Proposal for the inclusion of mesna (sodium 2-mercaptoethane

17th Expert Committee on the Selection and Use of Essential Medicines Geneva, 2009

Proposal for the inclusion of mesna (sodium 2-mercaptoethane sulfonate) for the prevention of ifosfamide and cyclophosphamide (oxazaphosphorine

cytotoxics) induced haemorrhagic cystitis

FINAL REPORT

Paul A. Carless BHSc, MMedSc.(Clin.Epid)

Discipline of Clinical Pharmacology School of Medicine and Public Health

Faculty of Health University of Newcastle

Level 5, Clinical Sciences Building, NM2 Newcastle Mater Hospital

Edith Street, Waratah, 2298

New South Wales AUSTRALIA

Tel +61-02-49211726 Fax + 61-02-49602088

WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008

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1. Summary statement of the proposal Mesna is proposed for the inclusion in the World Health Organisation (WHO) Model List of Essential Medicines for the prevention of oxazaphosphorine-induced (ifosfamide and cyclophosphamide) hemorrhagic cystitis. 2. Name of focal point in WHO submitting or supporting the application 3. Name of the organisation(s) consulted and/or supporting the application Discipline of Clinical Pharmacology, School of Medicine and Public Health, Faculty of Health, University of Newcastle, Level 5, Clinical Sciences Building, NM2, Newcastle Mater Hospital, Edith Street, Waratah, 2298, New South Wales, Australia. 4. International Nonpropriety Name (INN, generic name) of the medicine Mesna (Chemical name: sodium 2-mercaptoethane sulfonate). 5. Formulation proposed for inclusion Tablets: 400 mg, 600 mg Injection: 400 mg / 4 ml, 1g / 10 ml 6. International availability – sources, if possible manufactures (Appendix A) Mesna is marketed under 14 different trade names in 32 countries worldwide. A detailed list of manufacturers and distributors is presented in Appendix A. 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group Listing is requested on the Model List of Essential Medicines as an individual medicine. 8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population)

8.1 Global burden of disease The global burden of cancer continues to increase with the number of new cases expected to grow by 50% over the next 20 years to reach 15 million by 2020 (World Cancer Report 2003).1 Data available from the International Agency for Research on Cancer (IARC: Globocan 2002)2 indicates that in 2002 cancer claimed 6.7 million lives worldwide. In 2002 there were 10.9 million new cases of cancer diagnosed worldwide and between 1998-2002 there were 24.6 million people living with cancer. Cancer is the second leading cause of death in developed countries and is among the three leading causes of death in developing countries. A summary of global cancer deaths by region is presented in Table 1.1.


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Table 1.1: Summary of worldwide cancer deaths by region Region Deaths

2002 Predicted deaths

2020 North America 631,900 951,400Central America, South America, and Carribbean 479,900 833,800Northern Europe 241,100 297,600Central and Eastern Europe 637,000 742,800Western Europe 475,100 617,100Southern Europe 348,400 427,300Eastern Asia 2,016,300 3,223,700South-Central Asia 845,200 1,389,800South-Eastern Asia 363,400 709,300Northern Africa and Western Asia 224,000 389,200Sub-Saharan Africa 412,100 626,400Oceania 49,500 77,300Total 6,723,900 10,285,700

Source: IARC, Globocan 20022

More recent data indicates that in 2005 cancer killed 7.6 million people which accounts for around 13% of all deaths worldwide.3 Of all these cancer deaths 70% occurered in low and middle income countries. The WHO predicts that deaths from cancer in the world will continue to rise with an estimated 9 million people dying from cancer in 2015 and by 2030 the number of deaths from cancer is anticipated to be 11.4 million of whom 8.9 million will be from low-middle income countries compared to 2.5 million will be from high income countries. A summary of the types of cancer leading to overall cancer mortality in 2002 is presented in Table 1.2 and Figure 1.1.

Table 1.2: Summary of the types of cancer leading to overall cancer mortality in 2002 Type of cancer Number of cases Mouth and oropharynx cancers 317,894 Oesophagus cancer 446,166 Stomach cancer 850,401 Colon and rectum cancers 622,256 Liver cancer 618,124 Pancreas cancer 230,957 Trachea, bronchus, lung cancers 1,243,199 Melanoma and other skin cancers 66,034 Breast cancer 477,196 Cervix uteri cancer 238,814 Corpus uteri cancer 71,387 Ovary cancer 134,623 Prostate cancer 269,292 Bladder cancer 178,850 Lymphomas, multiple myeloma 334,421 Leukemia 264,229 Other malignant neoplasms 756,924 Other neoplasms 148,910

Source: Global Action Against Cancer - Updated Edition 20053


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810

254

405

383

204

226

99

93

80

109

111

56

292

372

237

241

164

233

110

33

67

47

85

101

114

34

0 100 200 300 400 500 600 700 800 900

Lung

Breast

Colorectum

Stomach

Liver

Prostate

Cervix uteri

Oesophagus

Bladder

Non-Hodgkin lymphoma

Oral cavity

Leukaemia

Pancreas

Ovary

Kidney

Number (Thousands)

Mortality Female

Mortality Male

Fig. 1.1 Mortality of the most common cancers worldwide by sex. Source: World Cancer Report 2003.1 In terms of incidence, the most common cancers worldwide (excluding non-melanoma skin cancers) are lung (12.3% of all cancers), breast (10.4%) and colorectum (9.4%)(Fig.1.2). As stated in the World Cancer Report (2003),1 for any disease the relationship of incidence to mortality is an indication of prognosis, similar incidence and mortality rates being indicative of an essentially fatal condition. Thus, lung cancer is the largest single cause of deaths from cancer in the world (1.1 million annually), since it is almost invariably associated with poor prognosis.


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901

498

558

398

542

278

259

166

169

144

115

118

337

1,050

445

317

165

470

133

76

120

97

112

100

192

70

0 100 200 300 400 500 600 700 800 900 1000 1100 1200

Lung

Breast

Colorectum

Stomach

Liver

Prostate

Cervix uteri

Oesophagus

Bladder


Oral cavity

Leukaemia

Pancreas

Ovary

Kidney

Number (Thousands)

Incidence Female

Incidence Male

Fig. 1.2 Incidence of the most common cancers worldwide by sex. Source: World Cancer Report 2003.1 The burden of cancer is not distributed evenly between the developing and developed world, with specific cancer types displaying different patterns of distribution (Fig.1.3 and 1.4). As discussed in the World Cancer Report (2003),1 many differences in the distribution of cancer between regions are explicable with reference to etiological factors. In developing countries for example, populations are vulnerable to cancers in which infectious agents (and associated non-malignant diseases) play a major role. These include cancers of the stomach, uterine cervix, liver and possibly oesophagus. Whereas other cancers such as colorectal and prostate cancers, the burden of disease falls disproportionately on the developed world.


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Male

471

208

416

319

73

55

164

60

80

58

62

79

66

37

41

431

350

127

180

325

224

96

110

86

86

80

39

50

64

59

0 50 100 150 200 250 300 350 400 450 500

LungStomachProstate

ColorectumLiver

OesophagusBladder

Oral cavityNon-Hodgkin lymphoma

LeukaemiaLarynxKidney

PancreasOther pharynx

Brain, etc

Number (Thousands)

Less developed

More developed

Fig. 1.3 Comparison of the most common cancers in males in more and less developed countries in 2000. NHL = Non Hodgkin lymphoma. Source: World Cancer Report, 2003.1

Female

579

91

291

175

125

91

113

33

16

66

47

61

24

35

48

471

379

154

161

192

101

75

132

117

54

65

39

72

53

27

0 100 200 300 400 500 600 700

Breast

Cervix uteriColorectum

Lung

StomachOvary

Corpus uteri

LiverOesophagus


LeukaemiaPancreas

Oral cavity

ThyroidBladder

Number (Thousands)

Less developed

More developed

Fig. 1.4 Comparison of the most common cancers in females in more and less developed countries in 2000. NHL = Non Hodgkin lymphoma. Source: World Cancer Report, 2003.1 Data available from the IARC (Globocan 2002)2 indicates that more than 160,000 children worldwide are diagnosed with cancer each year, and it is estimated that 90,000 will eventually die of cancer. In the United States cancer is the second leading cause of death


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among children between the ages of 1 and 14 years.4 The principle subtype of paedatric cancer in affluent societies is acute leukaemia where the incidence rate is within the range of 30-45 per 106 children per year.5 In the United Kingdom there around 500 new cases of acute leukaemia diagnosed each year in children up to 15 years. Other common childhood cancers include cancer of the brain and other nervous system cancers, soft tissue sarcomas, non-Hodgkin Lymphoma, and renal (Wilms) tumors. In the United States advances in the treatment of childhood cancers have led to an improved 5-year survival rate from 56% for patients diagnosed in 1974-1976 to 79% in children diagnosed with cancer in 1995 to 2001.4 In the case of acute leukaemia, controlled clinical trials of chemotherapy in the United States and Europe have steadily improved the survival of children to 85%.5 However, not all children worldwide have access to optimal treatment. As 80% of children live in developing countries where effective treatment is not available, one in two children diagnosed with cancer will die.3 8.2 Cancer treatment - Chemotherapy Chemotherapy was first used to treat cancer in 1943 following the observation of leukopenia in military personnal exposed to mustard gas.1 Although significant advances have been made in chemotherapy since then the therapeutic use and benefit of chemotherapy is restricted by toxic lesions which are often organospecific. Examples of this include the cardiotoxic effects of doxorubicin, the hepatotoxicity of methotrexate, nephrotoxicity of cisplatin, neurotoxicity of vincristine, pulmonary fibrosis induced by bleomycin, and urotoxicity of the two oxazaphosphorines cyclophosphamide and ifosfamide.6 The toxicities of chemotherapy can adversely affect both the short and long-term quality of life of patients, it can limit the dose and duration of treatment, can be life-threatening, and may contribute to the medical and non-medical costs of cancer care.7 To ameliorate the toxicity associated with cytotoxic agents a number of chemoprotectants have been developed to provide site-specific protection for normal tissues, without compromsing antitumour efficacy.8 Mesna (sodium-2-mercaptoethane sulfonate) was developed as a specific chemoprotective compound against acrolein-induced bladder toxicity, a dose-limiting side-effect of both cyclophosphamide and ifosfamide. Cyclophosphamide was first synthesized in 1958 and was the prototype of the oxazaphosphorines without a direct alkylating action. It is a prodrug of nor-N-mustard requiring biotransformation to hydroxylated intermediates by hepatic cytochrome P-450 mixed-function oxidase system to exert cytotoxic activity.9-11 The hydroxylated intermediates undergo breakdown to form active compounds, phosphoramide mustard and acrolein, a urotoxic agent. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step.10 Cyclophosphamide is indicated for the treatment of myeloproliferative and lymphoproliferative disorders; disseminated neuroblatoma; ovarian adenocarcinoma; retinoblastoma; breast and lung carcinoma; autoimmune disease; and transplant rejection prevention. Ifosfamide was first synthesized in the late 1960’s and is an oxazaphosphorine alkylating agent closely related structurally to cyclophosphamide except for the displacement of one chlorethyl residue from the extracyclic to the ring nitrogen (cyclophosphamide analogue). The location of the ring chlorethyl side chain significantly slows hydroxylation which produces isofosforamide mustard, the primary alkylating compound, and the urotoxic agent acrolein.12 This slight modification results in a clinically significant change in the activity and toxicity of ifosfamide compared to cyclophosphamide.13 Ifosfamide is indicated for the


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treatment of germ cell tumours, sarcomas, and lymphomas; ovarian, cervical, lung, and breast cancers. Mesna (sodium-2-mercaptoethane sulfonate) is a thiol compound, which functions as a regional detoxificant of urotoxic oxazaphosphorine cytostatic agents, ifosfamide and cyclophosphamide. As described by Links and Lewis (1999),8 mesna inactivates alkylating metabolites by forming an inert thioether. Upon entering the bloodstream mesna is immediately converted to an inactive disulfide form, dimesna (dithiodiethanesulfate) which is subsequently filtered and secreted by the kidneys, where the enzymes thiol transferase and glutathione reductase reduce dimesna back to mesna. The free sulfhydryl (thiol) groups of mesna combine directly with a double bond of acrolein and with other urotoxic 4-hydroxy-oxazaphosphorine metabolites (4-hydroxycyclophosphamide and 4-hydroxyifosfamide) to form stable nontoxic compounds. The metabolite acrolein has been implicated as the major causative agent in oxazaphosphorine-induced urothelial toxicity.7 8.3 Haemorrhagic cystitis The American Society of Clinical Oncology (ASCO)7 suggests that the overall reported incidence of oxazaphosphorine-induced haemorrhagic cystitis varies considerably due to a lack of agreement for diagnostic criteria, variability in definition of the relevant time frame, and uncertainty regarding the relative contributing factors such as thrombocytopenia, concurrent or previous chemotherapy or radiotherapy, and viral infections. These guidelines indicate that in patients treated with ifosfamide without urothelial protection the overall incidence of haemorrhagic cystitis ranges from 18% to 40% and is considered dose-limiting. In the case of high-dose cyclophosphamide, patients treated with aggressive hydration in the context of bone marrow transplantation, the incidence of severe haemorrhagic cystitis ranges from 0.5% to 40%. In patients who develop severe bladder haemorrhage mortality rates range from 2% to 4%.7 Haemorrhagic cystitis is generally graded as mild, moderate or severe according to the degree of pain and haematuria. Severe haemorrhagic cystitis typically includes the presence of gross haematuria with clots and occurrence of clinical complications, it can be extremely painful and debilitating, requiring prolonged and expensive hospitalisation.14 9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostic or treatment facilities and skills) 9.1 Indications for use Although there are global variations in the listed indications for mesna, generally mesna is indicated for the prevention of urothelial toxicity in patients treated with oxazaphosphorine cytotoxics, predominantly ifosfamide and cyclophophamide. The United States Food and Drug Administration (FDA) approved indications for mesna are as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis. AHFS Drug Information (2007)15 states that the use of mesna to prevent cyclophosphamide-induced hemorrhagic cystitis is not an FDA approved indication, mesna has been designated an orphan drug by the FDA for inhibition of the urotoxic effects induced by other oxazaphosphorine compounds such as cyclophosphamide.


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9.2 Dosage regimens 9.2.1 Intravenous mesna regimen in patients receiving ifosfamide According to the American Society of Health-System Pharmacists15 the regimen recommended by the manufacturers16 and the American Society of Clinical Oncology (ASCO)7,17 for the prophylaxis of ifosfamide-induced hemorrhagic cystitis, is mesna be 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. 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 minutes 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. 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. 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.15 In patients receiving ifosfamide by continuous IV infusion, the American Society of Clinical Oncology (ASCO) guidelines state that mesna may be administered at a dosage equivalent to 60% of the ifosfamide daily dosage.17 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.17 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.17 As stated in the AHFS Drug Information guide for mesna (2007),15 some clinicians suggest that infusions of mesna be continued for 8–24 hours after completion of the ifosfamide infusion. As stated in the ASCO guidelines the 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.17 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.7 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.7,17 9.2.2 Intravenous and oral mesna regimen in patients receiving ifosfamide In the IV and oral regimen recommended by the manufacturer and ASCO guidelines 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.16,17 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. 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. This


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regimen is given each day that ifosfamide is administered and, if ifosfamide dosage is increased or decreased, the ratio of mesna to ifosfamide should be maintained. 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 (Mesnex® - Product Information, Baxter Healthcare Corporation, May 2002).16 9.2.3 Prophylaxis in patients receiving cyclophosphamide According to the American Society of Health-System Pharmacists15 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. Mesna should be administered each day cyclophosphamide is administered, and probably should be continued for at least 24 hours after cyclophosphamide is discontinued. 9.2.4 Mesna regimen for intravenous bolus of ifosfamide or cyclophosphamide If ifosfamide or cyclophosphamide is given as an intravenous bolus, the intravenous dose of mesna is 20% of the dose of the antineoplastic on a weight for weight basis given on 3 occasions over 15 to 30 minutes at intervals of 4 hours beginning at the same time as the antineoplastic injection; thus the total dose of mesna is equivalent to 60% of the antineoplastic given.18 This regimen is repeated each time the antineoplastic is used. Each individual dose of mesna may be increased to 40% of the dose of the antineoplastic and given 4 times at intervals of 3 hours for children and patients at high risk of urotoxicity; in such cases the total dose of mesna is equivalent to 160% of the antineoplastic given. The oral dose of mesna is 40% of the dose of the antineoplastic given on 3 occasions at intervals of 4 hours beginning 2 hours before the antineoplastic injection; thus a total dose of mesna equivalent to 120% of the antineoplastic is given. Alternatively, the initial dose of mesna may be given intravenously (20% of the dose of the antineoplastic), followed by two oral doses (each 40% of the dose of the antineoplastic) given 2 and 6 hours after the intravenous dose. Any of these regimens may be used if cyclophosphamide is given orally.18 9.2.5 Mesna regimen for intravenous infusion of ifosfamide or cyclophosphamide If the antineoplastic is given as an intravenous infusion over 24 hours, an initial intravenous injection of mesna as 20% of the total antineoplastic dose is followed by 100% of the total dose by intravenous infusion concurrently over 24 hours, followed by 60% by intravenous infusion over a further 12 hours (total dose 180% of the antineoplastic).18 The final 12-hour infusion may be replaced either by 3 intravenous injections each of 20% of the antineoplastic dose at intervals of 4 hours, the first injection being given 4 hours after the infusion has been stopped, or by oral mesna given in 3 doses each of 40% of the antineoplastic dose, the first dose being given when the 24-hour infusion is stopped, and the second and third doses being given 2 and 6 hours later.18 9.3 Duration of therapy and patient monitoring The aim of mesna therapy is to ensure adequate levels of mesna in the urine throughout the period during which toxic metabolites are present. The duration of mesna treatment should therefore equal that of the antineoplastic treatment plus the time taken for the concentration of antineoplastic metabolites in the urine to fall to non-toxic concentrations. Urinary output should be maintained at 100 ml/hr and the urine monitored for haematuria and proteinuria throughout the treatment period.


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9.4 Reference to existng WHO and other clinical guidelines The ASCO Clinical Practice Guidelines published in 19997 and updated in 200217 recommend the use of mesna as a uroprotectant in patients treated with ifosfamide and cyclophosphamide. A summary of these guidelines is presented in Table 1.3. Table 1.3: Summary of ASCO Clinical Practice Guidelines for the use of mesna as a urothelial protectant published in 1999 and updated in 2002 1. Mesna use with ifosfamide

The use of mesna is recommended to decrease the incidence of ifosfamide-associated urothelial toxicity.

a. Mesna dosing with standard-dose ifosfamide

It is suggested that the daily dose of mesna be calculated to equal 60% of the total daily dose of ifosfamide, administered as three bolus doses given 15 minutes before and 4 and 8 hours after administration of each dose of ifosfamide when the ifosfamide dose is less than 2.5 g/m2/d administered as a short infusion. For use with contiunous infusion ifosfamide, mesna may be administered as a bolus dose equal to 20% of the total ifosfamide dose followed by a continuous infusion of mesna equal to 40% of the ifosfamide dose, continuing for 12 to 24 hours after completion of the ifosfamide infusion.

b. Mesna dosing with high-dose ifosfamide There is insufficient evidence on which to base a recommendation for the use of mesna with ifosfamide doses in excess of 2.5 g/m2/d. The efficacy of mesna for urothelial protection with very high-dose ifosfamide has not been proven. Based on the longer half-life of ifosfamide in these dosages, more frequent and prolonged mesna dosage regimens may be necessary for maximum protection from urotoxicity.

c. Mesna administration by the oral route Administration of the first dose of mesna intravenously (IV) at a dose equal to 20% of the

total daily ifosfamide dose, followed at 2 and 8 hours by 40% weight/ weight of the ifosfamide dose administered orally, amy be considered an acceptable alternative to the three-dose IV mesna reigmen when the total ifosfamide daily dose is less than 2.0g/m2.

2002 Recommendation: Mesna tablets have been approved by the United States Food and

Drug Administration (FDA) to prevent hemorrhagic cystitis in patients receiving ifosfamide chemotherapy. The recommended dose and schedule is to administer mesna as an IV bolus injection in a dosage equal to 20% of the ifosfamide dosage (weight/weight) at the time of ifosfamide administration. Mesna tablets are given in a dosage equal to 40% of the ifosfamide dose at 2 and 6 hours after each dose of ifosfamide. The total daily dose of mesna is 100% of the ifosfamide dose. Patients who vomit within 2 hours of taking mesna should repeat the dose or receive IV mesna. The dosing schedule should be repeated on each day that ifosfamide is administered.

2. Mesna use with cyclophosphamide

Mesna plus saline diuresis or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide in the setting of stem-cell transplantation.

3. Surveillance of patients receiving ifosfamide and/or cyclophosphamide and mesna There are insufficient data to make a recommendation regarding specific monitoring for hemorrhagic cystitis in patients who receive mesna to ameliorate ifosfamide-or-high-dose cyclophosphamide associated urothelial toxicity. Recommendations for monitoring reflect the design of clinical trials involving mesna use and the opinion of the Panel.

Source: Hensley et al. 19997


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9.5 Need for special diagnostic or treatment facilities and skills In the case of haemorrhagic cystitis there is no need for special diagnostic facilities, but frequent clinical assessment of patients for the presence of haemorrhagic cystitis and the side effects associated with mesna treatment is required. The two most commonly used and relatively simple methods to detect haematuria is urinanalysis and urine microscopy. Urinalysis can be performed by nursing staff using a sample of urine collected from the patient and analysed using a testing dipstick. However, urine microscopy requires urine samples to be sent to specialist testing facilities to be analysed. Given that mesna is given concurrently with ifosfamide and cyclophosphamide, which are frequently combined with other chemotherapy drugs (e.g combination chemotherapy regimens such MINE; mitoxantrone, ifosfamide, mesna, etoposide), initial and maintenance therapy involving intravenous adminstration of these two oxazaphosphorine cytotoxic agents requires specialist facilities capable of delivering these drugs in a safe and effective manner by suitably qualified staff. 10. Summary of comparative effectiveness in a variety of clinical settings 10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data) To identify systematic reviews and randomised clinical trials of mesna the following databases were searched: Medline (1950 to July, 2007), EMBASE (1980 to July, 2007), CancerLit (to July, 2007), the Cochrane Database of Systematic Reviews (Issue 2, 2007), and the Cochrane Central Register of Controlled Trials (CENTRAL). To maximise the sensitivity for the retrieval of all potentially relevant studies, the electronic searches of these databases were searched initially using an unrestricted search strategy, employing exploded MeSH terms (exp Mesna/) and specific text-word terms for mesna. The specific text-word terms included: ‘sodium-2-mercaptoethane sulfonate’, ‘sodium 2-mercaptoethanesulfonate’, ‘mercaptoethane sulfonate’, ‘mesnil’, ‘mesnex’,‘mexan’, ‘mitexan’, ‘uromitexan’, and ‘ziken’. To restrict and improve the specificity of these searches, three search filters were used. First, a filter to identify randomised controlled trials,19 second a filter to identify systematic reviews and meta-analyses, and thirdly a filter to identify studies of the urinary system (Medline and EMBASE search strategies are provided in Appendix B). The internet was widely searched using Google™ and Google™ Scholar. The reference lists of identified trials, reviews, reports and guidelines were searched for potentially relevant studies. Studies were included for review if they were either systematic reviews, randomised controlled parallel group trials, randomised head-to-head comparison trials, or observational studies with concurrent or non-concurrent control groups, and evaluated the effectiveness of mesna in reducing the urotoxic side effects of ifosfamide and/or cyclophosphamide. Studies that evaluated the use of mesna outside its indication for the reduction and prevention of urothelial toxicity induced by oxazaphosphorine cytotoxics (ifosfamide, cyclophosphamide) were not included for review. 10.2 Summary of available data (appraisal of quality, outcome measures, summary of results) No systematic reviews or meta-analyses were identified during the extensive search of the literature. Thirteen randomised trials of mesna were identified and included for review. These trials were either randomised placebo-controlled trials, randomised head-to-head comparative trials, or randomised crossover trials.20-32 One of the included randomised controlled trials27 reported preliminary data of a subsequently published trial.28 Therefore, only the latter trial is


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reviewed in this report. A summary of the results for the randomised controlled trials of mesna is presented in Table 10.2. 10.2.1 Mesna and ifosfamide In a randomised controlled trial by Araujo and Tessler,24 70 patients were randomly allocated to standard prophylaxis (raised fluid intake and forced diuresis) or prophylaxis wih oral mesna. In group I, 37 patients with squamous cell carcinoma were treated with intravenous adriamycin (ADM) 40 mg/m2 given on day 1 followed by four times IV ifosfamide 2250 mg/m2 given on days 2-5. In group II, 33 patients with non-squamous cell carcinoma (adenocarcinoma 21, small-cell carcinoma 9, large-cell carcinoma 3) were treated with IV dicarbazine (DTIC) 800 mg/m2 given on day 1, IV methotrexate (MTX) 30 mg/m2 given on day 2, and daily IV ifosfamide 2250 mg/m2 given on days 2-5. Of the 37 patients in group I, 12 received standard prophylaxis and 25 received oral mesna. Of the 33 patients in group II, 13 received standard prophylaxis and 20 received oral mesna. All patients received hydration therapy during ifosfamide treatment on days 2-5 of each cycle of treatment. Ifosfamide was infused in 500 ml of normal saline over 3 hours. The first oral dose of mesna 840 mg/m2 was given at the start of the ifosfamide infusion. The second and third doses of 840 mg/m2 were given 4 and 8 hours later. All patients enrolled in the trial were scheduled to receive at least 2 courses of chemotherapy, this was continued if patients showed satble disease or evidence of tumour regression. All chemotherapy was ceased if tumour progression was observed or when a cumulative dose of 550 mg/m2 of adriamycin was reached. Of the 45 patients who received oral mesna, there was four episodes of cystitis during 88 courses of treatment, and 10 episodes of microscopic haematuria. Of the 25 patients who received standard prophylaxis, there were 38 episodes of cysitits during 50 courses of treatment, 10 episodes of microscopic haematuria, and 26 reported episodes of gross haematuria. The differences in the incidence of cystitis and haematuria between mesna and standard prophylaxis was statistically significant (P < 0.0001). Moderate diarrhoea was only observed in patients receiving mesna treatment (6 episodes over 88 courses of chemotherapy; P<0.02). The overall response rates with the two regimens were not statistically significantly different. The overall response rate (complete response + partial response) was 28.5%. Complete remission (CR) was observed in 11% of the patients treated with mesna and 4% in the patients treated with standard prophylaxis. Partial remission was observed in 20% of patients in both groups. The median survival time under both treatment regimens was 6 months. A randomised, head-to-head comparative trial by Legha et al.23,33 evaluated the uroprotective effect of IV mesna compared to IV n-acetylcysteine (NAC) in 62 heavily pre-treated sarcoma patients treated with ifosfamide 2 g/m2 on days 1-5. Both NAC and mesna were commenced immediately prior to ifosfamide and were administered every 4 hours three times a day at doses of 1.5 g/m2 and 400 mg/m2, respectively. Subsequent doses of ifosfamide were adjusted to achieve a polymorphonuclear (PMN) nadir of 500+/-250/µL. Mesna was to be substituted for NAC or the number of mesna doses could be increased up to four per day in those patients developing severe haematuria. Of the 62 patients enrolled in the trial, 31 were randomised to receive NAC and 31 were randomised to receive mesna treatment. The study participants was predominantly male. Histological diagnoses of randomised patients included; leiomyosarcoma, osteosarcoma, unclassified sarcoma, synovial sarcoma, MFH, and Ewing’s sarcoma. The results showed that the incidence of haematuria (>4 RBC/HPF) was related to the ifosfamide dose. When ifosfamide was administered at 2 g/m2 for 5 days the rate of haematuria (Grade 2) was 6% in those patients treated with mesna compared to 29% (Grade


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3-4) in NAC treated patients (P<0.04). The published abstract of this trial23 reported that severe haematuria (>50 RBC/HPF) was also more frequent in the NAC arm than the mesna arm (6 versus 1, respectively). When these six NAC patients were swtiched to mesna treatment no further episodes of haematuria were observed. A randomised placebo-controlled double-blind comparative trial by Fukuoka et al.20 evaluated the efficacy of intravenous mesna in 101 patients diagnosed with lung cancer. Of the 101 randomised patients, 91 were available for data analysis (evaluable patients), 10 were excluded because of poor performance status (ECOG Grade 4) and pre-existent haematuria (n = 2), and/or ifosfamide discontinuation due to non-urinary related side effects (n = 8). Fourty-five patients received intravenous mesna and 46 patients received an identical placebo. Thirty 4 ml ampoules of the test drug (mesna or placebo) were put into one package to be used in each patient. After an independent authority confirmed the test drugs to be indistinguishable, random allocation was performed on an institution basis. Random allocation codes were kept concealed until data analysis. Ifosfamide was dissolved in 100 ml of saline and administered by 10-15 minute intravenous infusion at a dose of 2 g/m2 for 5 consecutive days. Mesna or placebo was administered intravenously at 4 ml/m2 (mesna: 400 mg/m2, corresponding to 20% of the ifosfamide dose) immediately after, then 4 hours and 8 hours after the ifosfamide administration (mesna: 1200 mg/m-2/day-1, corresponding to 60% of the ifosfamide dose) for 5 consecutive days. All patients received hydration therapy with a daily volume of 2000 ml until test drug administration was completed. Forced oral intake of large volumes of water was not conducted. Additional hydration was allowed in cases of ifosfamide-induced nausea, vomiting and subsequent dehydration. Patients were predominantly male (~ 76%) with a mean age of 60.9 years (placebo arm) and 62.3 years (mesna arm). The majority of patients were diagnosed with squamous cell carcinoma and adenocarcinoma (84.4% mesna arm compared to 76.1% in the placebo arm). Prior chemotherapy was similar across treatment arms (P = 0.9528). The results of this study20 showed that the incidence of moderate or severe haematuria was significantly reduced in those patients receiving mesna (6.7%) compared to placebo (32.6%; P = 0.0008). Mild haematuria was not observed in any patient treated with mesna, but was observed in 8.7% of patients treated with placebo. No patient treated with mesna experienced moderate or severe graded micturition pain or the feeling of residual urine compared to 19.6% and 15.2% of patients in the placebo arm respectively. No side-effects attributable to mesna were observed. Of the 39 evaluable mesna patients, there was no change observed in tumour response in 84.6% of patients and progressive disease 15.4%. Of the 32 evaluable placebo patients a partial response was observed in 3.1% of patients, no change in 81.3%, and progressive disease in 15.6%.There was no statistically significant difference between mesna and placebo in observed tumour response (P = 0.7898). In a single-blind crossover trial by Bryant et al.22 eight patients, with advanced bronchogenic carcinoma undergoing treatment with two courses of ifosfamide (2 g/m2 by intravenous bolus separated by a 2-week interval) were given one course of chemotherapy with and one without mesna. Mesna was given in a dose of 400 mg/m2 by intravenous (IV) bolus at 0, 4, and 8 hours after ifosfamide. In addition a 24 hour IV infusion of detrose/saline was administered at a rate of 1 litre over 8 hours given immediately after ifosfamide. Frusemide 40 mg was given intravenously if the two hourly urine output fell below 100 ml/hr. Five of the original eight patients were subsequently treated with a total of 15 courses of ifosfamide in increasing doses of 4 to 8 g/m2 by intravenous bolus or 24 hour infusion. During each course mesna was given 4-hourly as an IV bolus to a total course of 60% of the ifosfamide dose. One patient received


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8 g/m2 of ifosfamide as a 24-hour infusion and was treated with a continuous infusion of mesna. The results of this crossover trial showed that when mesna was given to the eight patients treated with two courses of ifosfamide (2 g/m2 by intravenous bolus) haematuria developed in only one patient compared with seven patients when mesna was not given concomitantly with ifosfamide. The incidence of urinary frequency and dysuria was reduced from five to just one episode when mesna was administered. Although one patient who was treated with mesna developed frequency and microhaematuria this patient was found to have had a urinary tract infection which may have accounted for the adverse findings. For the five patients that received mesna and escalating doses of ifosfamide of 4 to 8 g/m2 over a total of 15 courses of treatment there were three incidences of microhaematuria and one incidence of frequency and dysuria. A randomised non-blinded crossover trial by Frustaci et al.25 compared oral mesna with oral argimensa (arginine 2-mercaptoethanesulfonate) in the prevention of haemorrhagic cystitis in 27 patients with various metastatic malignancies. Of these 27 randomised patients, 26 were fully evaluable (2 completed crossover uroprotective modalities). All patients received the first mesna dose intravenously as 20% of the ifosfamide total dose; whereas subsequent uroprotection was randomly assigned to either oral mesna or oral argimensa. Treatment A consisted of argimesna (capsules) at a dose of 20% of the total ifosfamide dose, for 4 doses every 2 hours. Treatment B consisted of mesna (Uromitexan® vials) diluted in 15 ml of cold soft drink at a dose of 40% of the total ifosfamide dose for 2 doses every 4 hours. Although a maximum of four consecutive cycles using a crossover design was planned for each patient (ABAB or BABA) the completion of two cycles was considered sufficient for the evaluability of each case. There were 13 males and 14 females enrolled in the trial, with a median age (range) of 56 years (17-74 years). Patient malignancies included; sarcomas (n = 22), testicular cancer (n = 2), endometrial cancer (n = 2), and breast cancer (n = 1). Twenty patients received IV ifosfamied of 1.8 g/m2/day for 5 days, four patients received 2-2.5 g/m2/day for 2 days, and three patients received 3 g/m2/day for 2 days. Ifosfamide was diluted in 500 ml of Ringers acetate and infused IV over 1 hour. Pre-hydration and post-hydration were performed in each cycle with 500 ml and 2000 ml of fluids (Ringers solutions, 5% glucose, normal saline), respectively. Ifosfamide was always combined with other antineoplastic agents including; epirubicin, doxorubicin, cisplatin, vinblastine, and dacarbazine. Overall, 78 cycles of oral uroprotection were assessed, 41 for oral mesna (vials) and 37 for oral argimensa (capsules). The results of this trial showed that microhaematuria occurred in 12 patients, with an incidence of 7 out of 37 cycles of argimesna and 11 out of 42 cycles of mesna (P > 0.05). Macroscopic or symptomatic haematuria, and urinary symptoms such as dysuria were not observed in either treatment arm. Subjective assessment of gastrointestinal discomfort indicated that argimesna was better tolerated than mesna. GI discomfort was reported in 12 cycles out of 37 for argimesna, as compared to 34 out of 42 for oral mesna (P < 0.001). From the results of this crossover trial Frustaci et al. claimed that oral argimensa is as effective and safe as oral mesna. A randomised crossover trial by Sakurai et al.21 involved 13 patients with advanced non-small cell lung cancer. All patients had been previously treated with chemotherapy and had demonstrated refractoriness to prior treatment more than 4 weeks before enrolment into the trial. High-dose ifosfamide was administered as an IV infusion of 6 g/m2 over 30 minutes. Unless there was evidence of disease progression ifosfamide treatment was repeated twice in a 21-day cycle. Mesna was administered three times at 1.2 g/m2 every four hours on days 1-3.


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Patients randomised to group A received ifosfamide and mesna with the first course of therapy and ifosfamide alone at the time of the second treatment. Patients randomised to group B received the treatment in reverseorder. All patients were hydrated with an IV infusion of 2,500 ml of 5% detrose and electrolytes on days 1-7. Of the initial 13 patients enrolled in the trial 10 completed the trial treatment protocol. A total of 10 patients received treatment with ifosfamide plus mesna and 10 patients received ifosfamide alone. The results showed a significant decrease in the incidence of haematuria in when patients were treated with mesna combined with ifosfamide (P < 0.05). Only one patient developed macrohaematuria when treated with ifosfamide and mesna compared to seven patients when treated with ifosfamide alone (P < 0.025). There was no statistically significant difference in the rates of urinary frequency and dysuria between the two treatment regimens. The results of this small randomised crossover trial suggest mesna effectively reduced the incidence of haemorrhagic cystitis induced by high-dose ifosfamide. Munshi et al.34 conducted a prospective cohort study of 318 consecutive patients with refractory germ cell neoplasms were enrolled between January 1983 to August 1988 to receive ifosfamide containing combination chemotherapy with either intravenous mesna or n-acetylcysteine (NAC) as the uroprotector. Of these patients, 277 were evaluable. Of the 41 patients that were not able to be evaluated, complete data were not available for 27 patients and 14 patients did not receive at least one course of treatment. Between January 1983 and March 1985, all patients received ifosfamide combination chemotherapy and oral NAC as the uroprotector. After April 1985, all subsequent patients received IV mesna. NAC was administered orally at a dose of 2 gram every 6 hours on days 1-7. Mesna was administered as an IV bolus at 120 mg/m2 before ifosfamide and then 1200 mg/m2 by continuous infusion on days 1-5. Hydration was given to all patients by a continuous infusion of 3 litres/day of normal saline. Cycles were repeated every three weeks for four cycles or until tumour progression. Patients developing haematuria were treated with continued hydration and the uroprotector until the haematuria resolved. Ifosfamide was withheld if patients developed grade 2-3 haematuria until resolution then the dose was reduced by 25%. The results of this prospective observational study showed that the overall rate of haematuria was statistically significantly reduced in patients receiving mesna (4.2%) compared to NAC (27.9%; P < 0.0001). Grade 3 haematuria (>50 RBCs/hpf) was reported in 9.3% of NAC patients compared to 1.1% of mesna treated patients. One of the two patients that developed grade 3 haematuria in the mesna group had received a ureteral stent which was considered the etiologic cause of the haematuria. Ifsofamide dose reduction solely for urothelial toxicity was not required in any mesna treated patient whereas 12.8% of NAC patients required a reduction in ifosfamide dose (P < 0.0001). There was no statistically significant difference between mesna and NAC groups in the rates chemotherapy associated myelosuppression, neurotxicity, or nausea and vomiting. Renal toxicity (serum creatinine >2.0 mg/dl) developed in 5.8% of NAC treated patients compared to 4.7% of mesna patients. Survival and response rates were similar between groups. Although the results of this study suggest mesna is more effective than NAC in reducing urothelial toxicity, a number of study factors proposed by the investigators may have impacted on the results. Firstly, IV mesna was compared with oral NAC – possible poor oral absorption of NAC or decreased compliance secondary to chemotherapy induced emesis may have reduced the comparative effectiveness of NAC. Secondly, pharmacokinetic characteristic of NAC or its inferior biologic activity compared to mesna. Given the lack of demographic information provided in the published study report, it is difficult to ascertain the comparability of the two groups at baseline. Significant between


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group differences in pre-existing co-morbidities and cancer status at enrollment for example, may have biased the results in favour of mesna. 10.2.2 Mesna and cyclophosphamide/ifosfamide A randomised controlled trial of 20 cancer patients by Scheef et al.26 evaluated the efficacy of IV mesna to prevent urotoxic side effects during cytostatic therapy with cyclofosfamide and ifosfamide. Ten patients from two institutions were investigated separately. Patients were randomly allocated to either mesna (n = 11) or standard prophylaxis only (n = 9). Tumour types included; testicular tumour (n = 4), bronchogenic carcinoma (n = 7), thyroid carcinoma (n = 2), miscellaneous malignant tumours (n = 3), and malignant lymphoma (n = 4). All patients received IV single-agent therapy with either ifosfamide or cyclofosfamide. Of the 11 patients who were randomised to IV mesna prophylaxis nine received ifosfamide and two received cyclophosphamide chemotherapy. Six patients randomised to mesna treatment were administered ifosfamide at a total dose of 300 mg/kg and three patients received a total ifosfamide dose of 270 mg/kg. The two remaining mesna patients received single-dose cyclophosphamide of 48 mg/kg or 50 mg/kg. Patients randomised to standard prophylaxis were administered a total dose of 300 mg/kg of ifosfamide. Ifosfamide was given in fractionated doses with the total dose divided into daily doses of between 60 and 100 g/kg on 3-5 consecutive days. Cyclophosphamide was given as a single dose of 44 mg/kg to 45 mg/kg. Mesna was administered intravenously three times a day concurrently with either cyclophosphamide or ifosfamide, at 4 and 8 hours after initial dose. During the study the dose of mesna was given as a percentage (weight/weight) of the cytostatic dose and arbitrarily reduced from 66% + 66% + 66% of the cytostatic to 17% + 17% + 17% as the minimum dose schedule for uroprotection. The results of this trial showed that no patient treated with mesna developed macrohaematuria (>50 RBC/µL) compared to eight (89%) patients treated with standard prophylaxis. Microhaematuria (16-50 RBC/µL) was observed in two mesna patients compared with one standard prophylaxis patient. Nine of the mesna patients had urine samples with ≤15 RBC/µL. Seven patients in each group developed nausea, with vomiting occurring in six mesna patients and four standard prophylaxis patients. Four patients treated with mesna experienced diarrhoea. Increased vomiting and diarrhoea occurred only when the mesna doses >80 mg/kg. Mesna prophylaxis did not appear to interfere with the antitumour efficacy of ifosfamide or cyclophosphamide. 10.2.3 Mesna and cyclophosphamide A randomised controlled trial by Vose et al.30 evaluated the use of intravenous hydration plus either continuous bladder irrigation (CBI) or intravenous mesna in 200 patients undergoing high-dose cyclophosphamide-based chemotherapy and transplantation for malignant neoplasm. Ninety-seven patients were randomised to received continuous bladder irrigation and 103 patients were randomised to mesna prophylaxis. Thirty patients received an allogeneic bone marrow transplant and 170 patients received an autologous bone marrow or peripheral stem-cell transplant. Eligible patients were 19 to 60 years of age. Malignancies included; non-Hodgkin’s lymphoma (n = 66), Hodgkin’s disease (n = 72), breast cancer (n = 25), acute myeloid leukaemia (n = 23), and other miscellaneous types (n = 24). The male-to-female ratio varied between trial arms with 47.6% of mesna patients being female compared to 38.1% in the bladder irrigation arm. All patients received IV hydration with normal saline at a rate of 250 ml/hr. Patients randomised to continuous bladder irrigation received normal saline at 200 ml/hr through a three-way Foley catheter. Bladder irrigation continued for a minimum of 12 hours after the last dose of cyclophosphamide, or until there was no or a slight trace of blood on the urine dipstick. Patients randomised to IV mesna received a dose of 1 g of mesna per 1 g of cyclophosphamide (100% of the cyclophosphamide dose)


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administered as a continuous infusion one hour before the first dose of cyclophosphamide and continued for 24 hours after the last dose of cyclophosphamide. Low-dose cyclophosphamide was adminstered as two doses of 60 mg/kg (n = 79) or two doses of 2.5 g/m2 (n = 21). High-dose cyclophosphamide was administered as four doses of 35 mg/kg (n = 15) or four doses of 1.5 g/m2 (n = 85). Haemorrhagic cystitis was defined as grade III or IV haematuria (gross haematuria). The results of this trial showed that there was no statistically significant difference in the rate of grade III and IV haematuria (haemorrhagic cystitis) between IV mesna (18%) and continuous bladder irrigation (18%). Although the overall incidence of haemorrhagic cystitis was higher in the patients who received an allogeneic transplant (23.3%) compared to those who received an autologous transplant (5.9%; P = 0.002) no statistically significant difference was observed between allogeneic transplant patients who received mesna prophylaxis and those who received continuous bladder irrigation. Of the viral cultures obtained from patients with grade IV haematuria none were positive. Of the patients who received continuous bladder irrigation 27% developed culture proven bacterial or fungal urinary tract infections (UTIs) compared to 14% of mesna treated patients. There was no differences in the rates of nausea and vomiting, headaches, or diarrhoea between the two treatment arms. The use of continuous bladder irrigation was associated with more restricted movement, bladder spasm, and overall moderate or severe discomfort compared to mesna (84% versus 2%; respectively). A cost analysis performed during the trial indicated that based on a 70 kg patient, the average cost of mesna administration was US$430 compared to US$223 for continuous bladder irrigation. When adjusted for the treatment of UTIs across both trial arms the total average cost for mesna treatment was estimated to be US$550 compared to US$460 for continuous bladder irrigation. A randomised controlled trial by Shepherd et al.29 evaluated the efficacy of mesna compared to forced saline diuresis (hyperhydration) in reducing haemorrhagic cystitis in 100 patients undergoing autologous or allogeneic bone marrow transplant conditioning with high-dose cyclophosphamide (≥120 mg/kg) and at least one other agent. Fifty-one patients were randomised to receive mesna and 49 were randomised to hyperhydration. Patients were assigned by the hospital pharmacy, using random-number tables, to receive either mesna or hyperhydration. The median age of mesna treated patients was 35 years (range; 13-61) compared to 34 years (range; 14-55) in hyperhydration treated patients. Malignancies included; acute myeloid leukaemia (n=41), acute lymphocytic leukaemia (n = 11), chronic myeloid leukaemia (n = 22), non-Hodgkin’s lymphoma (n = 13), Hodgkin’s disease (n = 3), myeloma (n = 8), and other (n = 2). There were no statistically significant differences in baseline characteristics including marrow source and conditioning therapy. Cyclophosphamide was administered intravenously in 500 ml of 5% dextrose solution over 2 hours each day. Cyclophosphamide dose varied with the conditioning therapy: 180 mg/kg of cyclophosphamide and total body irradiation (n = 28), busulfan and cyclophosphamide 120 mg/kg (n = 68), and other regimens containing a minimum of cyclophosphamide 120 mg/kg (n = 4). Viral cultures were not routinely performed. Mesna was administered at a daily dose of 160% of the daily cyclophosphamide dose, divided into four separate doses given at 0, 3, 6, and 9 hours after each dose of cyclophosphamide. Patients received an identical dose of mesna at the same times on the day after the last dose of cyclophosphamide. To compensate for decreased oral intake due to nausea and vomiting these patients received a baseline fluid intake of 1.5 L/m2/day. Oral intake was not controlled in mesna treated patients. Patients randomised to the


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hyperhydration arm of the trial received a minimum of 3 L/m2/day of fluid, commencing the morning of the first dose of cyclophosphamide and continued for 48 hours after the last dose of cyclophosphamide. In addition, these patients received IV furosemide (diuretic therapy) after each dose of cyclophosphamide and at any time the urine output fell to less than 400 ml over any 4-hour period. The results of this trial showed that there was no statistically significant difference between mesna and hyperhydration in the incidence of severe haematuria in evaluable patients (33% versus 20%; P = 0.31). Although severe haemorrhagic cystitis developed in five patients treated with mesna (12.5%) and three patients treated with hyperhydration (7.5%; P = 0.71), the difference was not statistically significant. Significant side effects were not observed for either prophylactic therapy. The median time to attain a neutrophil count greater than 0.5 ×109/L was 20 days (range, 13 to 45 days) in the mesna arm and 21 days (range, 12 to 66 days) in the hyperhydration arm. There were no episodes of primary graft rejection in any of the 100 patients. A randomised controlled trial by Hows et al.28 compared mesna with forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in 61 patients undergoing bone marrow transplantation (BMT). Thirty-four patients were randomised to mesna prophylaxis and 27 patients were randomised to forced diuresis. Of the 61 randomised patients, 35 were leukaemic patients and 26 were being transplanted for aplastic anaemia, had severe disease, and were recipients of more than 10 units of blood before BMT. The median age (range) of patients was 24 years (3-44 years) in the mesna arm and 26 years (11-39 years) in the forced diuresis arm. Of the 34 patients randomised to mesna five had a history of pre-exisiting urinary tract infection (UTI) or haematuria compared to two in the forced diuresis arm. Aplastic patients received intravenous high-dose cyclophosphamide 50 mg/kg on four consecutive days whilst leukaemic patients received 60 mg/kg on 2 days and total body irradiation (TBI) 100-1200 cGy in fractions of 200 cGy over 3 days. All patients received cyclosporine in the post transplant period. Mesna was administered as an IV bolus injection 20-25 mg/kg over 30 minutes before the administration of cyclophosphamide. The dose was repeated at 3, 6, and 9 hours after high-dose cyclophosphamide (HDC). The mesna schedule was continued on the day following the last dose of HDC. Mesna patients also received 3 litres of dextrose saline over 24 hours on the days of HDC administration. No diuretics or electrolytes were given only when necessary. Sodium bicarbonate was not given and the urinary pH was 7.0-8.0. Patients randomised to forced diuresis received 6 litres of dextrose saline as per the mesna arm. Fifty mmol of sodium bicarbonate, 20 mmol of potassium chloride and 10 mg of frusemide were added to each litre of fluid. Acetazolamide 150 mg/m2 and frusemide 20 mg/m2 were given 30 minutes before HDC. The urinary pH during diuresis was 7.5-8.5. The results of this trial showed that of the 26 patients receiving forced diuresis nine (36%) developed macroscopic haematuria compared to four patients treated with mesna (12.5%; P < 0.05). Ten patients treated with mesna (31%) and eight patients treated with forced diuresis (31%) developed microscopic haematuria. Of the 7 patients with pre-existing microscopic haematuria or urinary tract infection only two developed macroscopic haematuria. Three patients died within the study period, two in the mesna group and one in the forced diuresis group. Although these patients were excluded from the final analysis none of these patients had developed macroscopic haematuria at the time of death. Although the use of mesna was not associated with any specific side effects false positive results for urinary ketones was observed using the Ames multistix reagent. There was no statistically significant difference


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between trial arms in the incidence of cyclophosphamide induced vomiting and the incidence of graft versus host disease (GVHD). A randomised comparative trial by Bedi et al.31 compared intravenous mesna with forced diuresis to prevent cyclophosphamide-induced haemorrhagic cystitis in 147 patients undergoing bone marrow transplantation (BMT). Patients were excluded if microscopic or macroscopic haematuria was present before the beginning of high-dose cytotoxic therapy. Patients received the standard preparative regimen dictated by their primary transplantation protocols. Bone marrow was infused one day after completion of cyclophosphamide and total body irradiation, and two days after completion of the busulfan-containing regimens. Malignancies included; acute myeloid leukaemia (n = 31), acute lymphoblastic leukaemia (n = 13), chronic myeloid leukaemia (n = 27), Hodgkin’s disease (n = 12), non-Hodgkin’s lymphoma (n = 58), and multiple myeloma (n = 6). The 71 patients randomised to mesna received 60 mg/kg/day of IV mesna in five divided doses 30 minutes before and 3, 6, 9, and 12 hours after each dose of cyclophosphamide (120% of the daily cyclophosphamide dose). Mesna patients also received IV hydration at 2 ml/kg/hr beginning 12 hours before cyclophosphamide administration and continued until 24 hours after the last dose of cyclophosphamide. Diuretic therapy (IV frusemide) was administered if the urine output fell to less than 1.5 ml/kg/hr in any 4-hour period, urine specific gravity was greater than 1.010, or body weight increased by more than 1 kg above dry weight defined at admission. If IV frusemide was required, the total dose of mesna was increased to 80 mg/kg/day (160% of the daily cyclophosphamide dose) and the interval between doses was decreased to 2 hours. The 76 patients randomised to forced diuresis generally followed the same treatment protocol as for mesna patients except they received IV hydration at 4 ml/kg/hr increasing to 5 ml/kg/hr if the urine output average less than 3 ml/kg/hr. The diagnosis of haemorrhagic cystitis was made when clinically signficant macroscopic haematuria (Grade 2-4) was present. Grade 1 haematuria was defined as >100 RBC/hfp on more than 2 consecutive days; Grade 2 was defined as macroscopic haematuria; Grade 3 was defined as macroscopic haematuria with clots; Grade 4 was defined as macroscopic haematuria with clots and an elevated creatinine secondary to obstruction. The results of this trial showed that of the 147 randomised patient 37 BMT recipients developed haemorrhagic cystitis (25.2%). There was no statistically significant difference in the rates of haemorrhagic cystitis between those patients randomised to mesna (26.8%) compared to those patients randomised to forced diuresis (23.7%; P = 0.41). There appeared to be no statistically significant difference in the rates of haemorrhagic cystitis when compared across all patient subgroups (P ≥ 0.8). This trial also showed that in 95 consecutive BMT recipients studied for the association between BK virus and haemorrhagic cystitis (HC), virtually every case of HC that occurred dispite uroprophylaxis was associated with BK virus with persistent BK virus excretion associated with 19 of 20 cases of HC. A randomised placebo-controlled trial by Henslee et al.32 evaluated the efficacy of mesna as a uroprotector compared to placebo (normal saline) in 25 patients undergoing bone marrow transplantation for haematological malignancies. All patients received pre-transplant therapy of high-dose cyclophosphamide, cytosine, arabinoside, and total body irradiation (TBI). Malignancies included; chronic myelogenous leukaemia (n = 11), acute non-lymphocytic leukaemia (n = 6), acute lymphoblastic leukaemia (n = 5), and myelodysplasia with leukaemic transformation (n = 3). The mean age of mesna patients was 30.7 years compared to 29.6 years for the control group. The male-to-female ratio was not similar between mesna (4:9) and the control group (11:1). Thirteen patients received 12 mg/kg of intravenous mesna


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prior to each dose of cyclophosphamide then at 3, 6, 9, and 12 hours after the initial dose of IV cyclophosphamide. The remaining 12 patients were randomised to receive a placebo solution of normal saline at identical times as mesna administration. All patients received IV therapy at a rate ≥3000 ml/m2/day and were requested to void at least hourly. Haemorrhagic cystitis was diagnosed on the basis of a urinalysis demonstrating >5 RBC/hpf on days 1-5 and on weekly follow-up over 3 months. The results of this trial showed that eight patients randomised to mesna (61.5%) developed delayed haemorrhagic cystitis (onset 1 week or greater after cyclophosphamide) compared to five patients treated with placebo (41.7%; P > 0.05). One patient randomised to mesna developed haemorrhagic cystitis druing the first 5 days after cyclophosphamide. This published abstract showed no apparent benefit of mesna prophylaxis to prevent haemorrhagic cystitis was demonstrated. In a non-randomised quasi-experimental study by Sato et al.35 the efficacy of mesna to prevent haemorrhagic cystitis was compared to control in 40 children receiving high-dose cyclophosphamide combination chemotherapy undergoing peripheral blood stem cell autografts (PBSCT). Fifteen patients received mesna prophylaxis and 25 did not receive mesna. Of the 15 mesna patients, 10 were male and five were female with a collective median age of 8 years (range, 1-17 years). Of the 25 control group patients 16 were male and 9 were female with a collective median age of 8 years (range, 1-16 years). Malignancies included; acute lymphoblastic leukaemia (n = 28), acute myeloblastic leukaemia (n = 7), and non-Hodgkin’s lymphoma (n = 5). Patients were pre-treated with combination therapy as follows: ranimustine administered on day 8 (250 mg/m2) and day 3 (200 mg/m2) preceeding PBSCT (day 0); etoposide 200 mg/m2 × 8 doses and cytosine arabinoside 2 g/m2 × 8 doses on days 7-3 pre-PBSCT (day 0); cyclophosphamide 50 mg/kg was administered over 12 hours on day 2 and day 1 (2 doses) pre-PBSCT (day 0). Mesna 20 mg/kg was administered intravenously over 30 minutes before the cyclophosphamide dose. All patients received concomitant hyperhydration of 3000 ml/m2/day. The results of this study showed that transient haemorrhagic cystitis developed in one patient treated with mesna (6.7%) compared to three control group patients (12%; P > 0.05). There were no reported cases of renal dysfunction in either group or toxicity attributed to the use of mesna. Table 10.2: Summary of results for RCTs of mesna – urological outcomes

Study Year Cytotoxic agent

Mesna No mesna

Araujo et al.24 1983 IFO N = 45 Cystitis = 4/88* Microhaematuria = 10/88*

N = 25 Cystitis = 38/50* Microhaematuria = 10/50* Gross haematuria = 26/50* Overall: P < 0.0001

Legha et al.23 1990 IFO N=31 Grade 2 haematuria = 2/31 Grade 3 haematuria = 0/31

N=31 Grade 2 haematuria = 4/31 Grade 3 haematuria = 5/31

Fukuoka et al.20 1991 IFO N = 45 Mild haematuria = 0/45 Moderate haematuria = 1/45 Severe haematuria = 2/45 Overall incidence = 6.7%

N = 46 Mild haematuria = 4/46 Moderate haematuria = 4/46 Severe haematuria = 11/46 Overall incidence = 32.6% Overall: P = 0.0008

Scheef et al.26 1979 IFO/CY N = 11 Microhaematuria = 2/11 Macrohaematuria = 0/11

N = 9 Microhaematuria = 1/9 Macrohaematuria = 8/9

Vose et al.30 1993 CY N = 103 Grade 1 haematuria = 18% Grade 2 haematuria = 17% Grade 3 haematuria = 10% Grade 4 haematuria = 8%

N = 97 Grade 1 haematuria = 26% Grade 2 haematuria = 32% Grade 3 haematuria = 13% Grade 4 haematuria = 5%


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Study Year Cytotoxic agent

Mesna No mesna

Grade 3-4: P > 0.05 Overall: P = 0.007

Shepherd et al.29 1991 CY N=51 Assessable patients n = 40 Minor haematuria = 14/40 Consistent haematuria = 8/40 Severe haematuria = 5/40

N=49 Assessable patients n = 40 Minor haematuria = 19/40 Consistent haematuria = 5/40 Severe haematuria = 3/40 Severe haematuria: P = 0.71

Hows et al.28 1984 CY N=34 Microhaematuria = 10/32† Macrohaematuria = 4/32†

N=27 Microhaematuria = 8/26† Macrohaematuria = 9/26†

Macrohaematuria: P < 0.05 Bedi et al. 31 1995 CY N=71

HC = 19/71 N=76 HC = 18/76 P = 0.41

Henslee et al.32 1988 CY N=13 HC = 8/13

N=12 HC = 5/12 P > 0.05

CY = cyclophosphamide, IFO = ifosfamide, NR = Not reported, HC = haemorrhagic cystitis * Incidence/courses † Assessable patients When considered in aggregate, the evidence of efficacy for mesna in reducing the incidence of urotoxicity associated with isfosfamide and/or cyclophosphamide chemotherapy is mixed. As summarised in Table 10.2, five of the nine RCTs reviewed show that mesna is effective in reducing the incidence of moderate to severe haematuria whereas the results of four trials show mesna prophylaxis to be ineffective. It is important to note that the three largest trials which randomised between 50 to 100 patients in each trial arm showed mesna was not effective in preventing haemorrhagic cystitits or moderate-severe haematuria. The five trials that showed mesna to be statistically significantly better than standard prophylaxis or placebo-control, were small with between 9 to 46 patients randomised to each trial arm. Generally, the methodological quality of the reviewed trials was poor, with little methodological detail provided in the trial reports. Only two trials20,29 reported the methods used to randomise patients and methods used to conceal treatment allocation. Given the caveats that apply to small, methodologically poor randomised trials, it is recommended the results of the reviewed trials be interpreted with caution. Currently, there appears to be no good quality evidence (Level I evidence) to support the use of mesna in preventing urothelial toxicity in patients treated with ifosfamide and/or cyclophosphamide chemotherapy. 11. Summary of comparative evidence on safety As stated in the critical review by Siu and Moore,36 and supported by the review by Links and Lewis,8 adverse effects with mesna prophylaxis are uncommon although when administered orally mesna is associated with gastrointestinal effects including nausea, vomiting and crampy abdominal pain. Sui and Moore36 suggest the nausea and vomiting reported with mesna use is most probably secondary to the unpleasant taste of the oral mesna solution (sulphurous taste), which can be minimised by diluting oral aqueous mesna in juice or carbonated drink.37 The availability of mesna tablets has obviated this practice and improved the tolerability of mesna. Siu and Moore36 claim adverse effects associated with mesna are generally less with intravenous doses, especially at the doses routinely administered. Adverse effects reported with intravenous mesna include; diarrhoea, abdominal pain, headache, fatigue, limb and joint pain,depression, hypotension, tachycardia, and skin rash. Hypersensitivity reactions including rash, fever, nausea, facial and periorbital oedema, ulceration of mucous membranes, and tachycardia have been attributed to mesna.18 Siu and


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Moore36 state that allergic reactions consisting of itching and urticaria have been reported only rarely following the administration of intravenous mesna, and that these effects respond to antihistamines and corticosteroids. These findings are supported by DRUGDEX® Evaluations38 which provides a detailed overview of reported adverse reactions associated with mesna. Mesnex® - Product Information (May 2002)16 provides adverse reaction data from four phase I studies in which single IV bolus doses of 600-1200 mg of Mesnex® without concurrent chemotherapy were adminstered to a total of 53 subjects and a single oral doses of 600-2400 mg of oral Mesnex® were administered to a total of 82 subjects. Data from studies showed that the most frequently reported side effects (observed in two or more patients) for patients receiving single doses of IV Mesnex® were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhoea, anorexia, fever, pharyngitis, hyperaesthesia, influenza-like symptoms, and coughing. In those patients treated with a single dose of 1200 mg of oral Mesnex® solution the most frequently reported side effects included rigors, back pain, rash, conjunctivitis, and arthralgia. Data from two phase I multi-dose studies where patients received Mesnex® tablets alone or IV Mesnex® followed by repeated doses of Mesnex® tablets reported episodes of flatulence, rhinitis, and constipation. Mesnex® - Product Information (May 2002)16 provides tabulated data from four controlled studies in which patients received ifosfamide or ifosfamide-containing regimens. These results are summaried in Table 11.1.


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Table 11.1: Incidence of adverse events and incidence of most frequently reported adverse events in controlled studies Mesna Regimen I.V.-I.V.-I.V. I.V.-Oral-Oral N exposed 119 (100.0%) 119 (100.0%) Incidence of AEs 101 (84.9%) 106 (89.1%)

Most Frequently Reported Adverse Events (Preferred Terms) N (%) N (%) Nausea 65 (54.6) 64 (53.8) Vomiting 35 (29.4) 45 (37.8) Constipation 28 (23.5) 21 (17.6) Leukopenia 25 (21.0) 21 (17.6) Fatigue 24 (20.2) 24 (20.2) Fever 24 (20.2) 18 (15.1) Anorexia 21 (17.6) 19 (16.0) Thrombocytopenia 21 (17.6) 16 (13.4) Anemia 20 (16.8) 21 (17.6) Granulocytopenia 16 (13.4) 15 (12.6) Asthenia 15 (12.6) 21 (17.6) Abdominal Pain 14 (11.8) 18 (15.1) Alopecia 12 (10.1) 13 (10.9) Dyspnea 11 (9.2) 11 (9.2) Chest Pain 10 (8.4) 9 (7.6) Hypokalemia 10 (8.4) 11 (9.2) Diarrhea 9 (7.6) 17 (14.3) Dizziness 9 (7.6) 5 (4.2) Headache 9 (7.6) 13 (10.9) Pain 9 (7.6) 10 (8.4) Sweating Increased 9 (7.6) 2 (1.7) Back Pain 8 (6.7) 6 (5.0) Hematuria* 8 (6.7) 7 (5.9) Injection Site Reaction 8 (6.7) 10 (8.4) Edema 8 (6.7) 9 (7.6) Edema Peripheral 8 (6.7) 8 (6.7) Somnolence 8 (6.7) 12 (10.1) Anxiety 7 (5.9) 4 (3.4) Confusion 7 (5.9) 6 (5.0) Face Edema 6 (5.0) 5 (4.2) Insomnia 6 (5.0) 11 (9.2) Coughing 5 (4.2) 10 (8.4) Dyspepsia 4 (3.4) 6 (5.0) Hypotension 4 (3.4) 6 (5.0) Pallor 4 (3.4) 6 (5.0) Dehydration 3 (2.5) 7 (5.9) Pneumonia 2 (1.7) 8 (6.7) Tachycardia 1 (0.8) 7 (5.9) Flushing 1 (0.8) 6 (5.0)

* All grades Source: Mesnex® - Product Information (May 2002)16 A summary of post-marketing surveillance presented in the Mesnex® - Product Information (May 2002),16 indicates the following adverse reactions have been reported: allergic reactions, decreased platelet counts associated with allergic reactions, hypertension, hypotension, increased heart rate, increased liver enzymes, injection site reactions (including pain and erythema), limb pain, malaise, myalgia, ST-segment elevation, tachycardia, and tachypnoea.


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12. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group Based on the results of a prospective study of 100 patients who underwent autologous or allogeneic bone marrow or stem cell transplantation Ballen et al.39 estimated the cost of mesna to be US$1,500/course compared to US$20/course of hyperhydration with normal saline. The cost analysis performed by Ballen et al. was based on UMass acquisition costs and on an average patient with a body surface area (BSA) of 2.0 m2 receiving a mesna dose of 120% cyclophosphamide over 4 days. With 171 courses of high-dose cyclophosphamide administered over a 3-year period, Ballen et al. estimated a saving of US$253,080 if hyperhydration was used rather than IV mesna (oral mensa was the same cost). This equated to an average saving of US$1,480 per patient. However, the cost of monitoring, nursing time, and whether the hyperhydration regimen could be safely used in an outpatient setting was not included in the analysis. As previously discussed, the randomised controlled trial by Vose et al.30 performed a cost analysis during the trial and based on a 70 kg patient, the average cost of mesna administration per patient was estimated to be US$430 compared to US$223 for continuous bladder irrigation. When adjusted for the treatment of UTIs across both trial arms the total average cost for mesna treatment was estimated to be US$550 compared to US$460 for continuous bladder irrigation. Based the findings of these two studies the average cost of mesna treatment per patient exceeds that of both hyperhydration and continuous bladder irrigation. Global costs of mesna British National Formulary (2007) Mesna (Uromitexan®, Baxter) – tablets, f/c, mesna 400 mg, net price 10-tab pack = ₤21.10; 600 mg, 10-tab pack = ₤27.40 Mesna (Uromitexan®, Baxter) – injection, mesna 100 mg/ml, net price 4-ml amp = ₤1.95; 10-ml amp = ₤4.38 International Drug Price Indicator (2007) – US$ Source Package Package Price Unit price Guatemala 1 Amp (4 ml) $1.68 0.4195 South Africa 1 Amp (4 ml) $2.84 0.7089 El Salvador 1 Amp (4 ml) $4.41 1.1025 Lowest price 0.4195 Median price 0.7089 Highest price 1.1025

Australian Pharmaceutical Benefits Scheme (PBS) pricing details (http://mims.com.au) – AUD$ Mesna (Uromitexan®, Baxter) – tablets, mesna 400 mg, net price 50-tab pack = $175.25; 600 mg, 50-tab pack = $259.25. Mesna (Uromitexan®, Baxter) – injection, mesna 400 mg/ 4 ml, 15 amps: Restricted – PBS/RPBS (Rp 5) = $71.54; Section 100 – CT (Chemotherapy Scheme) Restricted (Rp 5) PBS: $56.13. Mesna (Uromitexan®, Baxter) – injection, mesna 1 g / 10 ml, 15 amps: Restricted – PBS/RPBS (Rp 5) = $156.90; Section 100 – CT (Chemotherapy Scheme) Restricted (Rp 5) PBS: $128.30.


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13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well) As discussed in Section 6 of this report, mesna is marketed under 14 different trade names in 32 countries worldwide (Appendix A). The regulatory status of mesna in each country where mesna is available is difficult to ascertain but it is likely to vary from country to country. In the case of the United States (U.S.) mesna for intravenous administration was initially approved by the U.S. Food and Drug Administration (FDA) in 1988 for use as a prophylactic agent to reduce the incidence of ifosfamide cystitis. On March 21, 2002, U.S. Food and Drug Administration (FDA) approved mesna tablets for this same indication. In Australia, intravenous mesna (Uromitexan®) was approved by the TGA (Therapeutic Goods Adminstration) for registration in 1993 for use as a prophylactic agent to reduce/prevent urothelial toxicity caused by oxazaphosphorine cytotoxics (cyclophosphamide, ifosfamide). Although oral mesna is available in Australia (marketed as Uromitexan® Tablets) it is not Government subsidised through the Pharmaceutical Benefits Scheme (PBS). 14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopeia) British Pharmacopoeia: Yes (2007, British National Formulary, 53 ed.) International Pharmacopoeia: Yes (2007, Martindale: The Complete Drug Reference) United States Pharmacopeia: No 15. Proposed (new/adapted) text for the WHO Model Formulary Information sourced from MIMS Australia Pty Ltd 2003 (http://www.mims.com.au) Indications Reduction and prevention of urinary tract toxicity (haemorrhagic cystitis) of oxazaphosphorines (see Adverse Reactions in the product information for cyclophosphamide and ifosfamide). Contraindications Known hypersensitivity to the drug and other thiols. Precautions The protective effect of mesna applies only to the urothelial toxic effects of oxazaphosphorines (i.e. ifosfamide or cyclophosphamide) not to their renal and other toxic effects. Additional prophylactic or accompanying measures recommended during treatment with oxazaphosphorines are thus not affected and should not be discontinued. Severe allergic symptoms, such as systemic anaphylactic reactions, have occurred with mesna, especially in patients suffering from autoimmune diseases. Due to the possibility of anaphylactoid reactions, it should be ensured that adequate emergency medication is available. Patients with autoimmune diseases who were treated with cyclophosphamide and mesna appeared to have a higher incidence of hypersensitivity reactions including skin and mucosal reactions of varying extent and severity (rash, itching, redness, vesiculation, Lyell syndrome, Stevens-Johnson syndrome), local tissue swelling (urticarial oedema), conjunctivitis, rare cases of hypotension associated with circulatory reactions and increased pulse rate above 100


26

beats/minute (tachycardia), as well as increased respiration rate (tachypnoea) due to severe acute hypersensitivity (anaphylactoid) reactions, hypertension, ST segment elevation, myalgia and also a transient rise in certain liver function tests (e.g. transaminases). Protection of the urinary tract with mesna should therefore only be undertaken in such patients with autoimmune diseases, following careful risk/ benefit analysis and under medical supervision. Mesna does not prevent haemorrhagic cystitis in all patients. As a result, a morning specimen of urine should be examined for the presence of haematuria (microscopic evidence of red blood cells) and proteinuria, each day prior to oxazaphosphorine therapy. If haematuria develops when mesna is given with oxazaphosphorines according to the recommended dosage schedule, depending on the severity of the haematuria, dosage reduction or discontinuation of oxazaphosphorine therapy may be indicated. Urinary output should be maintained at 100 ml/hour (as required for oxazaphosphorine treatment). The urine should be monitored for haematuria and proteinuria throughout the treatment period. Carcinogenesis, mutagenesis, impairment of fertility No long-term animal studies have been performed to evaluate the carcinogenic potential of mesna. Use in pregnancy Teratology studies with oral doses of mesna given to rabbits at up to 1,000 mg/kg/day and to rats at up to 2,000 mg/kg/day have revealed no harm to the fetus. Animal studies of potential toxicity in a fertility and general reproductive screen and in a perinatal and postnatal screen have not been carried out. It is not known whether mesna can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. Mesna should be given to a pregnant woman only if the benefits clearly outweigh any possible risks. Use in lactation It is not known whether mesna or dimesna are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Adverse reactions Infections and infestations: pharyngitis. Blood and lymphatic system disorders: thrombocytopenia (hypersensitivity). Immune system disorders: hypersensitivity reactions, anaphylactoid reactions. Metabolism and nutrition disorders: anorexia. Nervous system disorders: dizziness, somnolence, headache. Eye disorders: conjunctivitis. Cardiac disorders: ST segment elevation, tachycardia. Vascular disorders: flushing. Very rare: circulatory reactions, hypotension, hypertension. Respiratory disorders: coughing. Very rare: tachypnoea. Gastrointestinal disorders: nausea, vomiting, diarrhoea, constipation, colic, abdominal pain, flatulence. Skin, mucosal and subcutaneous tissue disorders: rash, itching, redness, vesiculation, Lyell syndrome, Stevens-Johnson syndrome, urticarial oedema, local tissue swelling. Musculoskeletal and connective tissue disorders: arthralgia, back pain. Very rare: myalgia, limb and joint pain.


27

General disorders and administration site conditions: fever, rigors, influenza-like reactions. Injection site reactions: weakness, mucosal reactions, lack of energy, exhaustion. Investigations: decreased platelet count, increased respiration rate, rise in certain liver function tests, rise in transaminases. Interactions In vitro and in vivo animal tumour models have shown that mesna does not have any effect on the antitumour efficacy of concomitantly administered cytotoxic agents. Laboratory tests: A false positive test for urinary ketones may arise in patients treated with mesna. In this test, a red violet colour develops which, with the addition of glacial acetic acid, will return to violet. Mesna may cause false positive or false negative reactions in the dipstick test for erythrocytes in urine. To exactly determine erythrocytes in the urine, urinary microscopy is recommended. Dosage and administration (Intravenous) Sufficient mesna must be given to protect the patient adequately from the urothelial toxic effects of the oxazaphosphorine. When calculating the dose of mesna, the quantity should be rounded up to the nearest whole ampoule. Mesna should be administered by intravenous injection over 15 to 30 minutes, usually at 20% of the respective oxazaphosphorine dose, at each of the times 0 (= administration of the cytostatic agent), four and eight hours. The total dose of mesna is 60% of the oxazaphosphorine dose and is repeated on each occasion that the cytotoxic agents are used. Preparation: For intravenous administration the drug can be diluted by adding the contents of a mesna ampoule to any of the following fluids, obtaining final concentrations of mesna 1.5 to 3 mg/mL fluid: glucose injection 5%, sodium chloride injection 0.9%, sodium chloride and glucose injection (with concentrations ranging from 0 to 0.9% sodium chloride and 0 to 5% glucose), lactated Ringer's injection. Solutions of mesna when diluted in the solutions nominated above may be prepared and, if necessary, stored for short periods under refrigeration. However, the diluted solutions do not contain an antimicrobial preservative, and in order to reduce microbial hazards it is recommended that dilution should be effected as soon as practicable prior to use, and infusion commenced as soon as practicable thereafter. Infusion should be started within six to eight hours of preparation of the admixture and completed within 24 hours, with any residue discarded. Diluted solutions should be inspected visually before use. Any solutions which are discoloured, hazy or contain visible particulate matter should not be used. Compatibility and stability. In vitro, mesna is incompatible with cisplatin. The combination of an oxazaphosphorine cytostatic agent with mesna and cisplatin in the same infusion solution is not stable and is not to be used. Ifosfamide (3 mg/mL) may be admixed with diluted mesna solutions 1.5 to 3.0 mg/mL (0.15 to 0.3%). The admixture, when diluted in sodium chloride injection 0.9%, compound sodium lactate injection, glucose injection 5% or glucose 2.5% plus sodium chloride 0.45% injection


28

and packaged in PVC plastic bags, has been shown to be chemically and physically stable when refrigerated for 24 hours. Admixtures are to be administered within six to eight hours of preparation due to the risk of microbial contamination. Dosage and administration (Oral) Adults: Intermittent oxazaphosphorine therapy. Oral mesna, 40% (w/w) of the oxazaphosphorine dose, should be given two hours prior to the oxazaphosphorine dose, and repeated at two and six hours after oxazaphosphorine administration. Alternatively, an initial intravenous dose of mesna, 20% (w/w) of the oxazaphosphorine dose, can be given with the cytotoxic dose and additional oral mesna, 40% (w/w) of the oxazaphosphorine dose, given at two and six hours after the oxazaphosphorine. Following 24 hour infusion of ifosfamide and mesna. The first oral mesna dose of 40% (w/w) of the ifosfamide dose is given as the infusion is stopped, and the same dose is repeated after two and six hours. Higher doses of mesna can be given if urothelial toxicity occurs. Elderly: No specific information on the use of this product in the elderly is available. Clinical trials have included patients over 65 years and no adverse reactions specific to this age group have been reported. Children: Due to increased micturition, children may require shorter intervals between doses and/or an increased number of individual doses. High risk patients: Patients who have had previous irradiation of the small pelvis, occurrence of cystitis during previous cyclophosphamide or ifosfamide therapy or a history of urinary tract lesions may require shorter intervals between doses and/or an increased number of doses. Overdosage Overdose may lead to the reactions such as: nausea, vomiting, colic, diarrhoea, headache, fatigue, limb and joint pains, lack of energy (like exhaustion) and weakness, depression, irritability, rash, hypotension and tachycardia.


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21 Sakurai M, Saijo N, Shinkai T, Eguchi K, Sasaki Y, Tamura T et al. The protective effect of 2-mercapto-ethane sulfonate (MESNA) on hemorrhagic cystitis induced by high-dose ifosfamide treatment tested by a randomized crossover trial. Jpn J Clin Oncol. 1986; 16(2): 153-156.

22 Bryant BM, Jarman M, Ford HT, Smith IE. Prevention of isophosphamide-induced urothelial toxicity with 2-mercaptoethane sulphonate sodium (mesnum) in patients with advanced carcinoma. Lancet. 1980; 2(8196): 657-659.

23 Legha S, Papdopoulos N, Plager C, Usakewicz J, Salem P, Nicaise C et al. A comparative evaluation of the uroprotective effect of mercaptoethane sulfonate (mesna) and n-acetylcysteine (NAC) in sarcoma patients treated with ifosfamide. Proceedings of the American Society of Clinical Oncology. 1990; 9(March): 311.

24 Araujo CE, Tessler J. Treatment of ifosfamide-induced urothelial toxicity by oral administration of sodium 2-mercaptoethane sulphonate (MESNA) to patients with inoperable lung cancer. Eur J Cancer Clin Oncol. 1983; 19(2): 195-201.

25 Frustaci S, Foladore S, De Pascale A, Freschi A, Lo Re G, Sorio R et al. Feasibility an efficacy of arginine 2-mercaptoethanesulfonate (ARGIMESNA) in the prevention of hemorrhagic cystitis from ifosfamide (IFO). Ann Oncol. 1992; 3((Suppl.2)): S115-S118.

26 Scheef W, Klein HO, Brock N, Burkert H, Gunther U, Hoefer-Janker H et al. Controlled clinical studies with an antidote against the urotoxicity of oxazaphosphorines: preliminary results. Cancer Treat Rep. 1979; 63(3): 501-505.

27 Hows J, Mehta A, Gordon-Smith EC. Mesna versus forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplant patients (preliminary data). Cancer Treat Rev. 1983; 10 Suppl A: 53-56.

28 Hows JM, Mehta A, Ward L, Woods K, Perez R, Gordon MY et al. Comparison of mesna with forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: a prospective randomised study. Br J Cancer. 1984; 50(6): 753-756.


31

29 Shepherd JD, Pringle LE, Barnett MJ, Klingemann HG, Reece DE, Phillips GL. Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. J Clin Oncol. 1991; 9(11): 2016-2020.

30 Vose JM, Reed EC, Pippert GC, Anderson JR, Bierman PJ, Kessinger A et al. Mesna compared with continuous bladder irrigation as uroprotection during high-dose chemotherapy and transplantation: a randomized trial. J Clin Oncol. 1993; 11(7): 1306-1310.

31 Bedi A, Miller CB, Hanson JL, Goodman S, Ambinder RF, Charache P et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol. 1995; 13(5): 1103-1109.

32 Henslee PJ, Parr MD, Romond EH, Messino MJ, Doukas MA, MacDonald JS. A randomized trial to determine the prophylactic benefit of 2-mercaptoethane sulfonate (mesna) as a uroprotector in bone marrow transplatation (BMT). Proceedings of the American Society of Clinical Oncology. 1988; 7(1155, March): 297.

33 Benjamin RS, Legha SS, Patel SR, Nicaise C. Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the M.D. Anderson experience. Cancer Chemother Pharmacol. 1993; 31 Suppl 2: S174-S179.

34 Munshi NC, Loehrer PJ, Sr., Williams SD, Langefeld C, Sledge G, Nichols CR et al. Comparison of N-acetylcysteine and mesna as uroprotectors with ifosfamide combination chemotherapy in refractory germ cell tumors. Invest New Drugs. 1992; 10(3): 159-163.

35 Sato J, Takaue Y, Saito S, Okamoto Y, Hirao A, Shimizu T et al. Evaluation of the benefits of sodium 2-mercaptoethane sulfonate (MESNA) therapy for children undergoing high-dose chemotherapy. [Japanese]. Rinsho Ketsueki. 1993; 34(1): 7-12.

36 Siu LL, Moore MJ. Use of mesna to prevent ifosfamide-induced urotoxicity. [Review] [75 refs]. Support Care Cancer. 1998; 6(2): 144-154.

37 Burkert H. Clinical overview of mesna. Cancer Treat Rev. 1983; 10 Suppl A: 175-181.

38 MESNA - DRUGDEX® Evaluations. Thomson MICROMEDEX 1974-2006. 2006.

39 Ballen KK, Becker P, Levebvre K, Emmons R, Lee K, Levy W et al. Safety and cost of hyperhydration for the prevention of hemorrhagic cystitis in bone marrow transplant recipients. Oncology. 1999; 57(4): 287-292.


32

Appendix A Table A1: Summary of mesna availability worldwide Country Drug trade name Manufacturer/distributor Argentina Delinar

Teva Tuteur S.A. Encarnación Ezcurra 365 Piso 3 Puerto Madero, Buenos Aires Argentina Telephone: +54 (0) 11 57872222 http://www.tevatuteur.com.ar/

Argentina Mesnex

Kampel Martian Lab. Kampel Martian S.A. Av. del Libertador 6550, 5 piso 1428 Buenos Aires Argentina Telephone: +54 (0) 11 47881171 Fax: +54 (0) 11 47881171 http://www.kampelmartian.com/

Argentina Mestian

LKM, Laboratorio LKM SA Monroe 1378 1428 Buenos Aires Argentina

Argentina Neper

Ivax Argentina SA JJ Castelli 6701 1605 Munro Buenos Aires Argentina

Argentina Uromitexan

Sandoz SA Cramer 4130 1429 Buenos Aires Argentina

Argentina Varimesna

Lab. Varifarma S.A. Ernesto de las Carreras 2469 1643 Beccar, Buenos Aires Argentina Telephone: +54 (0) 11 47232830 Fax: +54 (0) 11 47230069

Australia Uromitexan

Baxter Healthcare P/L P.O. Box 88 Toongabbie NSW 2146 Australia Telephone: +61 (0) 2 98481111 Fax: +61 (0) 2 98481123 http://www.baxterhealthcare.com.au/

Austria Uromitexan

Baxter AG Industriestrasse 67 A-1221 Vienna Austria Telephone: +43 (0) 1 201000 Fax: +43 (0) 1 2037124 http://www.baxter.at/

Belgium Uromitexan

Baxter SA Bvld de la Plaine 5 1050 Brussels Belgium Telephone: +32 (0) 2 6501711


33

Country Drug trade name Manufacturer/distributor Fax: +32 (0) 2 6501881 http://www.baxter.be/

Brazil Mesnil*

Zodiac, Brazil Zodiac Prods. Farms. S.A. Rua Venancio Aires 417 05024-030 São Paulo SP Brazil Telephone: +55 (0) 11 36773200 Fax: +55 (0) 11 36760524

Brazil Mitexan

Asta Oncologia, Brazil Asta Medica Oncologia Ltda Rua Eng. Franisco Pitta Brito 779 4753080 São Paulo Brazil

Canada Uromitexan

Baxter, Canada Baxter Corporation 4 Robert Speck Pkwy Suite 700 Mississauga Ontario L4Z 3YA Canada Telephone: +1 905 2701125 Fax: +1 905 2816560 http://www.baxter.ca/

Chile Uromitexan

Baxter, Chile Laboratorio Baxter/Asta Medica General Salvo 68 Providencia Santiago Chile

Chile Uroprot

Laboratorios Chile SA Av. Marathon 1315 Nunoa Santiago Chile

Czech Republic Uromitexan

Asta Medica, Czech Republic Asta Medica sro Čistovicka 11/249 163 00 Prague 6 Czech Republic Telephone: +420 (0) 2 3023626 Fax: +420 (0) 2 35301185 E-mail: [email protected] http://www.astamedica.cz/

Denmark Uromitexan

Baxter A/S Gydevang 43 3450 Allerød Denmark Telephone: +45 48166400 Fax: +45 48166464 http://www.baxter.com/

Finland Uromitexan

Baxter Oy Pakkalankuja 6 PL 46 01511 Vantaa Finland


34

Country Drug trade name Manufacturer/distributor Telephone: +358 (0) 9 8621111 Fax: +358 (0) 9 86211211 http://www.baxter.fi/

France Uromitexan

Baxter SA 6 av Louis-Pasteur B.P. 56 78311 Maurepas cdx France Telephone: +33 (0) 1 34615050 Fax: +33 (0) 1 34615025 http://www.baxter.com/

Germany Uromitexan

Baxter Oncology, Germany Baxter Oncology GmbH Daimlerstr. 40 60314 Frankfurt am Main Germany Telephone: +49 (0) 69 96866000 E-mail: [email protected] http://www.baxter-oncology.com/

Greece Uromitexan

Baxter Hellas EPE Ethnarhou Makariou 34 163 41 Ilioupolis Greece Telephone: +30 210 9987000 Fax: +30 210 9959820 http://www.baxter.com/

Hong Kong Uromitexan

Baxter Healthcare Ltd Rm 2006 MassMutual Tower 38 Gloucester Rd Wanchai Hong Kong Telephone: +852 28078500 Fax: +852 28078596 http://www.baxter.com/

Hungary Uromitexan

Baxter Hungary Kft Buday László utca 12 1024 Budapest Hungary Telephone: +36 3454519 Fax: +36 3454518

Hungary Uromitexan

Pliva, Hungary Pliva d d Magyarországi Kereskedelmi Képviselete Galagonya u 5 1036 Budapest Hungary Telephone: +36 2502450 Fax: +36 2502460

India Uromitexan

German Remedies Ltd Shivsagar Estate 'A' Dr Annie Besant Rd Worli Mumbai 400 018 India Telephone: +91 (0) 22 4935528 Fax: +91 (0) 22 4950327 http://www.germanremedies.com/

Ireland Uromitexan Asta Medica, Ireland


35

Country Drug trade name Manufacturer/distributor Viatris, United Kingdom

Meda, United Kingdom Meda Pharmaceuticals Building 2000 Beach Drive Cambridge Research Park Cambridge Cambridgeshire CB5 9PD UK Telephone: +44 (0) 1223 205999 Fax: +44 (0) 1223 205998 E-mail: [email protected] http://www.meda.se/

Israel Mexan

Teva, Israel Teva Pharmaceuticals Ind. Ltd P.O. Box 8077 Kiryat Nordau Netanya Israel Telephone: +972 (0) 9 8639777 Fax: +972 (0) 9 8653764 http://www.tevapharm.com/

Italy Uromitexan

Baxter, Italy Baxter S.p.A. Viale Tiziano 25 00100 Rome Italy Telephone: +39 06 324911 Fax: +39 06 32491329 http://www.baxter.com/

Japan Uromitexan

Shionogi & Co. Ltd 3-1-8 Dosho-machi Chuo-ku Osaka 541-0045 Japan Telephone: +81 (0) 6 62022161 Fax: +81 (0) 6 62299596 http://www.shionogi.co.jp/

Malaysia Uromitexan

Baxter Oncology, Malaysia Zuellig, Malaysia Zuellig Pharma Sdn Bhd Level 3A, No 10 Jln Bersatu 13/4 46200 Petaling Jaya Selangor Malaysia Telephone: +60 (0) 3 79856688 Fax: +60 (0) 3 79551388 http://www.zuelligpharma.com/

Mexico Filesna*

Serono de Mexico S.A. de C.V. Av. Insurgentes Sur No. 1898 Piso 16 Colonia Florida 01030 Mexico D.F. Mexico Telephone: +52 55 53220225 Fax: +52 55 53220269 http://www.serono.com/

Mexico Mesnil Asofarma de Mexico S.A. de C.V.


36

Country Drug trade name Manufacturer/distributor Calz. Mexico-Xochimilco No. 43

Col. San Lorenzo Huipulco Deleg. Tlalpan 14370 Mexico D.F. Mexico Telephone: +52 55 55130660 Fax: +52 55 55130660 http://www.asofarma.com.mx/

Mexico Mesoda

Probiomed, S.A. de C.V. San Esteban 88 Azcapotzalco Santo Tomas 2020 Mexico D.F. Mexico Telephone: +52 55 53523122 Fax: +52 55 53527651 http://www.probiomed.com.mx/

Mexico Uromes

Laboratorios Sanfer S.A. de C.V. Calz. de Tlalpan No. 550 Col. Moderna Deleg. Benito Juarez 03510 Mexico D.F. Mexico Telephone: +52 55 56348800 Fax: +52 55 56348746 http://www.sanfer.com.mx/

Mexico Uromitexan

Baxter, S.A de C.V. Insurgentes Sur 1196 Col. del Valle 03200 Mexico D.F. Mexico Telephone: +52 55 54885000 http://www.baxter.com/

Mexico Uroprot

Lemery S.A. de C.V. Calle 1 No. 5-A Interior 101 Mabuel Avila Camacho 11610 Mexico D.F. Mexico Telephone: +52 55 52945275 Fax: +52 55 55895021

Mexico Ziken

Laboratorios Kendrick, S.A. de C.V. Paseo de los Laureles No. 458-205 Col. Bosques de las Lomas Deleg. Cuajimalpa 05120 Mexico D.F. Mexico Telephone: +52 55 52596011 Fax: +52 55 52571192 http://www.kendrick.com.mx/

The Netherlands Uromitexan

Baxter BV Kobaltweg 49 3542 CE Utrecht Netherlands http://www.baxter.nl/

Norway Uromitexan

Baxter, Norway Baxter AS Gjerdrumsv. 11 Postboks 70 Grefsen 0409 Oslo Norway


37

Country Drug trade name Manufacturer/distributor Telephone: +47 22584800 Fax: +47 22584801 http://www.baxter.no/

New Zealand Uromitexan

Baxter, New Zealand Baxter Healthcare Ltd 33 Vestey Drive Mt Wellington Auckland New Zealand Telephone: +64 (0) 9 5742400 Fax: +64 (0) 9 5742450 http://www.baxter.co.nz/

Portugal Uromitexan

Asta Medica, Portugal Viatris, Portugal Viatris Farmacêutica SA Rua do Centro Cultural 13 1749-066 Lisbon Portugal Telephone: +351 21 8420300 Fax: +351 21 8492042 E-mail: [email protected] http://www.viatris.pt/

South Africa Uromitexan

Sanofi-Aventis Aventis Pharma (Pty) Ltd Private Bag X207 Midrand 1683 South Africa Telephone: +27 (0) 11 2563700 Fax: +27 (0) 11 2563722 http://www.sanofi-aventis.com/

Singapore Uromitexan

Baxter Oncology, Singapore Zuellig, Singapore Zuellig Pharma Pte Ltd 19 Loyang Way 08-20 S 508724 Singapore Telephone: +65 6546 8188 Fax: +65 6546 8288 E-mail: [email protected] http://www.zuelligpharma.com/

Spain Uromitexan

Prasfarma, Spain Almirall, Spain Almirall Prodesfarma S.A. Rda Gral Mitre 151 08022 Barcelona Spain Telephone: +34 93 2913000 Fax: +34 93 2913180 http://www.almirall.es/

Sweden Uromitexan

Baxter, Sweden Baxter Medical AB Box 63 164 94 Kista Sweden Telephone: +46 (0) 8 6326400 Fax: +46 (0) 8 7520112 http://www.baxter.se/


38

Country Drug trade name Manufacturer/distributor Switzerland Uromitexan

Baxter, Switzerland Baxter AG Mullerenstrasse 3 8604 Volketswil. Switzerland Telephone: +41 (0) 1 9085050 Fax: +41 (0) 1 9085040 http://www.baxter.ch/

Thailand Uromitexan

Baxter, Thailand Baxter Healthcare (Thailand) Co. Ltd 10 Fl, Tanapoom Tower 1550 New Petchburi Rd Makasan, Rajthevi Bangkok 10310 Telephone: +66 2 652 7779 Fax: +66 2 652 7770 E-mail: [email protected] http://www.baxter.com/

Turkey Uromitexan

Eczacibasi-Baxter, Turkey Eczacıbaşı-Baxter Hastane Ürünleri San. ve Tic. A.Ş. Ayazağa Cendere Yolu No: 19 Şişli İstanbul Turkey Telephone: +90 (0) 212 3296200 Fax: +90 (0) 212 2899275 E-mail: [email protected] http://www.eczacibasi-baxter.com.tr/

United Kingdom Uromitexan

Baxter Healthcare Ltd, Surecall Medical Information Salthouse Rd Brackmills Industrial Estate Northampton NN4 7UF UK Fax: +44 (0) 1604 704631

United States Mesnex

BMS, United States Bristol-Myers Squibb P.O. Box 4500 Princeton NJ 08543-4500 USA Telephone: +1 609 897 2000 http://www.bms.com/


39

Combination agents (India) Holoxan Uromitexan (Ifosfamide/mesna) German Remedies, India German Remedies Ltd Shivsagar Estate 'A' Dr Annie Besant Rd Worli Mumbai 400 018 India Telephone: +91 (0) 22 4935528 Fax: +91 (0) 22 4950327 http://www.germanremedies.com/ Ifex-M (Ifosfamide/mesna) Biochem, India Biochem Pharmaceutical Industries Aidun Building John Crasto Lane Mumbai 400 002 India Telephone: +91 (0) 22 22085457 Fax: +91 (0) 22 22082560 http://www.biochemgroup.com/ Ipamide with mesna Dabur, India Dabur Pharmaceuticals Ltd Kaushambi Ghaziabad 201 010 India Telephone: +91 (0) 120 2777901 http://www.dabur.com/


40

Appendix B Database: Ovid MEDLINE(R) 1950 to Present with Daily Update Search Strategy: ------------------------------------------------------------ 1 exp Mesna/ (946) 2 sodium-2-mercaptoethane sulfonate.tw. (45) 3 sodium 2-mercaptoethansulfonate.tw. (1) 4 2-mercaptoethanesulfonic acid.tw. (57) 5 mercaptoethane sulfonate.tw. (84) 6 ausobronc.tw. (0) 7 filesna.tw. (0) 8 mesnil.tw. (37) 9 mexan.tw. (3) 10 mistabron.tw. (16) 11 mistabronco.tw. (1) 12 mitexan.tw. (2) 13 mucofluid.tw. (2) 14 mucolene.tw. (0) 15 uromitexan.tw. (18) 16 ziken.tw. (0) 17 mesnex.tw. (5) 18 or/1-17 (1037) 19 limit 18 to human (662) *************************** Database: Ovid MEDLINE(R) 1950 to Present with Daily Update Search Strategy: ------------------------------------------------------------ 1 exp Mesna/ (946) 2 sodium-2-mercaptoethane sulfonate.tw. (45) 3 sodium 2-mercaptoethansulfonate.tw. (1) 4 2-mercaptoethanesulfonic acid.tw. (57) 5 mercaptoethane sulfonate.tw. (84) 6 ausobronc.tw. (0) 7 filesna.tw. (0) 8 mesnil.tw. (37) 9 mexan.tw. (3) 10 mistabron.tw. (16) 11 mistabronco.tw. (1) 12 mitexan.tw. (2) 13 mucofluid.tw. (2) 14 mucolene.tw. (0) 15 uromitexan.tw. (18) 16 ziken.tw. (0) 17 mesnex.tw. (5) 18 or/1-16 (1032) 19 exp Hemorrhage/ (180978) 20 bladder bleed$.tw. (7) 21 bladder hemorrhag$.tw. (73) 22 hemorrhag$ cystitis.tw. (736) 23 or/19-22 (181325) 24 exp Cystitis, Interstitial/ or exp Cystitis/ (6180) 25 exp Urinary Bladder/ (34855) 26 cystitis.tw. (5918) 27 urinary bladder.tw. (15772) 28 or/24-27 (49955) 29 18 and 23 and 28 (85) 30 limit 28 to human (68) ***************************


41

Database: Ovid MEDLINE(R) 1950 to Present with Daily Update Search Strategy: ------------------------------------------------------------ 1 exp Mesna/ (946) 2 sodium-2-mercaptoethane sulfonate.tw. (45) 3 sodium 2-mercaptoethansulfonate.tw. (1) 4 2-mercaptoethanesulfonic acid.tw. (57) 5 mercaptoethane sulfonate.tw. (84) 6 ausobronc.tw. (0) 7 filesna.tw. (0) 8 mesnil.tw. (37) 9 mexan.tw. (3) 10 mistabron.tw. (16) 11 mistabronco.tw. (1) 12 mitexan.tw. (2) 13 mucofluid.tw. (2) 14 mucolene.tw. (0) 15 uromitexan.tw. (18) 16 ziken.tw. (0) 17 mesnex.tw. (5) 18 or/1-17 (1033) 19 randomized controlled trial.pt. (240134) 20 controlled clinical trial.pt. (75712) 21 randomized controlled trials.sh. (50264) 22 random allocation.sh. (58682) 23 double blind method.sh. (92697) 24 single blind method.sh. (11221) 25 or/19-24 (406983) 26 (animal not human).sh. (0) 27 25 not 26 (406983) 28 clinical trial.pt. (439486) 29 exp Clinical trials/ (194924) 30 (clin$ adj25 trial$).ti,ab. (134050) 31 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. (92111) 32 placebos.sh. (26425) 33 placebo$.ti,ab. (104219) 34 random$.ti,ab. (381536) 35 research design.sh. (48722) 36 or/28-35 (863728) 37 36 not 26 (863728) 38 37 not 27 (489180) 39 comparative study.sh. (0) 40 exp Evaluation studies/ (609964) 41 follow up studies.sh. (343922) 42 prospective studies.sh. (226333) 43 (control$ or prospectiv$ or volunteer$).ti,ab. (1824011) 44 or/39-43 (2628863) 45 44 not 26 (2628863) 46 44 not (27 or 38) (2095590) 47 27 or 38 or 46 (2991753) 48 18 and 47 (409) 49 limit 48 to human (366) ***************************


42

Database: Ovid MEDLINE(R) 1950 to Present with Daily Update Search Strategy: ------------------------------------------------------------ 1 exp Mesna/ (946) 2 sodium-2-mercaptoethane sulfonate.tw. (45) 3 sodium 2-mercaptoethansulfonate.tw. (1) 4 2-mercaptoethanesulfonic acid.tw. (57) 5 mercaptoethane sulfonate.tw. (84) 6 ausobronc.tw. (0) 7 filesna.tw. (0) 8 mesnil.tw. (37) 9 mexan.tw. (3) 10 mistabron.tw. (16) 11 mistabronco.tw. (1) 12 mitexan.tw. (2) 13 mucofluid.tw. (2) 14 mucolene.tw. (0) 15 uromitexan.tw. (18) 16 ziken.tw. (0) 17 mesnex.tw. (5) 18 or/1-17 (1033) 19 exp Meta-Analysis/ (7642) 20 meta-analys$.mp. (28468) 21 systematic review$.mp. (11695) 22 critical review$.mp. (6739) 23 cochrane review$.mp. (538) 24 literature review$.mp. (19706) 25 overview$.mp. (45882) 26 or/19-25 (105939) 27 18 and 26 (8) 28 limit 27 to human (8) *************************** Database: EMBASE <1980 to 2007 Week 28> Search Strategy: -------------------------------------------------------------- 1 exp Mesna/ (3392) 2 sodium-2-mercaptoethane sulfonate.tw. (41) 3 odium 2-mercaptoethansulfonate.tw. (1) 4 2-mercaptoethanesulfonic acid.tw. (48) 5 mercaptoethane sulfonate.tw. (79) 6 ausobronc.tw. (0) 7 filesna.tw. (0) 8 mesnil.tw. (4) 9 mexan.tw. (11) 10 mistabron.tw. (44) 11 mistabronco.tw. (10) 12 mitexan.tw. (6) 13 mucofluid.tw. (35) 14 mucolene.tw. (3) 15 uromitexan.tw. (222) 16 ziken.tw. (0) 17 mesnex.tw. (51) 18 or/1-17 (3429) ***************************


43

Database: EMBASE <1980 to 2007 Week 28> Search Strategy: -------------------------------------------------------------- 1 exp Mesna/ (3392) 2 sodium-2-mercaptoethane sulfonate.tw. (41) 3 sodium 2-mercaptoethansulfonate.tw. (1) 4 2-mercaptoethanesulfonic acid.tw. (48) 5 mercaptoethane sulfonate.tw. (79) 6 ausobronc.tw. (0) 7 filesna.tw. (0) 8 mesnil.tw. (4) 9 mexan.tw. (11) 10 mistabron.tw. (44) 11 mistabronco.tw. (10) 12 mitexan.tw. (6) 13 mucofluid.tw. (35) 14 mucolene.tw. (3) 15 uromitexan.tw. (222) 16 ziken.tw. (0) 17 mesnex.tw. (51) 18 or/1-17 (3429) 19 exp Hemorrhage/ (208060) 20 bladder bleed$.tw. (10) 21 bladder hemorrhag$.tw. (45) 22 hemorrhag$ cystitis.tw. (612) 23 or/19-22 (208518) 24 exp Cystitis, Interstitial/ or exp Cystitis/ (7867) 25 exp Urinary Bladder/ (30557) 26 cystitis.tw. (4783) 27 urinary bladder.tw. (11266) 28 or/24-27 (43010) 29 18 and 23 and 28 (182) 30 limit 29 to human (166) *************************** Database: EMBASE <1980 to 2007 Week 28> Search Strategy: --------------------------------------------------------------- 1 exp Mesna/ (3392) 2 sodium-2-mercaptoethane sulfonate.tw. (41) 3 sodium 2-mercaptoethansulfonate.tw. (1) 4 2-mercaptoethanesulfonic acid.tw. (48) 5 mercaptoethane sulfonate.tw. (79) 6 ausobronc.tw. (0) 7 filesna.tw. (0) 8 mesnil.tw. (4) 9 mexan.tw. (11) 10 mistabron.tw. (44) 11 mistabronco.tw. (10) 12 mitexan.tw. (6) 13 mucofluid.tw. (35) 14 mucolene.tw. (3) 15 uromitexan.tw. (222) 16 ziken.tw. (0) 17 mesnex.tw. (51) 18 or/1-17 (3429) 19 exp clinical trial/ (444983) 20 controlled study/ (2461691) 21 randomized controlled trial$.tw. (18839) 22 comparative stud$.ti,ab. (35083) 23 random allocation.tw. (581)


44

24 crossover trial.ti,ab. (2823) 25 double blind procedure.sh. (64962) 26 (cli$ adj25 trial$).ti,ab. (125490) 27 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. (88090) 28 placebo$.sh. (101779) 29 placebo$.ti,ab. or placebo$.tw. (99839) 30 random$.ti,ab. or random$.tw. (343108) 31 or/19-30 (2912183) 32 animal/ not (human/ and animal/) (12862) 33 31 not 32 (2911400) 34 "COMPARATIVE STUDY".mp. (117824) 35 "EVALUATION STUDIES".mp. (695) 36 "FOLLOW UP STUDIES".mp. (5179) 37 "CROSSOVER TRIAL$".mp. (2981) 38 exp prospective study/ (67008) 39 exp longitudinal study/ (15807) 40 (control$ or prospectiv$ or volunteer$).ti,ab. (1567029) 41 or/34-40 (1676305) 42 41 not 32 (1674823) 43 33 or 42 (3653266) 44 18 and 43 (1666) 45 limit 44 to human (1547) *************************** Database: EMBASE <1980 to 2007 Week 28> Search Strategy: ------------------------------------------------------------------- 1 exp Mesna/ (3392) 2 sodium-2-mercaptoethane sulfonate.tw. (41) 3 sodium 2-mercaptoethansulfonate.tw. (1) 4 2-mercaptoethanesulfonic acid.tw. (48) 5 mercaptoethane sulfonate.tw. (79) 6 ausobronc.tw. (0) 7 filesna.tw. (0) 8 mesnil.tw. (4) 9 mexan.tw. (11) 10 mistabron.tw. (44) 11 mistabronco.tw. (10) 12 mitexan.tw. (6) 13 mucofluid.tw. (35) 14 mucolene.tw. (3) 15 uromitexan.tw. (222) 16 ziken.tw. (0) 17 mesnex.tw. (51) 18 or/1-17 (3429) 19 exp Meta-Analysis/ (31350) 20 meta-analys$.mp. (37847) 21 systematic review$.mp. (25391) 22 critical review$.mp. (5198) 23 cochrane review$.mp. (440) 24 literature review$.mp. (16668) 25 overview$.mp. (41416) 26 or/19-25 (110851) 27 18 and 26 (90) 28 limit 27 to human (90) ***************************

Documents

Proposal for the inclusion of mesna (sodium 2-mercaptoethane