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. 1 WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008 Table 1.1: Summary of worldwide cancer deaths by region Region Deaths Predicted deaths 2002 2020 North America 631,900 951,400 Central America, South America, and Carribbean 479,900 833,800 Northern Europe 241,100 297,600 Central and Eastern Europe 637,000 742,800 Western Europe 475,100 617,100 Southern Europe 348,400 427,300 Eastern Asia 2,016,300 3,223,700 South-Central Asia 845,200 1,389,800 South-Eastern Asia 363,400 709,300 Northern Africa and Western Asia 224,000 389,200 Sub-Saharan Africa 412,100 626,400 Oceania 49,500 77,300 Total 6,723,900 10,285,700 Source: IARC, Globocan 20022 More recent data indicates that in 2005 cancer killed 7.6 million people which accounts for around 13% of all deaths worldwide.3 Of all these cancer deaths 70% occurered in low and middle income countries. The WHO predicts that deaths from cancer in the world will continue to rise with an estimated 9 million people dying from cancer in 2015 and by 2030 the number of deaths from cancer is anticipated to be 11.4 million of whom 8.9 million will be from low-middle income countries compared to 2.5 million will be from high income countries. A summary of the types of cancer leading to overall cancer mortality in 2002 is presented in Table 1.2 and Figure 1.1. Table 1.2: Summary of the types of cancer leading to overall cancer mortality in 2002 Type of cancer Number of cases Mouth and oropharynx cancers 317,894 Oesophagus cancer 446,166 Stomach cancer 850,401 Colon and rectum cancers 622,256 Liver cancer 618,124 Pancreas cancer 230,957 Trachea, bronchus, lung cancers 1,243,199 Melanoma and other skin cancers 66,034 Breast cancer 477,196 Cervix uteri cancer 238,814 Corpus uteri cancer 71,387 Ovary cancer 134,623 Prostate cancer 269,292 Bladder cancer 178,850 Lymphomas, multiple myeloma 334,421 Leukemia 264,229 Other malignant neoplasms 756,924 Other neoplasms 148,910 Source: Global Action Against Cancer - Updated Edition 20053 2 WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008 Kidney 34 56 Ovary 114 Pancreas 101 111 Leukaemia 85 109 Oral cavity 47 80 Non-Hodgkin lymphoma 67 93 Bladder 33 99 Mortality Female 110 Oesophagus Mortality Male 226 Cervix uteri 233 Pr os tate 204 Liver 164 383 Stomach 241 405 Colorectum 237 254 Breast 372 Lung 292 810 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. 3 WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008 Kidney 70 118 Ovary 192 Pancreas 100 115 Leukaemia 112 144 Oral cavity 97 169 Non-Hodgkin lymphoma 120 166 Bladder 76 259 Oesophagus 133 278 Incidence Female 470 Cervix uteri Incidence Male Pr os tate 542 Liver 165 398 Stomach 317 558 Colorec tum 445 498 Breast 1,050 Lung 337 901 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. 4 WHO EML - Final Report - MESNA (sodium 2-mercaptoethane sulfonate) – February 2008 Male Brain, etc 59 41 Other pharynx 64 37 Pancreas 50 66 Kidney 39 79 Larynx 80 62 Leukaemia 86 58 Non-Hodgkin lymphoma 86 Less developed 80 Oral cavity 110 More developed 60 Bladder 96 164 Oesophagus 224 55 Liver 325 73 Colorectum 180 319 Pr os tate 127 416 Stomach 350 208 Lung 431 471 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 Bladder 27 48 Thyroid 53 35 Oral cavity 72 24 Pancreas 39 61 Leukaemia 65 47 Non-Hodgkin lymphoma 54 66 Oesophagus 117 16 Liver 132 Less developed 33 Corpus uteri 75 More developed 113 Ovary 101 91 Stomach 192 125 Lung 161 175 Colorectum 154 291 Cervix uteri 379 91 Breast 471 579 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 5 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, non- Hodgkin Lymphoma, and renal (Wilms) tumors. In the United States advances in the treatment of childhood cancers have led to an improved 5-year survival rate from 56% for patients diagnosed in 1974-1976 to 79% in children diagnosed with cancer in 1995 to 2001.4 In the case of acute leukaemia, controlled clinical trials of chemotherapy in the United States and Europe have steadily improved the survival of children to 85%.5 However, not all children worldwide have access to optimal treatment.