MESNEX

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 MESNEX 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 Baxter Healthcare at 1-866-888-2472, 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. MESNEX adverse reaction data are available from four Phase 1 studies in which single intravenous doses of 600-1200 mg MESNEX Injection without concurrent chemotherapy were administered to a total of 53 healthy volunteers and single oral doses of 600-2400 mg of MESNEX 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 MESNEX 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 MESNEX Tablets alone or intravenous MESNEX followed by repeated doses of MESNEX Tablets, flatulence and rhinitis were reported. In addition, constipation was reported by healthy volunteers who had received repeated doses of intravenous MESNEX. Additional adverse reactions in healthy volunteers receiving MESNEX 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, MESNEX was commonly associated with a rapid (within 24 hours) decrease in lymphocyte count, which was generally reversible within one week of administration. Because MESNEX is used in combination with ifosfamide or ifosfamide-containing chemotherapy regimens, it is difficult to distinguish the adverse reactions which may be due to MESNEX from those caused by the concomitantly administered cytotoxic agents. Adverse reactions reasonably associated with MESNEX administered intravenously and orally in four controlled studies in which patients received ifosfamide or ifosfamide-containing regimens are presented in . Table 3: Adverse Reactions in ≥ 5% of Patients Receiving MESNEX in combination with Ifosfamide-containing Regimens MESNEX Regimen Intravenous-Intravenous-Intravenous Intravenous dosing of ifosfamide and MESNEX followed by either intravenous or oral doses of MESNEX according to the applicable dosage schedule. [see Dosage and Administration (2)]. Intravenous-Oral-Oral N exposed 119 (100.0%) 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) 6.2 Postmarketing Experience The following adverse reactions have been reported in the postmarketing experience of patients receiving MESNEX in combination with ifosfamide or similar drugs, making it difficult to distinguish the adverse reactions which may be due to MESNEX 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 MESNEX is contraindicated in patients known to be hypersensitive to MESNEX or to any of the excipients [ see Warnings and Precautions (5.1) ]. Known hypersensitivity to MESNEX or to any of the excipients, including benzyl alcohol. (4)

11 DESCRIPTION MESNEX 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 + MESNEX (mesna) injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multidose vials for intravenous administration. MESNEX injection contains 100 mg/mL mesna, 0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. MESNEX Injection multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. The solution has a pH range of 7.5-8.5. MESNEX (mesna) tablets are white, oblong, scored biconvex film-coated tablets with the imprint M4. They contain 400 mg mesna. The excipients are calcium phosphate, cornstarch, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and titanium dioxide.

2 DOSAGE AND ADMINISTRATION MESNEX may be given on a fractionated dosing schedule of three bolus intravenous injections or a single bolus injection followed by two oral administrations of MESNEX 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 MESNEX to ifosfamide should be maintained. (2) Intravenous Dosing Schedule: 0 Hours 4 Hours 8 Hours Ifosfamide 1.2 g/m 2 -- -- MESNEX 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 -- -- MESNEX Injection 240 mg/m 2 -- -- MESNEX 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 MESNEX may be given on a fractionated dosing schedule of three bolus intravenous injections as outlined below. MESNEX 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 MESNEX is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below in . Table 1. Recommended Intravenous Dosing Schedule 0 Hours 4 Hours 8 Hours Ifosfamide 1.2 g/m 2 - - MESNEX Injection 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 MESNEX to ifosfamide should be maintained. 240 mg/m 2 240 mg/m 2 240 mg/m 2 2.2 Intravenous and Oral Dosing MESNEX may be given on a fractionated dosing schedule of a single bolus injection followed by two oral administrations of MESNEX tablets as outlined below. MESNEX 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. MESNEX 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 MESNEX is 100% of the ifosfamide dose. The recommended dosing schedule is outlined in . Table 2. Recommended Intravenous and Oral Dosing Schedule 0 Hours 2 Hours 6 Hours Ifosfamide 1.2 g/m 2 - - MESNEX injection 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 MESNEX to ifosfamide should be maintained. 240 mg/m 2 - - MESNEX tablets - 480 mg/m 2 480 mg/m 2 The efficacy and safety of this ratio of intravenous and oral MESNEX 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 MESNEX should repeat the dose or receive intravenous MESNEX. 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 MESNEX 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 MESNEX injection for the intended dose. Dilute the volume of MESNEX 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 MESNEX injection multidose 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 MESNEX injection with epirubicin, cyclophosphamide, cisplatin, carboplatin, and nitrogen mustard. The benzyl alcohol contained in MESNEX injection vials can reduce the stability of ifosfamide. Ifosfamide and MESNEX 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 MESNEX 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 MESNEX is indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis. Limitation of Use: MESNEX is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia. MESNEX is a cytoprotective agent indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis. (1) Limitation of Use: MESNEX 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 MESNEX. In a clinical trial, 11 patients received intravenous MESNEX 10 mg/kg to 66 mg/kg per day for 3 to 5 days. Patients also received ifosfamide or cyclophosphamide. Adverse reactions included nausea, vomiting, diarrhea and fever. An increased rate of these adverse reactions has also been found in oxazaphosphorine-treated patients receiving ≥80 mg MESNEX per kg per day intravenously compared with patients receiving lower doses or hydration treatment only. Postmarketing, administration of 4.5 g to 6.9 g of MESNEX resulted in hypersensitivity reactions including mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.

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

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Mesna reacts chemically with the urotoxic ifosfamide metabolites, acrolein and 4-hydroxy-ifosfamide, resulting in their detoxification. The first step in the detoxification process is the binding of mesna to 4‑hydroxy-ifosfamide forming a non-urotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites and inhibits their effects on the bladder. 12.3 Pharmacokinetics Absorption Following oral administration, peak plasma concentrations were reached within 1.5 to 4 hours and 3 to 7 hours for free mesna and total mesna (mesna plus dimesna and mixed disulfides), respectively. Oral bioavailability averaged 58% (range 45 to 71%) for free mesna and 89% (range 74 to 104%) for total mesna based on plasma AUC data from 8 healthy volunteers who received 1200 mg oral or intravenous doses. Food does not affect the urinary availability of orally administered MESNEX. Distribution Mean apparent volume of distribution (V d ) for mesna is 0.652 ± 0.242 L/kg after intravenous administration which suggests distribution to total body water (plasma, extracellular fluid, and intracellular water). Metabolism Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Plasma concentrations of mesna exceed those of dimesna after oral or intravenous administration. Excretion Following intravenous administration of a single 800 mg dose, approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. Mean plasma elimination half-lives of mesna and dimesna are 0.36 hours and 1.17 hours, respectively. Mesna has a plasma clearance of 1.23 L/h/kg.

12.1 Mechanism of Action Mesna reacts chemically with the urotoxic ifosfamide metabolites, acrolein and 4-hydroxy-ifosfamide, resulting in their detoxification. The first step in the detoxification process is the binding of mesna to 4‑hydroxy-ifosfamide forming a non-urotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites and inhibits their effects on the bladder.

12.3 Pharmacokinetics Absorption Following oral administration, peak plasma concentrations were reached within 1.5 to 4 hours and 3 to 7 hours for free mesna and total mesna (mesna plus dimesna and mixed disulfides), respectively. Oral bioavailability averaged 58% (range 45 to 71%) for free mesna and 89% (range 74 to 104%) for total mesna based on plasma AUC data from 8 healthy volunteers who received 1200 mg oral or intravenous doses. Food does not affect the urinary availability of orally administered MESNEX. Distribution Mean apparent volume of distribution (V d ) for mesna is 0.652 ± 0.242 L/kg after intravenous administration which suggests distribution to total body water (plasma, extracellular fluid, and intracellular water). Metabolism Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Plasma concentrations of mesna exceed those of dimesna after oral or intravenous administration. Excretion Following intravenous administration of a single 800 mg dose, approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. Mean plasma elimination half-lives of mesna and dimesna are 0.36 hours and 1.17 hours, respectively. Mesna has a plasma clearance of 1.23 L/h/kg.

20180724

5

3 DOSAGE FORMS AND STRENGTHS • MESNEX injection: 1 g Multidose Vial, 100 mg/mL • MESNEX tablets: 400 mg film-coated tablets with functional score ---------------------DOSAGE FORMS AND STRENGTHS---------------------- • Injection: 1g (100 mg/mL) Multidose vials (3) • Tablets: 400 mg with functional score (3)

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

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate the carcinogenic potential of mesna. Mesna was not genotoxic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte chromosomal aberration assay or the in vivo mouse micronucleus assay. No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity were seen in 6-month oral rat studies (≤ 2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day) at doses approximately 10-fold higher than the maximum recommended human dose on a body surface area basis.

NDA019884

MESNEX

MESNA

0338-1307

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Container Label 1 Multidose Vial NDC 0338-1307-10 MESNEX (mesna) Injection 1 g /vial Rx only FOR INTRAVENOUS USE NOVAPLUS Logo N+ and NOVAPLUS are registered trademarks of Vizient, Inc. Each vial contains 1 gram of mesna in 10 mL water. 1% benzyl alcohol is added as a preservative. See insert for dosing information. Store at 20°C-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Baxter Healthcare Corporation Deerfield, IL 60015 USA USA HA-65-01-567 C 785 Barcode (01)10303381307100 Lot Number / Expires: Carton Label MESNEX (mesna) Injection 1g /vial Schwarz P 286 C P152 C 1 Multidose Vial NDC 0338-1307-05 MESNEX (mesna) Injection 1g /vial Rx only Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA NovaPlus Logo N+ and NOVAPLUS are registered trademarks of Vizient, Inc. FOR INTRAVENOUS USE 1 Multidose Vial HA-80-02-157 USA Fragile: Handle with care. Store at 20° – 25°C (68° – 77°F), excursions permitted to 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature]. Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA C 103 1 Multidose Vial NDC 0338-1307-05 MESNEX (mesna) Injection 1g /vial FOR INTRAVENOUS USE Rx Only Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA LotT/Exp.: 2639B3996 Bar code Folding Box Can Be Recycled Logo Each vial contains 1 g mesna in 10 mL water. Mesnex is a sterile and nonpyrogenic solution containing 10% sodium-2-mercaptoethane sulfonate (mesna) in water for injection with 0.025% edetate disodium and sodium hydroxide to adjust pH to 7.5 to 8.5. 1% benzyl alcohol is added as a preservative. Dosage: See package insert for directions for use. Should not be prescribed without thorough knowledge of dose, indications and toxicology as contained in accompanying literature. Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in Germany Representative Mesnex NovaPlus container label NDC 0338-1307-10 Representative Mesnex NovaPlus carton label NDC 0338-1307-05

17 PATIENT COUNSELING INFORMATION • Advise the patient to discontinue MESNEX and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction, including systemic anaphylactic reactions occur [ see Warnings and Precautions (5.1) ]. • Advise the patient to take MESNEX at the exact time and in the exact amount as prescribed. Advise the patient to contact their healthcare provider if they vomit within 2 hours of taking oral MESNEX, or if they miss a dose of oral MESNEX [ see Dosage and Administration (2.2) ]. • MESNEX does not prevent hemorrhagic cystitis in all patients nor does it prevent or alleviate any of the other adverse reactions or toxicities associated with ifosfamide. Advise the patient to report to their healthcare provider if his/her urine has turned a pink or red color [ see Dosage and Administration (2.3) ]. • Advise the patient to drink 1 to 2 liters of fluid each day during MESNEX therapy [ see Dosage and Administration (2.3) ]. • Advise the patient that Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions have occurred with MESNEX. Advise the patient to report to their healthcare provider if signs and symptoms of these syndromes occur [ see Warnings and Precautions (5.2) ]. MESNEX (mesna) injection manufactured by: MESNEX (mesna) tablets manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1800 ANA DRUG (1-800-262-3784) Made in Germany NOVAPLUS is a registered trademark of Vizient, Inc. Baxter, Mesnex, and Ifex are trademarks of Baxter International Inc. HA-30-01-554 Revised May 2016 NovaPlus Logo

14 CLINICAL STUDIES 14.1 Intravenous MESNEX 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 MESNEX was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%. Table 4. Percent of MESNEX Patients Developing Hematuria (≥50 RBC/hpf or macrohematuria) Study Conventional Uroprophylaxis (number of patients) Standard MESNEX 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 MESNEX Clinical studies comparing recommended intravenous and oral MESNEX dosing regimens demonstrated incidences of grade 3 to 4 hematuria of <5%. Study 7 was an open label, randomized, two-way crossover study comparing three intravenous doses with an initial intravenous dose followed by two oral doses of MESNEX in patients with cancer treated with ifosfamide at a dose of 1.2 g/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. Percent of MESNEX Patients Developing Grade 3 or 4 Hematuria MESNEX Dosing Regimen Study Standard Intravenous Regimen (number of patients) Intravenous + Oral Regimen (number of patients) Study 7 0% (0/30) 3.6% (1/28) Study 8 3.7% (1/27) 4.3% (1/23)

8.5 Geriatric Use Clinical studies of MESNEX 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 MESNEX should remain unchanged.

8.3 Nursing Mothers It is not known whether mesna or dimesna is excreted in human milk. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from MESNEX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Safety and effectiveness of MESNEX in pediatric patients have not been established. MESNEX contains benzyl alcohol (10.4 mg benzyl alcohol per mL) which has been associated with serious adverse reactions and death in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis and gasping respirations) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates, premature, and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Neonates, premature, and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources [ see Warnings and Precautions (5.3) ] .

8.1 Pregnancy Pregnancy Category B Risk Summary There are no studies of MESNEX in pregnant women. Reproduction studies performed in rats and rabbits at oral doses approximately 10 times the maximum recommended total daily intravenous-oral-oral human dose on a body surface area basis (1000 mg/kg in rabbits and 2000 mg/kg in rats) revealed no evidence of harm to the fetus due to mesna. The incidence of malformations in human pregnancies has not been established for MESNEX. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations and 15 to 20% for pregnancy loss. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Use only if clearly needed. (8.1) • Nursing mothers: Women should not breastfeed during therapy. (8.3) • Geriatric use: Dose selection should be cautious. (8.5) 8.1 Pregnancy Pregnancy Category B Risk Summary There are no studies of MESNEX in pregnant women. Reproduction studies performed in rats and rabbits at oral doses approximately 10 times the maximum recommended total daily intravenous-oral-oral human dose on a body surface area basis (1000 mg/kg in rabbits and 2000 mg/kg in rats) revealed no evidence of harm to the fetus due to mesna. The incidence of malformations in human pregnancies has not been established for MESNEX. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations and 15 to 20% for pregnancy loss. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether mesna or dimesna is excreted in human milk. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from MESNEX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of MESNEX in pediatric patients have not been established. MESNEX contains benzyl alcohol (10.4 mg benzyl alcohol per mL) which has been associated with serious adverse reactions and death in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis and gasping respirations) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates, premature, and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Neonates, premature, and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources [ see Warnings and Precautions (5.3) ] . 8.5 Geriatric Use Clinical studies of MESNEX 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 MESNEX 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 MESNEX. 8.7 Use in Patients with Hepatic Impairment No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of MESNEX.

16 HOW SUPPLIED/STORAGE AND HANDLING MESNEX (mesna) injection 100 mg/mL • NDC 0338-1307-05 1 g Multidose Vial, Box of 1 vial of 10 mL Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].