Mesna is a synthetic sulfhydryl (thiol) compound that acts as a sulfydryl donor and uroprotective agent1, 3, 4, 5 by interacting chemically with urotoxic metabolites of oxazaphosphorine derivatives (e.g., ifosfamide, cyclophosphamide).1, 2, 3, 4, 5
Mesna is used prophylactically as a uroprotective agent to decrease the incidence of hemorrhagic cystitis in patients receiving ifosfamide,1, 2, 3, 4, 5, 6, 8, 9, 37, 38, 39, 40, 43, 44, 47, 60 and has been designated an orphan drug by the US Food and Drug Administration (FDA) for this use.27 Mesna also is designated an orphan drug by the FDA for inhibition of the urotoxic effects induced by other oxazaphosphorine compounds,27 and has been used prophylactically in patients receiving cyclophosphamide†.5, 7, 8, 9, 10, 11, 12, 13, 14, 10, 13, 26, 28, 45, 46, 60
Although use of mesna does not prevent bladder toxicity (e.g., hemorrhagic cystitis, hematuria) in all patients receiving oxazaphosphorine derivatives, reported rates of hemorrhagic cystitis in patients receiving only conventional uroprophylaxis (e.g., high fluid intake, frequent urination, administration of diuretics) generally are higher than those reported in patients receiving mesna.1, 3, 4, 7, 8, 9, 11, 12, 13, 14, 15, 26, 45, 46, 47
Prophylaxis in Patients Receiving Ifosfamide
Mesna is used in patients receiving ifosfamide as the principal prophylactic measure to decrease the incidence of ifosfamide-induced hemorrhagic cystitis.1, 2, 3, 4, 5, 6, 8, 9, 37, 38, 39, 40, 43, 44, 47, 60 Adequate oral and/or IV hydration of the patient also is employed.1, 3, 4 In studies in patients receiving ifosfamide in a dosage of 1.2 g/m2 IV daily for 5 days, hematuria (more than 50 erythrocytes/high power field [HPF] or macrohematuria) occurred in 16-26% of patients receiving only conventional uroprophylaxis (high fluid intake, urine alkalinization, administration of diuretics) but did not occur in patients receiving mesna.1 In patients receiving higher ifosfamide dosages (2-4 g/m2 daily for 3-5 days), hematuria developed in 31-100% of patients receiving only conventional uroprophylaxis but occurred in less than 7% of patients receiving IV mesna.1, 15
Efficacy of the oral regimen of mesna compared with that of the standard IV regimen was established in 2 randomized, comparative studies involving a total of more than 100 patients with cancer receiving ifosfamide in dosages of 1.2-2 g/m2 for 3-5 days.1 In these studies, grade 3 or 4 hematuria occurred in 0-3.7% of patients receiving the standard IV regimen of mesna (consisting of three IV doses) and in 3.6-4.3% of patients receiving the oral regimen (consisting of one IV dose and 2 oral doses).1
Prior to the introduction of mesna as a uroprotective agent, urotoxicity was a major dose-limiting adverse effect of ifosfamide.3, 4, 17 Mesna does not prevent nephrotoxic effects of ifosfamide.3, 4
Prophylaxis in Patients Receiving Cyclophosphamide
Mesna is used prophylactically to decrease the incidence of hemorrhagic cystitis in bone marrow transplantation (BMT) patients receiving high-dose cyclophosphamide†.7, 9, 10, 11, 12, 13, 14, 26, 28, 45, 46, 60 The American Society of Clinical Oncology (ASCO) currently recommends that prophylactic therapy with either mesna plus saline diuresis or forced saline diuresis be considered for this purpose.60, 61
Clinical studies in patients undergoing BMT indicate that mesna is at least as effective9, 11, 12, 13, 26, 45, 46, 61 as hyperhydration in conjunction with diuretic administration in preventing bladder toxicity (e.g., hemorrhagic cystitis, hematuria) associated with high-dose cyclophosphamide (i.e., 50-60 mg/kg daily for 2-4 days). While a definitive statement concerning the relative efficacy of mesna versus hyperhydration for prophylaxis of cyclophosphamide-induced bladder toxicity in BMT patients cannot be made, mesna may be preferred in patients in whom adverse effects associated with hyperhydration (i.e., fluid overload, electrolyte imbalance) would be problematic.11, 45 Mesna therapy is associated with fewer urinary tract infections and greater patient comfort and mobility compared with bladder irrigation,13, 28, 45 and ASCO states that mesna plus saline diuresis is superior to continuous bladder irrigation for prevention of hemorrhagic cystitis.61 Prior to the introduction of uroprophylaxis, hemorrhagic cystitis occurred in up to 68% of patients receiving high-dose cyclophosphamide.8, 14, 45 However, uroprophylaxis with mesna therapy, hyperhydration, or bladder irrigation does not prevent cyclophosphamide-induced bladder toxicity in all patients and about 20-25% of patients experience hemorrhagic cystitis despite uroprophylaxis. 7, 9, 10, 11, 12, 13, 28, 46 Limited evidence suggests that the occurrence of hemorrhagic cystitis in some BMT patients who have received uroprophylaxis may be associated with reactivation and excretion of BK-type human polyomavirus14, 46 or other viruses.14, 51
Mesna has been used as a uroprotective agent in a limited number of patients receiving antineoplastic regimens containing high-dose cyclophosphamide†50 and has been used in a limited number of patients receiving cyclophosphamide for immunologically mediated disorders (e.g., Wegener's granulomatosis, systemic lupus erythromatosus, dermatomyositis, polyarteritis)†.20, 21
Mesna usually is administered IV by direct injection 1, 2, 3, 7, 8, 10, 15, 34, 38, 41, 43, 44 or orally.1 Some clinicians state that the drug may be administered IV by infusion over 15-30 minutes†18, 32 or by continuous infusion†.3, 4, 5, 10, 17, 34, 37, 38, 39, 40, 41, 42, 60
Patients receiving mesna for the prevention of ifosfamide-induced hemorrhagic cystitis should be adequately hydrated (i.e., at least 1 liter of oral or IV fluid daily, prior to and during ifosfamide therapy).1, 3, 4, 8, 10, 12, 15, 35, 38, 39, 41, 44, 52, 53
For IV administration, the required dose of mesna should be withdrawn from the multidose vial labeled as containing 100 mg/mL and diluted with an appropriate volume of a compatible IV solution (i.e., 5% dextrose; 5% dextrose and 0.2, 0.33, or 0.45% sodium chloride; 0.9% sodium chloride; lactated Ringer's) to obtain a solution containing 20 mg/mL.1, 2, 4, 18 The diluted solution may then be given by direct IV injection1, 2, 3 orinfused IV over a period of 15-30 minutes†.18 In patients who are receiving ifosfamide bycontinuous IV infusion†, the appropriate dosage of mesna has been admixed with ifosfamide and the drugs administered simultaneously.3, 4, 5, 17, 18, 39, 40
Mesna solutions should be inspected visually for discoloration and particulate matter prior to administration.1, 2
Mesna is commercially available as tablets for oral administration.1 Prior to availability of the oral dosage form, extemporaneous oral solutions of the drug were prepared using the parenteral dosage form†. 3, 4, 5, 6, 8, 16, 26, 29 Because commercially available mesna injection has a disagreeable taste, extemporaneous oral solutions usually were prepared by diluting the appropriate dose of mesna injection in syrup, carbonated beverage, or fruit juice.3, 5, 6, 26 (See Chemistry and Stability: Stability.)
Mesna dosage for prophylaxis of oxazaphosphorine-induced bladder toxicity (e.g., hemorrhage cystitis, hematuria) in patients receiving ifosfamide or cyclophosphamide† is based on the dosage of the oxazaphosphorine derivative.1, 2, 3, 60 Various mesna dosages have been used, and optimum dosages and methods of administration have not been established.3, 4, 10, 16, 17, 34
Prophylaxis in Patients Receiving Ifosfamide
In the regimen recommended by the manufacturers and some clinicians for prophylaxis of ifosfamide-induced hemorrhagic cystitis, mesna is administered IV in a total daily dosage equivalent to 60% of the ifosfamide daily dosage and is given in 3 divided doses (i.e., each mesna dose is equivalent to 20% of the ifosfamide daily dosage) when the ifosfamide dose is less than 2.5 g/m2 daily administered as a short infusion.1, 2, 3, 60, 61 In patients receiving IV ifosfamide at a dosage of 1.2 g/m2, the recommended dosage of mesna is 240 mg/m2 given IV 15 minutes60 before or at the time of administration of the ifosfamide dose, followed by 240 mg/m2 of mesna IV at 4 and 8 hours after the ifosfamide dose.1, 2 To maintain adequate urinary prophylaxis, this regimen is given each day that ifosfamide is administered and, if ifosfamide dosage is increased or decreased, dosage of mesna should be adjusted accordingly.1, 2, 3 Alternatively, the daily dosage of mesna has been given IV in 4 divided doses just before and at 4, 8, and 12 hours after the ifosfamide dose or just before and at 3, 6, and 9 hours after the ifosfamide dose.4, 5, 36, 44
In patients receiving ifosfamide by continuous IV infusion, the American Society of Clinical Oncology (ASCO) states that mesna may be administered at a dosage equivalent to 60% of the ifosfamide daily dosage.60 In this regimen, an initial loading dose of mesna equivalent to 20% of the ifosfamide daily dosage is given by IV injection; this loading dose is followed by continuous infusion of the drug at a dosage equivalent to 40% of the ifosfamide daily dosage, which can be administered concomitantly with ifosfamide.60 Because mesna has a shorter half-life than ifosfamide, ASCO recommends that IV infusions of mesna be continued for an additional 12-24 hours after completion of the ifosfamide infusion;60 other clinicians suggest that infusions of mesna be continued for 8-24 hours after completion of the ifosfamide infusion.3, 4, 30, 42
Safety and efficacy of mesna for prophylaxis of hemorrhagic cystitis induced by high dosages of ifosfamide (i.e., more than 2.5 g/m2 daily) have not been established.60 Although mesna has been given in dosages equivalent to 60-160% of the ifosfamide daily dosage, safety and efficacy of dosages exceeding 60% of the ifosfamide daily dosage have not been established, and dosages exceeding 120% of the ifosfamide daily dosage may be associated with increased GI toxicity.61 In patients receiving high-dose ifosfamide, ASCO states that more frequent and prolonged mesna dosage regimens may be required for maximum protection against urotoxicity, since elimination of ifosfamide is dose dependent.60, 61
In the IV and oral regimen recommended by the manufacturer and some clinicians for prophylaxis of ifosfamide-induced hemorrhagic cystitis, mesna generally is given in a dosage equivalent to 100% of the ifosfamide daily dosage when the ifosfamide dosage is less than 2 g/m2 daily.1, 60 In this regimen, an initial dose of mesna equivalent to 20% of the ifosfamide daily dosage is given by IV injection at the time of administration of the ifosfamide dose; this dose is followed by 2 oral doses, each equivalent to 40% of the ifosfamide daily dosage, administered as tablets at 2 and 6 hours after the ifosfamide dose.1, 60 The manufacturer recommends that patients receiving IV ifosfamide at a dosage of 1.2 g/m2 receive 240 mg/m2 of mesna IV at the time of administration of the ifosfamide dose and 480 mg/m2 of mesna orally at 2 and 6 hours after the ifosfamide dose; if the patient vomits a dose within 2 hours of administration, the dose should be repeated, or IV administration should be considered.1, 60 This regimen is given each day that ifosfamide is administered60 and, if ifosfamide dosage is increased or decreased, the ratio of mesna to ifosfamide should be maintained.1 Safety and efficacy of the recommended ratio of IV and oral mesna to ifosfamide have not been established for ifosfamide dosages exceeding 2 g/m2 daily.1
Prophylaxis in Patients Receiving Cyclophosphamide
For prophylaxis of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplant (BMT) recipients†, mesna has been administered in a daily dosage equivalent to 60-160% of the cyclophosphamide daily dosage and given by IV injection in 3-5 divided doses daily or by continuous IV infusion†.4, 10, 11, 14, 45, 46 In one study in BMT patients receiving cyclophosphamide (50 mg/kg IV daily for 3-4 days), mesna doses of 12 mg/kg were administered by IV injection 30 minutes prior to each cyclophosphamide dose and at 3, 6, 9, and 12 hours after each dose.46 Alternatively, in BMT patients receiving cyclophosphamide (50-60 mg/kg IV daily for 2-4 days), a loading dose of 10 mg/kg of mesna has been given IV with the cyclophosphamide dose followed by 60 mg/kg of mesna given by continuous IV infusion over 24 hours.12 Mesna should be administered each day cyclophosphamide is administered,7, 11, 12, 45, 46 and probably should be continued for at least 24 hours after cyclophosphamide is discontinued.7, 11, 45, 52
Dosage in Renal and Hepatic Impairment
The manufacturers currently make no specific dosage recommendations for use of mesna in patients with renal and/or hepatic impairment, and mesna dosage in these patients should be based on the ifosfamide or cyclophosphamide dosage.1, 2, 52, 53
Information on adverse effects of mesna initially was obtained from phase I studies in a limited number of individuals who received the drug orally or IV and from 2 controlled studies where mesna was administered to patients receiving ifosfamide.1 2 The most common adverse effects reported in patients receiving single or repeated IV doses of mesna without concurrent chemotherapy include headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperesthesia, influenza-like symptoms, coughing, and constipation.1 In patients receiving mesna tablets alone or IV mesna followed by tablets without concurrent chemotherapy, the most commonly reported adverse effects include flatulence and rhinitis.1 Rigors, back pain, rash, conjunctivitis, and arthralgia were reported in patients receiving a single 1.2-g dose of mesna as an oral solution.1 Although mesna reportedly is well tolerated,3, 5, 8, 15 evaluation of adverse effects and establishment of a causal relationship to mesna have been difficult since the drug is used in conjunction with antineoplastic agents that have documented toxicities.1, 12 Adverse effects reasonably associated with IV or oral mesna were derived from clinical studies in which patients received the drug in conjunction with ifosfamide or ifosfamide-containing regimens.1
The most common adverse GI effect associated with IV or oral regimens of mesna is nausea, which occurred in 54-55% of patients who received the drug in controlled studies.1 Anorexia, abdominal pain, diarrhea, or dyspepsia occurred in 3-18% of patients receiving the IV regimen and in 5-16% of those who received the oral regimen.1 Vomiting or constipation occurred in 29 or 24%, respectively, of patients receiving the IV regimen and in 38 or 18%, respectively, of those who received the oral regimen.1 In phase I studies in a limited number of individuals who received 1 or 3 IV doses of mesna (0.8-1.6 g/m2), an unpleasant taste occurred in all individuals2, 3, 4, 5 and soft stools occurred in 70%.2 In a study in a limited number of individuals who received oral or IV mesna doses of 2.4 g/m2 (approximately 10 times the usually recommended dosage for prophylaxis of ifosfamide-induced hemorrhagic cystitis), diarrhea occurred in 83%2, 3, 4, 5 and nausea occurred in 33% of these individuals.2
Dermatologic and Sensitivity Reactions
Alopecia occurred in 10-11% of patients receiving IV or oral regimens of mesna in controlled studies.1 Injection site reactions occurred in 7-8% of patients receiving IV doses of mesna, and flushing occurred in 1-5% of patients receiving IV or oral regimens of mesna.1
Hypersensitivity reactions, ranging from mild allergic reactions to systemic anaphylactic reactions, have been reported in patients receiving mesna.1, 2 In a phase I study, allergic reactions were reported in 17% of individuals who received oral or IV mesna doses of 2.4 g/m2;2, 3, 4 however, a lower incidence of hypersensitivity reactions to mesna have been reported in other studies.4, 19, 20, 22, 23, 24, 53 The incidence of mesna-induced hypersensitivity reactions appears to be higher in patients with autoimmune disorders who were treated with cyclophosphamide; most of these patients received mesna orally.1 Hypersensitivity reactions have included pruritus,3, 4, 19 rash,20, 21, 23 generalized urticaria,3, 19, 20 decreased platelet counts,1 and facial edema;4, 19 hypersensitivity reactions generally have responded to symptomatic treatment with antihistamines and corticosteroids.3, 4, 19 Although it has been suggested that pretreatment with an antihistamine and/or corticosteroid may be indicated in patients who have had a delayed hypersensitivity reaction to mesna,4, 52, 53 the manufacturer states that mesna is contraindicated in patients with a history of hypersensitivity to the drug.1
Fatigue or asthenia occurred in 20 or 13-18%, respectively, of patients receiving IV or oral regimens of mesna in controlled studies.1 Dizziness, headache, somnolence, anxiety, confusion, or insomnia have been reported in 3-11% of patients receiving mesna IV and/or orally in controlled studies.1
Leukopenia, thrombocytopenia, anemia, or granulocytopenia has been reported in 18-21, 13-18, or 17-18, or 6-7%, respectively, of patients receiving mesna IV and/or orally in controlled studies.1
Chest pain, edema, peripheral edema, hypotension, or tachycardia has been reported in up to 8% of patients receiving mesna IV and/or orally in controlled studies.1 Hypertension,25 increased heart rate, and ST-segment elevation also have been reported during postmarketing surveillance.1
Dyspnea, coughing, or pneumonia occurred in up to 8% of patients receiving mesna IV and/or orally in controlled studies.1 Tachypnea also has been reported during postmarketing surveillance.1
Fever has been reported in 15-20% of patients receiving mesna IV and/or orally in controlled studies.1 Other adverse effects reported with IV or oral regimens of mesna include hypokalemia, hematuria (all grades), increased sweating, back pain, pallor, dehydration, increased hepatic enzyme concentrations, limb pain, malaise, and myalgia.1
Precautions and Contraindications
Although mesna may prevent bladder toxicity (e.g., hemorrhagic cystitis, hematuria) induced by oxazaphosphorine derivatives (i.e., ifosfamide, cyclophosphamide), mesna does not prevent ifosfamide-induced nephrotoxicity3, 4, 30, 34 and does not prevent or decrease the incidence of nonurologic toxicities associated with oxazaphosphorine derivatives (e.g., myelosuppression, neurotoxicity, alopecia).1, 2, 3, 8 In addition, mesna does not prevent or decrease hematuria associated with other conditions such as thrombocytopenia.1, 2, 14
Because mesna prophylaxis does not prevent bladder toxicity in all patients receiving ifosfamide or cyclophosphamide,1, 2, 36, 40 patients receiving mesna should be instructed to notify the clinician if discoloration of urine occurs.1 In addition, urine of patients receiving the drug should be monitored for the presence of erythrocytes, which may precede hemorrhagic cystitis.1 Urine (e.g., a morning specimen) should be examined for the presence of erythrocytes before each scheduled dose of ifosfamide.1, 2, 52 In patients who develop microscopic hematuria (more than 10 erythrocytes per high power field [HPF]), ifosfamide therapy should be discontinued until the hematuria resolves, and vigorous oral or parenteral hydration as well as mesna should be used in these patients for subsequent courses of ifosfamide.49 Because hemorrhagic cystitis can be severe and may be fatal, ifosfamide or cyclophosphamide therapy should be discontinued or dosage of the drugs reduced in patients who develop hematuria (more than 50 erythrocytes/HPF or WHO grade 2 or higher) despite mesna prophylaxis.1, 2
Hypersensitivity reactions, ranging from mild allergic reactions to systemic anaphylactic reactions, have been reported in patients receiving mesna.1, 2 Patients with autoimmune disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus [SLE], nephritis) may be at increased risk of developing hypersensitivity reactions to mesna.1
Each 400-mg Mesnex® tablet contains 59.3 mg lactose;53 patients with a history of lactose intolerance may be sensitive to this formulation of the drug.
Mesna is contraindicated in patients with a history of hypersensitivity to mesna or other sulfhydryl (thiol) compounds.1, 2
Safety and efficacy of mesna in children have not been established.1, 53 However, mesna has been used for prophylaxis of ifosfamide-induced hemorrhagic cystitis in infants and children 4 months to 16 years of age32, 33, 34 and for prophylaxis of cyclophosphamide-induced hemorrhagic cystitis in children 5 months and older4 without unusual adverse effects. Each mL of mesna in multidose vials contains 1.04 mg of benzyl alcohol as a preservative.1, 2 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.54, 55, 56, 57, 58, 59 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.54, 55, 56, 57, 58, 59 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, 54, 56 the American Academy of Pediatrics (AAP) states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.54 Although not commercially available, a preservative-free formulation of mesna is available from the manufacturer. (See Chemistry and Stability: Chemistry and see Preparations.)53 The manufacturers state that mesna injection containing benzyl alcohol as a preservative should not be used in neonates and infants and should be used with caution in children and adolescents.1, 2
Mesna has been used in geriatric individuals during clinical studies;15 however, these studies did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.1, 3, 4, 53 Dosage of mesna should be selected carefully for geriatric patients since these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 However, the ratio of ifosfamide to mesna should remain unchanged.1
Mutagenicity and Carcinogenicity
No evidence of mutagenicity was seen with mesna in various in vitro and in vivo test systems including the Ames microbial ( Salmonella typhimurium ) test, mouse micronucleus test, sister chromatid exchange, or chromosome aberrations test in PHA-stimulated lymphocytes.1, 2
Long-term animal studies to determine the carcinogenic potential of mesna have not been preformed to date.1, 2
Pregnancy, Fertility, and Lactation
Reproductive studies using mesna oral dosages up to 1 g/kg in rabbits and 2 g/kg in rats (approximately 10 times the maximum recommended total daily human dosage [administered as 1 IV and 2 oral doses] on a body surface area basis) have not revealed evidence of harm to the fetus.1 Mesna has not been shown to be teratogenic in rats and rabbits.2 However, there are no adequate and controlled studies to date using mesna in pregnant women, and the drug should be used during pregnancy only when clearly needed.1
Reproduction studies to evaluate effects on male or female fertility have not been performed to date.1 However, no signs of male or female reproductive organ toxicity were seen in rats receiving oral dosages up to 2 g/kg daily (approximately 10 times the maximum recommended human dosage on a body surface area basis) for 6 months or in dogs receiving dosages up to 520 mg/kg daily (approximately 10 times the maximum recommended human dosage on a body surface area basis) for 29 weeks.1
It is not known whether mesna or dimesna is distributed into human milk.1, 2 Because of the potential for adverse reactions to mesna in nursing infants if the drug were distributed into milk, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1, 2
There is no evidence from in vitro and in vivo tumor models that concomitant mesna interferes with the antitumor activity of antineoplastic agents,1, 2, 8, 9 including ifosfamide, cyclophosphamide, doxorubicin, methotrexate, or vincristine.1, 8, 9
Mesna reportedly may interfere with sodium nitroprusside tests3, 4, 48 for urinary ketone determinations and cause falsely positive results.1, 2, 3, 48 This reaction presumably occurs because the sulfonate group contained in mesna interacts with the sodium nitroprusside reagent.4, 48
Oral doses of 6.1 and 4.3 g/kg were lethal to mice and rats, respectively; these doses are approximately 15 and 22 times, respectively, the maximum recommended human dose on a body surface area basis.1 Death was preceded by diarrhea, tremor, seizures, dyspnea, and cyanosis.1
There is no known specific antidote for mesna overdosage.1, 2
Mesna chemically interacts with urotoxic metabolites of oxazaphosphorine derivatives (e.g., ifosfamide, cyclophosphamide) to prevent or decrease the incidence and severity of bladder toxicity (e.g., hemorrhagic cystitis, hematuria) induced by these drugs.1, 2, 3, 4, 5 In urine, mesna reacts chemically with the urotoxic metabolites of ifosfamide or cyclophosphamide (e.g., binding with double-bonds of acrolein) and with their precursors (e.g., binding with 4-hydroxyifosfamide to form 4-sulfoethylthioifosfamide or with 4-hydroxycyclophosphamide to form 4-sulfoethylthiocyclophosphamide) resulting in detoxification of these metabolites.1, 2, 3, 4, 5 In addition, mesna enhances urinary excretion of cysteine, which also can react chemically with acrolein, and this effect may contribute to the uroprotective activity of mesna.5, 6
Although mesna can undergo alkylation and presumably could reduce the cytotoxic effectiveness of oxazaphosphorine derivatives by interfering with their mechanism of action, mesna exhibits detoxification activity only in the urinary tract and, thus, does not appear to alter systemic activity or nonurologic toxicity of oxazaphosphorine derivatives.62 In addition, mesna and dimesna (the principal form circulating in plasma) are hydrophilic and do not enter most cells, including tumor cells. 3, 4, 5, 7, 8, 9 Evidence from in vitro and in vivo tumor models and clinical studies in humans indicate that mesna does not deactivate active oxazaphosphorine metabolites in tumor cells nor interfere with the antineoplastic activity of oxazaphosphorine agents.1, 2, 3, 4, 5, 7, 8, 9, 17
Although some sulfhydryl-containing compounds are free radical scavengers and have been shown to be radioprotective,5, 9 results from in vitro test systems and clinical experience indicate that mesna may safely be used in regimens that include total body irradiation.7, 9, 10, 11, 12, 46
Whether mesna affects bone marrow engraftment has not been conclusively determined.7, 9, 10, 11, 28, 45, 46, 52 In one study, a higher incidence of graft failure was reported when mesna was used concurrently with cyclophospamide in a limited number of patients receiving an allogenic bone marrow transplant for aplastic anemia; however, there was no clinically important difference in the incidence or severity of graft-versus-host disease (GVHD) in these patients and graft failure has not been reported in other studies. 7, 9, 10, 11, 28, 45, 46
Like acetylcysteine, mesna reduces the viscosity of pulmonary secretions.5, 8, 51 The mucolytic effect of the drug depends on the free sulfhydryl group, which reduces the disulfide linkages of mucoproteins.5, 51
Efficacy of mesna as an uroprotective agent has been attributed to its distinctive pharmacokinetic profile.1, 2, 3, 4, 5, 29, 30 In systemic circulation, mesna is rapidly oxidized to the chemically stable and pharmacologically inert disulfide metabolite, dimesna (mesna disulfide).1, 2, 3, 4, 5, 29 Dimesna subsequently is rapidly filtered and eliminated by the kidneys, where it is partially reduced to the active drug, mesna.1, 2, 3, 4, 5, 29, 62 In urine, mesna reacts chemically with urotoxic metabolites of oxazaphosphorine derivatives resulting in their detoxification.1, 2, 3, 4, 5
Following IV or oral administration, mesna is rapidly and almost completely oxidized in systemic circulation to the chemically stable and pharmacologically inert disulfide metabolite dimesna (mesna disulfide).1, 2, 3, 4, 5 In a limited number of healthy adults who received a single 800-mg IV dose of mesna, peak plasma concentrations of mesna and dimesna averaged 18.2 and 59.7 mcg/mL, respectively.29 Following oral administration of a single 800-mg dose in these healthy adults, peak plasma concentrations of mesna and dimesna were achieved within 4 and 3 hours and averaged 3.3 and 7.3 mcg/mL, respectively.29 For a discussion of urinary bioavailability of mesna, see Pharmacokinetics: Elimination.
Because mesna and dimesna are hydrophilic, they remain principally in the intravascular compartment and appreciable distribution outside the compartment does not occur.3, 4, 5 The volume of distribution for mesna has been reported to be approximately 0.65 L/kg in healthy adults.2, 4, 29 The drug does not cross the blood-brain barrier.6
Approximately 69-75% of circulating mesna/dimesna is bound to plasma proteins.1
Plasma concentrations of mesna reportedly decline in a linear manner following IV administration.4, 29 In healthy adults who received a single 800-mg IV dose of mesna, the terminal plasma elimination half-lives of mesna and dimesna averaged 0.36 and 1.17 hours, respectively.1, 2, 4, 29
Mesna and dimesna are eliminated principally in urine,29 and most of a dose of mesna is eliminated in urine within 4 hours.1, 2 Because mesna and dimesna are highly water soluble and poorly distributed outside the vascular compartment, they are rapidly cleared from the plasma by the kidney.1, 2, 3, 4, 5 In the kidney, dimesna is partially reduced to the active drug, mesna.1, 2, 3, 4, 5, 62 Following glomerular filtration, reabsorption in the proximal tubule, and secretion into the tubule lumen, about 30% of filtered dimesna is reduced to mesna by the glutathione system.1, 2, 3, 4, 5
In healthy adults who received a single 800-mg IV dose of mesna, approximately 31 and 28% of the dose were excreted in urine within 4 hours as mesna and dimesna, respectively; approximately 32 and 33% were excreted within 24 hours as mesna and dimesna, respectively.1, 29 Following IV administration of a single 800-mg mesna dose, peak urine concentrations are achieved within 4 hours and average 1.57 and 1.4 mg/mL for mesna and dimesna, respectively.29 Urinary bioavailability of mesna following oral administration is approximately 45-79% compared with that following IV administration; food does not appear to affect the urinary bioavailability of orally administered mesna.1 Peak urine concentrations are achieved within 8 hours and average 0.41 and 0.59 mg/mL for mesna and dimesna, respectively, following oral administration of a single 800-mg dose.29 A urine mesna concentration of 0.1 mg/mL has been proposed as the minimum effective uroprotective concentration.4, 16, 29, 31
Following administration of the oral regimen of mesna, which consists of IV and oral doses of the drug (see Dosage and Administration), approximately 18-26% of the combined IV and oral mesna doses was detected as free mesna in urine.1 The oral regimen of mesna appears to produce higher systemic exposure (150%) than the IV regimen and provides a more sustained excretion of the drug in urine over a 24-hour period.1 The half-life of mesna ranges from 1.2-8.3 hours following administration of the oral regimen of the drug.1
Mesna and dimesna do not undergo hepatic metabolism.1, 2, 4
Mesna is a synthetic sulfhydryl (thiol) compound that acts as a sulfydryl donor and uroprotective agent.1, 2, 3, 4, 5 Mesna contains free sulfhydryl groups that can interact chemically with urotoxic metabolites of oxazaphosphorine derivatives (e.g., ifosfamide, cyclophosphamide).1, 2, 3, 4, 5
Mesna is commercially available as tablets for oral administration and as an injection for parenteral administration.1, 2 Commercially available tablets of the drug contain lactose as an excipient.1 (See Cautions: Precautions and Contraindications.) Mesna injection is a sterile, nonpyrogenic, clear and colorless aqueous solution containing edetate disodium as an antioxidant and sodium hydroxide for pH adjustment (to a range of 6.5-8.5).1, 2 Mesna injection is commercially available in 10-mL multidose vials containing 100 mg/mL of drug; each multidose vial contains 10.4 mg of benzyl alcohol as a preservative.1, 2 (See Cautions: Pediatric Precautions.) Although not commercially available, a preservative-free formulation of mesna (containing 200 mg of the drug in single-use ampuls) is available from the manufacturer through a compassionate use program for neonates, infants, or patients who are intolerant of benzyl alcohol.53 (See Preparations.) Mesna solutions containing 100 mg/mL have an osmolality of approximately 1563 mOsm/kg.18
Mesna injection should be stored at 15-30°C.2 Multidose vials may be stored and used for up to 8 days after initial entry.1
Mesna injection is compatible with 5% dextrose injection; 5% dextrose and 0.2, 0.33, or 0.45% sodium chloride injection; 0.9% sodium chloride injection; or lactated Ringer's injection.1, 2, 18 Following dilution to a concentration of 20 mg/mL in one of these IV solutions, mesna is chemically and physically stable for 24 hours at 25°C.1, 2
When exposed to oxygen, mesna is partially oxidized to dimesna (mesna disulfide); any unused mesna injection remaining in an opened ampul (available only through a compassionate use program) should be discarded.4, 18 Although short-term use of plastic or glass syringes for the preparation of mesna infusions appears to be acceptable, the drug should not be stored in glass or plastic syringes with Luer-Lok® fittings for longer than 12 hours because particulates may form.4, 18, 53
Mesna injection has been reported to be physically and chemically compatible with ifosfamide4, 18 or cyclophosphamide18 and is chemically stable for at least 24 hours in 5% dextrose injection or lactated Ringer's injection containing either drug.18 Mesna is incompatible with cisplatin1, 4, 18 or carboplatin.1, 18, 52 Specialized references should be consulted for specific compatibility information.18
Mesna tablets should be stored at a controlled room temperature of 20-25°C.1 Extemporaneous oral solutions containing 20 or 50 mg of mesna per mL prepared be diluting commercially available mesna injection in flavored syrup are stable for 7 days when stored at 24°C.26 Extemporaneous oral solutions containing 1, 10, or 50 mg/mL, prepared by diluting mesna in carbonated beverages or apple or orange juice, are stable for at least 24 hours at 5°C.26
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 400 mg | Mesnex® (scored) | |
Parenteral | Injection | 100 mg/mL | ||
Mesnex® | Bristol-Myers Squibb |
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2. American Pharmaceutical Partners, Inc. Mesna injection prescribing information. Los Angeles, CA; 2001 Jun.
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