INDICATIONS & USAGE SECTION.

1 INDICATIONS USAGE. Mesna Injection is indicated as 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 cytoprotective agent indicated as 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information). Hypersensitivity Advise the patient to discontinue mesna 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 Instructions Advise the patient to take mesna 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 mesna, or if they miss dose of oral mesna [see Dosage and Administration (2.2)]. Hemorrhagic Cystitis Mesna 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 mesna therapy [see Dosage and Administration (2.3)]. Dermatologic Toxicity 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 mesna. 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 Toxicity Advise patients that serious adverse reactions are associated with the benzyl alcohol found in mesna 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 Toxicity Mesna 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)]. Contraception Advise females of reproductive potential to use effective contraception during treatment with mesna 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 mesna in combination with ifosamide and for months after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise lactating women not to breastfeed during treatment with mesna or ifosfamide and for week after the last dose [see Use in Specific Populations (8.2)]. Manufactured by: Gland Pharma Limited D.P.Pally, Dundigal Post Hyderabad -500043, India Revised: December 2019. Patient Information Mesna (MESS-nah) InjectionWhat is the most important information should know about mesna injectionMesna injection can cause serious allergic reactions and skin reactions. These serious reactions can happen the first time you are treated with mesna injection or after several months of treatment with mesna injection. Stop treatment with mesna injection and go to the nearest hospital emergency room right away if you develop any of the symptoms listed below:. 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 mesna injection for more information about side effects. What is mesna injection Mesna injection 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).Mesna injection is not for use to reduce the risk of blood in the urine (hematuria) due to other medical conditions. Do not receive mesna injection by intravenous (IV) infusion if you are allergic to mesna or any of the ingredients in mesna injection. See the end of this leaflet for complete list of ingredients in mesna injection. Before you receive mesna injection, tell your healthcare provider about all of your medical conditions, including if you: 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 mesna and ifosfamide. You should use effective birth control (contraception) during treatment with mesna and ifosfamide and for months after the last dose. Tell your healthcare provider if you become pregnant during treatment with mesna and ifosfamide. Males with female partners who are able to become pregnant should use effective birth control during treatment with mesna 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 mesna passes into your breast milk. Do not breastfeed during treatment and for week after the last dose of mesna 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 mesna injection Mesna is given on the same day that you receive ifosfamide. Mesna can be given by an intravenous (IV) infusion into vein or tablets taken by mouth. You will receive mesna in one of two ways: Mesna intravenous (IV) infusion into vein at the time you receive ifosfamide and and hours after you receive ifosfamide, OR Mesna intravenous (IV) infusion into vein at the time you receive ifosfamide and mesna tablets taken by mouth and hours after you receive ifosfamide. Take mesna tablets at the exact times and the exact dose your healthcare provider tells you to take it. During treatment with mesna intravenous (IV) infusion or mesna tablets, you should drink to cups of liquid (1 to liters) each day. Tell your healthcare provider if you: vomit within hours of taking mesna tablets by mouth miss dose of mesna tablets have pink or red colored urine What are the possible side effects of mesna injection Mesna injection may cause serious side effects, including: See What is the most important information should know about mesna injection Mesna injection 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 mesna injection in premature newborns and low birth weight infants. Mesna tablets do not contain benzyl alcohol. The most common side effects of mesna injection when given with ifosfamide include: 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 These are not all the possible side effects of mesna injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store mesna injection Store at 20 to 25C (68 to 77F). Keep mesna injection and all medicines out of the reach of children. General information about the safe and effective use of mesna injection. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use mesna injection for condition for which it was not prescribed. Do not give mesna injection 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 mesna injection that is written for health professionals. What are the ingredients in mesna injection Active ingredient: mesna Inactive ingredients: Mesna injection: edetate disodium, sodium hydroxide, and benzyl alcohol as preservative.This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured by: Gland Pharma Limited D.P.Pally, Dundigal Post Hyderabad -500043, India Revised: December 2019.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of mesna injection 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 mesna should remain unchanged.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Mesna Injection is supplied as follows:NDCMesna Injection (100 mg per mL)Package Factor68083-161-01 g/10 mL Multi-Dose Vial vial per carton 68083-161-10 g/10 mL Multi-Dose Vial 10 vials per carton Storage Conditions Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.] If mesna is co-administered with ifosfamide, refer to the ifosfamide prescribing information for safe handling instructions. Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex.

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)] 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 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 studies in which single intravenous doses of 600 to 1200 mg mesna injection without concurrent chemotherapy were administered to total of 53 healthy volunteers and single oral doses of 600 to 2400 mg of mesna 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 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 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 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.T able 3: Adv er se e ctions in >= 5% of ati ents eceiving Mesna in ombin ation with fo famid - cont aining Re gim ensMesna e gim en Int av enous Int ra enous Int av enous1 Int av enous -O ral -O ral1 e xpos ed 119 (100.0 %) 119 (100 %) n cid en ce of AEs 101 (84.9 %) 106 (89.1 %) aus ea 65 (54.6) 64 (53.8) Vomiting 35 (29.4) 45 (37.8) Constip ation 28 (23.5) 21 (17.6) euko enia 25 (21.0) 21 (17.6) Fat gue 24 (20.2) 24 (20.2) Fev er 24 (20.2) 18 (15.1) Ano re xia 21 (17.6) 19 (16.0) Th rombo yto enia 21 (17.6) 16 (13.4) An emia 20 (16.8) 21 (17.6) ranulo ytop enia 16 (13.4) 15 (12.6) Asth enia 15 (12.6) 21 (17.6) Abdomin al ain 14 (11.8) 18 (15.1) Alop ecia 12 (10.1) 13 (10.9) ysp ea 11 (9.2) 11 (9.2) Ch est ain 10 (8.4) 11 (9.2) ypo al emia 10 (8.4) 11 (9.2) Di arrh ea (7.6) 17 (14.3) Di zzin ess (7.6) (4.2) ead che (7.6) 13 (10.9) ain (7.6) 10 (8.4) Sw eating In r eas ed (7.6) (1.7) ack ain (6.7) (5.0) em atu ria (6.7) (5.9) Inj ction Site eaction (6.7) 10 (8.4) Ed ema (6.7) (7.6) Ed ema eriph r al (6.7) (6.7) Somnol en ce (6.7) 12 (10.1) An xi ty (5.9) (3.4) Con fusion (5.9) (5.0) Fa ce Ed ema (5.0) (4.2) Insomnia (5.0) 11 (9.2) Cou ghi ng (4.2) 10 (8.4) ys epsia (3.4) (5.0) ypot ension (3.4) (5.0) allor (3.4) (5.0) e yd ration (2.5) (5.9) Pn eumonia (1.7) (6.7) ac y ardia (0.8) (5.9) Flushing (0.8) (5.0) 1Intravenous 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 population of unknown size, precise estimates of frequency cannot be made.Cardiovascular: Hypertension Gastrointestinal: Dysgeusia Hepatobiliary: Hepatitis Nervous System: Convulsion Respiratory: 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 vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte chromosomal aberration assay or the in vivo mouse micronucleus assay.No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity were seen in 6-month oral rat studies (<=2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day) at doses approximately 10-fold higher than the maximum recommended human dose on 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. Absorption Following 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 mesna.Distribution Mean apparent volume of distribution (Vd) 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 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 Mesna Injection. Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At dose of 1.2 g/m2 ifosfamide 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/m2 to g/m2 administered for to days, produced hematuria in 31 to 100% of the patients. When mesna injection was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%. Table 4: Percent of Mesna Injection Patients Developing Hematuria(>=50 RBC/hpf or macrohematuria) Study Conventional Uroprophylaxis (number of patients) Standard Mesna Intravenous Regimen (number of patients) Uncontrolled Studies Study 116% (7/44) Study 226% (11/43) Study 318% (7/38) 0% (0/21) Study 4- 0% (0/32) Controlled Studies+Study 531% (14/46) 6% (3/46) Study 6100% (7/7) 0% (0/8) Ifosfamide dose 1.2 g/m2 x +Ifosfamide dose g/m2 to g/m2 x to 5. 14.2 Oral Mesna. Clinical studies comparing recommended intravenous and oral mesna 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 mesna in patients with cancer treated with ifosfamide at dose of 1.2 g/m2 to 2.0 g/m2 for to days. Study was randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m2 for 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 Mesna Patients Developing Grade or Hematuria Mesna Dosing RegimenStudyStandard Intravenous Regimen (number of patients)Intravenous Oral Regimen (number of patients)Study 0% (0/30) 3.6% (1/28) Study 3.7% (1/27) 4.3% (1/23).

CONTRAINDICATIONS SECTION.

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)]. o Known hypersensitivity to mesna or to any of the excipients in mesna injection, including benzyl alcohol. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Mesna injection 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 C2H5NaO3S2 and molecular weight of 164.18. Its structural formula is as follows:HS--CH2--CH2SO3--Na+ Mesna Injection is sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multi-dose 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 multi-dose vials also contain 10.4 mg/mL of benzyl alcohol as preservative. The solution has pH range of between 7.5 and 8.5.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE ADMINISTRATION. Mesna injection may be given on fractionated dosing schedule of three bolus intravenous injections or 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: Hours Hours Hours Ifosfamide 1.2 g/m2 - Mesna Injection 240 mg/m2 240 mg/m2 240 mg/m2 Intravenous and Oral Dosing Schedule: Hours Hours Hours Ifosfamide 1.2 g/m2 - Mesna Injection 240 mg/m2 - Mesna Tablets 480 mg/m2 480 mg/m2 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 fractionated dosing schedule of three bolus intravenous injections as outlined below.Mesna 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 mesna injection is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below in Table 1.Table 1. Recommended Intravenous Dosing Schedule Hours Hours Hours Ifosfamide 1.2 g/m2 - Mesna Injection1 240 mg/m2 240 mg/m2 240 mg/m2 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 fractionated dosing schedule of single bolus injection followed by two oral administrations of mesna tablets as outlined below. Mesna injection is given as intravenous bolus injections in dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. Mesna 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 mesna is 100% of the ifosfamide dose. The recommended dosing schedule is outlined in Table 2.Table 2. Recommended Intravenous and Oral Dosing Schedule Hours Hours Hours Ifosfamide 1.2 g/m2 - Mesna Injection1 240 mg/m2 - Mesna Tablets 480 mg/m2 480 mg/m2 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 g/m2. 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 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 Ringers Injection, USPStability The mesna 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 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS STRENGTHS. Mesna Injection: 10 mL Multi-Dose Vial, g/10 mL (100 mg/mL). Mesna Injection: g (100 mg/mL) Multi-Dose vials. (3).

DRUG INTERACTIONS SECTION.

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

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

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 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 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 months after the last dose.

LACTATION SECTION.

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 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 mesna or ifosfamide.

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.

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 vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte chromosomal aberration assay or the in vivo mouse micronucleus assay.No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity were seen in 6-month oral rat studies (<=2000 mg/kg/day) or 29-week oral dog studies (520 mg/kg/day) at doses approximately 10-fold higher than the maximum recommended human dose on body surface area basis.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no known antidote for mesna injection.In clinical trial, 11 patients received intravenous mesna injection 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 mesna injection per kg per day intravenously compared with patients receiving lower doses or hydration treatment only.Postmarketing, administration of 4.5 to 6.9 of mesna 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. Mesna Injection 1g/10 mL(100 mg/mL) For Intravenous Use Vial label Mesna Injection 1g/10 mL(100 mg/mL) For Intravenous Use Mono Carton label-one multi dose vial Mesna Injection g/10 mL(100 mg/mL) For Intravenous Use Outer Carton label-ten multi dose vials. image01. image02. image03.

PEDIATRIC USE SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption Following 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 mesna.Distribution Mean apparent volume of distribution (Vd) 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 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 Summary Mesna injection 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. Mesna 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 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, 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. Mesna injection may be given on fractionated dosing schedule of three bolus intravenous injections as outlined below.Mesna 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 mesna injection is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below in Table 1.Table 1. Recommended Intravenous Dosing Schedule Hours Hours Hours Ifosfamide 1.2 g/m2 - Mesna Injection1 240 mg/m2 240 mg/m2 240 mg/m2 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Mesna injection 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 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 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 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 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, 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 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 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 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 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 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 months after the last dose.. 8.4 Pediatric Use. Mesna 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 mesna injection in premature neonates and low-birth weight infants [see Warnings and Precautions (5.3)]. 8.5 Geriatric Use. Clinical studies of mesna injection 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 mesna 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 mesna injection.. 8.7 Use in Patients with Hepatic Impairment. No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of mesna injection.

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 mesna injection 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 mesna injection 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 mesna 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. Mesna 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 mesna 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. Mesna 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 mesna 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. Mesna injection contains 10.4 mg/mL of the preservative benzyl alcohol. Avoid use of mesna injection in premature neonates and low-birth weight infants [see Use in Specific Populations (8.4)]. 5.4 Laboratory Test Interferences. False-Positive Urine Tests for Ketone Bodies false positive test for urinary ketones may arise in patients treated with mesna injection 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 Activity Mesna may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use thiol compound (e.g., N-acetylcysteine) for CPK reactivation. This may result in falsely low CPK level.False-Positive Tests for Ascorbic Acid Mesna 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. Mesna 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 mesna.