Download Proposal for the inclusion of mesna (sodium 2

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
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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Table 1.1: Summary of worldwide cancer deaths by region
Region
North America
Central America, South America, and Carribbean
Northern Europe
Central and Eastern Europe
Western Europe
Southern Europe
Eastern Asia
South-Central Asia
South-Eastern Asia
Northern Africa and Western Asia
Sub-Saharan Africa
Oceania
Total
Source: IARC, Globocan 20022
Deaths
2002
631,900
479,900
241,100
637,000
475,100
348,400
2,016,300
845,200
363,400
224,000
412,100
49,500
6,723,900
Predicted deaths
2020
951,400
833,800
297,600
742,800
617,100
427,300
3,223,700
1,389,800
709,300
389,200
626,400
77,300
10,285,700
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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
34
Kidney
56
114
Ovary
101
Pancreas
85
Leukaemia
109
47
Oral cavity
111
80
67
Non-Hodgkin lymphoma
33
Bladder
93
Mortality Female
99
110
Oesophagus
Mortality Male
226
233
Cervix uteri
Prostate
164
Liver
204
Stomach
241
Colorectum
237
383
405
254
372
Breast
292
Lung
810
0
100
200
300
400
500
600
700
800
900
Number (Thousands)
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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70
Kidney
118
192
Ovary
100
Pancreas
115
112
Leukaemia
97
Oral cavity
144
169
120
Non-Hodgkin lymphoma
76
Bladder
166
133
Oesophagus
259
Incidence Female
278
470
Cervix uteri
Prostate
542
165
Liver
398
317
Stomach
Incidence Male
558
445
Colorectum
498
1,050
Breast
337
Lung
901
0
100
200
300
400
500
600
700
800
900 1000 1100 1200
Number (Thousands)
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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Male
59
Brain, etc
41
Other pharynx
37
Pancreas
64
50
66
39
Kidney
79
80
Larynx
62
Leukaemia
86
58
Less developed
86
Non-Hodgkin lymphoma
80
Oral cavity
More developed
110
60
96
Bladder
164
Oesophagus
224
55
Liver
325
73
180
Colorectum
319
127
Prostate
416
350
Stomach
208
431
Lung
471
0
50
100
150
200
250
300
350
400
450
500
Number (Thousands)
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
27
Bladder
48
53
Thyroid
35
Oral cavity
24
Pancreas
72
39
61
65
Leukaemia
47
54
Non-Hodgkin lymphoma
66
Oesophagus
117
16
Liver
132
33
Corpus uteri
Less developed
75
More developed
113
101
Ovary
91
Stomach
192
125
Lung
161
175
154
Colorectum
291
Cervix uteri
379
91
471
Breast
579
0
100
200
300
400
500
600
700
Number (Thousands)
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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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, nonHodgkin 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-2mercaptoethane 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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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-hydroxyoxazaphosphorine 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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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). Fourtyfive 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 nonsmall 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 nacetylcysteine (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-tofemale 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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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
19
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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 nonHodgkin’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 73 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
Araujo et al.24
1983
Cytotoxic
agent
IFO
Legha et al.23
1990
IFO
Fukuoka et al.20
1991
IFO
Scheef et al.26
1979
IFO/CY
Vose et al.30
1993
CY
Mesna
N = 45
Cystitis = 4/88*
Microhaematuria = 10/88*
N=31
Grade 2 haematuria = 2/31
Grade 3 haematuria = 0/31
N = 45
Mild haematuria = 0/45
Moderate haematuria = 1/45
Severe haematuria = 2/45
Overall incidence = 6.7%
N = 11
Microhaematuria = 2/11
Macrohaematuria = 0/11
N = 103
Grade 1 haematuria = 18%
Grade 2 haematuria = 17%
Grade 3 haematuria = 10%
Grade 4 haematuria = 8%
No mesna
N = 25
Cystitis = 38/50*
Microhaematuria = 10/50*
Gross haematuria = 26/50*
Overall: P < 0.0001
N=31
Grade 2 haematuria = 4/31
Grade 3 haematuria = 5/31
N = 46
Mild haematuria = 4/46
Moderate haematuria = 4/46
Severe haematuria = 11/46
Overall incidence = 32.6%
Overall: P = 0.0008
N=9
Microhaematuria = 1/9
Macrohaematuria = 8/9
N = 97
Grade 1 haematuria = 26%
Grade 2 haematuria = 32%
Grade 3 haematuria = 13%
Grade 4 haematuria = 5%
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WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Study
Year
Cytotoxic
agent
Mesna
Shepherd et al.29
1991
CY
N=51
Assessable patients n = 40
Minor haematuria = 14/40
Consistent haematuria = 8/40
Severe haematuria = 5/40
Hows et al.28
1984
CY
N=34
†
Microhaematuria = 10/32
†
Macrohaematuria = 4/32
Bedi et al. 31
1995
CY
N=71
HC = 19/71
Henslee et al.32
1988
CY
N=13
HC = 8/13
No mesna
Grade 3-4: P > 0.05
Overall: P = 0.007
N=49
Assessable patients n = 40
Minor haematuria = 19/40
Consistent haematuria = 5/40
Severe haematuria = 3/40
Severe haematuria: P = 0.71
N=27
†
Microhaematuria = 8/26
Macrohaematuria = 9/26†
Macrohaematuria: P < 0.05
N=76
HC = 18/76
P = 0.41
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
21
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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.
22
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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.
23
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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$460
for continuous bladder irrigation. Based the findings of these two studies the average cost of
mesna treatment per patient exceeds that of both hyperhydration and continuous bladder
irrigation.
Global costs of mesna
British National Formulary (2007)
Mesna (Uromitexan®, Baxter) – tablets, f/c, mesna 400 mg, net price 10-tab pack = ₤21.10;
600 mg, 10-tab pack = ₤27.40
Mesna (Uromitexan®, Baxter) – injection, mesna 100 mg/ml, net price 4-ml amp = ₤1.95; 10ml amp = ₤4.38
International Drug Price Indicator (2007) – US$
Source
Guatemala
South Africa
El Salvador
Lowest price
Median price
Highest price
Package
1 Amp (4 ml)
1 Amp (4 ml)
1 Amp (4 ml)
Package Price
$1.68
$2.84
$4.41
Unit price
0.4195
0.7089
1.1025
0.4195
0.7089
1.1025
Australian Pharmaceutical Benefits Scheme (PBS) pricing details (http://mims.com.au) –
AUD$
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.
24
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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
25
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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.
26
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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
27
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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.
28
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Reference List
1
Stewart BW, Kleihues P, (Eds). World Cancer Report. IARC Press. Lyon. 2003.
2
Globocan 2002. International Agency for Research on Cancer. 2002.
3
Global Action Against Cancer - Updated Edition. World Health Organisation. 2005.
4
Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C et al. Cancer statistics, 2006. CA
Cancer J Clin. 2006; 56(2): 106-130.
5
Greaves M. Infection, immune responses and the aetiology of childhood leukaemia.
[Review] [143 refs]. Nature Reviews - Cancer. 2006; 6(3): 193-203.
6
Brock N, Pohl J. The development of mesna for regional detoxification. Cancer Treat
Rev. 1983; 10 Suppl A: 33-43.
7
Hensley ML, Schuchter LM, Lindley C, Meropol NJ, Cohen GI, Broder G et al.
American Society of Clinical Oncology clinical practice guidelines for the use of
chemotherapy and radiotherapy protectants.[see comment]. J Clin Oncol. 1999; 17(10):
3333-3355.
8
Links M, Lewis C. Chemoprotectants: a review of their clinical pharmacology and
therapeutic efficacy. [Review] [94 refs]. Drugs. 1999; 57(3): 293-308.
9
Brock N. Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial
Award lecture. [Review] [57 refs]. Cancer Res. 1989; 49(1): 1-7.
10 Brock N. The oxazaphosphorines. Cancer Treat Rev. 1983; 10 Suppl A: 3-15.
11 Dubourg L, Michoudet C, Cochat P, Baverel G. Human kidney tubules detoxify
chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide. J Am Soc Nephrol.
2001; 12(8): 1615-1623.
12 Dechant KL, Brogden RN, Pilkington T, Faulds D. Ifosfamide/mesna. A review of its
antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer.
[Review] [250 refs]. Drugs. 1991; 42(3): 428-467.
13 Sutton G. Ifosfamide and mesna in epithelial ovarian carcinoma. [Review] [25 refs].
Gynecol Oncol. 1993; 51(1): 104-108.
14 Seber A, Shu XO, Defor T, Sencer S, Ramsay N. Risk factors for severe hemorrhagic
cystitis following BMT. Bone Marrow Transplant. 1999; 23(1): 35-40.
15 American Society of Health-System Pharmacists. Mesna - AHFS Drug Information,
Bethesda, MD 20814.
2007.http://www.medicinescomplete.com/mc/ahfs/2007/a395034.htm.
16 Baxter Healthcare Corporation. Product Information - Mesnex® (mesna) Injection,
Mesnex® Tablet. Product Information - Mesnex® (mesna) Injection, Mesnex® Tablet.
2002; Issued May.
29
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
17 Schuchter LM, Hensley ML, Meropol NJ, Winer EP, American Society of Clinical
Oncology Chemotherapy and Radiotherapy Expert Panel., Schuchter LM et al. 2002
update of recommendations for the use of chemotherapy and radiotherapy protectants:
clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol.
2002; 20(12): 2895-2903.
18 Sweetman S. Mesna - Martindale: The Complete Drug Reference. London:
Pharmaceutical Press. Electronic version. 2007.http://www.medicinescomplete.com.
19 Dickersin K, Larson K. Establishing and maintaining an international register of RCTs.
1996.
20 Fukuoka M, Negoro S, Masuda N, Furuse K, Kawahara M, Kodama N et al. Placebocontrolled double-blind comparative study on the preventive efficacy of mesna against
ifosfamide-induced urinary disorders. J Cancer Res Clin Oncol. 1991; 117(5): 473-478.
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 nacetylcysteine (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): 753756.
30
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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): 13061310.
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.
31
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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
32
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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
Canada
Uromitexan
Chile
Uromitexan
Chile
Uroprot
Czech Republic
Uromitexan
Denmark
Uromitexan
Asta Oncologia, Brazil
Asta Medica Oncologia Ltda
Rua Eng. Franisco Pitta Brito 779
4753080 São Paulo
Brazil
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/
Baxter, Chile
Laboratorio Baxter/Asta Medica
General Salvo 68
Providencia
Santiago
Chile
Laboratorios Chile SA
Av. Marathon 1315
Nunoa
Santiago
Chile
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/
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
33
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Country
Drug trade name
Manufacturer/distributor
Telephone: +358 (0) 9 8621111
Fax: +358 (0) 9 86211211
http://www.baxter.fi/
France
Uromitexan
Germany
Uromitexan
Greece
Uromitexan
Hong Kong
Uromitexan
Hungary
Uromitexan
Hungary
Uromitexan
India
Uromitexan
Ireland
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/
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/
Baxter Hellas EPE
Ethnarhou Makariou 34
163 41 Ilioupolis
Greece
Telephone: +30 210 9987000
Fax: +30 210 9959820
http://www.baxter.com/
Baxter Healthcare Ltd
Rm 2006
MassMutual Tower
38 Gloucester Rd
Wanchai
Hong Kong
Telephone: +852 28078500
Fax: +852 28078596
http://www.baxter.com/
Baxter Hungary Kft
Buday László utca 12
1024 Budapest
Hungary
Telephone: +36 3454519
Fax: +36 3454518
Pliva, Hungary
Pliva d d Magyarországi Kereskedelmi Képviselete
Galagonya u 5
1036 Budapest
Hungary
Telephone: +36 2502450
Fax: +36 2502460
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/
Asta Medica, Ireland
34
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Country
Drug trade name
Israel
Mexan
Italy
Uromitexan
Japan
Uromitexan
Malaysia
Uromitexan
Mexico
Filesna*
Mexico
Mesnil
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/
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/
Baxter, Italy
Baxter S.p.A.
Viale Tiziano 25
00100 Rome
Italy
Telephone: +39 06 324911
Fax: +39 06 32491329
http://www.baxter.com/
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/
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/
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/
Asofarma de Mexico S.A. de C.V.
35
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Country
Drug trade name
Mexico
Mesoda
Mexico
Uromes
Mexico
Uromitexan
Mexico
Uroprot
Mexico
Ziken
The Netherlands
Uromitexan
Norway
Uromitexan
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/
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/
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/
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/
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
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/
Baxter BV
Kobaltweg 49
3542 CE Utrecht
Netherlands
http://www.baxter.nl/
Baxter, Norway
Baxter AS
Gjerdrumsv. 11
Postboks 70 Grefsen
0409 Oslo
Norway
36
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Country
Drug trade name
Manufacturer/distributor
Telephone: +47 22584800
Fax: +47 22584801
http://www.baxter.no/
New Zealand
Uromitexan
Portugal
Uromitexan
South Africa
Uromitexan
Singapore
Uromitexan
Spain
Uromitexan
Sweden
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/
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/
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/
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/
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/
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/
37
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Country
Switzerland
Drug trade name
Uromitexan
Thailand
Uromitexan
Turkey
Uromitexan
United Kingdom
Uromitexan
United States
Mesnex
Manufacturer/distributor
Baxter, Switzerland
Baxter AG
Mullerenstrasse 3
8604 Volketswil.
Switzerland
Telephone: +41 (0) 1 9085050
Fax: +41 (0) 1 9085040
http://www.baxter.ch/
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/
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/
Baxter Healthcare Ltd, Surecall Medical Information
Salthouse Rd
Brackmills Industrial Estate
Northampton
NN4 7UF
UK
Fax: +44 (0) 1604 704631
BMS, United States
Bristol-Myers Squibb
P.O. Box 4500
Princeton
NJ 08543-4500
USA
Telephone: +1 609 897 2000
http://www.bms.com/
38
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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/
39
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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)
***************************
40
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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$).ti,ab. (1824011)
44
or/39-43 (2628863)
45
44 not 26 (2628863)
46
44 not (27 or 38) (2095590)
47
27 or 38 or 46 (2991753)
48
18 and 47 (409)
49
limit 48 to human (366)
***************************
41
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Database: Ovid MEDLINE(R) 1950 to Present with Daily Update
Search Strategy:
-----------------------------------------------------------1
exp Mesna/ (946)
2
sodium-2-mercaptoethane sulfonate.tw. (45)
3
sodium 2-mercaptoethansulfonate.tw. (1)
4
2-mercaptoethanesulfonic acid.tw. (57)
5
mercaptoethane sulfonate.tw. (84)
6
ausobronc.tw. (0)
7
filesna.tw. (0)
8
mesnil.tw. (37)
9
mexan.tw. (3)
10
mistabron.tw. (16)
11
mistabronco.tw. (1)
12
mitexan.tw. (2)
13
mucofluid.tw. (2)
14
mucolene.tw. (0)
15
uromitexan.tw. (18)
16
ziken.tw. (0)
17
mesnex.tw. (5)
18
or/1-17 (1033)
19
exp Meta-Analysis/ (7642)
20
meta-analys$.mp. (28468)
21
systematic review$.mp. (11695)
22
critical review$.mp. (6739)
23
cochrane review$.mp. (538)
24
literature review$.mp. (19706)
25
overview$.mp. (45882)
26
or/19-25 (105939)
27
18 and 26 (8)
28
limit 27 to human (8)
***************************
Database: EMBASE <1980 to 2007 Week 28>
Search Strategy:
-------------------------------------------------------------1
exp Mesna/ (3392)
2
sodium-2-mercaptoethane sulfonate.tw. (41)
3
odium 2-mercaptoethansulfonate.tw. (1)
4
2-mercaptoethanesulfonic acid.tw. (48)
5
mercaptoethane sulfonate.tw. (79)
6
ausobronc.tw. (0)
7
filesna.tw. (0)
8
mesnil.tw. (4)
9
mexan.tw. (11)
10
mistabron.tw. (44)
11
mistabronco.tw. (10)
12
mitexan.tw. (6)
13
mucofluid.tw. (35)
14
mucolene.tw. (3)
15
uromitexan.tw. (222)
16
ziken.tw. (0)
17
mesnex.tw. (51)
18
or/1-17 (3429)
***************************
42
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
Database: EMBASE <1980 to 2007 Week 28>
Search Strategy:
-------------------------------------------------------------1
exp Mesna/ (3392)
2
sodium-2-mercaptoethane sulfonate.tw. (41)
3
sodium 2-mercaptoethansulfonate.tw. (1)
4
2-mercaptoethanesulfonic acid.tw. (48)
5
mercaptoethane sulfonate.tw. (79)
6
ausobronc.tw. (0)
7
filesna.tw. (0)
8
mesnil.tw. (4)
9
mexan.tw. (11)
10
mistabron.tw. (44)
11
mistabronco.tw. (10)
12
mitexan.tw. (6)
13
mucofluid.tw. (35)
14
mucolene.tw. (3)
15
uromitexan.tw. (222)
16
ziken.tw. (0)
17
mesnex.tw. (51)
18
or/1-17 (3429)
19
exp Hemorrhage/ (208060)
20
bladder bleed$.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)
43
WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008
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)
***************************
44