Label: MESNEX- mesna injection, solution

  • NDC Code(s): 0338-1305-01, 0338-1305-03
  • Packager: Baxter Healthcare Corporation
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated December 17, 2018

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use MESNEX safely and effectively. See full prescribing information for MESNEX.

    MESNEX (mesna) tablets, for oral use
    MESNEX (mesna) injection, for intravenous use
    Initial U.S. Approval: 1988

    RECENT MAJOR CHANGES

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

    INDICATIONS AND USAGE

    MESNEX is a cytoprotective agent indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis. (1)

    Limitation of Use:

    MESNEX is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia. (1)

    DOSAGE AND ADMINISTRATION

    MESNEX may be given on a fractionated dosing schedule of three bolus intravenous injections or a single bolus injection followed by two oral administrations of MESNEX tablets as outlined below. The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is adjusted, the ratio of MESNEX to ifosfamide should be maintained. (2)

    Intravenous Dosing Schedule:

    0 Hours

    4 Hours

    8 Hours

    Ifosfamide

    1.2 g/m2

    --

    --

    MESNEX injection

    240 mg/m2

    240 mg/m2

    240 mg/m2

    Intravenous and Oral Dosing Schedule:

    0 Hours

    2 Hours

    6 Hours

    Ifosfamide

    1.2 g/m2

    --

    --

    MESNEX injection

    240 mg/m2

    --

    --

    MESNEX 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)

    DOSAGE FORMS AND STRENGTHS

    Injection: 1g (100 mg/mL) Multidose vials (3)
    Tablets: 400 mg with functional score (3)

    CONTRAINDICATIONS

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

    WARNINGS AND PRECAUTIONS

    Hypersensitivity reactions: Anaphylactic reactions have been reported. Less severe hypersensitivity reactions may also occur. Monitor patients. If a reaction occurs, discontinue MESNEX and provide supportive care. (5.1)
    Dermatologic toxicity: Skin rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Skin rash, urticaria, and angioedema have also been seen. Monitor patients. If a reaction occurs, discontinue MESNEX and provide supportive care. (5.2)
    Benzyl alcohol toxicity: Serious and fatal adverse reactions can occur in premature neonates and low-birth weight infants treated with benzyl alcohol-preserved drugs, including MESNEX injection. Avoid use in premature neonates and low-birth weight infants. (5.3)
    Laboratory test alterations: False positive tests for urinary ketones and interference with enzymatic CPK activity tests have been seen. (5.4)

    ADVERSE REACTIONS

    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

    USE IN SPECIFIC POPULATIONS

    Pregnancy: MESNEX in combination with ifosfamide can cause fetal harm. Advise patients of potential risk to a fetus. (8.1)
    Lactation: Do not breastfeed. (8.2)
    Females and Males of Reproductive Potential: Advise patients to use effective contraception. Verify pregnancy status prior to initiation of 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)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 12/2018

  • Table of Contents
  • 1 INDICATIONS AND USAGE

    MESNEX is indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.

    Limitation of Use:
    MESNEX is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Intravenous Dosing

    MESNEX may be given on a fractionated dosing schedule of three bolus intravenous injections as outlined below.

    MESNEX injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage weight by weight (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide. The total daily dose of MESNEX is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below in Table 1.

    Table 1. Recommended Intravenous Dosing Schedule
    *
    The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or decreased, the ratio of MESNEX to ifosfamide should be maintained.

     

    0 Hours

    4 Hours

    8 Hours

    Ifosfamide

    1.2 g/m2

    MESNEX injection*

    240 mg/m2

    240 mg/m2

    240 mg/m2

    2.2 Intravenous and Oral Dosing

    MESNEX may be given on a fractionated dosing schedule of a single bolus injection followed by two oral administrations of MESNEX tablets as outlined below.

    MESNEX injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. MESNEX tablets are given orally in a dosage equal to 40% of the ifosfamide dose 2 and 6 hours after each dose of ifosfamide. The total daily dose of MESNEX is 100% of the ifosfamide dose. The recommended dosing schedule is outlined in Table 2.

    Table 2. Recommended Intravenous and Oral Dosing Schedule
    *
    The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or decreased, the ratio of MESNEX to ifosfamide should be maintained.

     

    0 Hours

    2 Hours

    6 Hours

    Ifosfamide

    1.2 g/m2

    MESNEX injection*

    240 mg/m2

    MESNEX tablets

    480 mg/m2

    480 mg/m2

    The efficacy and safety of this ratio of intravenous and oral MESNEX has not been established as being effective for daily doses of ifosfamide higher than 2 g/m2.

    Patients who vomit within two hours of taking oral MESNEX should repeat the dose or receive intravenous MESNEX.

    2.3 Monitoring for Hematuria

    Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. If severe hematuria develops when MESNEX is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.

    2.4 Preparation for Intravenous Administration and Stability

    Preparation

    Determine the volume of MESNEX injection for the intended dose.

    Dilute the volume of MESNEX injection for the dose in any of the following fluids to obtain a final concentration of 20 mg/mL:

    5% Dextrose Injection, USP
    5% Dextrose and 0.2% Sodium Chloride Injection, USP
    5% Dextrose and 0.33% Sodium Chloride Injection, USP
    5% Dextrose and 0.45% Sodium Chloride Injection, USP
    0.9% Sodium Chloride Injection, USP
    Lactated Ringer’s Injection, USP

    Stability

    The MESNEX injection multidose vials may be stored and used for up to 8 days after initial puncture.

    Store diluted solutions at 25°C (77°F). Use diluted solutions within 24 hours.

    Do not mix MESNEX injection with epirubicin, cyclophosphamide, cisplatin, carboplatin, and nitrogen mustard.

    The benzyl alcohol contained in MESNEX injection vials can reduce the stability of ifosfamide. Ifosfamide and MESNEX may be mixed in the same bag provided the final concentration of ifosfamide does not exceed 50 mg/mL. Higher concentrations of ifosfamide may not be compatible with MESNEX and may reduce the stability of ifosfamide.

    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any solutions which are discolored, hazy, or contain visible particulate matter should not be used.

  • 3 DOSAGE FORMS AND STRENGTHS

    MESNEX (mesna) injection: 1 g Multidose Vial, 100 mg/mL
    MESNEX (mesna) tablets: 400 mg film-coated tablets with functional score
  • 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)].

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hypersensitivity Reactions

    MESNEX may cause systemic hypersensitivity reactions, including anaphylaxis. These reactions may include fever, cardiovascular symptoms (hypotension, tachycardia), acute renal impairment, hypoxia, respiratory distress, urticaria, angioedema, laboratory signs of disseminated intravascular coagulation, hematological abnormalities, increased liver enzymes, nausea, vomiting, arthralgia, and myalgia. These reactions may occur with the first exposure or after several months of exposure. Monitor for signs or symptoms. Discontinue MESNEX and provide supportive care.

    5.2 Dermatologic Toxicity

    Drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions, consistent with Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. MESNEX may cause skin and mucosal reactions characterized by urticaria, rash, erythema, pruritus, burning sensation, angioedema, periorbital edema, flushing and stomatitis. These reactions may occur with the first exposure or after several months of exposure. Discontinue MESNEX and provide supportive care.

    5.3 Benzyl Alcohol Toxicity

    Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low-birth weight infants who received benzyl alcohol dosages of 99 to 234 mg/kg/day (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Symptoms associated with “gasping syndrome” and other potential adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Premature neonates and low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known. MESNEX injection contains 10.4 mg/mL of the preservative benzyl alcohol. Avoid use of MESNEX injection in premature neonates and low-birth weight infants. MESNEX tablets do not contain benzyl alcohol [see Use in Specific Populations (8.4)].

    5.4 Laboratory Test Interferences

    False-Positive Urine Tests for Ketone Bodies

    A false positive test for urinary ketones may arise in patients treated with MESNEX when using nitroprusside sodium-based urine tests (including dipstick tests). The addition of glacial acetic acid can be used to differentiate between a false positive result (cherry-red color that fades) and a true positive result (red-violet color that intensifies).

    False-Negative Tests for Enzymatic CPK Activity

    MESNEX may interfere with enzymatic creatinine phosphokinase (CPK) activity tests that use a thiol compound (e.g., N-acetylcysteine) for CPK reactiviation. This may result in a falsely low CPK level.

    False-Positive Tests for Ascorbic Acid

    MESNEX may cause false-positive reactions in Tillman’s reagent-based urine screening tests for ascorbic acid.

    5.5 Use in Patients with a History of Adverse Reactions to Thiol Compounds

    MESNEX is a thiol compound, i.e., a sulfhydryl (SH) group-containing organic compound. Hypersensitivity reactions to mesna and to amifostine, another thiol compound, have been reported. It is not clear whether patients who experienced an adverse reaction to a thiol compound are at increased risk for a hypersensitivity reaction to MESNEX.

  • 6 ADVERSE REACTIONS

    The following are discussed in more detail in other sections of the labeling.

    Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
    Dermatological Toxicity [see Warnings and Precautions (5.2)]
    Benzyl Alcohol Toxicity [see Warnings and Precautions (5.3)]
    Laboratory Test Interferences [see Warnings and Precautions (5.4)]
    Use in Patients with a History of Adverse Reactions to Thiol Compounds [see Warnings and Precautions (5.5)]

    6.1 Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    MESNEX adverse reaction data are available from four Phase 1 studies in which single intravenous doses of 600-1200 mg MESNEX injection without concurrent chemotherapy were administered to a total of 53 healthy volunteers and single oral doses of 600-2400 mg of MESNEX tablets were administered to a total of 82 healthy volunteers. The most frequently reported side effects (observed in two or more healthy volunteers) for healthy volunteers receiving single doses of MESNEX injection alone were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperesthesia, influenza-like symptoms, and coughing. In two Phase 1 multiple-dose studies where healthy volunteers received MESNEX tablets alone or intravenous MESNEX followed by repeated doses of MESNEX tablets, flatulence and rhinitis were reported. In addition, constipation was reported by healthy volunteers who had received repeated doses of intravenous MESNEX.

    Additional adverse reactions in healthy volunteers receiving MESNEX alone included injection site reactions, abdominal pain/colic, epigastric pain/burning, mucosal irritation, lightheadedness, back pain, arthralgia, myalgia, conjunctivitis, nasal congestion, rigors, paresthesia, photophobia, fatigue, lymphadenopathy, extremity pain, malaise, chest pain, dysuria, pleuritic pain, dry mouth, dyspnea, and hyperhidrosis. In healthy volunteers, MESNEX was commonly associated with a rapid (within 24 hours) decrease in lymphocyte count, which was generally reversible within one week of administration.

    Because MESNEX is used in combination with ifosfamide or ifosfamide-containing chemotherapy regimens, it is difficult to distinguish the adverse reactions which may be due to MESNEX from those caused by the concomitantly administered cytotoxic agents.

    Adverse reactions reasonably associated with MESNEX administered intravenously and orally in four controlled studies in which patients received ifosfamide or ifosfamide-containing regimens are presented in Table 3.

    Table 3: Adverse Reactions in ≥ 5% of Patients Receiving MESNEX in combination with Ifosfamide-containing Regimens
    *
    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)].

    MESNEX Regimen

    Intravenous-Intravenous-Intravenous*

    Intravenous-Oral-Oral*

    N exposed

    119 (100.0%)

    119 (100%)

    Incidence of AEs

    101 (84.9%)

    106 (89.1%)

    Nausea

    65 (54.6)

    64 (53.8)

    Vomiting

    35 (29.4)

    45 (37.8)

    Constipation

    28 (23.5)

    21 (17.6)

    Leukopenia

    25 (21.0)

    21 (17.6)

    Fatigue

    24 (20.2)

    24 (20.2)

    Fever

    24 (20.2)

    18 (15.1)

    Anorexia

    21 (17.6)

    19 (16.0)

    Thrombocytopenia

    21 (17.6)

    16 (13.4)

    Anemia

    20 (16.8)

    21 (17.6)

    Granulocytopenia

    16 (13.4)

    15 (12.6)

    Asthenia

    15 (12.6)

    21 (17.6)

    Abdominal Pain

    14 (11.8)

    18 (15.1)

    Alopecia

    12 (10.1)

    13 (10.9)

    Dyspnea

    11 (9.2)

    11 (9.2)

    Chest Pain

    10 (8.4)

    11 (9.2)

    Hypokalemia

    10 (8.4)

    11 (9.2)

    Diarrhea

    9 (7.6)

    17 (14.3)

    Dizziness

    9 (7.6)

    5 (4.2)

    Headache

    9 (7.6)

    13 (10.9)

    Pain

    9 (7.6)

    10 (8.4)

    Sweating Increased

    9 (7.6)

    2 (1.7)

    Back Pain

    8 (6.7)

    6 (5.0)

    Hematuria

    8 (6.7)

    7 (5.9)

    Injection Site Reaction

    8 (6.7)

    10 (8.4)

    Edema

    8 (6.7)

    9 (7.6)

    Edema Peripheral

    8 (6.7)

    8 (6.7)

    Somnolence

    8 (6.7)

    12 (10.1)

    Anxiety

    7 (5.9)

    4 (3.4)

    Confusion

    7 (5.9)

    6 (5.0)

    Face Edema

    6 (5.0)

    5 (4.2)

    Insomnia

    6 (5.0)

    11 (9.2)

    Coughing

    5 (4.2)

    10 (8.4)

    Dyspepsia

    4 (3.4)

    6 (5.0)

    Hypotension

    4 (3.4)

    6 (5.0)

    Pallor

    4 (3.4)

    6 (5.0)

    Dehydration

    3 (2.5)

    7 (5.9)

    Pneumonia

    2 (1.7)

    8 (6.7)

    Tachycardia

    1 (0.8)

    7 (5.9)

    Flushing

    1 (0.8)

    6 (5.0)

    6.2 Postmarketing Experience

    The following adverse reactions have been reported in the postmarketing experience of patients receiving MESNEX in combination with ifosfamide or similar drugs, making it difficult to distinguish the adverse reactions which may be due to MESNEX from those caused by the concomitantly administered cytotoxic agents. Because these reactions are reported from a population of unknown size, precise estimates of frequency cannot be made.

    Cardiovascular: Hypertension

    Gastrointestinal: Dysgeusia

    Hepatobiliary: Hepatitis

    Nervous System: Convulsion

    Respiratory: Hemoptysis

  • 7 DRUG INTERACTIONS

    No clinical drug interaction studies have been conducted with MESNEX.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    MESNEX is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm when administered to a pregnant woman. Refer to the ifosfamide prescribing information for more information on use during pregnancy.

    MESNEX injection contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].

    The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

    Data

    Animal Data

    MESNEX is used in combination with ifosfamide or other cytotoxic agents. Ifosfamide can cause fetal harm including embryo-fetal lethality. Refer to the ifosfamide prescribing information for more information on use during pregnancy.

    In embryo-fetal development studies, oral administration of mesna to pregnant rats (500, 1000, 1500, and 2000 mg/kg) and rabbits (500 and 1000 mg/kg) during the period of organogenesis revealed no adverse developmental outcomes at doses approximately 10 times the maximum recommended total daily human equivalent dose based on body surface area.

    8.2 Lactation

    Risk Summary

    MESNEX 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 a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].

    Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment and for 1 week after the last dose of 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 a pregnant woman. Refer to the ifosfamide prescribing information for more information on contraception and effects on fertility.

    Pregnancy Testing

    Verify the pregnancy status of females of reproductive potential prior to initiation of MESNEX in combination with ifosfamide.

    Contraception

    Females

    Advise females of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosfamide and for 6 months after the last dose.

    Males

    Advise males with female partners of reproductive potential to use effective contraception during treatment with MESNEX in combination with ifosfamide and for 3 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.

  • 10 OVERDOSAGE

    There is no known antidote for MESNEX.

    In a clinical trial, 11 patients received intravenous MESNEX 10 mg/kg to 66 mg/kg per day for 3 to 5 days. Patients also received ifosfamide or cyclophosphamide. Adverse reactions included nausea, vomiting, diarrhea and fever. An increased rate of these adverse reactions has also been found in oxazaphosphorine-treated patients receiving ≥80 mg MESNEX per kg per day intravenously compared with patients receiving lower doses or hydration treatment only.

    Postmarketing, administration of 4.5 g to 6.9 g of MESNEX resulted in hypersensitivity reactions including mild hypotension, shortness of breath, asthma exacerbation, rash, and flushing.

  • 11 DESCRIPTION

    MESNEX (mesna) is a detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide. The active ingredient, mesna, is a synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2 and a molecular weight of 164.18. Its structural formula is as follows:

    HS–CH2–CH2SO3–Na+

    MESNEX injection is a 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 a preservative. The solution has a 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.

  • 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 a non-urotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites and inhibits their effects on the bladder.

    12.3 Pharmacokinetics

    Absorption

    Following oral administration, peak plasma concentrations were reached within 1.5 to 4 hours and 3 to 7 hours for free mesna and total mesna (mesna plus dimesna and mixed disulfides), respectively. Oral bioavailability averaged 58% (range 45 to 71%) for free mesna and 89% (range 74 to 104%) for total mesna based on plasma AUC data from 8 healthy volunteers who received 1200 mg oral or intravenous doses.

    Food does not affect the urinary availability of orally administered MESNEX.

    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 a single 800 mg dose, approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. Mean plasma elimination half-lives of mesna and dimesna are 0.36 hours and 1.17 hours, respectively. Mesna has a plasma clearance of 1.23 L/h/kg.

  • 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 a body surface area basis.

  • 14 CLINICAL STUDIES

    14.1 Intravenous MESNEX

    Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 4). At a dose of 1.2 g/m2 ifosfamide administered daily for 5 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 3 and 4). In two randomized studies, (Studies 5 and 6), higher doses of ifosfamide, from 2 g/m2 to 4 g/m2 administered for 3 to 5 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)
    *
    Ifosfamide dose 1.2 g/m2 d x 5
    Ifosfamide dose 2 g/m2 to 4 g/m2 d x 3 to 5

    Study

    Conventional Uroprophylaxis (number of patients)

    Standard MESNEX Intravenous Regimen (number of patients)

    Uncontrolled Studies*

    Study 1

    16% (7/44)

    -

    Study 2

    26% (11/43)

    -

    Study 3

    18% (7/38)

    0% (0/21)

    Study 4

    -

    0% (0/32)

    Controlled Studies

    Study 5

    31% (14/46)

    6% (3/46)

    Study 6

    100% (7/7)

    0% (0/8)

    14.2 Oral MESNEX

    Clinical studies comparing recommended intravenous and oral MESNEX dosing regimens demonstrated incidences of grade 3 to 4 hematuria of <5%. Study 7 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 a dose of 1.2 g/m2 to 2.0 g/m2 for 3 to 5 days. Study 8 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m2 for 5 days. In both studies, development of grade 3 or 4 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 3 or 4 Hematuria

    MESNEX Dosing Regimen

    Study

    Standard Intravenous Regimen

    (number of patients)

    Intravenous + Oral Regimen

    (number of patients)

    Study 7

    0% (0/30)

    3.6% (1/28)

    Study 8

    3.7% (1/27)

    4.3% (1/23)

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    MESNEX (mesna) injection 100 mg/mL

    NDC 0338-1305-01 1 g Multidose Vial, Box of 1 vial of 10 mL
    NDC 0338-1305-03 1 g Multidose Vial, Box of 10 vials of 10 mL
     
    Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]

    If MESNEX is co-administered with ifosfamide, refer to the ifosfamide prescribing information for safe handling instructions.

    MESNEX (mesna) tablets

    NDC 67108-3565-9 400 mg scored tablets packaged in box of 10 tablets
     
    Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]
  • 17 PATIENT COUNSELING INFORMATION

    See FDA-approved patient labeling (Patient Information).

    Hypersensitivity

    Advise the patient to discontinue MESNEX and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction, including systemic anaphylactic reactions occur [see Warnings and Precautions (5.1)].

    Dosing Instructions

    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 2 hours of taking oral MESNEX, or if they miss a dose of oral MESNEX [see Dosage and Administration (2.2)].

    Hemorrhagic Cystitis

    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 a pink or red color [see Dosage and Administration (2.3)].
    Advise the patient to drink 1 to 2 liters of fluid each day during MESNEX 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 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 Toxicity

    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)].

    Embryo-Fetal Toxicity

    MESNEX is used in combination with ifosfamide. Ifosfamide or other cytotoxic agents can cause fetal harm when administered to a pregnant woman. Inform female patients of the risk to a 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 MESNEX in combination with ifosamide and for 6 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 3 months after the last dose [see Use in Specific Populations (8.3)].

    Lactation

    Advise lactating women not to breastfeed during treatment with MESNEX or ifosfamide and for 1 week after the last dose [see Use in Specific Populations (8.2)].
  • SPL UNCLASSIFIED SECTION

    Baxter Logo
    MESNEX (mesna) injection manufactured by:

    MESNEX (mesna) tablets manufactured for:

     
    Baxter Healthcare Corporation
    Deerfield, IL 60015 USA
    For Product Inquiry 1800 ANA DRUG (1-800-262-3784)

    Made in Germany

    Baxter and Mesnex are registered trademarks of Baxter International Inc.

    Material No. HA-30-01-814

  • PATIENT MEDICATION INFORMATION

    Patient Information
    MESNEX (MES-nex)
    (mesna)
    tablets

    MESNEX (MES-nex)
    (mesna)
    injection

    What is the most important information I should know about MESNEX?

    MESNEX 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:

    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.

    What is MESNEX?

    MESNEX is a 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 if you are allergic to mesna or any of the ingredients in MESNEX. See the end of this leaflet for a 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 medicines
    are pregnant or plan to become pregnant.
     
    Females who are able to become pregnant:
    o
    Your healthcare provider will verify if you are pregnant or not before you start treatment with MESNEX and ifosfamide.
    o
    You should use effective birth control (contraception) during treatment with MESNEX and ifosfamide and for 6 months after the last dose.
    o
    Tell your healthcare provider if you become pregnant during treatment with MESNEX and ifosfamide.
     
    Males with female partners who are able to become pregnant should use effective birth control during treatment with MESNEX and ifosfamide and for 3 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 1 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 I receive MESNEX?

    MESNEX is given on the same day that you receive ifosfamide.
    MESNEX can be given by an intravenous (IV) infusion into a vein or tablets taken by mouth.
    You will receive MESNEX in one of two ways:
    o
    MESNEX intravenous (IV) infusion into a vein at the time you receive ifosfamide and 4 and 8 hours after you receive ifosfamide, OR
    o
    MESNEX intravenous (IV) infusion into a vein at the time you receive ifosfamide and MESNEX tablets taken by mouth 2 and 6 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 4 to 8 cups of liquid (1 to 2 liters) each day.
    Tell your healthcare provider if you:
    o
    vomit within 2 hours of taking MESNEX tablets by mouth
    o
    miss a dose of MESNEX tablets
    o
    have pink or red colored urine

    What are the possible side effects of MESNEX?

    MESNEX may cause serious side effects, including:

    See “What is the most important information I 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:

    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 MESNEX.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store MESNEX tablets?

    Store MESNEX tablets at room temperature between 68°F to 77°F (20°C to 25°C).

    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 a Patient Information leaflet. Do not use MESNEX for a 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 MESNEX?

    Active ingredient: mesna

    Inactive ingredients:

    MESNEX injection: edetate disodium, sodium hydroxide, and benzyl alcohol as a 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

  • PACKAGE LABEL - PRINCIPAL DISPLAY PANEL

    Representative Container Label 1g

    1g Multidose Vial

    1g Multidose Vial

    1 Multidose Vial NDC 0338-1305-01

    Mesnex
    (mesna) Injection

    FOR INTRAVENOUS USE

    1g/vial Rx only

    N (01) 1 03 0338 1305 01 4

    Lot Number / Expires:

    JMXXX

    MM.JJJJ

    Each vial contains 1 gram of
    mesna in 10 mL water.
    1% benzyl alcohol is added as a
    preservative.
    See insert for dosing information.
    Store at 20° - 25°C (68° - 77°F),
    excursions permitted to
    15° - 30°C (59° - 86°F)[see USP
    Controlled Room Temperature]

    Manufactured by:
    Baxter Healthcare Corporation
    Deerfield, IL 60015 USA

    USA HA-65-01-568 C 93

    Mesnex Representative Carton Label 1g NDC 0338-1305-01  1 of 2
    Mesnex Representative Carton Label 1g NDC 0338-1305-01  2 of 2

    Carton Label

    1 Multidose Vial
    NDC 0338-1305-01

    MESNEX
    (mesna) Injection

    1g/vial

    FOR INTRAVENOUS USE

    Rx only

    Baxter Logo
    Manufactured by
    Baxter Healthcare Corporation
    Deerfield, IL 60015 USA

    (01) 00303381305017
    (21) XXXXXXXXXXXX
    (17) JJMMTT
    (10) JMXXXA

    Barcode

    MESNEX
    mesna Injection

    1g/vial

    Barcode

    HA-80-02-158
    USA

    Fragile:
    Handle with care.
    Store at 20° - 25°C
    (68°-77°F) excursions
    permitted to 15° - 30°C
    (59° - 86°F) [see USP
    Controlled Room Temperature].

    Baxter Logo
    Manufactured by
    Baxter Healthcare Corporation
    Deerfield, IL 60015 USA

    C
    203

    1 Multidose Vial
    NDC 0338-1305-01

    MESNEX
    (mesna) Injection

    1g/vial

    FOR INTRAVENOUS USE

    Rx only

    Baxter Logo
    Manufactured by
    Baxter Healthcare Corporation
    Deerfield, IL 60015 USA

    Lot/Exp:
    JMXXXA
    MM.JJJJ

    2639B3994

    Barcode

    Folding Box Logo
    Can Be Recycled

    Each vial contains 1 g mesna in
    10 mL water, Mesnex is a 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
    a 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 Germany

    Representative Box Label 1g panel 1 of 4
    Representative Box Label 1g panel 2 of 4
    Representative Box Label 1g panel 3 of 4
    Representative Box Label 1g panel 4 of 4

    Schwarz

    P 186 C

    10 Multidose Vials NDC 0338-1305-03

    1g

    MESNEX

    (mesna) Injection

    Baxter Logo
    Manufactured by
    Baxter Healthcare Corporation
    Deerfield, IL 60015 USA

    10 Multidose Vials NDC 0338-1305-03

    1g

    N3 0338130503 1

    MESNEX
    (mesna) Injection

    Each vial contains 1 g mesna in 10mL water. Mesnex is a 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
    a preservative.

    Fragile: Handle with care. Store at 20° - 25°C (68°-77°F) see excursions permitted to 15° - 30°C
    (59° - 86°F) [see USP Controlled Room Temperature] U.S. Patent No 5,696, 172

    FOR INTRAVENOUS USE

    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 Germany

    Rx only

    HA-80-01-627
    USA

    10 Multidose Vials NDC 0338-1305-03

    1g

    MESNEX
    (mesna) Injection

    FOR INTRAVENOUS USE
    10 Multidose Vials

    C
    53

    10 Multidose Vials NDC 0338-1305-03

    1g

    2639B3913

    Lot:
    Exp.:

    MESNEX
    (mesna) Injection

    Each vial contains 1 g mesna in 10mL water. Mesnex is a 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
    a preservative.

    Fragile: Handle with care. Store at 20° - 25°C (68°-77°F) see excursions permitted to 15° - 30°C
    (59° - 86°F) [see USP Controlled Room Temperature] U.S. Patent No 5,696, 172

    FOR INTRAVENOUS USE

    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 Germany

    Rx only

    Folding Box
    Logo
    Can Be Recycled

    10 Multidose Vials NDC 0338-1305-03

    1g

    MESNEX
    (mesna) Injection

    FOR INTRAVENOUS USE
    10 Multidose Vials

  • INGREDIENTS AND APPEARANCE
    MESNEX 
    mesna injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0338-1305
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    MESNA (UNII: NR7O1405Q9) (2-MERCAPTOETHANESULFONIC ACID - UNII:VHD28S0H7F) MESNA100 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    EDETATE DISODIUM (UNII: 7FLD91C86K) 0.25 mg  in 1 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    BENZYL ALCOHOL (UNII: LKG8494WBH) 1.04 mg  in 1 mL
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:0338-1305-011 in 1 BOX12/30/1988
    110 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product
    2NDC:0338-1305-0310 in 1 BOX12/30/1988
    210 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA01988412/30/1988
    Labeler - Baxter Healthcare Corporation (005083209)
    Registrant - Baxter Healthcare Corporation (005083209)
    Establishment
    NameAddressID/FEIBusiness Operations
    Baxter Oncology GmbH344276063ANALYSIS(0338-1305) , MANUFACTURE(0338-1305) , LABEL(0338-1305) , PACK(0338-1305) , STERILIZE(0338-1305)
    Establishment
    NameAddressID/FEIBusiness Operations
    Baxter Oncology GmBH312520353API MANUFACTURE(0338-1305)