Limitation of Use:

Mesna Injection is not indicated to reduce the risk of hematuria due to other pathological conditions such as thrombocytopenia.

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.

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 mesna 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. Mesna 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.

The efficacy and safety of this ratio of intravenous and oral mesna 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 mesna 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

5.1 Hypersensitivity Reactions

Mesna 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 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 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 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. Mesna tablets do not contain benzyl alcohol [see Use in Specific Populations (8.4)].

5.4 Laboratory Test Interferences

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.

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.

Mesna adverse reaction data are available from four Phase 1 studies in which single intravenous doses of 600 to 1200 mg mesna injection without concurrent chemotherapy were administered to a total of 53 healthy volunteers. The most frequently reported side effects (observed in two or more healthy volunteers) for healthy volunteers receiving single doses of mesna 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 mesna tablets alone or intravenous mesna followed by repeated doses of mesna tablets, flatulence and rhinitis were reported. In addition, constipation was reported by healthy volunteers who had received repeated doses of intravenous mesna.

Additional adverse reactions in healthy volunteers receiving mesna 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, mesna was commonly associated with a rapid (within 24 hours) decrease in lymphocyte count, which was generally reversible within one week of administration.

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

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

6.2 Postmarketing Experience

The following adverse reactions have been reported in the postmarketing experience of patients receiving mesna in combination with ifosfamide or similar drugs, making it difficult to distinguish the adverse reactions which may be due to mesna 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

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Mesna 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.

8.4 Pediatric Use

Mesna 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 mesna injection in premature neonates and low-birth weight infants [see Warnings and Precautions (5.3)].

8.5 Geriatric Use

Clinical studies of mesna 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 mesna 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 mesna.

8.7 Use in Patients with Hepatic Impairment

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

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

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.

14.1 Intravenous Mesna

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 mesna was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.

Storage Conditions

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.]

Sterile, Nonpyrogenic.

The container closure is not made with natural rubber latex.

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

Hypersensitivity

• Advise the patient to discontinue mesna 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)].

Hemorrhagic Cystitis

• Mesna 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 mesna 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 mesna. 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 mesna 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

• Mesna 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 mesna 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 mesna 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 mesna or ifosfamide and for 1 week after the last dose [see Use in Specific Populations (8.2)].

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©2021 Sagent Pharmaceuticals, Inc.

Revised: January 2021

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