mesna 400 MG Oral Tablet

1. INDICATIONS AND USAGE Mesna injection is indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis. Limitation of Use: Mesna injection is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia. Mesna injection is a cytoprotective agent indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis. ( 1 ) Limitation of Use: Mesna injection is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia. ( 1 )

2. DOSAGE AND ADMINISTRATION Mesna injection 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 mesna to ifosfamide should be maintained. ( 2 ) Intravenous Dosing Schedule: 0 Hours 4 Hours 8 Hours Ifosfamide 1.2 g/m 2 -- -- Mesna 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 -- -- Mesna 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. ( 2.3 ) 2.1 Intravenous Dosing Mesna injection may be given on a fractionated dosing schedule of three bolus intravenous injections as outlined below. Mesna 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 mesna injection is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below in Table 1 . Table 1. Recommended Intravenous Dosing Schedule 1 The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or decreased, the ratio of mesna to ifosfamide should be maintained. 0 Hours 4 Hours 8 Hours Ifosfamide 1.2 g/m 2 - - Mesna injection 1 240 mg/m 2 240 mg/m 2 240 mg/m 2 2.2 Intravenous and Oral Dosing Mesna injection may be given on a fractionated dosing schedule of a single bolus injection followed by two oral administrations of MESNEX tablets as outlined below. Mesna 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 mesna is 100% of the ifosfamide dose. The recommended dosing schedule is outlined in Table 2 . Table 2. Recommended Intravenous and Oral Dosing Schedule 1 The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or decreased, the ratio of mesna to ifosfamide should be maintained. 0 Hours 2 Hours 6 Hours Ifosfamide 1.2 g/m 2 - - Mesna injection 1 240 mg/m 2 - - MESNEX tablets - 480 mg/m 2 480 mg/m 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/m 2 . Patients who vomit within two hours of taking oral MESNEX should repeat the dose or receive intravenous mesna injection. 2.3 Monitoring for Hematuria Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. If severe hematuria develops when mesna injection is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required. 2.4 Preparation for Intravenous Administration and Stability Preparation Determine the volume of mesna injection for the intended dose. Dilute the volume of mesna injection for the dose in any of the following fluids to obtain 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 mesna 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 mesna injection with epirubicin, cyclophosphamide, cisplatin, carboplatin, and nitrogen mustard. The benzyl alcohol contained in mesna injection vials can reduce the stability of ifosfamide. Ifosfamide and mesna injection may be mixed in the same bag provided the final concentration of ifosfamide does not exceed 50 mg/mL. Higher concentrations of ifosfamide may not be compatible with mesna injection and may reduce the stability of ifosfamide. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any solutions which are discolored, hazy, or contain visible particulate matter should not be used.

5. WARNINGS AND PRECAUTIONS Hypersensitivity reactions: Anaphylactic reactions have been reported. Less severe hypersensitivity reactions may also occur. Monitor patients. If a reaction occurs, discontinue mesna injection and provide supportive care. ( 5.1 ) Dermatologic toxicity: Skin rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Skin rash, urticaria, and angioedema have also been seen. Monitor patients. If a reaction occurs, discontinue mesna injection and provide supportive care. ( 5.2 ) Benzyl alcohol toxicity: Serious and fatal adverse reactions can occur in premature neonates and low-birth weight infants treated with benzyl alcohol-preserved drugs, including mesna injection. Avoid use in premature neonates and low-birth weight infants. ( 5.3 ) Laboratory test alterations: False positive tests for urinary ketones and interference with enzymatic CPK activity tests have been seen. ( 5.4 ) 5.1 Hypersensitivity Reactions Mesna injection may cause systemic hypersensitivity reactions, including anaphylaxis. These reactions may include fever, cardiovascular symptoms (hypotension, tachycardia), acute renal impairment, hypoxia, respiratory distress, urticaria, angioedema, laboratory signs of disseminated intravascular coagulation, hematological abnormalities, increased liver enzymes, nausea, vomiting, arthralgia, and myalgia. These reactions may occur with the first exposure or after several months of exposure. Monitor for signs or symptoms. Discontinue mesna injection and provide supportive care. 5.2 Dermatologic Toxicity Drug rash with eosinophilia and systemic symptoms and bullous and ulcerative skin and mucosal reactions, consistent with Stevens-Johnson syndrome or toxic epidermal necrolysis have occurred. Mesna injection may cause skin and mucosal reactions characterized by urticaria, rash, erythema, pruritus, burning sensation, angioedema, periorbital edema, flushing and stomatitis. These reactions may occur with the first exposure or after several months of exposure. Discontinue mesna injection and provide supportive care. 5.3 Benzyl Alcohol Toxicity Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low-birth weight infants who received benzyl alcohol dosages of 99 to 234 mg/kg/day (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Symptoms associated with “gasping syndrome” and other potential adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Premature neonates and low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Mesna injection contains 10.4 mg/mL of the preservative benzyl alcohol. Avoid use of mesna injection in premature neonates and low-birth weight infants. 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 mesna 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 Mesna 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 Mesna 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 Mesna 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 mesna.

CONTRAINDICATIONS Mesna is contraindicated in patients known to be hypersensitive to mesna or to any of the excipients [see Warnings and Precautions (5.1) ]. Known hypersensitivity to mesna or to any of the excipients in mesna tablets and MESNEX injection, including benzyl alcohol. ( 4 )

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.