Application for Inclusion of Azithromycin for Yaws in the Who Model List of Essential Medicines

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WORLD HEALTH ORGANIZATION EDM/EC/ESD

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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

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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

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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);

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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]

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 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.

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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. trachomatis, M. genitalium or H. ducreyi, and to N. gonorrhoeae in combination with ceftriaxone. It is also used to treat T. pallidum in special circumstances (when benzathine or procaine penicillin cannot be used) only when local susceptibility to azithromycin is likely.

Comprehensive reviews on azithromycin have been published1,2,3, including specific reviews on paediatric patients4,5. Other review articles discuss the selection of the right macrolide antibiotic6.

The above information is for reference only; listing of azithromycin is not requested for general infections.

7.2. Genital Chlamydia trachomatis and trachoma

Azithromycin (as capsules, 250mg, 500mg and as an oral suspension, 200mg/5ml) was added to the WHO Model List as a core list medicine (in section 6.2.2), for the single dose treatment of genital C. trachomatis infection and of trachoma only. This recommendation was made in view of the effectiveness and safety of azithromycin as documented in the applications because of its ease of use relative to the principal alternatives (i.e. doxycycline twice daily for a week, or tetracycline ophthalmic ointment for 6 weeks). The Committee recommended that the entry be annotated with the following footnote: only listed for single dose treatment of genital C. trachomatis and of trachoma.

7.3. Yaws

Listing of azithromycin is requested for treatment of yaws. Listing is being sought in the core list. The proposed therapeutic dosage and duration of treatment are the following:

- Adult and adolescents ≥ 16 years : Oral 1-day regimen: 2 g as a single dose

- Children ≥ 6 months : Oral 1-day regimen: 30 mg/kg as a single dose (maximum dose: 2 g)

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7.3.1. WHO Guideline for the treatment of yaws 7

The current WHO guideline recommends either:

- Azithromycin at 30 mg/kg (maximum 2 gm) OR - Benzathine penicillin (single intramuscular dose) at 1.2 million units (adults) and 600 000 units (children). Ben Alternative regimens are:

- Doxycycline (500mg q12h for 15 days) - Tetracycline (500mg q6h for 15 days) - Erythromycin (8-10 mg/kg, q6h for 15 days) - Penicillin V (12.5 mg/kg q6h; maximum dose 300 mg q6h for 7-10 days)

Azithromycin has the clear advantage that it is easy to administer (just 1 single oral dose); injectable benzathine penicillin needs use of needles and syringes, and trained personnel; alternative oral antibiotics need a 7- 14 day course with 2-4 doses per day, which might reduce effectiveness through poor compliance.

7.3.2. Diagnostic tests for Yaws

Laboratory tests are required to confirm skin ulcers and lesions as due to yaws. The serological tests used to diagnose yaws are the same as those used to diagnose syphilis including a nonspecific, nontreponemal antibody test (e.g., the rapid plasma reagin [RPR] test, or the VDRL slide test) followed by a more specific treponemal test (e.g., the T pallidum haemagglutination assay [TPHA], the T. pallidum particle agglutination assay [TPPA], and the fluorescent treponemal antibody absorption [FTA-Abs] test) for diagnostic confirmation. Nontreponemal tests become reactive during the initial stage of infection and may revert to negative after treatment. By contrast, treponemal serological tests often remain reactive for life, despite treatment. A rapid diagnostic test that detects both treponemal and nontreponemal antibodies, the Dual Path Platform (DPP) assay, has demonstrated high accuracy for diagnosis of yaws8,9. The DPP tests can be performed outside a laboratory setting with minimal training.

In a meta-analysis of 9 studies on the DPP test10, including 1611 patients with suspected yaws, there was a good concordance with standard laboratory tests for samples with high titre serology RPR ≥1:16 (sensitivity 97.6% compared to the treponemal test and 96.6%, compared with the nontreponemal test). However, concordance was relatively low with RPR titre < 1:16 (sensitivity 73.5% compared to the treponemal test and 59.1%, compared with the nontreponemal test. Cases with RPR titres ≥1:16 have previously been associated with proven infectious lesions; therefore since the DPP test is capable of detecting non-treponemal antibody in over 95% of those cases, benefits of field testing outweigh the logistics of providing a reliable laboratory- based service in impoverished yaws-endemic regions11. Studies confirmed low-titre RPR (< 1:16) seropositivity was not associated with any lesion actively shedding T. p. pertenue and in a majority of cases it can be related to the so-called serofasting status (i.e. persisting low titre antibodies after successful treatment) 11.

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7.3.3. Mass treatment for yaws

For mass treatment campaigns, WHO recommends to treat the entire population in areas known to harbour yaws, irrespective of their yaws status12. In the early eradication programs by WHO and UNICEF, reactivation of infectious skin lesions highlighted the importance of subclinical or latent cases as a source of reinfection13,14,15. It was estimated that there could be as many as six latent cases for every clinically apparent case, and treatment of active cases only had little impact on the prevalence of yaws one year later. Subsequently, treatment of the entire population (rather than just active cases) in a Nigeria eradication campaign resulted in a rapid reduction in prevalence within 12 months.14

Azithromycin is well tolerated and it is given as one supervised dose, so compliance is high. Treatment of all members of a yaws-endemic community irrespective of their clinical status, allows individuals harbouring latent infection to be treated. Clearance of the pathogen responsible for yaws from individuals with active and latent infection, which constitute the infectious reservoir, has the potential to interrupt transmission.

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8. INFORMATION SUPPORTING THE PUBLIC HEALTH RELEVANCE

8.1. Yaws burden

Yaws is a neglected tropical disease (NTD), caused by the bacteria Treponema pallidum subsp. pertenue, that affects people living in warm, humid tropical, impoverished regions of Africa, Asia and the Pacific. It is endemic at least in 13 countries but the global burden of the disease is unknown; more than 40 million people are at risk of developing the disease. It causes symptoms primarily in children between 5-15 years of age; 60.000 new cases are diagnosed every year.

Yaws is part of the group of NTDs with a cutaneous manifestation: it results in chronic lesions of the skin, bone and cartilage. Severe manifestations of the disease can lead to permanent disabilities. Children suffering from skin ulcers do not attend school and are stigmatised. If disfigured, stigmatisation aggravates. People suffering from disabilities are unable to work and become a burden for the development of families and communities. Yaws highlights the existence of a vicious circle between diseases and poverty, which feed on one another.

There is no vaccine for yaws; prevention is based on the interruption of transmission through early diagnosis and treatment of individual cases and contacts, and mass or targeted treatment of affected populations or communities.

8.2 Assessment of the current use

In 2012 the WHO changed the yaws treatment policies which currently favour azithromycin as first line treatment. WHO also developed the Morges Yaws Eradication Strategy to eradicate yaws from endemic countries. One of its seminal recommendations is to use mass drug administration (MDA) with a single dose of azithromycin as a treatment strategy. In 2013, WHO organized a meeting to draft guidelines for programme managers and criteria for the certification of countries.

Medicins Sans Frontières carried out the first implementation of the Morges strategy in the Congo in 2012. Ghana, Papua New Guinea, and Vanuatu also began implementation of azithromycin MDA for yaws on a pilot basis. In 2012-2015, 90.000 people were treated with single-dose azithromycin (30mg / Kg) in the pilot countries with marked reductions in the prevalence of clinical yaws. Combined trachoma and yaws MDA was also carried out in the Solomon Islands. Further information is provided in paragraph 9.2.

8.3 Target population

The latest systematic review on yaws epidemiology reveals that 13 countries are endemic, while there are 19 previously endemic countries where the current incidence of the disease is unknown16. In the period 2010–2013, 256.343 active yaws cases were reported to WHO from 13 endemic countries (average of 64,000 cases per annum), all of which are low-income and middle-income countries. Of 256.343 cases reported to WHO, 215.308 (84%) were from three countries—Papua New Guinea, Solomon Islands, and Ghana—where ongoing pilot programs are active. The number of latent cases compared to active cases could be as high as 6:1. Approximately 89 million people in the 13 endemic countries are living in yaws-endemic areas and need azithromycin treatment. This is based on the assumption that the population at risk for

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ISGLOBAL yaws is, at a minimum, 5% of the population of 11 endemic countries; in Solomon Islands and Vanuatu, 100% of the population is assumed at risk17.

8.4. Likely impact of treatment of the diseases:

The discovery of the effectiveness of azithromycin has led the WHO to include yaws among the list of diseases targeted for eradication. In the WHO 2012 Roadmap18, aimed at accelerating efforts to combat NTDs, it is stated that large-scale administration of the antibiotic is expected to increase the prospects for regional elimination. The WHO eradication strategy builds on the Roadmap’s affirmation and stresses that, despite the need to mobilise other resources (e.g., political commitment or the support of funding agencies), azithromycin is the key instrument to reach eradication12.

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9. REVIEW OF BENEFITS: SUMMARY OF COMPARATIVE EFFECTIVENESS IN A VARIETY OF CLINICAL SETTINGS

9.1. Identification of clinical evidence

We searched Medline, Cochrane Library, and WHO databases from Jan 1, 1905, to Nov 1, 2016, in all languages. Search terms were “yaws”, “Treponema pallidum pertenue”, “azithromycin”, and “penicillin”. Data from original articles, reviews, and book chapters published in English, French, Spanish, and Portuguese were reviewed.

We identified two RCT in different geographical areas that have found that a single dose of azithromycin is as effective in achieving clinical and serological cure of active yaws as a single dose of benzathine penicillin. Rates of adverse effects were low and similar19,20.

We identified two studies that assessed the impact of MDA with azithromycin (30mg/Kg) for yaws21,22, and two studies that assessed the impact on yaws of an MDA with azithromycin (20mg/Kg) for trachoma.23,24

Recommendations for alternative agents (i.e. doxycycline, tetracycline, erythromycin) are based upon experience with syphilis and several small series of yaws patients treated more than 60 years ago25-28. The efficacy of benzathine penicillin for the treatment of yaws has been documented in several observational studies29,30.

9.2. Summary of available data

Azithromycin is an effective treatment for yaws.

9.2.1. Studies on susceptibility of Treponema pallidum pertenue to azithromycin

In ‘in vitro’ susceptibility testing assays, T. p. pertenue was found to be sensitive to penicillin, chloramphenicol, tetracycline, and erythromycin at concentrations achievable in the serum of patients receiving the drug according to recommended regimens. The same in vitro system demonstrated insensitivity to streptomycin (up to 500 ug/mL and to rifampin (up to 100 ug/mL) (Table 1)31. It should be noted that these in vitro studies were not coupled with in vivo testing for efficacy.

Table 1. In vitro assay results for drug susceptibility Inhibition of protein synthesis Antibiotic and T. pallidum pallidum T. pallidum pertenue concn (ug/ml) Nichols strain (%) Gauthier strain (%) Chloramphenicol 20 92.5 86.4 200 93.3 94.6 Tetracycline 4 86.9 88.8 40 94.5 96.3 Erythromycin

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10 86.8 83.7 100 89.5 86.5 Streptomycin 50 32.6 6.7 500 60.9 42.4 Rifampin 10 24.8 0 100 41.5 0.2 Penicillin G 0.03 51.7 29.8 0.3 64.6 Not tested * Extracted from Stamm LV et al, AAC 1988

Laboratory ‘in vivo’ studies with animal models have been consistent with the in vitro susceptibility findings for penicillin and macrolide antibiotics; other drugs tested in vitro have not been examined in vivo. Tests on experimentally infected animals and infected patients showed that benzylpenicillin levels >0.03 units/mL of serum maintained for at least 7 days were treponemicidal32. Clarithromycin was shown to be curative in T. p. pertenue infections in animal models with concentrations of the drug in serum similar to those achieved in humans33 (Table 2).

Table 2. Burden of T. pallidum pertenue in lymph node tissue on hamsters treated with antibiotics Dose (per Schedule No. of organisms / Treatment Kg) (days) lymph- node (105) Penicillin 250U QD x 1 day 13.5 2500U QD x 1 day 0.8 25000U QD x 1 day 0.0 Clarithromycin 2.5mg QD x 7days 0.5 12.5mg QD x 7days 0.0 25.0mg QD x 7days 0.0 None NA NA 23.3 *QD, once daily; * Outcome no. of organisms by microscopy only. Extracted from Alder et al. AAC 1993

9.2.2. Studies on efficacy of azithromycin to treat yaws in humans

A single oral dose of azithromycin (30 mg/kg, maximum 2 g) was shown to be non-inferior to intramuscular benzathine penicillin for treatment of yaws in a randomized trial of 250 children in Papua New Guinea19. Efficacy of azithromycin to induce both clinical and serological cure was 96% (95%CI 91·0–98·6) compared with 93% (86·7–96·4) in the benzathine penicillin group (treatment difference –3∙4%; 95%CI 9∙3–2∙4) achieving the specified criteria for non-inferiority. In subgroup analysis, efficacy of azithromycin was 91% (78·8–96·4) for patients with primary stage lesions, and 100% (94·5–100) for patients with secondary stage disease, including polyarthralgia or bone pain and swelling.

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Similar findings on efficacy were reported among 500 patients with primary yaws in Ghana21. Clinical cure rates were 98.2 % (95%CI 96.2–100) in the azithromycin group and 96.9 % (94.1– 99.6) in the benzathine penicillin group. The serological cure rates defined as 4-fold drop in RPR titer at 6 months were 57.4% (49.9–64.9) in the azithromycin group and 49.1% (41.2–56.9) in the benzathine penicillin group. The lower serological cure rates in both treatment arms as compared to the PNG study are the result of inclusion of patients with low titre RPR (1:2 to 1:8) which may be related to a serofast status (i.e. persisting low titre antibodies after successful treatment), and do not revert to negative after treatment. Serological cure was higher in azithromycin as comparted to benzathine penicillin. In addition, the excellent clinical cure rates, which are critical to reduce transmission, provide additional support for the WHO policy for use of oral azithromycin for yaws.

9.2.3. Studies on efficacy of mass azithromycin treatment for yaws

The approach to eradication consists of a single dose of oral azithromycin (30 mg/kg, maximum 2 g) to be given to entire populations in areas known to harbour yaws12. Benzathine penicillin may be used as an alternative for individuals who cannot be treated with azithromycin or for mass treatment in places where azithromycin is not available. Mass treatment is followed by surveys every six months to detect and treat remaining cases. In the interval between surveys, local health facilities must treat infected individuals and their close contacts.

The efficacy of this approach was demonstrated in a study of mass treatment performed in rural villages on Lihir Island, Papua New Guinea19. Of 16,092 residents, 83% received mass treatment with single-dose azithromycin and were monitored for one year; the prevalence of active yaws decreased from 2.4% to 0.3% (difference -2.1%; 95%CI, 1.9 to 2.4; P<0.001), and the prevalence of latent yaws with high-titre seroreactivity (RPR ≥1:16) in children 1 – 5 years decreased from 13.7% to 0.9% (difference, -12.8%; 95% CI, 6.3 to 19.3; P = 0.02). This finding is significant since it shows greatly reduced ongoing transmission. No evidence of macrolide resistance was observed. The long term outcome of the intervention is still being monitored.

In Ghana, Ghinai et al.21 conducted a cross-sectional survey in thirty communities in two districts of Ghana (Northern region) where MDA with azithromycin (20mg/kg) for trachoma had previously been conducted. Of 3000 examined, 90 children were identified with suspected yaws ulcers; samples for treponemal serology and lesion PCR were collected from those. Syphilis serology and PCR for T. p. pertenue was negative in all of them. In these communities, previously treated for trachoma, no evidence of ongoing transmission of yaws was found.

Another study conducted in the Eastern Region of Ghana, assessed the impact of MDA with azithromycin (30mg/kg) for yaws in a target population of 15,310 persons 22. The pre- and post- MDA prevalence of yaws was measured on a sub-sample of 943 and 1211 randomly selected schoolchildren, respectively. The prevalence on PCR-positive active yaws was significantly reduced from 3.1% to 0% (difference -3.1%, 95%IC 2.1–4.4). While yaws PCR was positive in 29 (18%) of 158 skin ulcers found at baseline, 0 of 49 were positive 1-year after mass treatment. The rate of latent yaws also decreased significantly from 10.7% to 2.1% (difference -8.7%, 95%CI 6.6 – 10.9).

In Solomon Islands, a cross sectional survey was conducted to assess the impact on yaws of an MDA with azithromycin (20mg/kg) for trachoma. The post-MDA prevalence of yaws was

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ISGLOBAL measured on a sub-sample of 897 at 6 months and 1284 children at 18 months. The intervention resulted in a significant decrease in active and latent yaws 6-months post-treatment23, and the benefits extended to 18 months without any further intervention24. Active yaws prevalence decreased from 1.5% to 0.0%; latent yaws prevalence decreased from 21.7% to 4.3% (95% CI 2.1-8.7%; p<0,0001) at 18 months.

9.3. Summary of available estimates of comparative effectiveness

Comparison with other drugs that have been proposed by WHO for the treatment of yaws:

Benzathine penicillin single intramuscular dose at 1.2 million units (adults) and 600 000 units (children) (recommended) Doxycycline, 500mg q12h for 15 days (alternative) Tetracycline, 500mg q6h for 15 days (alternative) Erythromycin, 8-10 mg/kg, q6h for 15 days (alternative)

Yaws has been treated with parenteral antibiotics since the 1920s and long acting penicillin has been the drug of choice for over 50 years. WHO previously recommended regimen consisted of benzathine penicillin 1.2 million units for adults and 0.6 million units for children under 10 years of age; the dosing being lower that for syphilis. Benzathine penicillin achieved cure rates (defined by serological cure or serological improvement) of 86 to 100% when used to treat yaws in Thailand 29. Similar cure rates were seen with dosages of 1.2 million units and with 2.4 million units for adults in Haiti30. Disadvantages of using benzathine penicillin however, include the need for needles and syringes, and trained personnel. Moreover, the supply of benzathine penicillin is irregular, as exemplified by the current global shortage of the compound.

The efficacies of injectable benzathine penicillin (1.2 million units) and oral azithromycin (30mg/Kg) are comparable for treatment of yaws; thus, in 2013 WHO changed its treatment policies to favour azithromycin because of the ease of administration. The WHO currently recommended oral antibiotic is azithromycin, as a single dose of 2 grams in adults and 30 mg/kg in children. Azithromycin has low plasma levels but high intracellular concentrations and a long half-life and has been shown to be an effective treatment of yaws.

An advantage with azithromycin is its activity against endemic treponematoses and proven efficacy when administered as a single oral 30mg/Kg dose19. The main advantage of azithromycin is oral versus parenteral administration of benzathine penicillin. Oral azithromycin is safe and easy to administer, avoids the need for injection, no trained staff are needed to treat cases in remote areas, infection and anaphylactic shock control measures are not necessary, and treatment is more acceptable to communities who need it. Azithromycin needs to be taken only once (single dose) which improves patient compliance, compared to all other oral antibiotics that require multiple dosages for 7 days or more.

Azithromycin can be used in pregnancy (category B), but the safety of benzathine penicillin and erythromycin has been better established. Benzathine penicillin and erythromycin are therefore preferred treatments in pregnant women.

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Doxycycline and oral tetracycline are considered a good alternative for patients over the age of 8 who are allergic to drugs of choice, but doxycycline must be taken twice daily and tetracycline four times per day for 14 days. Doxycycline and tetracycline are contraindicated in pregnancy.

Azithromycin has several distinct advantages over erythromycin: it is better tolerated; there is better tissue penetration; and there are more favourable pharmacokinetics.

The short duration of treatment used, once daily dosing, and the acceptable taste to most children make azithromycin a good first choice in paediatric infections.

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10. REVIEW OF HARMS AND TOXICITY: SUMMARY OF EVIDENCE ON SAFETY

10.1. Estimate of total patient exposure to date

Initial studies in 4000 adults and 2000 children indicated that azithromycin is well-tolerated35. This has been confirmed in further use and studies36.

In 2011, approximately 40.3 million individuals in the U.S. received an outpatient prescription for the macrolide azithromycin.37

Azithromycin is the drug of choice for treatment of Chlamydia. Between 2000 and 2015, 18.2 million cases were detected and treated in the US, where Chlamydia is the most commonly STD reported38. The recommended regime is 1 g orally in a single dose, which launches a figure of 36 million tablets (500mg) consumed to treat Chlamydia alone in the US.

Azithromycin is also the most commonly prescribed antibiotic in children, with a prescription rate of between 4% and 14%. Since its approval in the USA and Europe, it has been used extensively for the treatment of several paediatric infectious diseases.

Owing to lack of efficacy and safety studies, oral formulations are not recommended for children less than 6 months.39

Conclusion: experience with azithromycin is substantial.

10.2 Description of the adverse effects/reactions and estimates of their frequency

Azithromycin has similar side-effects as erythromycin, but at lower frequencies. A review of safety issues when treating is available36,40.

>10%: Gastrointestinal: Loose stools (≤14%; single-dose regimens tend to be associated with increased incidence), vomiting (children, single-dose regimens tend to be associated with increased incidence: 1% to 14%; adults: ≤2%; adults, single 2 g dose: 1% to 7%), diarrhoea (2% to 9%; single-dose regimens 4% to 14%), nausea (≤7%; single-dose regimens 4% to 18%).

1% to 10%:

Cardiovascular: Chest pain (≤1%), palpitations (≤1%) Central nervous system: Dizziness (≤1%), drowsiness (≤1%), fatigue (≤1%), headache (≤1%), vertigo (≤1%) Dermatologic: Skin rash (≤5%; single-dose regimens tend to be associated with increased incidence), dermatitis (children: ≤2%), pruritus (≤2%), skin photosensitivity (≤1%) Endocrine & metabolic: Increased lactate dehydrogenase (1% to 3%), increased gamma- glutamyl transferase (1% to 2%), increased serum potassium (1% to 2%), decreased serum bicarbonate (adults: ≥1%), decreased serum glucose (adults: >1%)

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Gastrointestinal: Abdominal pain (1% to 7%; single-dose regimens tend to be associated with increased incidence), anorexia (≤2%), dysgeusia (≤1%), dyspepsia (≤1%), flatulence (≤1%), gastritis (≤1%), melena (adults, multiple-dose regimens: ≤1%), mucositis (≤1%), oral candidiasis (≤1%) Genitourinary: Vaginitis (≤3%), genital candidiasis (adults, multiple-dose regimens: ≤1%) Hematologic & oncologic: Decrease in absolute neutrophil count (children: 15% to 16%; 500 to 1500 cells/mm3), decreased hematocrit (adults: >1%), decreased hemoglobin (adults: >1%), increased neutrophils (adults: >1%), thrombocytopeniia (adults: >1%), change in neutrophil count (children: ≥1%), eosinophilia (≥1%), lymphocytopenia (≥1%) Hepatic: Increased serum ALT (≤6%), increased serum AST (≤6%), increased serum bilirubin (≤3%), cholestatic jaundice (≤1%) Local (adults with IV administration): Pain at injection site (7%), local inflammation (3%) Neuromuscular & skeletal: Increased creatine phosphokinase (1% to 2%) Renal: Increased serum creatinine (≤6%), increased blood urea nitrogen (≤1%), nephritis (adults, multiple-dose regimens: ≤1%) Respiratory: Bronchospasm (≤1%) Miscellaneous: Fever (children: (≤2%)

<1% (Limited to important or life-threatening): anaphylaxis (rarely fatal), photosensitivity, edema and angioedema, confusion, drowsiness, headache, fatigue and paresthesia, aggressive reactions, agitation and anxiety, syncope, dizziness, convulsions, hyperactivity, hypoesthesia, malaise and asthenia, disturbances or loss of smell / taste, hearing loss (with high doses over a prolonged period), hypotension, heart palpitations, QT prolongation, torsades de pointes (TdP) and arrhythmias -see below-, pseudomembranous colitis, pancreatitis and a darkening of the tongue, impaired liver function including hepatitis and cholestatic jaundice and hepatic necrosis and hepatic failure, reversible elevations in liver transaminases, severe skin reactions, arthralgia, interstitial nephritis and acute renal failure.

Concerns related to Cardiac Risk: A retrospective cohort study done in Tennessee Medicaid patients demonstrated an increased cardiac risk with azithromycin relative to amoxicillin or ciprofloxacin41; however, these data may not be generalizable to the population as a whole. In another retrospective population study of US veterans, azithromycin was shown to significantly increase the risk of mortality and arrhythmia on days 1 to 5, but not on days 6 to 10 after dispensing the prescription.42 In contrast, 2 additional large retrospective cohort studies did not demonstrate an increased risk of cardiovascular events, including all-cause mortality or cardiovascular death.43,44 The implications of these data have yet to be determined. The FDA issued a drug safety communication that is publicly available on-line. 45

10.3. Summary of available data (appraisal of quality, summary of results)

Observational and clinical trial studies in adults and children indicate that azithromycin is well- tolerated. Potentially serious side effects of angioedema and cholestatic jaundice are reported rarely. Adverse effects of azithromycin are mainly gastrointestinal in nature and occur less frequently than with erythromycin Since its release in early 1990s, it has become the most commonly prescribed macrolide antibiotics in the US. Results assessing a small cardiovascular

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Adult patients- 1-day single 2-gram dose regimen: The tolerance and safety profile of azithromycin were assessed in a study of 4,000 patients of different ages and genders.36 Patients with infections of the respiratory tract or skin/skin structure received 1.5 g azithromycin over 5 days; patients with urethritis/cervicitis caused by Chlamydia were treated with 1 g as a single dose. Overall, side effects were recorded in 12.0% of patients, significantly less (p<0.05) than with twelve standard comparative antibiotics (14.2%). The most common side effects were diarrhoea (3.6%), abdominal pain (2.5%), and other gastrointestinal symptoms. 93% of side effects were classed as mild or moderate, and only 0.7% of patients withdrew from treatment, significantly less (p<0.001) than with comparative agents (2.6%).

Another study in patients receiving a single 2-gram dose of zithromax showed that common adverse reactions in adults were nausea (18%), diarrhoea (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%), and dizziness (1%).40 The majority of these complaints were mild in nature.

Pediatric patients – 1-day 30mg/Kg dose regimen: A double blind, controlled, randomized trial performed at nine clinical centers pediatric patients from 6 months to 12 years of age were randomized 1:1 to treatment with either azithromycin (given at 30 mg/kg as a single dose on Day 1) or amoxicillin/clavulanate potassium (7:1). In the safety analysis, the incidence of treatment-related adverse events, primarily gastrointestinal, was 16.8% with azithromycin, and 22.5% with the comparator. The most common side effects with azithormcyin were diarrhea (6.4%), vomiting (4%), rash (1.7%) and nausea (1.7%).46

In a non-comparative clinical and microbiological trial, 248 patients from 6 months to 12 years of age with documented acute otitis media were dosed with a single oral dose of azithromycin (30 mg/kg on Day 1). In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all the subjects treated was 12.1%. The most common side effects were vomiting (5.6%), diarrhea (3.2%), and abdominal pain (1.6%).47

10.3.1 Safety in mass drug administration programs.

In a meta-analysis of antibiotic treatments for trachoma, investigators reported no serious adverse events after one 20 mg/kg dose of azithromycin48. In the studies that reported minor side effects, such as nausea, vomiting, and other gastrointestinal disturbances, incidence ranged between 10% and 15%.

In the largest longitudinal study of azithromycin MDA for yaws, investigators reported no serious adverse events after a single 30 mg /kg dose of azithromycin21. 13,490 were administered the study drug and no severe adverse events attributable to the study drug were reported by means of passive surveillance during the study. Active surveillance of 316 participants from 60 households yielded 54 participants (17.1%) who reported adverse events (all mild), including 30 (9.5%) with nausea or abdominal pain, 25 (7.9%) with diarrhea, and 15 (4.7%) with vomiting.

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10.4. Summary of comparative safety against comparators

Compared to injectable penicillin, oral azithromycin is safer because it avoids the need for injection, and the risk of blood-borne infections and anaphylactic shock. Injectable penicillin causes anaphylactic shock in a small proportion of patients. Although the risk is small (<1 patient in 50 000), the consequences can be severe, and control programmes using benzathine penicillin need to train staff and provide them with the means to treat anaphylaxis. Importantly, attempts to control yaws by mass treatment with injectable drugs have previously led to the transmission of blood-borne viruses, such as hepatitis C49.

By contrast, oral azithromycin has been shown to be safe to administer during community-based mass treatment programmes using this antibiotic for the control of trachoma. The programmes have been well accepted by rural communities in many parts of Africa, have been effective in reducing the prevalence of trachoma, and could have collateral benefits. In one study in Ethiopia, mass treatment every year with azithromycin reduced all-cause mortality by 50% in children aged 1 – 5 years50.

Compared to doxycycline: doxycycline is contraindicated in pregnancy and children aged less than 8 while azithromycin can be used if needed (class B).

10.5. Identification of variation in safety due to health systems and patient factors

Pregnancy:

U.S. Food and Drug Administration's Pregnancy Category B (risk not excluded; use only when needed) Australian Drug Evaluation Committee's (ADEC) Category B1

A Cochrane systematic review on the use of azithromycin in pregnancy for Chlamydia trachomatis concludes:51

With the relatively small amount of data presented, azithromycin appears to be very well tolerated. The number of women included in these trials is too small to assess whether azithromycin is safe for use in pregnancy, as rare adverse outcomes are unlikely to be detected and clinical experience with their use is limited. Clindamycin and azithromycin may be considered further alternatives if erythromycin and amoxicillin are contra-indicated or not tolerated.

Adverse events were not observed in animal reproduction studies. Azithromycin crosses the placenta52. The maternal serum half-life of azithromycin is unchanged in early pregnancy and decreased at term; however, high concentrations of azithromycin are sustained in the myometrium and adipose tissue 53. Azithromycin is recommended for the treatment of several infections, including chlamydia, gonococcal infections, and Mycobacterium avium complex (MAC) in pregnant patients (consult current guidelines)54.

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Lactation: Azithromycin is excreted in low amounts into breast milk. Safe use of azithromycin during lactation has not been established; the recommendation is to use with caution.

Renal failure: normal dosage can be used55 (only 10% excreted by kidneys). Recommendation to use caution in patients with Clcr <10 ml/minute on the basis of a study in 42 adults with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin, mean Cmax and AUC0–120 increased by 5.1% and 4.2%, respectively, in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). The mean Cmax and AUC0–120 increased 61% and 35%, respectively, in subjects with severe renal impairment (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min).

Hepatic insufficiency: A study in 16 cirrhotic patients with mild or moderate hepatic impairment suggests that no modification of azithromycin dosage is necessary, despite its hepatic metabolism56. However, the manufacturer suggests it should not be used in hepatic insufficiency.

Drug interactions: Representing the macrolide subclass (the azalides), azithromycin has fewer reverse effects than erythromycin, which is associated to a number of clinically significant drug interactions. Review of drug interactions with Azithromycin are available56,57.

Table 3. Drug-drug interactions Anticoagulants (warfarin) Possible increased anticoagulant effects Carbamazepine Data suggest that, unlike many of the macrolides, azithromycin does not appear to inhibit the hepatic metabolism of carbamazepine Cyclosporine Periodic monitoring recommended when used concurrently with azithromycin Digitoxin Azithromycin may elevate digitoxin concentrations Ergot alkaloids The concurrent use of ergot alkaloids and macrolide antibiotics has been found to accelerate the development of ergotism. The interactions between ergot alkaloids and azithromycin have not been studied. The development of ergotism is however possible, so that Azithromycin and ergot alkaloid derivatives should not be administered simultaneously (db.cbg-meb.nl/mri/spc/nlh-0544- 001.pdf) Lumefrantine Using lumefrantine and azithromycin can increase the risk of an irregular heart disease that may be serious although it is a rare side effect. Lovastatin Azithromycin should be used with caution in patients taking HMG- CoA inhibitors Phenytoin Azithromycin will decrease the level or effect of phenytoin oral Quinine Quinine sulfate oral and azithromycin increase QTc interval, which may cause abnormal heart rhythm Rifabutin Azithromycin may increase the toxicity of rifabutin Tacrolimus Azithromycin oral will increase the level or effect of tacrolimus oral by P-glycoprotein (MDR1) efflux transporter.

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Theophylline Reduces excretion of theophylline, with possible significant toxicity

Contra-indications:

known allergy against macrolides (erythromycin), hepatic impairment.

11. SUMMARY OF AVAILABLE DATA ON COMPARATIVE COST AND COST-EFFECTIVENESS WITHIN THE PHARMACOLOGICAL CLASS OR THERAPEUTIC GROUP

11.1. Range of costs of the proposed medicine

The costs related to drug acquisition and administration of low-cost generic preparations of azithromycin are highly competitive and may be lower than those of the classic treatment for yaws.

The MSH Price Indicator Guide 2014 lists azithromycin as follows:

Azithromycin 250 mg Tab-cap Po (06.2.2.)Other antibacterials

Azithromycin 200 mg/5 ml Suspen Po (06.2.2.)Other antibacterials

Azithromycin 500 mg Tab-cap Po (06.2.2.)Other antibacterials

For 500 mg, the buyer prices (2014) range from 0.10/tab-cap to 2.98/tab-cap. See below. The original products from Pliva (Surnamed, Central and Eastern Europe) and Pfizer (Zithromax, in USA and Western Europe) remain expensive, whereas generics are available at fractions of the cost.

Table 4. Buyer Prices of azithromycin 500mg tablets (Prices are in US$, year 2014) Source Package Package Price Unit Price 1 Tab-cap DOMREPUB $0.10 0.1000 /tab-cap (Capsules) 100 Tab-cap PERU (Tablets, illustrative $13.19 0.1319 /tab-cap pack size) SAFRICA 3 Tab-cap (Tablets) $1.13 0.3777 /tab-cap 30 Tab-cap OECS/PPS $11.40 0.3800 /tab-cap (Tablets) CRSS 100 Tab-cap $298.00 2.9800 /tab-cap

Median Price 0.3777/tab-cap ↑50% Lowest Price 0.1000/tab-cap High/Low Ratio 29.8 Highest Price 2.9800/tab-cap Source: International Price Indicator Guide 2014

Table 5. Buyer Prices of azithromycin suspension (Prices are in US$, year 2014)

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Source Package Package Price Unit Price DOMREPUB 1 Bott (30 ml) $ 0.51 0.0170/ml PERU 1 Bott (60 ml) $ 1.06 0.0177/ml OECS/PPS 1 Bott (15 ml) $ 3.19 0.212/ml

Median Price 0.0177/ml Lowest Price 0.0170/ml High/Low Ratio 12.51 Highest Price 0.2127/ml Source: International Price Indicator Guide 2014

Assuming a 2g adult single dose, the cost of treatment varies according to source. The range given is the lowest available price to the median price.

4 x 500mg caps @ USD 0.10 – 0.37 = USD 0.40 – USD 1.48 per treatment

Treatment cost will be substantially lower for children < 15 years of age.

For children aged less than 6 years, syrup is preferable. Paediatric dosages using suspension will cost USD 0.21-0.22.

Table 6. Price of azithromycin by age (recommended dosages of azithromycin by WHO)

Age (in years) Total dose(mg) Number of Syrup(ml) Lowest Median Tablets price price (USD) (USD) <6 500 Xx 12.5 0.21 0.22 6-9 1000 2 xx 0.20 0.74 10-15 1500 3 xx 0.30 1.11 >15 2000 4 xx 0.40 1.48 Source: International Price Indicator Guide 2014

11.2. Comparative cost-effectiveness presented as range of cost per routine outcome

The only alternative (tested) treatment available for yaws is penicillin.

Cost per treatment episode:

Benzathine penicillin: 1.2m iu  Lowest price: USD 0.11/vial  Median price: USD 0.13/vial

Benzathine penicillin: 2.4m iu  Lowest price: USD 0.17/vial

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 Median price: USD 0.28/vial

Other costs associated with the use of benzhatine penicillin are:

Water for injection: 5ml  Lowest price: USD 0.015/ampoule  Median price: USD 0.05/ampoule

Syringes and needles: Optimal combination: syringe, 10ml, sterile, with bi-packed needle, 21G (0.80 x 38- 40mm), disposable  Tentative price: UNICEF Procurement Services-Supply Catalogue: 0.045 USD/unit (4.49 USD/box 100 units)

Sticking plasters to reduce risk of infections after injection.  Tentative price: UNICEF Procurement Services-Supply Catalogue: 0.006 USD/unit (1.48 USD/roll 10cm x 5m, equivalent to 250 units)

Plastic gloves:  Tentative price: UNICEF Procurement Services-Supply Catalogue: 0.06 USD/unit (3.19 USD/box 100 units)

Safety box for syringe disposal: According to the WHO, unsafe injections cause 32% of hepatitis B, 40% of hepatitis C and 5% of new HIV infections annually. Therefore, a proper system for disposal of syringes and needles is to be added to the calculation of the total cost of a treatment based on benzhatine penicillin. The maximum capacity of a safety box is 20 syringes per nominal litre; hence 5 lt safety box accepts no more than 100 syringes.

 Tentative price UNICEF Procurement Services-Supply Catalogue: 0.71 USD/unit (5 lt) (17.94USD/box of 25, Safety box f.used syrgs/ndls 5lt/BOX-25)

Anaphylaxis drugs: Anaphylaxis drugs are Adrenaline and Anti-histamines (1 ampoule / 10,000 children treated)

Table 7. Comparative cost of benzathine penicillin and azithromycin for yaws by age according recommended dosages of azithromycin by WHO (lowest price)

6-9 years 10-15 years <6 years of age >15 years of age

Injection Injection Injection Injection Azithromycin Azithromycin Azithromycin Azithromycin penicillin penicillin penicillin penicillin

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(USD) (USD) (USD) (USD) (USD) (USD) (USD) (USD)

0.055 (0.6 0.21 (500 0.055 (0.6 0.20 (1000 0.110 (1.2 0.30 (1500 0.110 (1.2 b Drug a,b b a,b b b b b 0.40 (2 g) MU) mg) MU) mg) MU) mg) MU) Water for b 0.015 -- 0.015 -- 0.015 -- 0.015 -- injection Syringe and c 0.050 -- 0.050 -- 0.050 -- 0.050 -- needle Alcohol c 0.050 -- 0.050 -- 0.050 -- 0.050 -- swab Sticking 0.006 0.006 0.006 0.006 plastersc Plastic c 0.060 0.060 0.060 0.060 gloves Safety boxc 0.007 0.007 0.007 0.007 TOTAL 0.24 0.27 0.24 0.20 0.30 0.30 0.30 0.40 a Calculation considering the use of a single drug vial (1.2 MUI) for multiple patients b Source: International Price Indicator Guide 2014 c Source: UNICEF Supply Catalogue

Whereas the amount of penicillin required to treat yaws is cheaper than the amount of azithromycin, the additional commodities required to administer a treatment based on this compound add up to the overall cost. Consequently, administration of azithromycin emerges as a cheaper option in the 6-9 and 10-15 age groups which are most commonly affected by yaws.

Moreover, non-financial costs are also to be added to the overall cost of the treatment based on benzathine penicillin, such as the time to prepare and give the injection, the risk of abscesses, or the volume and weight of drug and all the accompanying materials. None of these costs is to be added to the distribution of azithromycin. Another non-quantifiable cost of injected penicillin is the pain it causes on the part of the patient, which translates to poor compliance or refusal of treatment. Again, azithromycin is cost-saving relative to penicillin.

As evidenced in chapter 9, a single dose of penicillin and a single dose of azithromycin are equally effective in curing T. p. pertenue infection.19,20 Notwithstanding, administration of penicillin is more expensive, given that it requires of a combination of elements that are not required for successful administration of azithromycin, including highly trained personnel. It also entails non-financial costs that result in lower compliance. In fact, studies demonstrating the equivalence in efficacy of both regimens were made in controlled trials, where adherence to benzathine penicillin is likely to be higher than in the field. As a result, azithromycin is the most cost-effective treatment for yaws.

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REGULATORY INFORMATION

12. SUMMARY OF REGULATORY STATUS OF THE MEDICINE

Registered in USA, UK, South Africa and most other developed countries (except Central Eastern Europe): Azithromax, Pfizer.

Registered in Central Eastern Europe: Sumamed, Pliva (Croatia = country of origin).

Generics are produced under the following brands:

 3Z (Jaba - PORTUGAL)  ABACTEN (Andromaco - CHILE)  ARZOMICINA (APS - PORTUGAL)  ASIPRAL (Labomed - CHILE)  ATIZOR (Medipharm - CHILE)  ATROMICIN (Teuto - BRAZIL)  AZADOSE (Pfizer - FRANCE)  AZENIL (Pfizer - ISRAEL)  AZI (Sigma - BRAZIL  AZIMAX (EMS - BRAZIL)  AZITRAX (Farmoquimica - BRAZIL)  AZITRIX (Tecnimede - PORTUGAL)  AZITROCIN (Cibran - BRAZIL)  AZITROM (Laboratorios Chile - CHILE)  AZITROMERCK (Merck - NETHERLANDS)  AZITROMIN (Farmasa - BRAZIL)  AZITRON (Cifarma - BRAZIL)  AZITROX (Leciva – CZECH REPUBLIC)  AZITROXIL (De Mayo - BRAZIL)  AZOMYCIN (Julphar - UNITED ARAB EMIRATES)  CLINDAL (Merck - BRAZIL)  CLINDAZ (Merck - BRAZIL)  FARMIZ (Neo-Farmaceutica - PORTUGAL)  GIGATROM (Baldacci - PORTUGAL)  GOXIL (Pharmacia - SPAIN)  MAZITROM (Uniao Quimica - BRAZIL)  MERCKAZITRO (Merck - NETHERLANDS)  NEOFARMIZ (Neo-Farmaceutica - PORTUGAL)  NOVATREX (Ache - BRAZIL)  RIBOTREX (Pierre Fabre - ITALY)  RICILINA (Recalcine - CHILE)  SELIMAX (Libbs - BRAZIL)  SUMAMED (Pliva - HUNGARY)  TORASEPTOL (Vita - SPAIN)  TREX (Saval -CHILE)  TROZOCINA (Sigma-Tau - ITALY)  TROZYMAN (IQB - BRAZIL)  ULTREON (Pfizer - GERMANY)  UNIZITRO (Helfarma - PORTUGAL)

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 VINZAM (Almirall - SPAIN)  ZENTAVION (Vita - SPAIN)  ZETO(Unipharm - ISRAEL)  ZIMICINA (Hexal - BRAZIL)  ZITRONEO (Neo Quimica - BRAZIL)  ZITROZINA (Neves - PORTUGAL)  Z-PAK (Pfizer - CANADA)

13. AVAILABILITY OF PHARMACOPOEIAL STANDARDS British Pharmacopoeia: no International Pharmacopoeia: no United States Pharmacopoeia: yes European Pharmacopeia: yes

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14. REFERENCES

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