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 oxazaphosphorinetreated 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.
MESNEX is contraindicated in patients known to be hypersensitive to MESNEX or to any of the excipients.
The following are discussed in more detail in other sections of the labeling.
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
| MESNEX Regimen | Intravenous-Intravenous-Intravenous1 | Intravenous-Oral-Oral1 |
| 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) |
| Thrombocytop eni a | 21 (17.6) | 16 (13.4) |
| Anemia | 20 (16.8) | 21 (17.6) |
| Granul ocytopenia | 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) |
| 1Intravenous dosing of ifosfamide and MESNEX followed by either intravenous or oral doses of MESNEX according to the applicable dosage schedule.. |
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
MESNEX is indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.
Limitation of UseMESNEX is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia.
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.
DistributionMean 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).
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 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.
Pregnancy Category B.
Risk SummaryThere are no studies of MESNEX in pregnant women. Reproduction studies performed in rats and rabbits at oral doses approximately 10 times the maximum recommended total daily intravenous-oral-oral human dose on a body surface area basis (1000 mg/kg in rabbits and 2000 mg/kg in rats) revealed no evidence of harm to the fetus due to mesna. The incidence of malformations in human pregnancies has not been established for mesna. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations and 15 to 20% for pregnancy loss. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
NDC 0338-1305-01
1 g Multidose Vial, Box of 1 vial of 10 mLNDC 0338-1305-03
1 g Multidose Vial, Box of 10 vials of 10 mLStore at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).
MESNEX (mesna) tabletsNDC 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).
Manufactured by: Baxter Healthcare Corporation, Deerfield, IL 60015 USA. Revised: Mar 2014
Included as part of the PRECAUTIONS section.
PRECAUTIONS Hypersensitivity ReactionsMESNEX 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.
Dermatologic ToxicityDrug 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.
Benzyl Alcohol ToxicityBenzyl alcohol, a preservative in MESNEX, has been associated with serious adverse reactions and death (including gasping syndrome) in neonates, premature and low-birth weight infants. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Consider the combined daily metabolic load of benzyl alcohol from all sources when prescribing MESNEX (10.4 mg benzyl alcohol per mL). Neonates, premature, and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Monitor patients for signs or symptoms of toxicity. Avoid use in neonates, premature and low-birth weight infants.
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 a false positive (cherry-red color that fades) and a true positive result (redviolet color that intensifies).
False-Negative Tests for Enzymatic CPK ActivityMESNEX 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 AcidMESNEX may cause false-positive reactions in Tillman's reagent-based urine screening tests for ascorbic acid.
Use In Patients With A History Of Adverse Reactions To Thiol CompoundsMESNEX is a thiol compound, i.e., a sulfhydryl (SH) group-containing organic compound. Hypersensitivity reactions to MESNEX 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.
Patient Counseling InformationSee FDA-approved patient labeling (PATIENT INFORMATION).
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
| 0 Hours | 4 Hours | 8 Hours | |
| Ifosfamide | 1.2 g/m² | - | - |
| MESNEX Injection1 | 240 mg/m² | 240 mg/m² | 240 mg/m² |
| 1The 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. |
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
| 0 Hours | 2 Hours | 6 Hours | |
| Ifosfamide | 1.2 g/m² | - | - |
| MESNEX injection1 | 240 mg/m² | - | - |
| MESNEX tablets | - | 480 mg/m² | 480 mg/m² |
| 1The 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. |
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.
Monitoring For HematuriaMaintain 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.
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 a final concentration of 20 mg/mL:
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.
The following are discussed in more detail in other sections of the labeling.
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
| MESNEX Regimen | Intravenous-Intravenous-Intravenous1 | Intravenous-Oral-Oral1 |
| 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) |
| Thrombocytop eni a | 21 (17.6) | 16 (13.4) |
| Anemia | 20 (16.8) | 21 (17.6) |
| Granul ocytopenia | 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) |
| 1Intravenous dosing of ifosfamide and MESNEX followed by either intravenous or oral doses of MESNEX according to the applicable dosage schedule.. |
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
DRUG INTERACTIONSNo clinical drug interaction studies have been conducted with MESNEX.
