MESNEX

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 )

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. 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. 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.

4 CONTRAINDICATIONS MESNEX 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 MESNEX, including benzyl alcohol. ( 4 )

5 WARNINGS AND PRECAUTIONS • Hypersensitivity reactions: Anaphylactic reactions have been reported. Less severe hypersensitivity reactions may also occur. Monitor patients. If a reaction occurs, discontinue MESNEX 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 a reaction occurs, discontinue MESNEX 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 MESNEX 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 MESNEX 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 MESNEX 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. MESNEX 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 MESNEX 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. MESNEX injection contains 10.4 mg/mL of the preservative benzyl alcohol. Avoid use of MESNEX injection in premature neonates and low-birth weight infants. MESNEX tablets do not contain benzyl alcohol [see Use in Specific Populations (8.4) ]. 5.4 Laboratory Test Interferences False-Positive Urine Tests for Ketone Bodies A false positive test for urinary ketones may arise in patients treated with MESNEX when using nitroprusside sodium-based urine tests (including dipstick tests). The addition of glacial acetic acid can be used to differentiate between a false positive result (cherry-red color that fades) and a true positive result (red-violet color that intensifies). False-Negative Tests for Enzymatic CPK Activity MESNEX may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use a thiol compound (e.g., N-acetylcysteine) for CPK reactiviation. This may result in a falsely low CPK level. False-Positive Tests for Ascorbic Acid MESNEX may cause false-positive reactions in Tillman’s reagent-based urine screening tests for ascorbic acid. 5.5 Use in Patients with a History of Adverse Reactions to Thiol Compounds MESNEX is a thiol compound, i.e., a 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 a thiol compound are at increased risk for a hypersensitivity reaction to MESNEX.

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

8.1 Pregnancy Risk Summary MESNEX 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. MESNEX 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 2-4% and 15-20%, respectively. Data Animal Data MESNEX 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.