Mesnex Tablet, Film Coated
FDA Label NDC 67108-3565

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. 

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.

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.

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.

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.

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.

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

MESNEX is contraindicated in patients known to be hypersensitive to mesna or to any of the excipients [see Warnings and Precautions (5.1)].

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.

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.

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)].

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.

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.

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)]

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.

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

No clinical drug interaction studies have been conducted with MESNEX.

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.

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.

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.

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)].

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.

No clinical studies were conducted to evaluate the effect of renal impairment on the pharmacokinetics of MESNEX.

No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of MESNEX.

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.

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.

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.

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 (V_d) for mesna is 0.652 ± 0.242 L/kg after intravenous administration which suggests distribution to total body water (plasma, extracellular fluid, and intracellular water).

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.

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.

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%.

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.

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]

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)].

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-30-01-811

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 12 2018

Representative Container Blister Pack Labeling 400 mg (Image 01)

Container Label 400 mg Tablets

List 3565-9

Rx only

400 mg

Mesnex®
(mesna) Tablets

Baxter Healthcare
Corporation
460-656-00

Lot-number/Expires:

JMXXX MM.JJJJ

Mesnex Representative Carton Label 1 Of 2 67108-3565-9 (Image 02)

Mesnex Representative Carton Label 2 Of 2 67108-3565-9 (Image 03)

10 400 mg Tablets

NDC 67108-3565-9

400 mg

Mesnex®
(mesna) Tablets

Rx only

Each tablet contains 400 mg mesna.
Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F)
[see USP Controlled Room Temperature].

For ORAL ADMINISTRATION

Dosage: See package insert for directions for use. Should not be prescribed without thorough
knowledge of dose, indications, and toxicology as contained in the accompanying literature.

Manufactured for :
Baxter Logo
Baxter Healthcare Corporation
Deerfield, IL 60015

Barcode
N3 6710835659 1

C
926

10 400 mg Tablets

400
mg

Mesnex®
(mesna) Tablets

NDC 67108-3565-9

HA-80-02-274
USA

10 400 mg Tablets

400
mg

Mesnex®
(mesna) Tablets

NDC 67108-3565-9

2640B4050

Barcode

10 400 mg Tablets

400
mg

Mesnex®
(mesna) Tablets

NDC 67108-3565-9

Rx only

Each tablet contains 400 mg mesna.
Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F)
[see USP Controlled Room Temperature].

For ORAL ADMINISTRATION

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 for:
Baxter Logo
Baxter Healthcare Corporation
Deerfield, IL 60015

10 400 mg Tablets

400
mg

Mesnex®
(mesna) Tablets

NDC 67108-3565-9

51741274