21st WHO Expert Committee on the Selection and Use of Essential Medicines: Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) Submitted: December 2016 Submitted by: Dr. Antonio Montresor Department of Control of Neglected Tropical Diseases Preventive Chemotherapy and Transmission Control World Health Organization Geneva, Switzerland Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) Contents General items ...................................................................................................................... 4 1. Summary statement of the proposal for inclusion, change or deletion ........................... 4 2. Name of the WHO technical department and focal point supporting the application .... 5 3. Name of organization consulted and/or supporting the application ............................... 5 4. International Nonproprietary Name (INN) and anatomical therapeutic chemical (ATC) code of the medicine ................................................................................................................. 6 5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric .. 6 5.1 Strongyloidiasis ....................................................................................................................... 6 5.2 Soil-transmitted helminthiasis ................................................................................................ 6 6. Whether listing is requested as an individual medicine or as a representative of a pharmacological class ......................................................................................................................... 6 Treatment details, public health relevance and evidence appraisal and synthesis.................. 6 7. Treatment details (requirements for diagnosis, treatment and monitoring) ................... 6 7.1 Strongyloidiasis ....................................................................................................................... 6 7.2 Soil-transmitted helminthiasis ................................................................................................ 8 8. Information supporting the public health relevance ...................................................... 11 8.1 Strongyloidiasis ..................................................................................................................... 11 8.2 Soil-transmitted helminthiasis .............................................................................................. 13 9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings .................................................................................................................................... 15 9.1 Strongyloidiasis ..................................................................................................................... 15 9.2 Soil-transmitted helminthiasis .............................................................................................. 20 10. Review of harms and toxicity: summary of evidence on safety.................................. 28 10.1 Summary of methods ............................................................................................................ 28 10.2 Estimate of total patient exposure to date ........................................................................... 29 10.3 Strongyloidiasis ..................................................................................................................... 30 10.4 Soil-transmitted helminthiasis .............................................................................................. 33 10.5 Reports for ivermectin in the WHO global database of reports of adverse drug reactions (VigiBase) ........................................................................................................................... 43 11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group ........................................................................... 45 11.1 Range of costs of the proposed medicine ............................................................................. 45 11.2 Resource use and comparative cost-effectiveness ............................................................... 46 Regulatory information...................................................................................................... 46 2 Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) 12. Summary of regulatory status of the medicine .......................................................... 46 12.1 Regulatory approval .............................................................................................................. 46 12.2 Existing or planned listing on the WHO list of prequalified medical products ..................... 47 13. Availability of pharmacopoeial standard .................................................................... 48 14. Reference list ............................................................................................................... 49 3 Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) General items 1. Summary statement of the proposal for inclusion, change or deletion This application is in support of the inclusion of ivermectin as an intestinal anthelminthic in the WHO Model List of Essential Medicines for adults (EML) and children (EMLc) (i.e. Section 6.1.1). This proposal is an expansion of the indication for ivermectin, which is currently included in the EML as an antifilarial (i.e. Section 6.1.2) (WHO 2015b). Ivermectin has been used extensively for human use, alone against onchocerciasis and in combination with albendazole against lymphatic filariasis (LF) since the 1980s (WHO 2006). It has played a key role in the elimination programmes of these two neglected tropical diseases. Despite being included in the EML as an antifilarial only, ivermectin is considered to be the drug of choice or an alternative therapy for a wide range of diseases, including scabies, mansonellosis, gnathostomiasis and head lice infestation (Omura and Crump 2014). It has also shown potential for use as an insecticidal (e.g. against malaria), antiviral (e.g. against dengue), antibacterial (e.g. against Chlamydia trachomatis) and anticancer drug (Omura and Crump 2014). The purpose of the proposed inclusion as an intestinal anthelminthic is twofold: i) To include ivermectin alone for use against Strongyloides stercoralis infection (an infection for which, at the moment, there is no drug indication in the EML); and ii) To include ivermectin co-administered with albendazole for use against soil- transmitted helminthiasis (i.e. Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), and Ancylostoma duodenale and Necator americanus (hookworms)). The goal of inclusion of ivermectin in the EML and EMLc is to increase the drug armamentarium for these neglected diseases. Improved sanitation will be required for permanent control and/or elimination of these diseases, but in the short-term, it is essential that the full range of treatment option is explored and implemented for improved control and delaying the insurgence of drug resistance (Keiser and Utzinger 2010). There is significant geographical overlap among the different intestinal parasites, but current control measures can differ. Ivermectin is currently recommended as the treatment option of choice for S. stercoralis infection (WHO 2006) but is not included in EML. The goal for the addition of ivermectin 4 Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) against strongyloidiasis would be predominantly for clinical use as, at the moment, there is no large-scale public health programme for this disease; however, where ivermectin has been distributed in the context of other large-scale programmes (i.e. for onchocerciasis or LF), there has been indication of a reduction in strongyloidiasis (Krotneva et al. 2015; Anselmi et al. 2015). Including an indication for the use of ivermectin specifically for S. stercoralis infection would provide much-needed attention to a truly neglected infection and guidance for its control with a public health intervention (Albonico et al. 2016). Soil-transmitted helminth infections are treated predominantly with albendazole or mebendazole, both of which are currently included in the EML (WHO 2015b). These drugs can be used in clinical settings, but are more often distributed in large-scale programmes to children and women of childbearing age (WHO 2006). Albendazole 400 mg and mebendazole 500 mg are recommended due to their high safety profile and ease of administration (i.e. single-dose drugs that can be administered once or twice per year). However, due to suboptimal efficacy of these drugs, particularly against T. trichiura infection, there has been interest in drug combinations for greater impact on achieving morbidity control in populations suffering from STH infections (Keiser and Utzinger 2010, 2008). A listing of ivermectin on the EML for the proposed new indications