg/kg per day for to 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 mesna per kg per day intravenously compared with patients receiving lower doses or hydration treatment only.Postmarketing, administration of 4.5 to 6.9 of mesna resulted in hypersensitivity reactions including mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial LabelNDC 25021-201-10Rx onlyMesna Injection1 gram per 10 mL(100 mg per mL)For Intravenous Use10 mL Multi-Dose Vial. PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Mesna injection contains the preservative benzyl alcohol which has been associated with serious adverse reactions and death when administered intravenously to premature neonates and low-birth weight infants. Avoid use of mesna injection in premature neonates and low-birth weight infants [see Warnings and Precautions (5.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing oral administration, peak plasma concentrations were reached within 1.5 to hours and to 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 healthy volunteers who received 1200 mg oral or intravenous doses.Food does not affect the urinary availability of orally administered mesna.. DistributionMean 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).. MetabolismAnalogous 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.. ExcretionFollowing intravenous administration of 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 plasma clearance of 1.23 L/h/kg.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryMesna is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to pregnant woman. Refer to the ifosfamide prescribing information for more information on use during pregnancy.Mesna injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by pregnant woman, benzyl alcohol exposure in the fetus is unlikely [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)]. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataMesna is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm including embryo-fetal lethality. Refer to the ifosfamide prescribing information for more information on use during pregnancy.In embryo-fetal development studies, oral administration of mesna to pregnant rats (500, 1000, 1500, and 2000 mg/kg) and rabbits (500 and 1000 mg/kg) during the period of organogenesis revealed no adverse developmental outcomes at doses approximately 10 times the maximum recommended total daily human equivalent dose based on body surface area.

SPL UNCLASSIFIED SECTION.

Limitation of Use:Mesna Injection is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia.

STORAGE AND HANDLING SECTION.

Storage ConditionsStore at 20 to 25C (68 to 77F); excursions permitted between 15 and 30C (59 and 86F). [See USP Controlled Room Temperature.]Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex.If Mesna Injection is co-administered with ifosfamide, refer to the ifosfamide prescribing information for safe handling instructions.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Mesna in combination with ifosfamide can cause fetal harm. Advise patients of potential risk to fetus. (8.1)Lactation: Do not breastfeed. (8.2)Females and Males of Reproductive Potential: Advise patients to use effective contraception. Verify pregnancy status prior to initiation of mesna in combination with ifosfamide. (8.3)Pediatric use: In premature neonates and low-birth weight infants, avoid use of benzyl alcohol-containing solutions. (8.4)Geriatric use: Dose selection should be cautious. (8.5). Pregnancy: Mesna in combination with ifosfamide can cause fetal harm. Advise patients of potential risk to fetus. (8.1). Lactation: Do not breastfeed. (8.2). Females and Males of Reproductive Potential: Advise patients to use effective contraception. Verify pregnancy status prior to initiation of mesna in combination with ifosfamide. (8.3). Pediatric use: In premature neonates and low-birth weight infants, avoid use of benzyl alcohol-containing solutions. (8.4). Geriatric use: Dose selection should be cautious. (8.5). 8.1 Pregnancy. Risk SummaryMesna is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to pregnant woman. Refer to the ifosfamide prescribing information for more information on use during pregnancy.Mesna injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by pregnant woman, benzyl alcohol exposure in the fetus is unlikely [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)]. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataMesna is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm including embryo-fetal lethality. Refer to the ifosfamide prescribing information for more information on use during pregnancy.In embryo-fetal development studies, oral administration of mesna to pregnant rats (500, 1000, 1500, and 2000 mg/kg) and rabbits (500 and 1000 mg/kg) during the period of organogenesis revealed no adverse developmental outcomes at doses approximately 10 times the maximum recommended total daily human equivalent dose based on body surface area.. 8.2 Lactation. Risk SummaryMesna is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide is excreted in breast milk. Refer to the ifosfamide prescribing information for more information on use during lactation. There are no data on the presence of mesna in human or animal milk, the effect on the breastfed child, or the effect on milk production.Mesna injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].Because of the potential for serious adverse reactions in breastfed child, advise lactating women not to breastfeed during treatment and for week after the last dose of mesna or ifosfamide.. 8.3 Females and Males of Reproductive Potential. Mesna is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to pregnant woman. Refer to the ifosfamide prescribing information for more information on contraception and effects on fertility.. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiation of mesna in combination with ifosfamide.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with mesna in combination with ifosfamide and for months after the last dose.. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with mesna in combination with ifosfamide and for months after the last dose.. 8.4 Pediatric Use. Mesna injection contains the preservative benzyl alcohol which has been associated with serious adverse reactions and death when administered intravenously to premature neonates and low-birth weight infants. Avoid use of mesna injection in premature neonates and low-birth weight infants [see Warnings and Precautions (5.3)].. 8.5 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. The ratio of ifosfamide to mesna should remain unchanged.. 8.6 Use in Patients with Renal Impairment. No clinical studies were conducted to evaluate the effect of renal impairment on the pharmacokinetics of mesna.. 8.7 Use in Patients with Hepatic Impairment. No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of mesna.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity reactions: Anaphylactic reactions have been reported. Less severe hypersensitivity reactions may also occur. Monitor patients. If reaction occurs, discontinue mesna and provide supportive care. (5.1)Dermatologic toxicity: Skin rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Skin rash, urticaria, and angioedema have also been seen. Monitor patients. If reaction occurs, discontinue mesna and provide supportive care. (5.2)Benzyl alcohol toxicity: Serious and fatal adverse reactions can occur in premature neonates and low-birth weight infants treated with benzyl alcohol-preserved drugs, including mesna injection. Avoid use in premature neonates and low-birth weight infants. (5.3)Laboratory test alterations: False positive tests for urinary ketones and interference with enzymatic CPK activity tests have been seen. (5.4). Hypersensitivity reactions: Anaphylactic reactions have been reported. Less severe hypersensitivity reactions may also occur. Monitor patients. If reaction occurs, discontinue mesna and provide supportive care. (5.1). Dermatologic toxicity: Skin rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Skin rash, urticaria, and angioedema have also been seen. Monitor patients. If reaction occurs, discontinue mesna and provide supportive care. (5.2). Benzyl alcohol toxicity: Serious and fatal adverse reactions can occur in premature neonates and low-birth weight infants treated with benzyl alcohol-preserved drugs, including mesna injection. Avoid use in premature neonates and low-birth weight infants. (5.3). Laboratory test alterations: False positive tests for urinary ketones and interference with enzymatic CPK activity tests have been seen. (5.4). 5.1 Hypersensitivity Reactions. Mesna may cause systemic hypersensitivity reactions, including anaphylaxis. These reactions may include fever, cardiovascular symptoms (hypotension, tachycardia), acute renal impairment, hypoxia, respiratory distress, urticaria, angioedema, laboratory signs of disseminated intravascular coagulation, hematological abnormalities, increased liver enzymes, nausea, vomiting, arthralgia, and myalgia. These reactions may occur with the first exposure or after several months of exposure. Monitor for signs or symptoms. Discontinue mesna and provide supportive care.. 5.2 Dermatologic Toxicity. Drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions, consistent with Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. Mesna may cause skin and mucosal reactions characterized by urticaria, rash, erythema, pruritus, burning sensation, angioedema, periorbital edema, flushing and stomatitis. These reactions may occur with the first exposure or after several months of exposure. Discontinue mesna and provide supportive care.. 5.3 Benzyl Alcohol Toxicity. Serious adverse reactions including fatal reactions and the gasping syndrome occurred in premature neonates and low-birth weight infants who received benzyl alcohol dosages of 99 to 234 mg/kg/day (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Symptoms associated with gasping syndrome and other potential adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Premature neonates and low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Mesna injection contains 10.4 mg/mL of the preservative benzyl alcohol. Avoid use of mesna injection in premature neonates and low-birth weight infants. Mesna tablets do not contain benzyl alcohol [see Use in Specific Populations (8.4)].. 5.4 Laboratory Test Interferences. False-Positive Urine Tests for Ketone BodiesA false positive test for urinary ketones may arise in patients treated with mesna when using nitroprusside sodium-based urine tests (including dipstick tests). The addition of glacial acetic acid can be used to differentiate between false positive result (cherry-red color that fades) and true positive result (red-violet color that intensifies).. False-Negative Tests for Enzymatic CPK ActivityMesna may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use thiol compound (e.g., N-acetylcysteine) for CPK reactivation. This may result in falsely low CPK level.. False-Positive Tests for Ascorbic AcidMesna may cause false-positive reactions in Tillmans reagent-based urine screening tests for ascorbic acid.. 5.5 Use in Patients with History of Adverse Reactions to Thiol Compounds. Mesna is thiol compound, i.e., sulfhydryl (SH) group-containing organic compound. Hypersensitivity reactions to mesna and to amifostine, another thiol compound, have been reported. It is not clear whether patients who experienced an adverse reaction to thiol compound are at increased risk for hypersensitivity reaction to mesna.