Mesna Injection

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)

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 . T able 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 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 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 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.

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 injection 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 Gland Pharma at 864-879-9994 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 injection adverse reaction data are available from four Phase 1 studies in which single intravenous doses of 600 to 1200 mg mesna injection without concurrent chemotherapy were administered to a total of 53 healthy volunteers and single oral doses of 600 to 2400 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 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 injection 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 I ntravenous-Intravenous-Intravenous 1 I ntravenous-Oral-Oral 1 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) 1 Intravenous 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)] . 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

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 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.