NONCLINICAL TOXICOLOGY SECTION.

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 vitroAmes bacterial mutagenicity assay, the in vitromammalian lymphocyte chromosomal aberration assay or the in vivomouse 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 body surface area basis.

LACTATION SECTION.

8.2 Lactation. Risk SummaryMESNEX 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.MESNEX injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by 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 breastfed child, advise lactating women not to breastfeed during treatment and for week after the last dose of MESNEX or ifosfamide.

ADVERSE REACTIONS SECTION.

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 History of Adverse Reactions to Thiol Compounds [see Warnings and Precautions (5.5)] 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 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 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 studies in which single intravenous doses of 600-1200 mg MESNEX injection without concurrent chemotherapy were administered to total of 53 healthy volunteers and single oral doses of 600-2400 mg of MESNEX tablets were administered to 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 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 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 RegimensMESNEX RegimenIntravenous-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 exposed119 (100.0%)119 (100%)Incidence of AEs101 (84.9%)106 (89.1%)Nausea65 (54.6)64 (53.8)Vomiting35 (29.4)45 (37.8)Constipation28 (23.5)21 (17.6)Leukopenia25 (21.0)21 (17.6)Fatigue24 (20.2)24 (20.2)Fever24 (20.2)18 (15.1)Anorexia21 (17.6)19 (16.0)Thrombocytopenia21 (17.6)16 (13.4)Anemia20 (16.8)21 (17.6)Granulocytopenia16 (13.4)15 (12.6)Asthenia15 (12.6)21 (17.6)Abdominal Pain14 (11.8)18 (15.1)Alopecia12 (10.1)13 (10.9)Dyspnea11 (9.2)11 (9.2)Chest Pain10 (8.4)11 (9.2)Hypokalemia10 (8.4)11 (9.2)Diarrhea9 (7.6)17 (14.3)Dizziness9 (7.6)5 (4.2)Headache9 (7.6)13 (10.9)Pain9 (7.6)10 (8.4)Sweating Increased9 (7.6)2 (1.7)Back Pain8 (6.7)6 (5.0)Hematuria8 (6.7)7 (5.9)Injection Site Reaction8 (6.7)10 (8.4)Edema8 (6.7)9 (7.6)Edema Peripheral8 (6.7)8 (6.7)Somnolence8 (6.7)12 (10.1)Anxiety7 (5.9)4 (3.4)Confusion7 (5.9)6 (5.0)Face Edema6 (5.0)5 (4.2)Insomnia6 (5.0)11 (9.2)Coughing5 (4.2)10 (8.4)Dyspepsia4 (3.4)6 (5.0)Hypotension4 (3.4)6 (5.0)Pallor4 (3.4)6 (5.0)Dehydration3 (2.5)7 (5.9)Pneumonia2 (1.7)8 (6.7)Tachycardia1 (0.8)7 (5.9)Flushing1 (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 population of unknown size, precise estimates of frequency cannot be made.Cardiovascular: HypertensionGastrointestinal: DysgeusiaHepatobiliary: HepatitisNervous System: ConvulsionRespiratory: Hemoptysis.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 vitroAmes bacterial mutagenicity assay, the in vitromammalian lymphocyte chromosomal aberration assay or the in vivomouse 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 body surface area basis.

CLINICAL PHARMACOLOGY SECTION.

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 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. AbsorptionFollowing oral administration, peak plasma concentrations were reached within 1.5 to hours and to 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 healthy volunteers who received 1200 mg oral or intravenous doses.Food does not affect the urinary availability of orally administered MESNEX.DistributionMean 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). MetabolismAnalogous 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.ExcretionFollowing intravenous administration of 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 plasma clearance of 1.23 L/h/kg.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Intravenous MESNEX. Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At dose of 1.2 g/m 2ifosfamide administered daily for 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 and 4). In two randomized studies, (Studies and 6), higher doses of ifosfamide, from g/m 2to g/m 2administered for to 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)StudyConventional Uroprophylaxis (number of patients)Standard MESNEX Intravenous Regimen (number of patients)Uncontrolled StudiesIfosfamide dose 1.2 g/m d 5 Study 116% (7/44)-Study 226% (11/43)-Study 318% (7/38)0% (0/21)Study 4-0% (0/32)Controlled StudiesIfosfamide dose g/m to g/m d 3 to Study 531% (14/46)6% (3/46)Study 6100% (7/7)0% (0/8). 14.2 Oral MESNEX. Clinical studies comparing recommended intravenous and oral MESNEX dosing regimens demonstrated incidences of grade to hematuria of <5%. Study 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 dose of 1.2 g/m 2to 2.0 g/m 2for to days. Study was randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m 2for days. In both studies, development of grade or 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 MESNEX Patients Developing Grade or HematuriaMESNEX Dosing RegimenStudyStandard Intravenous Regimen(number of patients)Intravenous Oral Regimen(number of patients)Study 70% (0/30)3.6% (1/28)Study 83.7% (1/27)4.3% (1/23).

CONTRAINDICATIONS SECTION.

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, including benzyl alcohol. 4) Known hypersensitivity to mesna or to any of the excipients, including benzyl alcohol. 4).

DESCRIPTION SECTION.

11 DESCRIPTION. MESNEX (mesna) is detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide. The active ingredient, mesna, is synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate with molecular formula of 2H 5NaO 3S 2and molecular weight of 164.18. Its structural formula is as follows: HS-CH 2-CH 2SO 3-Na MESNEX injection is 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 preservative. The solution has pH range of 7.5-8.5.MESNEX 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.

MECHANISM OF ACTION SECTION.

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 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. MESNEX may be given on fractionated dosing schedule of three bolus intravenous injections or 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 Hours4 Hours8 HoursIfosfamide1.2 g/m ----MESNEX injection240 mg/m 240 mg/m 240 mg/m Intravenous and Oral Dosing Schedule:0 Hours2 Hours6 HoursIfosfamide1.2 g/m ----MESNEX injection240 mg/m ----MESNEX tablets--480 mg/m 480 mg/m 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 fractionated dosing schedule of three bolus intravenous injections as outlined below.MESNEX injection is given as intravenous bolus injections in dosage equal to 20% of the ifosfamide dosage weight by weight (w/w) at the time of ifosfamide administration and and 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 Hours4 Hours8 HoursIfosfamide1.2 g/m --MESNEX injectionThe 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 240 mg/m 240 mg/m . 2.2 Intravenous and Oral Dosing. MESNEX may be given on fractionated dosing schedule of single bolus injection followed by two oral administrations of MESNEX tablets as outlined below.MESNEX injection is given as intravenous bolus injections in dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. MESNEX tablets are given orally in dosage equal to 40% of the ifosfamide dose and 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 Hours2 Hours6 HoursIfosfamide1.2 g/m --MESNEX injectionThe 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 --MESNEX tablets-480 mg/m 480 mg/m 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 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. PreparationDetermine 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 final concentration of 20 mg/mL:5% Dextrose Injection, USP5% Dextrose and 0.2% Sodium Chloride Injection, USP5% Dextrose and 0.33% Sodium Chloride Injection, USP5% Dextrose and 0.45% Sodium Chloride Injection, USP0.9% Sodium Chloride Injection, USPLactated Ringers Injection, USPStabilityThe MESNEX injection multidose vials may be stored and used for up to days after initial puncture.Store diluted solutions at 25C (77F). 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.. 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 Ringers Injection, USP.

DOSAGE FORMS & STRENGTHS SECTION.

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

DRUG INTERACTIONS SECTION.

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

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. MESNEX is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to pregnant woman. Refer to the ifosfamide prescribing information for more information on contraception and effects on fertility.Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiation of MESNEX in combination with ifosfamide.ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosfamide and for months after the last dose.MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosfamide and for months after the last dose.

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. MESNEX (mesna) injection 100 mg/mLNDC 0338-1305-01 g Multidose Vial, Box of vial of 10 mLNDC 0338-1305-03 g Multidose Vial, Box of 10 vials of 10 mLStore at 20C to 25C (68F to 77F), excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]If MESNEX is co-administered with ifosfamide, refer to the ifosfamide prescribing information for safe handling instructions.MESNEX (mesna) tabletsNDC 67108-3565-9 400 mg scored tablets packaged in box of 10 tabletsStore at 20C to 25C (68F to 77F), excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. NDC 0338-1305-01 g Multidose Vial, Box of vial of 10 mL. NDC 0338-1305-03 g Multidose Vial, Box of 10 vials of 10 mL. Store at 20C to 25C (68F to 77F), excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. NDC 67108-3565-9 400 mg scored tablets packaged in box of 10 tablets. Store at 20C to 25C (68F to 77F), excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. MESNEX is indicated as 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 cytoprotective agent indicated as 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information).HypersensitivityAdvise the patient to discontinue MESNEX and seek immediate medical attention if any signs or symptoms of hypersensitivity reaction, including systemic anaphylactic reactions occur [see Warnings and Precautions (5.1)]. Dosing InstructionsAdvise 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 hours of taking oral MESNEX, or if they miss dose of oral MESNEX [see Dosage and Administration (2.2)]. Hemorrhagic CystitisMESNEX 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 pink or red color [see Dosage and Administration (2.3)]. Advise the patient to drink to liters of fluid each day during MESNEX therapy [see Dosage and Administration (2.3)]. Dermatologic ToxicityAdvise 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) ]. Benzyl Alcohol ToxicityAdvise patients that serious adverse reactions are associated with the benzyl alcohol found in MESNEX 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 ToxicityMESNEX is used in combination with ifosfamide. Ifosfamide or other cytotoxic agents can cause fetal harm when administered to pregnant woman. Inform female patients of the risk to 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)]. ContraceptionAdvise females of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosamide and for 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 MESNEX in combination with ifosamide and for months after the last dose [see Use in Specific Populations (8.3)]. LactationAdvise lactating women not to breastfeed during treatment with MESNEX or ifosfamide and for week after the last dose [see Use in Specific Populations (8.2)]. Advise the patient to discontinue MESNEX and seek immediate medical attention if any signs or symptoms of 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 hours of taking oral MESNEX, or if they miss 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 pink or red color [see Dosage and Administration (2.3)]. Advise the patient to drink to 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) ]. Advise patients that serious adverse reactions are associated with the benzyl alcohol found in MESNEX and other medications in premature neonates and low-birth weight infants [see Warnings and Precautions (5.3)and Use in Specific Populations (8.4)]. MESNEX is used in combination with ifosfamide. Ifosfamide or other cytotoxic agents can cause fetal harm when administered to pregnant woman. Inform female patients of the risk to 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)]. Advise females of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosamide and for 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 MESNEX in combination with ifosamide and for months after the last dose [see Use in Specific Populations (8.3)]. Advise lactating women not to breastfeed during treatment with MESNEX or ifosfamide and for week after the last dose [see Use in Specific Populations (8.2)].

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no known antidote for MESNEX.In clinical trial, 11 patients received intravenous MESNEX 10 mg/kg to 66 mg/kg per day for to 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 to 6.9 of MESNEX resulted in hypersensitivity reactions including mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL. 1g Multidose Vial1 Multidose Vial NDC 0338-1305-01Mesnex (mesna) Injection FOR INTRAVENOUS USE1g/vial Rx onlyN (01) 03 0338 1305 01 4Lot Number Expires:JMXXXAJJJJ MMEach vial contains gram of mesna in 10 mL water. 1% benzyl alcohol is added as preservative. See insert for dosing information. Store at 20 25C (68 77F), excursions permitted to 15 30C (59 86F)[see USP Controlled Room Temperature] Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA USAHA-65-01-568 93 Multidose Vial NDC 0338-1305-01 MESNEX (mesna) Injection 1g/vialFOR INTRAVENOUS USERx onlyBaxterLogo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA (01) 00303381305017 (21) XXXXXXXXXXXX (17) JJMMTT (10) JMXXXA BarcodeMESNEX mesna Injection 1g/vialBarcodeHA-80-02-158 USA Fragile: Handle with care. Store at 20 25C (68-77F) excursions permitted to 15 30C (59 86F) [see USP Controlled Room Temperature]. BaxterLogo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA 203 Multidose Vial NDC 0338-1305-01 MESNEX (mesna) Injection 1g/vialFOR INTRAVENOUS USERx onlyBaxterLogo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA Lot/Exp: JMXXXA JJJJ MM 2639B3994BarcodeFolding Box Logo Can Be Recycled Each vial contains g mesna in 10 mL water, Mesnex is sterile and nonpyrogenic solution containing 10% sodium-2-mercaptoehane 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 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 GermanySchwarzP 186 C10 Multidose Vials NDC 0338-1305-031gMESNEX(mesna) InjectionBaxterLogo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA 10 Multidose Vials NDC 0338-1305-031gN3 0338130503 1MESNEX (mesna) Injection Each vial contains g mesna in 10mL water. Mesnex is sterile and nonpyrogenic solution containing 10% sodium-2-mercaptoehane 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 preservative. Fragile:Handle with care. Store at 20 25C (68-77F) see excursions permitted to 15 30C (59 86F) [see USP Controlled Room Temperature] U.S. Patent No 5,696, 172 FOR INTRAVENOUS USEDosage: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 GermanyRx onlyHA-80-01-627 USA 10 Multidose Vials NDC 0338-1305-031gMESNEX (mesna) Injection FOR INTRAVENOUS USE10 Multidose VialsC 53 10 Multidose Vials NDC 0338-1305-031g2639B3913Lot: Exp.: MESNEX (mesna) Injection Each vial contains g mesna in 10mL water. Mesnex is sterile and nonpyrogenic solution containing 10% sodium-2-mercaptoehane 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 preservative. Fragile:Handle with care. Store at 20 25C (68-77F) see excursions permitted to 15 30C (59 86F) [see USP Controlled Room Temperature] U.S. Patent No 5,696, 172 FOR INTRAVENOUS USEDosage: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 GermanyRx onlyFolding Box Logo Can Be Recycled 10 Multidose Vials NDC 0338-1305-031gMESNEX (mesna) Injection FOR INTRAVENOUS USE10 Multidose Vials. Representative vial label 1g 0338-1305-01. Representative carton label 1g 0338-1305-01 of 4. Representative carton label 1g 0338-1305-01 of 4. Representative carton label 1g 0338-1305-01 of 4. Representative carton label 1g 0338-1305-01 of 4. Representative Box Label 1g panel of 4. Representative Box Label 1g panel of 4. Representative Box Label 1g panel of 4. Representative Box Label 1g panel of 4.

PATIENT MEDICATION INFORMATION SECTION.

Patient Information MESNEX (MES-nex) (mesna) tablets MESNEX (MES-nex) (mesna) injection What is the most important information should know about MESNEXMESNEX can cause serious allergic reactions and skin reactions.These serious reactions can happen the first time you are treated with MESNEX or after several months of treatment with MESNEX. Stop treatment with MESNEX and go to the nearest hospital emergency room right away if you develop any of the symptoms listed below: feverswelling of your face, lips, mouth, or tonguetrouble breathing or wheezingitchingburningskin rash or hivesskin redness or swellingskin blisters or peelingfeel lightheaded or faintfeel like your heart is racingnauseavomitingjoint or muscle achesmouth soresSee What are the possible side effects of MESNEX for more information about side effects. What is MESNEXMESNEX is prescription medicine used to reduce the risk of inflammation and bleeding of the bladder (hemorrhagic cystitis) in people who receive ifosfamide (a medicine used to treat cancer).MESNEX is not for use to reduce the risk of blood in the urine (hematuria) due to other medical conditions.Do not take MESNEX tablets or receive MESNEX by intravenous (IV) infusion ifyou are allergic to mesna or any of the ingredients in MESNEX. See the end of this leaflet for complete list of ingredients in MESNEX. Before you take or receive MESNEX, tell your healthcare provider about all of your medical conditions, including if you:are allergic to any medicinesare pregnant or plan to become pregnant.Females who are able to become pregnant:Your healthcare provider will verify if you are pregnant or not before you start treatment with MESNEX and ifosfamide. You should use effective birth control (contraception) during treatment with MESNEX and ifosfamide and for months after the last dose.Tell your healthcare provider if you become pregnant during treatment with MESNEX and ifosfamide. Maleswith female partners who are able to become pregnant should use effective birth control during treatment with MESNEX and ifosfamide and for months after the last dose. You should also read the ifosfamide Prescribing Information for important pregnancy, contraception, and infertility information.are breastfeeding or plan to breastfeed. It is not known if MESNEX passes into your breast milk. Do not breastfeed during treatment and for week after the last dose of MESNEX or ifosfamide.Tell your healthcare provider about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will receive MESNEXMESNEX is given on the same day that you receive ifosfamide.MESNEX can be given by an intravenous (IV) infusion into vein or tablets taken by mouth.You will receive MESNEX in one of two ways:MESNEX intravenous (IV) infusion into vein at the time you receive ifosfamide and and hours after you receive ifosfamide, OR MESNEX intravenous (IV) infusion into vein at the time you receive ifosfamide and MESNEX tablets taken by mouth and hours after you receive ifosfamide.Take MESNEX tablets at the exact times and the exact dose your healthcare provider tells you to take it.During treatment with MESNEX intravenous (IV) infusion or MESNEX tablets, you should drink to cups of liquid (1 to liters) each day.Tell your healthcare provider if you:vomit within hours of taking MESNEX tablets by mouthmiss dose of MESNEX tabletshave pink or red colored urineWhat are the possible side effects of MESNEXMESNEX may cause serious side effects, including:See What is the most important information should know about MESNEX MESNEX that is given by intravenous (IV) infusion contains the preservative benzyl alcohol.Benzyl alcohol has been shown to cause serious side effects and death in premature newborns and low-birth weight babies. Avoid use of MESNEX injection in premature newborns and low birth weight infants. MESNEX tablets do not contain benzyl alcohol. The most common side effects of MESNEX when given with ifosfamide include:nauseavomitingconstipationdecreased white blood cell counttirednessfeverdecreased appetitedecreased platelet countdecreased red blood cell countdiarrheaweaknessstomach (abdomen) painheadachehair losssleepinessThese are not all the possible side effects of MESNEX.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store MESNEX tabletsStore MESNEX tablets at room temperature between 68F to 77F (20C to 25C).Keep MESNEX and all medicines out of the reach of children.General information about the safe and effective use of MESNEX.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use MESNEX for condition for which it was not prescribed. Do not give MESNEX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about MESNEX that is written for health professionals.What are the ingredients in MESNEXActive ingredient:mesna Inactive ingredients:MESNEX injection:edetate disodium, sodium hydroxide, and benzyl alcohol as preservative. MESNEX tablets:calcium phosphate, cornstarch, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, and titanium dioxide. Manufactured by: Baxter Healthcare Corporation, Deerfield, IL 60015 USA Made in Germany Baxter and Mesnex are registered trademarks of Baxter International Inc. For more information, call 1-800-262-3784. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 12 2018. fever. swelling of your face, lips, mouth, or tongue. trouble breathing or wheezing. itching. burning. skin rash or hives. skin redness or swelling. skin blisters or peeling. feel lightheaded or faint. feel like your heart is racing. nausea. vomiting. joint or muscle aches. mouth sores. See What are the possible side effects of MESNEX for more information about side effects. are allergic to any medicines. are pregnant or plan to become pregnant.. Females who are able to become pregnant:. Your healthcare provider will verify if you are pregnant or not before you start treatment with MESNEX and ifosfamide. You should use effective birth control (contraception) during treatment with MESNEX and ifosfamide and for months after the last dose.Tell your healthcare provider if you become pregnant during treatment with MESNEX and ifosfamide. You should use effective birth control (contraception) during treatment with MESNEX and ifosfamide and for months after the last dose.. Tell your healthcare provider if you become pregnant during treatment with MESNEX and ifosfamide.. Maleswith female partners who are able to become pregnant should use effective birth control during treatment with MESNEX and ifosfamide and for months after the last dose. You should also read the ifosfamide Prescribing Information for important pregnancy, contraception, and infertility information.. are breastfeeding or plan to breastfeed. It is not known if MESNEX passes into your breast milk. Do not breastfeed during treatment and for week after the last dose of MESNEX or ifosfamide.. MESNEX is given on the same day that you receive ifosfamide.. MESNEX can be given by an intravenous (IV) infusion into vein or tablets taken by mouth.. You will receive MESNEX in one of two ways:. MESNEX intravenous (IV) infusion into vein at the time you receive ifosfamide and and hours after you receive ifosfamide, OR MESNEX intravenous (IV) infusion into vein at the time you receive ifosfamide and MESNEX tablets taken by mouth and hours after you receive ifosfamide.. Take MESNEX tablets at the exact times and the exact dose your healthcare provider tells you to take it.. During treatment with MESNEX intravenous (IV) infusion or MESNEX tablets, you should drink to cups of liquid (1 to liters) each day.. Tell your healthcare provider if you:. vomit within hours of taking MESNEX tablets by mouth. miss dose of MESNEX tablets. have pink or red colored urine. MESNEX that is given by intravenous (IV) infusion contains the preservative benzyl alcohol.Benzyl alcohol has been shown to cause serious side effects and death in premature newborns and low-birth weight babies. Avoid use of MESNEX injection in premature newborns and low birth weight infants. MESNEX tablets do not contain benzyl alcohol. nausea. vomiting. constipation. decreased white blood cell count. tiredness. fever. decreased appetite. decreased platelet count. decreased red blood cell count. diarrhea. weakness. stomach (abdomen) pain. headache. hair loss. sleepiness. Store MESNEX tablets at room temperature between 68F to 77F (20C to 25C).

PEDIATRIC USE SECTION.

8.4 Pediatric Use. MESNEX 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 MESNEX injection in premature neonates and low-birth weight infants [see Warnings and Precautions (5.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing oral administration, peak plasma concentrations were reached within 1.5 to hours and to 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 healthy volunteers who received 1200 mg oral or intravenous doses.Food does not affect the urinary availability of orally administered MESNEX.DistributionMean 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). MetabolismAnalogous 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.ExcretionFollowing intravenous administration of 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 plasma clearance of 1.23 L/h/kg.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryMESNEX is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to 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 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 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.DataAnimal DataMESNEX 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.

RECENT MAJOR CHANGES SECTION.

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

SPL UNCLASSIFIED SECTION.

2.1 Intravenous Dosing. MESNEX may be given on fractionated dosing schedule of three bolus intravenous injections as outlined below.MESNEX injection is given as intravenous bolus injections in dosage equal to 20% of the ifosfamide dosage weight by weight (w/w) at the time of ifosfamide administration and and 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 Hours4 Hours8 HoursIfosfamide1.2 g/m --MESNEX injectionThe 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 240 mg/m 240 mg/m.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: MESNEX in combination with ifosfamide can cause fetal harm. Advise patients of potential risk to 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 MESNEX 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) Pregnancy: MESNEX in combination with ifosfamide can cause fetal harm. Advise patients of potential risk to 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 MESNEX 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 SummaryMESNEX is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to 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 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 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.DataAnimal DataMESNEX 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.. 8.2 Lactation. Risk SummaryMESNEX 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.MESNEX injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by 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 breastfed child, advise lactating women not to breastfeed during treatment and for week after the last dose of MESNEX or ifosfamide.. 8.3 Females and Males of Reproductive Potential. MESNEX is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to pregnant woman. Refer to the ifosfamide prescribing information for more information on contraception and effects on fertility.Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiation of MESNEX in combination with ifosfamide.ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosfamide and for months after the last dose.MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosfamide and for months after the last dose.. 8.4 Pediatric Use. MESNEX 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 MESNEX injection in premature neonates and low-birth weight infants [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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity reactions: Anaphylactic reactions have been reported. Less severe hypersensitivity reactions may also occur. Monitor patients. If 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 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) Hypersensitivity reactions: Anaphylactic reactions have been reported. Less severe hypersensitivity reactions may also occur. Monitor patients. If 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 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 BodiesA 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 false positive result (cherry-red color that fades) and true positive result (red-violet color that intensifies).False-Negative Tests for Enzymatic CPK ActivityMESNEX may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use thiol compound (e.g., N-acetylcysteine) for CPK reactiviation. This may result in falsely low CPK level.False-Positive Tests for Ascorbic AcidMESNEX may cause false-positive reactions in Tillmans reagent-based urine screening tests for ascorbic acid.. 5.5 Use in Patients with History of Adverse Reactions to Thiol Compounds. MESNEX is thiol compound, i.e., 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 thiol compound are at increased risk for hypersensitivity reaction to MESNEX.