UROMITEXAN

(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 C 2 H 5 NaO 3 S and a molecular weight of 164.18.

Its structural formula is as follows

HS–CH 2 –CH 2 SO 3 –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.

Prevention of bladder bleeding (bladed bladder infection) during chemotherapy using ephosphamid.

Medically supervised: pregnancy and breastfeeding, where Mesna is used with cancer treatments that must not be treated during pregnancy and lactation, autoimmune disorder such as: lupus disease or rheumaid arthritis, if a cancer drug treatment called siclofosfamed is received.

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 to 7 hours for free mesna and total mesna (mesna plus dimesna and mixed disulfides), respectively.

Oral bioavailability averaged 58% (range to 71%) for free mesna and 89% (range 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.

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).

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.

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.

It is used as a detoxification agent, reducing the harmful effects of iphosfamede, an anti-tumor used to treat cancer.

Mesna helps reduce the chances of acute bladder infection that could lead to severe bleeding.

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

Hypersensitivity Reactions Dermatological Toxicity Benzyl Alcohol Toxicity Laboratory Test Interferences Use in Patients with a History of Adverse Reactions to Thiol Compounds 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.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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.

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-Intravenous Intravenous dosing of ifosfamide and MESNEX followed by either intravenous or oral doses of MESNEX according to the applicable dosage schedule.

N exposed 119 (100.0%) 119 (100%) Incidence of AEs 101 (84.9%) 106 (89.1%) Nausea 65 64 Vomiting 35 45 Constipation 28 21 Leukopenia 25 21 Fatigue 24 24 Fever 24 18 Anorexia 21 19 Thrombocytopenia 21 16 Anemia 20 21 Granulocytopenia 16 15 Asthenia 15 21 Abdominal Pain 14 18 Alopecia 12 13 Dyspnea 11 11 Chest Pain 10 11 Hypokalemia 10 11 Diarrhea 9 17 Dizziness 9 5 Headache 9 13 Pain 9 10 Sweating Increased 9 2 Back Pain 8 6 Hematuria 8 7 Injection Site Reaction 8 10 Edema 8 9 Edema Peripheral 8 8 Somnolence 8 12 Anxiety 7 4 Confusion 7 6 Face Edema 6 5 Insomnia 6 11 Coughing 5 10 Dyspepsia 4 6 Hypotension 4 6 Pallor 4 6 Dehydration 3 7 Pneumonia 2 8 Tachycardia 1 7 Flushing 1 6 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.

Hypertension Gastrointestinal: Dysgeusia Hepatobiliary: Hepatitis Nervous System: Convulsion Respiratory: Hemoptysis.

There is no known antidote for

In a clinical trial, 11 patients received intravenous MESNEX 10 mg/kg to 66 mg/kg per day for 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.

is contraindicated in patients known to be hypersensitive to mesna or to any of the excipients.

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

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.

Schedule: 0 Hours 4 Hours 8 Hours Ifosfamide 1.2 g/m 2 -

• MESNEX injection 240 mg/m 2 240 mg/m 2 240 mg/m 2 Intravenous and Oral Dosing Schedule: 0 Hours 2 Hours 6 Hours Ifosfamide 1.2 g/m 2 -

• MESNEX injection 240 mg/m 2 -

• MESNEX tablets -

• 480 mg/m 2 480 mg/m 2 Maintain sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. 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 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.

Schedule 0 Hours 4 Hours 8 Hours Ifosfamide 1.2 g/m 2 – – MESNEX injection 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. 240 mg/m 2 240 mg/m 2 240 mg/m 2 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 and 6 hours after each dose of ifosfamide.

MESNEX is 100% of the ifosfamide dose.

The recommended dosing schedule is outlined in Table 2.

Table 2.

Schedule 0 Hours 2 Hours 6 Hours Ifosfamide 1.2 g/m 2 – – MESNEX injection 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. 240 mg/m 2 – – MESNEX tablets – 480 mg/m 2 480 mg/m The efficacy and safety of this ratio of intravenous and oral MESNEX has not been established as being effective for daily doses of ifosfamide higher than 2 g/m 2.

Patients who vomit within two hours of taking oral MESNEX should repeat the dose or receive intravenous MESNEX. 2.3 Monitoring for Hematuria Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria.

If severe hematuria develops when

MESNEX is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required. 2.4 Preparation for Intravenous Administration and Stability 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.

(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) 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).

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.

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.

Ifosfamide can cause fetal harm including embryo-fetal lethality.

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.

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.

Clinical studies of

MESNEX did not include sufficient numbers of subjects aged 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.