WORLD HEALTH ORGANIZATION EDM/EC/ESD ORGANISATION MONDIALE DE LA SANTE ENGLISH ONLY EXPERT COMMITTEE ON THE SELECTION AND USE OF ESSENTIAL MEDICINES APPLICATION FOR INCLUSION OF AZITHROMYCIN FOR YAWS IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES FROM THE BARCELONA INSTITUTE FOR GLOBAL HEALTH (ISGLOBAL) APPLICATION FOR INCLUSION OF AZITHROMYCIN FOR YAWS IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES ISGLOBAL CONTENTS 1. Summary statement of the proposal for inclusion, change or deletion 4 2. Name of the focal point in WHO submitting the application 4 3. Name of the organization(s) consulted and/or supporting the application 4 4. International Nonproprietary Name (INN, generic name) of the medicine 4 5. Formulation(s) and strength(s) proposed for inclusion 4 6. Whether listing is requested as an individual medicine or as an example of a therapeutic group 6 7. Treatment details 7 7.1. General infections 7 7.2. Genital Chlamydia trachomatis and trachoma 7 7.3. Yaws 7 7.3.1. WHO Guideline 8 7.3.2. Diagnostic tests for yaws 8 7.3.3. Yaws for mass treatment 9 8. Information supporting the public health relevance 10 8.1. Yaws burden 10 8.2. Assessment of current use 10 8.3. Target populations 10 8.4. Likely impact of treatment on the disease 11 9. Summary of comparative effectiveness in a variety of clinical settings: 12 9.1. Identification of clinical evidence 12 9.2. Summary of available data 12 9.2.1. Studies on susceptibility of Treponema pallidum pertenue to azithromycin 12 9.2.2. Studies on efficacy of azithromycin to treat yaws 13 9.2.3. Studies on efficacy of mass azithromycin to treat yaws 14 9.3. Summary of available estimates of comparative effectiveness 15 10. Summary of comparative evidence on safety 17 10.1. Estimate of total patient exposure to date 17 10.2. Description of adverse effects/reactions 10.3 Summary of available data (appraisal of quality, summary of results) 18 10.3.1. Safety in mass drug administration programs 19 10.4. Summary of comparative safety against comparators 19 10.5. Identification of variation in safety due to health systems and patient factors 20 2 APPLICATION FOR INCLUSION OF AZITHROMYCIN FOR YAWS IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES ISGLOBAL CONTENTS (continued) 11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group 22 11.1. Range of costs of the proposed medicine 22 11.1.1. Donation programme 22 11.2.Comparative cost-effectiveness presented as range of cost per routine outcome 23 12. Summary of regulatory status of the medicine 26 13. Availability of pharmacopoeial standards 27 14. References 28 3 APPLICATION FOR INCLUSION OF AZITHROMYCIN FOR YAWS IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES ISGLOBAL GENERAL ITEMS 1. SUMMARY STATEMENT OF THE PROPOSAL FOR INCLUSION, CHANGE OR DELETION Azithromycin is proposed for inclusion into the core WHO Model list of Essential Medicines for the treatment of yaws. Azithromycin is also proposed for inclusion on the WHO Model List of Essential Medicines for Children. 2. NAME OF THE WHO TECHNICAL DEPARTMENT AND FOCAL POINT SUPPORTING THE APPLICATION Submitted by ISGlobal via WHO/EDM. ISGlobal asked WHO/NTD for technical support. 3. NAME OF THE ORGANIZATION(S) CONSULTED AND/OR SUPPORTING THE APPLICATION Barcelona Institute for Global Health (ISGlobal) London School of Hygiene and Tropical Medicine (LSHTM) Department of Medicine and Global Health, University of Washington (UW) 4. INTERNATIONAL NONPROPRIETARY NAME (INN, GENERIC NAME) OF THE MEDICINE Azithromycin (rINN, BAN, USAN) 5. FORMULATION(S) AND STRENGTH(S) PROPOSED FOR INCLUSION; INCLUDING ADULT AND PAEDIATRIC Capsule: 250 mg; 500 mg (anhydrous). Oral liquid: 200 mg/5 mL. Market availability: International Brand Names: Ajustin (KR); Aratro (ES); Atizor (CL); ATM-200 (TZ); Aza-250 (HK); Aza-500 (HK); Azadose (FR); Azas (KR); Azath (KR); Azatril (EE); Azax (TR); Azbact (LK); Azee (HK); Azeemycin (PH); Azenil (IL); Azi-500 (PH); Azibact (DE, IN); Azibiot (LV, RO); Azicine (HK, VN); Azilide-250 (PH); Azilide-500 (PH); Azimac (SA); Azimax (MY); Azimax-250 (HK, SG); Azimed (HR); Azin (BD, PH); Azinobin (CO); Aziphar (VN); Azirocin (KR); Azith (AU, TH); Azithral (IN); Azithrin (MT); Azithro (MY); Azithrom (TW); Azitops (KR); Azitrex (EC); Azitrix (PT); Azitrocin (IT, PH); Azitromax (NO, SE); Azitrox (SK); Aziwin (ID); Aziwok (BF, BJ, CI, ET, GH, GM, GN, IN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW); Azomax (BH, KW); Azomycin (AE, KW, QA, SA); Azomyne (JO, LB, QA); Azox (JO); Azro (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Aztrin (ID); Azyth (PH); Azytsyn (UA); Binozyt (HK, ID, KR, LK, SG, TH, VN); Clindal AZ (BR, HK); Cronopen (AR); Decantin (PH); Ethrimax DS (ID); Floctil (HK, MY, TH); Geozif (VN); Geozit (PH); Glazi (VN); Imexa (HK, MY); Inedol (PE); Jazit (PH); Koptin (CR, DO, GT, HN, NI, PA, SV); Kromicin (CO); Macromax (PH); Macrozit (CO, PE); Maxmor (ID); Meithromax (TH); Mezatrin (ID); Neazi (VN); OD Mac (PH); Odazyth (BD); Onzet (TH); Ormaks (UA); Shepherd (CN); Sumamed (BG, CN, CZ, EE, LV, PL, SK); Thromaxin (PH); 4 APPLICATION FOR INCLUSION OF AZITHROMYCIN FOR YAWS IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES ISGLOBAL Tromix (CO); Ultreon (DE); Uzet (LK); Vinzam (BD); Weihong (CN); Wiltrozin (PH); Xithrone (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Zaha-250 (TZ); Zaret (CO); Zarom (ID); Zedbac (GB); Zedd (AU); Zenith (PH); Zeto (IL); Zetron (LB); Zicho (ID); Zimac (SA); Zimax (LB); Zimericina (CO); Zinfect (TR); Zistic (ID); Zitaspen (ZW); Zithrax (ID); Zithromac SR (JP); Zithromax (AE, AT, AU, BD, BF, BH, BJ, CH, CI, CL, CN, CY, EG, ET, FI, FR, GB, GH, GM, GN, GR, HK, ID, IE, IL, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MT, MU, MW, MY, NE, NG, NL, NZ, OM, PH, PK, PT, PY, QA, SA, SC, SD, SE, SG, SL, SN, SY, TH, TN, TR, TW, TZ, UG,US, YE, ZA, ZM, ZW); Zithromax IV (MY, SG, US); Zithrox (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LK, LY, OM, QA, SA, SY, YE); Zitrim (CO); Zitrocin (PY); Zitromax (AR, BE, BR, CR, DK, EC, ES, GT, HN, IS, IT, LU, NI, PA, PE, SV, TR, UY, VE); Zmax (IL, SG, ZW); Zmax One Dose (PH); Zocin (AE, JO); Zomax (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Zymed (ID); Zynomax (MY); Zythrocin (TW); Zytroks (UA) FDA approved manufacturers: Azithromycin for suspension; oral Manufacturer: PFIZER Approval date: September 28, 1994 Strength(s): EQ 1GM BASE/PACKET [RLD] Manufacturer: PFIZER Approval date: October 19, 1995 Strength(s): EQ 100MG BASE/5ML [AB], EQ 200MG BASE/5ML [RLD] [AB] Manufacturer: PLIVA Approval date: July 5, 2006 Strength(s): EQ 100MG BASE/5ML [AB], EQ 200MG BASE/5ML [AB] Manufacturer: TEVA PHARMS Approval date: June 24, 2008 Strength(s): EQ 100MG BASE/5ML [AB], EQ 200MG BASE/5ML [AB] Azithromycin tablet; oral Manufacturer: PFIZER Approval date: June 12, 1996 Strength(s): EQ 600MG BASE [RLD] [AB] Manufacturer: PFIZER Approval date: July 18, 1996 Strength(s): EQ 250MG BASE [AB] Manufacturer: PFIZER Approval date: May 24, 2002 Strength(s): EQ 500MG BASE [AB] 5 APPLICATION FOR INCLUSION OF AZITHROMYCIN FOR YAWS IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES ISGLOBAL Manufacturer: APOTEX CORP Approval date: July 13, 2011 Strength(s): EQ 250MG BASE [AB], EQ 500MG BASE [AB], EQ 600MG BASE [AB] Manufacturer: LUPIN LTD Approval date: May 15, 2015 Strength(s): EQ 250MG BASE [AB], EQ 500MG BASE [AB], EQ 600MG BASE [AB] Manufacturer: MYLAN Approval date: January 8, 2007 Strength(s): EQ 600MG BASE [AB] Manufacturer: MYLAN Approval date: May 30, 2007 Strength(s): EQ 250MG BASE [AB], EQ 500MG BASE [AB] Manufacturer: PLIVA Approval date: November 14, 2005 Strength(s): EQ 250MG BASE [AB], EQ 500MG BASE [AB], EQ 600MG BASE [AB] Manufacturer: SANDOZ Approval date: November 14, 2005 Strength(s): EQ 250MG BASE [AB], EQ 500MG BASE [AB], EQ 600MG BASE [AB] Manufacturer: TEVA Approval date: November 14, 2005 Strength(s): EQ 250MG BASE [AB], EQ 500MG BASE [AB], EQ 600MG BASE [AB] Manufacturer: WOCKHARDT Approval date: February 11, 2008 Strength(s): EQ 250MG BASE [AB], EQ 500MG BASE [AB], EQ 600MG BASE [AB] Source: Drugs.com 6. WHETHER LISTING IS REQUESTED AS AN INDIVIDUAL MEDICINE OR AS AN EXAMPLE OF A THERAPEUTIC GROUP Azithromycin is the prototype of a subclass of macrolide antibiotics known as the azalides. Listing is requested as an individual medicine. If other equivalent molecules are developed, azithromycin can become an example of the therapeutic group. 6 APPLICATION FOR INCLUSION OF AZITHROMYCIN FOR YAWS IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES ISGLOBAL 7. TREATMENT DETAILS 7.1. General infections Azithromycin is effective in treating acute otitis media due to H. influenzae, M. catarrhalis, or S. pneumoniae; pharyngitis/tonsillitis due to S. pyogenes, community-acquired pneumonia due to Chlamydia (also known as Chlamydophila) pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae; acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) due to H. influenzae, M. catarrhalis, or S. pneumoniae; acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae; prevention of Mycobacterium avium complex (MAC) (alone or in combination with rifabutin) in patients with advanced HIV infection; treatment of disseminated MAC (in combination with ethambutol) in patients with advanced HIV infection; skin and skin structure infections (uncomplicated) due to S. aureus, S. pyogenes, or S. agalactiae; sexually transmitted infections (urethritis, cervicitis and chancroid and genital ulcer disease in men) due to C.