MESNA

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

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 . 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 withi …

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

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 )

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 Eugia US LLC at 1-866-850-2876, 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 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 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 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 MESNEX tablets alone or intravenous mesna 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 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 Intravenous-Intravenous-Intravenous 1 Intravenous-Oral-Oral 1 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) ]. 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. …

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

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 Mes …

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.

11 DESCRIPTION Mesna 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 multidose 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 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.

10. OVERDOSAGE There is no known antidote for mesna injection. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Mesna injection 100 mg/mL • NDC 10019-953-01 1 g Multidose Vial, Box of 1 vial of 10 mL • NDC 10019-953-02 1 g Multidose Vial, Box of 10 vials 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]. If mesna is co-administered with ifosfamide, refer to the ifosfamide prescribing information for safe handling instructions. MESNEX (mesna) tablets • NDC 67108-3565-9 400 mg scored tablets packaged in box of 10 tablets 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].