Application to Include Fomepizole on the WHO Model List of Essential Medicines Guangduo Zhang, Kasumi Crews, Heather Wiseman, Nicola Bates Medical Toxicology Information Services Ltd., London, UK Knut Erik Hovda The National NBC Center, Department of Acute Medicine, Oslo University Hospital Ullevaal, Oslo, Norway John RH Archer, Paul I Dargan Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust and King’s Health Partners, London, UK November 2012 Contact Details Heather Wiseman Medical Toxicology and Information Services Ltd. 13 St Thomas' Street, London, UK SE1 9RY [email protected] Knut Erik Hovda The National NBC Centre, Department of Acute Medicine, Oslo University Hospital Ullevaal, Oslo, Norway P.O. Box 4950 Nydalen, NO-0424 Oslo, Norway [email protected] Paul I Dargan Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust and King’s Health Partners Clinical Toxicology, South Wing, 3rd floor, Block C St Thomas' Hospital, Westminster Bridge Road, London, UK SE1 7EH [email protected] Application to Include Fomepizole on the WHO Model List of Essential Medicines 2/85 Contents 1. Summary Statement of the Proposal for Inclusion, Change or Deletion .................................................. 6 2. Name of the Focal Point in WHO Submitting or Supporting the Application ........................................... 7 3. Name of the Organisation(s) Consulted and/or Supporting the Application ............................................ 7 4. International Nonproprietary Name (INN, Generic Name) of the Medicine ............................................ 7 5. Formulation Proposed for Inclusion .......................................................................................................... 7 6. International Availability ........................................................................................................................... 8 7. Whether Listing is requested as an Individual Medicine or as an Example of a Therapeutic Group ........ 8 8. Information Supporting the Public Health Relevance ............................................................................... 8 8.1 Epidemiological Information on Disease Burden of Toxic Alcohol and Glycol Poisoning ................... 8 8.1.1 Toxic Alcohols and Glycols ............................................................................................................ 8 8.1.2 Ethylene Glycol ........................................................................................................................... 10 8.1.3 Methanol .................................................................................................................................... 10 8.1.4 Diethylene Glycol ........................................................................................................................ 12 8.1.5 Other Alcohols and Glycols ......................................................................................................... 13 8.1.6 Disease Burden ........................................................................................................................... 13 8.2 Assessment of Current Use ............................................................................................................... 13 8.2.1 Treatment of Ethylene Glycol and Methanol Poisoning in Adults and Children ........................ 13 8.2.2 Other Indications ........................................................................................................................ 15 8.3 Target Population .............................................................................................................................. 15 9. Treatment Details .................................................................................................................................... 15 9.1 Dosage Regimen and Duration .......................................................................................................... 15 9.1.1 Adults .......................................................................................................................................... 15 9.1.2 Children ...................................................................................................................................... 17 9.1.3 Other Toxic Alcohols ................................................................................................................... 17 9.1.4 Validation of the Current Fomepizole Treatment Regimen ....................................................... 17 9.1.5 Treatment Criteria ...................................................................................................................... 19 9.2 Need for Special Diagnostics ............................................................................................................. 19 9.3 Treatment or Monitoring Facilities and Skills .................................................................................... 20 9.3.1 Treatment Monitoring ................................................................................................................ 20 9.3.2 Need for Haemodialysis ............................................................................................................. 20 10. Summary of Comparative Effectiveness in a Variety of Clinical Settings .............................................. 21 10.1 Identification of Clinical Evidence ................................................................................................... 21 Application to Include Fomepizole on the WHO Model List of Essential Medicines 3/85 10.2 Experimental Evidence of Efficacy of Fomepizole ........................................................................... 22 10.2.1 In vitro Studies .......................................................................................................................... 22 10.2.2 Animal Studies .......................................................................................................................... 22 10.3 Clinical Evidence of Efficacy of Fomepizole ..................................................................................... 23 10.3.1 Quality of Evidence ................................................................................................................... 23 10.3.2 Fomepizole Treatment in Ethylene Glycol Poisoning ............................................................... 24 10.3.3 Fomepizole Treatment in Methanol Poisoning ........................................................................ 25 10.4 Ethanol Treatment in Ethylene Glycol and Methanol Poisoning .................................................... 27 10.5 Comparison of Fomepizole versus Ethanol Treatment ................................................................... 28 10.5.1 Comparison of Fomepizole and Ethanol in Ethylene Glycol Poisoning .................................... 28 10.5.2 Comparison of Fomepizole and Ethanol in Methanol Poisoning ............................................. 29 10.5.3 Practical Considerations ........................................................................................................... 30 10.6 Fomepizole Use in Epidemics .......................................................................................................... 31 11. Summary of Comparative Evidence on Safety ...................................................................................... 32 11.1 Estimate of Total Patient Exposure to Date .................................................................................... 32 11.2 Description of Adverse Effects/Reactions ....................................................................................... 32 11.2.1 Central Nervous System (CNS) Effects...................................................................................... 33 11.2.2 Cardiovascular Effects .............................................................................................................. 33 11.2.3 Gastrointestinal and Metabolic Effects .................................................................................... 34 11.2.4 Dermatological Effects ............................................................................................................. 34 11.2.5 Haematological Effects ............................................................................................................. 34 11.2.6 Other Effects ............................................................................................................................. 34 11.3 Identification of Variation in Safety due to Health Systems and Patient Factors ........................... 36 11.3.1 Paediatrics ................................................................................................................................ 36 11.3.2 Pregnancy and Breast Feeding ................................................................................................. 36 11.3.3 Haemodialysis ........................................................................................................................... 36 11.3.4 Other Factors ............................................................................................................................ 36 11.4 Summary of Comparative Safety against Comparators .................................................................. 37 11.4.1 Adverse Effects of Ethanol ......................................................................................................