Mesna

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 a 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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 a 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 1 studies in which single intravenous doses of 600 to 1,200 mg mesna injection without concurrent chemotherapy were administered to a total of 53 healthy volunteers and single oral doses of 600 to 2,400 mg of mesna tablets were administered to a total of 82 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 1 multiple-dose studies where healthy volunteers received mesna tablets alone or intravenous mesna injection 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 injection. 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 a 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 Regimens Mesna Regimen Intravenous-Intravenous-Intravenous 1 Intravenous-Oral-Oral 1 N exposed 119 (100%) 119 (100%) Incidence of AEs 101 (84.9%) 106 (89.1%) Nausea 65 (54.6) 64 (53.8) Vomiting 35 (29.4) 45 (37.8) Constipation 28 (23.5) 21 (17.6) Leukopenia 25 (21.0) 21 (17.6) Fatigue 24 (20.2) 24 (20.2) Fever 24 (20.2) 18 (15.1) Anorexia 21 (17.6) 19 (16.0) Thrombocytopenia 21 (17.6) 16 (13.4) Anemia 20 (16.8) 21 (17.6) Granulocytopenia 16 (13.4) 15 (12.6) Asthenia 15 (12.6) 21 (17.6) Abdominal Pain 14 (11.8) 18 (15.1) Alopecia 12 (10.1) 13 (10.9) Dyspnea 11 (9.2) 11 (9.2) Chest Pain 10 (8.4) 11 (9.2) Hypokalemia 10 (8.4) 11 (9.2) Diarrhea 9 (7.6) 17 (14.3) Dizziness 9 (7.6) 5 (4.2) Headache 9 (7.6) 13 (10.9) Pain 9 (7.6) 10 (8.4) Sweating Increased 9 (7.6) 2 (1.7) Back Pain 8 (6.7) 6 (5.0) Hematuria 8 (6.7) 7 (5.9) Injection Site Reaction 8 (6.7) 10 (8.4) Edema 8 (6.7) 9 (7.6) Edema Peripheral 8 (6.7) 8 (6.7) Somnolence 8 (6.7) 12 (10.1) Anxiety 7 (5.9) 4 (3.4) Confusion 7 (5.9) 6 (5.0) Face Edema 6 (5.0) 5 (4.2) Insomnia 6 (5.0) 11 (9.2) Coughing 5 (4.2) 10 (8.4) Dyspepsia 4 (3.4) 6 (5.0) Hypotension 4 (3.4) 6 (5.0) Pallor 4 (3.4) 6 (5.0) Dehydration 3 (2.5) 7 (5.9) Pneumonia 2 (1.7) 8 (6.7) Tachycardia 1 (0.8) 7 (5.9) Flushing 1 (0.8) 6 (5.0) 1 Intravenous dosing of ifosfamide and mesna injection followed by either intravenous or oral doses of mesna according to the applicable dosage schedule [see Dosage and Administration (2) ] . 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 a population of unknown size, precise estimates of frequency cannot be made. Cardiovascular: Hypertension Gastrointestinal: Dysgeusia Hepatobiliary: Hepatitis Nervous System: Convulsion Respiratory: Hemoptysis

4 CONTRAINDICATIONS Mesna Injection 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 Injection, including benzyl alcohol. ( 4 )

11 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 C 2 H 5 NaO 3 S 2 and a molecular weight of 164.18. Its structural formula is as follows: HS–CH 2 –CH 2 SO 3 –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.

2 DOSAGE AND ADMINISTRATION Mesna Injection may be given on a fractionated dosing schedule of three bolus intravenous injections or a 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 Hours 4 Hours 8 Hours Ifosfamide 1.2 g/m 2 -­ -­ Mesna injection 240 mg/m 2 240 mg/m 2 240 mg/m 2 Intravenous and Oral Dosing Schedule: 0 Hours 2 Hours 6 Hours Ifosfamide 1.2 g/m 2 -­ -­ Mesna injection 240 mg/m 2 -­ -­ Mesna tablets -­ 480 mg/m 2 480 mg/m 2 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 a fractionated dosing schedule of three bolus intravenous injections as outlined below. Mesna Injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage weight by weight (w/w) at the time of ifosfamide administration and 4 and 8 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 Schedule 0 Hours 4 Hours 8 Hours Ifosfamide 1.2 g/m 2 - - Mesna injection 1 240 mg/m 2 240 mg/m 2 240 mg/m 2 1 The 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 Injection to ifosfamide should be maintained. 2.2 Intravenous and Oral Dosing Mesna Injection may be given on a fractionated dosing schedule of a single bolus injection followed by two oral administrations of mesna tablets as outlined below. Mesna Injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. Mesna tablets are given orally in a dosage equal to 40% of the ifosfamide dose 2 and 6 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 Schedule 0 Hours 2 Hours 6 Hours Ifosfamide 1.2 g/m 2 - - Mesna injection 1 240 mg/m 2 - - Mesna tablets - 480 mg/m 2 480 mg/m 2 1 The 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. 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 2 g/m 2 . 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 Preparation Determine 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 a final concentration of 20 mg/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 0.9% Sodium Chloride Injection, USP Lactated Ringer’s Injection, USP Stability The Mesna Injection multiple dose vials may be stored and used for up to 8 days after initial puncture. Store diluted solutions at 25°C (77°F). 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/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.

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

10 OVERDOSAGE There is no known antidote for mesna. In a clinical trial, 11 patients received intravenous mesna injection 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 mesna injection 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 mesna resulted in hypersensitivity reactions including mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.

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

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 1,200 mg oral or intravenous doses. Food does not affect the urinary availability of orally administered mesna. 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.

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 1,200 mg oral or intravenous doses. Food does not affect the urinary availability of orally administered mesna. 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.

20190422

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3 DOSAGE FORMS AND STRENGTHS Mesna Injection: 1 gram per 10 mL (100 mg per mL) Multiple Dose Vial 1 gram per 10 mL (100 mg per mL) Multiple Dose Vial ( 3 )

Mesna MESNA MESNA 2-MERCAPTOETHANESULFONIC ACID EDETATE DISODIUM BENZYL ALCOHOL SODIUM HYDROXIDE

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 (≤ 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.

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 (≤ 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.

ANDA075811

Mesna

MESNA

63323-733

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE LABEL - PRINCIPAL DISPLAY - Mesna 10 mL Multiple Dose Vial Label NDC 63323-733-01 730310 Mesna Injection 1 gram per 10 mL (100 mg per mL) FOR INTRAVENOUS USE 10 mL Multiple Dose Vial Rx only PACKAGE LABEL - PRINCIPAL DISPLAY - Mesna 10 mL Multiple Dose Vial Tray Label NDC 63323-733-10 730310 Mesna Injection 1 gram per 10 mL (100 mg per mL) FOR INTRAVENOUS USE 10 x 10 mL Multiple Dose Vials Rx only vial label tray label

Warnings and Precautions, Benzyl Alcohol Toxicity ( 5.3 ) 12/2018

www.fresenius-kabi.com/us 45888G Revised: April 2019 address

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Hypersensitivity Advise the patient to discontinue mesna 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 mesna 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 mesna, or if they miss a dose of oral mesna [see Dosage and Administration ( 2.2 )]. Hemorrhagic Cystitis 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 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 mesna 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 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 Toxicity Advise patients that serious adverse reactions are associated with the benzyl alcohol found in Mesna Injection 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 Mesna 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 mesna in combination with ifosfamide 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 mesna in combination with ifosfamide 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 mesna or ifosfamide and for 1 week after the last dose [see Use in Specific Populations ( 8.2 )] .

14 CLINICAL STUDIES 14.1 Intravenous Mesna Injection Hemorrhagic cystitis produced by ifosfamide is dose dependent ( Table 4 ). At a dose of 1.2 g/m 2 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/m 2 to 4 g/m 2 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 4. Percent of Mesna 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/m 2 d x 5 † Ifosfamide dose 2 g/m 2 to 4 g/m 2 d x 3 to 5 14.2 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/m 2 to 2.0 g/m 2 for 3 to 5 days. Study 8 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m 2 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 Mesna 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)

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.

8.4 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 )] .

8.1 Pregnancy Risk Summary Mesna Injection is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to a 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 a 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 a 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 2 to 4% and 15 to 20%, respectively. Data Animal Data Mesna Injection 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, 1,000, 1,500, and 2,000 mg/kg) and rabbits (500 and 1,000 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 USE IN SPECIFIC POPULATIONS Pregnancy: Mesna Injection in combination with ifosfamide can cause fetal harm. Advise patients of potential risk to a 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 Injection 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 Summary Mesna Injection is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to a 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 a 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 a 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 2 to 4% and 15 to 20%, respectively. Data Animal Data Mesna Injection 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, 1,000, 1,500, and 2,000 mg/kg) and rabbits (500 and 1,000 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 Summary Mesna Injection 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 a 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 a breastfed child, advise lactating women not to breastfeed during treatment and for 1 week after the last dose of mesna or ifosfamide. 8.3 Females and Males of Reproductive Potential Mesna Injection is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to a pregnant woman. Refer to the ifosfamide prescribing information for more information on contraception and effects on fertility. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiation of Mesna Injection in combination with ifosfamide. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Mesna Injection in combination with ifosfamide and for 6 months after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with Mesna Injection in combination with ifosfamide and for 3 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Mesna Injection, is available as: Product Code Unit of Sale Strength Each 730310 NDC 63323-733-10 Unit of 10 1 gram per 10 mL (100 mg per mL) NDC 63323-733-01 10 mL Multiple Dose Vial 730311 NDC 63323-733-11 Individually packaged. 1 gram per 10 mL (100 mg per mL) 10 mL Multiple Dose Vial The container closure is not made with natural rubber latex. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. If Mesna is co-administered with ifosfamide, refer to the ifosfamide prescribing information for safe handling instructions.