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

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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

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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

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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 will appropriately address gaps in clinical practice and public health programmes for strongyloidiasis and soil- transmitted helminthaisis, and will also lead to ancillary benefits due to reduced morbidity from other co-endemic diseases, including ectoparasitic infections and enterobiasis (WHO 2006; Krotneva et al. 2015). With a continued focus on large-scale programmes against STHs, and a call for increasing attention to the negative consequences of strongyloidiasis, it is timely to update and harmonize international guidelines to reflect the evidence base and current and future global demand for ivermectin.

2. Name of the WHO technical department and focal point supporting the application Antonio Montresor, Department of Control of Neglected Tropical Diseases, Preventive Chemotherapy and Transmission Control (HQ/NTD/PCT)

3. Name of organization consulted and/or supporting the application Swiss Tropical and Public Health Institute, Basel, Switzerland (in alphabetical order): Ms. Spring Gombe; Dr. Serene Joseph; Dr. Jennifer Keiser; Dr. Peter Odermatt

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

4. International Nonproprietary Name (INN) and anatomical therapeutic chemical (ATC) code of the medicine INN: Ivermectin

ATC code: P02CF01 (WHO Collaborating Centre for Drug Statistics and Monitoring) P ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS P02 ANTHELMINTICS P02C ANTINEMATODAL AGENTS P02CF Avermectines

5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric 5.1 Strongyloidiasis

The proposed formulation of ivermectin is a tablet (scored) in 3 mg doses, to be administered in a single-dose of 200 µg ivermectin/kg body weight for both adults and children over the age of 5 or with a minimum body weight of 15 kg.

5.2 Soil-transmitted helminthiasis The proposed formulation of ivermectin is a tablet (scored) in 3 mg doses, to be administered in a single-dose of 200 µg ivermectin/kg body weight. It is to be co- administered with a single-dose tablet (chewable) of 400 mg albendazole (already included in Section 6.1.1 of the EML as an intestinal anthelminthic). This is the proposed dosing regimen for adults and children over the age of 5 or with a minimum body weight of 15 kg.

6. Whether listing is requested as an individual medicine or as a representative of a pharmacological class

The request for inclusion in the WHO Essential Medicine List is for an individual medicine.

Treatment details, public health relevance and evidence appraisal and synthesis 7. Treatment details (requirements for diagnosis, treatment and monitoring) 7.1 Strongyloidiasis 7.1.1 Proposed therapeutic dosage regimen and duration of treatment

A single oral dose of 200g/kg body weight in tablet form, taken in fasting state, with one glass of water.

7.1.2 Reference to current WHO guidelines

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

Ivermectin is currently recommended by WHO for treatment of Strongyloidiasis (WHO 2006) and has been included in previous versions of the WHO Model Formulary1. The drug is not included on the EML. Ivermectin is indicated as the drug of choice by the US, Australian and other formularies.

7.1.3 Additional requirements associated with treatment Diagnostic tests2: Three primary method are used for diagnosis i. Identification of larvae by microscopic examination of stool or the agar plate method – this is considered the gold standard ii. Serological tests iii. PCR and Enzyme immunoassay for antibodies

Other considerations: Pre-treatment diagnosis is necessary for loiasis, especially in endemic West and Central Africa due to the possibility of serious or fatal encephalopathy, in people with with > 8,000 Loa loa microfilariae mL/blood. Diagnosis of loiasis is done through EITHER observation of an adult worm subconjunctivally crossing the eye, OR identification and quantification of microfilariae in blood by microscopy or quantitative PCR. If loiasis is detected, treatment with ivermectin is contra-indicated. The geographical distribution of loasis is well known and limited to a relatively small area in central Africa.

Treatment: Refractory treatment may be required for the immune-compromised (including those with HIV or HTLV-1): repeated therapy every 2 weeks, and perhaps suppressive therapy once a month. In Japan it is estimated that 385 of people with strongyloidiasis are HTLV-1 positive.

Caution should be exercised in patients with hepatic and renal disease (this may require dosage adjustments). Use of ivermectin is contraindicated in people weighing

1 http://apps.who.int/medicinedocs/documents/s16879e/s16879e.pdf; 2 Source: http://www.merckmanuals.com/professional/infectious-diseases/nematodes- roundworms/strongyloidiasis; http://www.cdc.gov/parasites/strongyloides/health_professionals 7

Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

less than 15 kg and in pregnant women (i.e. ivermectin is pregnancy category C) or lactating women in the first week after birth.

7.1.4 Listing for core or complementary list The request is to list ivermectin in the core and complementary list.

7.2 Soil-transmitted helminthiasis 7.2.1 Proposed therapeutic dosage regimen and duration of treatment

The proposed regimen is to treat with ivermectin according to body weight (200 µg ivermectin per kg body weight) co-administered with one tablet of albendazole (400 mg). Since assessment of weight can be logistically cumbersome in large-scale programmes, dosing of ivermectin can also be determined based on tablet-poles (Table 1) (WHO 2006). The feasibility of this has been demonstrated in large-scale programmes against LF and onchocerciasis.

Table 1. Recommended dose of ivermectin and albendazole co-administered against soil-transmitted helminth infections (Adapted from WHO 2006).

Height Ivermectin dose Albendazole dose 90-119 cm 1 tablet (3 mg) 400 mg 120-139 cm 2 tablets (6 mg) 400 mg 141-159 cm 3 tablets (9 mg) 400 mg >159 cm 4 tablets (12 mg) 400 mg

Ivermectin should be co-administered with albendazole as a single administration. Since the treated population are exposed to re-infection (because of the poor sanitation infrastructure), the administration should be repeated once per year, in areas with 20-50% prevalence of any STH infection. Where prevalence is over 50%, treatment should be provided twice a year (i.e. every six months), or more frequently depending on local resources (WHO 2006). Where any STH prevalence is less than 20%, no large-scale programmes are recommended as only light intensity infection and low morbidity is expected in these areas. Therefore, individuals can be screened and treated if found to be positive. In these instances, treatment can be provided in a single-dose regimen similar to that used in large-scale programmes, or can be provided

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

according to clinical guidelines (e.g. with a 3-day treatment regimen in the case of more severe infections).

7.2.2 Reference to current WHO guidelines

WHO recommends the control of morbidity related to soil-transmitted helminth infection through large-scale preventive chemotherapy programmes using treatment with single-dose albendazole (400 mg) or mebendazole (500 mg) (WHO 2006). Levamisole and pyrantel can also be used against STH infection (primarily hookworm and A. lumbricoides) but are used to a lesser degree in large-scale programmes due to the ease of administration of and drug donation programmes for albendazole and mebendazole. All four drugs are listed in the EML (WHO 2015b). Ivermectin is not among the recommended drugs for STH treatment, but is considered to have some efficacy against A. lumbricoides and T. trichiura infections when administered alone (WHO 2006). Co-administration of ivermectin and albendazole is already recommended in areas where STH infections are co-endemic with lymphatic filariasis and/or onchocerciasis. These recommendations were established during the Informal Consultation on Preventive Chemotherapy in Human Helminthiasis in Geneva, Switzerland in 2006.

A recent update to the guidelines took place during a WHO Guideline Development Group (GDG) meeting in April 2016. The guidelines will be reviewed at a WHO Guideline Review Committee meeting in January 2017, and released shortly after. The guidelines focus predominantly on the use of single-dose albendazole and mebendazole treatment. However, based on discussions during the GDG meeting, it was clear that alternate treatment strategies for improving efficacy against T. trichiura and for reducing the risk of insurgence of drug resistance. The inclusion of ivermectin, to be co-administered with albendazole, could appropriately address this gap and be used as an alternative treatment strategy to albendazole only (or mebendazole), using many of the same control strategies that are currently recommended.

7.2.3 Additional requirements associated with treatment

Due to the public health nature of STH control, and the use of existing infrastructure to deliver drugs, few modifications to the current model of treatment are anticipated. In areas where LF programmes have been in place, there is already sensitization on the

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

use of a two-drug treatment regimen. In areas where LF is not endemic, or where mebendazole is more commonly used, additional training may be needed.

Specific considerations include:

 Diagnostic tests – the current recommendation is to treat all high-risk groups in areas with at least 20% prevalence of STH infection. Specific diagnostic screening is therefore not needed in these endemic areas; rather, all individuals are treated without the need for prior screening. Periodic surveys for community diagnosis and monitoring and evaluation purposes are already recommended, and can continue according to current recommendations in terms of drug efficacy and programme impact (WHO 2011).  Treatment facilities and health care providers – to target school-age children, school-based programmes are recommended as they can use existing infrastructure, have ready access to a high-risk group, and can take advantage of non-health personnel (e.g. teachers) to deliver medicines. This similar approach can be used. Additional training in places where co-administration has not been common may be needed so individuals can appropriately administer two treatments at once. The feasibility of community-based administration of the two drug regimen (i.e. using non-health personnel) has been demonstrated in LF programmes (WHO 2000).  Administration requirements – The administration of ivermectin is recommended based on body weight. Since it can be difficult to accurately measure this in large- scale programmes, it will be recommended that the dose-pole that is used in LF and onchocerciasis programmes continues to be used for calculating the number of tablets needed to distribute to school-age children. Since children under the age of 5 will be excluded from co-administration, difficulties with chewing or swallowing the tablet (which can be problematic in the case of benzimidazole treatment in children under the age of two (Albonico et al. 2008)) is not anticipated. As with strongyloidiasis, treatment is contra-indicated if loiasis is detected (see Section 10 for more detail).  Monitoring requirements – A standardized manual has been published on appropriate monitoring of drug efficacy (WHO 2013). Reference standards are in place for albendazole and mebendazole. Greater efficacy is anticipated with the co-administered drug regimen; however, exact reference standards are not yet

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

defined. Current safety monitoring for the single-drug regimens can also be adapted for the two-drug regimen based on monitoring in the LF programme (WHO 2006). Overall programme monitoring can continue according to those recommended for STH programmes (WHO 2011).

7.2.4 Listing for core or complementary list The request is to list ivermectin (to be co-administered with albendazole) in the core list.

8. Information supporting the public health relevance 8.1 Strongyloidiasis 8.1.1 Epidemiological information on disease burden Strongyloidiasis is globally distributed and is endemic in the tropics and subtropics (Schär et al. 2013, Olsen 2009). The map below presents the global distribution (Schär et al 2013). Strongyloidiasis is globally relevant as a public health concern.

Fig 1. Global Prevalence of Strongyloidiasis (source Schär 2013)

In high-income countries, it is concentrated among migrant and refugee populations from endemic countries, although it is also known to be endemic in parts of Japan and the USA. There is some speculation in the literature about endemicity of strongyloidiasis in Spain.

In low- and middle-income countries, strongyloidiasis is endemic and concentrated in sub-populations without access to improved sanitation. Among these communities,

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

children are at highest risk of chronic infection given the higher likelihood that they practice poorer hygiene.

8.1.2 Assessment of current use Ivermectin is used as the first line therapy of choice against strongyloidiasis in the United States, Australia, France and the UK.

8.1.3 Target population(s) Key target populations are: children and rural populations in endemic countries, and in high income countries, immunodeficient individuals and migrants from endemic countries.

8.1.4 Likely impact of treatment on the disease At the individual level, treatment should result in parasitological cure. At the community level, elimination of the disease is hard to achieve given the water, sanitation, hygiene and environmental factors that contribute to the presence of the disease. As such the community level goal is preventive chemotherapy following WHO guidelines as used with other STHs.

In the medium and longer term it is hoped that treatment contributes to improved growth and cognitive development of children. Parasitic worm infections are associated with malnutrition, impaired growth, cognitive development of children and poor school performance. Heavy worm infection is associated with anaemia in children. Poor nutrition and cognitive development are in turn factor in multigenerational poverty.

Community level control should also contribute to minimisation of complicated disease. Lack of access to primary care and the medicine mean acute infection is rarely diagnosed. Most patients present with chronic disease, which can lead to hyperinfection syndromes, especially in the immunocompromised, those on immune suppressive therapies, diabetics, alcoholics and people with renal and hepatic disease. In addition, the autoinfective capacity of Strongyloides makes elimination of the disease desirable from both a public health and a social development perspective.

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

8.2 Soil-transmitted helminthiasis 8.2.1 Epidemiological information on disease burden The STH disease cluster is considered the most widespread neglected tropical disease worldwide. The most recent estimates indicate that close to 1.5 billion people are infected with A. lumbricoides, T. trichiura, N. americanus and/or A. duodenale in over 100 endemic countries (Pullan et al. 2014; WHO 2016). There are 3.3 million disability- adjusted life years (DALYs) attributed to STH infection due to symptomatic infection, wasting, mild abdominopelvic problems and anaemia (Pullan et al. 2014; DALYs and Collaborators 2016).

As with strongyloidiasis, adverse consequences result predominantly from moderate to heavy intensity infection, but can occur at lower intensity levels, particularly with hookworm infection (Pullan et al. 2014; DALYs and Collaborators 2016). Hookworm species are most often grouped together as the eggs are indistinguishable upon microscopic examination. However, greater blood loss is known to result from infection with A. duodenale (Albonico et al. 1998).T. trichiura infection can lead to Trichuris dysentery syndrome, which is also associated with indirect blood loss. Death can result directly from intestinal obstruction due to A. lumbricoides (Pullan et al. 2014) or indirectly from anaemia and malnutrition (Walsh and Warren 1979; Kassebaum et al. 2014). The main consequence of STH infection, however, is of a chronic, insidious nature, affecting short and long-term health, nutrition, education, economic and social outcomes (Hall et al. 2008; Croke 2014; Baird et al. 2016; Ozier 2016).

Clinical diagnosis of STH infection is difficult due to the asymptomatic nature of the disease, non-specific symptomatology of those infected, suboptimal diagnostic methods and the resource intensive nature of screening large numbers of at-risk individuals. Reinfection is common due to the fact that infected individuals excrete eggs in faeces, which contaminate the environment in the absence of appropriate sanitation. Therefore, WHO recommends the large-scale, periodic distribution of safe and efficacious anthelminthic drugs to high-risk groups in endemic areas for appropriate control of STH infection and associated morbidity. The highest risk groups are children, who are in a critical phase of growth and development, and women of childbearing age, including pregnant women, who have increased nutritional requirements during pregnancy and lactation (WHO 2006).

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

8.2.2 Assessment of current use The co-administration of ivermectin and albendazole is not currently indicated for treatment specifically against STHs. However, this treatment has been used as a way to reach those suffering from LF and STH infections in co-endemic areas (WHO 2006). Ivermectin alone has also been used in areas co-endemic for onchocerciasis. The overlapping geographical distribution of these diseases and of large-scale control programmes has led to evidence on the positive impact of ivermectin on STH infection (Krotneva et al. 2015).

8.2.3 Target population(s)

The target populations for large-scale preventive chemotherapy programmes of albendazole or mebendazole against STH infection include preschool-age children (i.e. 1 to 4 years of age); school-age children (i.e. 5 to 14 years of age), and women of childbearing age, including pregnant women in the second and third trimester. These groups are specifically targeted as they are more susceptible to the adverse consequences of STH infection due to increased nutrient requirements in peak moments of growth and development, as well as peak prevalence and intensity of STH infection, particularly in childhood, but also in adulthood for hookworm.

Therefore the specific target populations are:

 School-age children (i.e. 5 to 14 years of age)  Women of childbearing age

For co-administration of ivermectin with albendazole, exclusion criteria will be the same as those that are currently in place for LF programmes.  pregnant women;  lactating women in the first week after birth;  children measuring less than 90 cm (approximately 15 kg/body weight);  severely ill individuals.

In clinical settings, any individual suspected of STH infection, other than those specified in the exclusion criteria, should be considered an appropriate group to

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

receive co-administration of ivermectin and albendazole. Those found to be infected with T. trichiura may especially benefit from this treatment regimen (see Section 9.2).

Other groups can be treated according to local context and available resources, for example, certain high-risk occupational groups, such as tea pluckers and miners (WHO 2006). However, WHO recommends against mass treatment of entire communities for STH infection due to the potential for the emergence of drug resistance, and the importance of maintaining a group of untreated individuals (i.e. refugia).

8.2.4 Likely impact of treatment on the disease WHO currently has a target of reaching 75% coverage of school-age and preschool-age children with anthelminthic drugs by 2020 (WHO 2012). This level of coverage is meant to result in less than 1% moderate or heavy intensity infection and a population free of STH-related morbidity. Single treatments with albendazole or mebendazole are considered to have low cure rates, but sufficient impact on reducing the intensity of infection (i.e. egg reduction rates), and, therefore, morbidity. Repeated, periodic treatment is necessary, however, to have an overall positive impact on prevalence and intensity (Tun et al. 2013; Casey et al. 2010; Knopp, Mohammed, Stothard, et al. 2010), and improved sanitation is considered necessary to sustainably control STH infections (WHO 2006).

It is anticipated that treatment with ivermectin and albendazole, with greater cure rates and egg reduction rates (See Section 9.2), will help to more quickly and sustainably reach appropriate targets for morbidity control, and will be an important tool for more expansive and permanent post-2020 targets.

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings 9.1 Strongyloidiasis 9.1.1 Identification of clinical evidence We conducted a PubMed search using terms ivermectin, avermectin, Strongyloidiasis, S. Stercoralis and treatment. We further conducted a review of the literature in StrongNet network database on all articles that examined efficacy and safety of ivermectin either in dose comparison studies or in clinical trials against other drugs.

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

Through the search, we identified two systematic reviews of ivermectin against other drugs: these were a Cochrane Review, January 2016 (Henriquez-Camacho et al. 2016) and a forthcoming paper (Schär 2016, unpublished). We compared the two systematic reviews for their inclusion and exclusion criteria. The Cochrane Review identified 51 papers, and excluded all those that were not well-designed randomised control studies (see pp 33-35 for exclusion criteria). The Schär study (2016) included all of the papers identified by Cochrane. To assure the highest quality evidence, we focused on the results of the Cochrane studies, and included only those additional studies that had particularly interesting aspects for consideration, even if they were the only studies of their kind to date. Inclusion criteria were: 1) Dose comparator studies for ivermectin only; 2) comparative studies of ivermectin with drugs other than albendazole or thiabendazole; 3) studies involving special subgroups of patients (those with hyperinfection syndromes, or who belonged to a risk group, studies involving children); 4) studies that had large patient test populations conducted at community level.

9.1.2 Summary of available data Cochrane Review papers. The review included seven randomised control trials (Adenusi 2003; Bisoffi 2011; Datry 1994; Gann 1994; Marti 1996; Suputtamongkol 2008; Suputtamongkol 2011). The studies involved at total of 1147 participants, and were conducted between 1994 and 2011 in Zanzibar, Nigeria, and Thailand (endemic countries) and with immigrants and refugees in Italy, France and the USA. All seven studies investigated treatment efficacy for uncomplicated chronic strongyloidiasis. Four studies compared ivermectin against albendazole, and three ivermectin against thiabendazole. One study was conducted exclusively on children.

Ivermectin dose studies: We found five studies (Naquira 1999, Heukelbach 2004a; Ordoñez 2004; Zaha 2002; Zaha 2004) which compared different dose regimens of ivermectin, with different quantities of the drug administered as a single dose, or repeated either over two days or with an interval of two weeks. Ordoñez (2004) was included because it involved children between the ages of 2 and 7 in an endemic setting. The cure rate was 94% (46/49 patients). Ten children experienced mild transitory side-effects, which resolved within 72 hours. Zaha (2002) involved 50 patients, of whom 24% (seven male and five female) were HTLV-1 positive. Each were given 200mcg/kg ivermectin, one dose, repeated after two weeks. The cure rate was 96% (48/50 patients).

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

Zaha (2004) involved two cohorts of patients 312 patients in the period 1990-1999 who were given 110g/kg of ivermectin and 97 patients who received 200g/kg ivermectin, repeated after two weeks. The long term cure rates for the 110mcg/kg cohort was 77% (117/152) at 12 months after 4 months from treatment. In the 200g/kg group, 25 patients were lost to follow-up. Of the remaining 62, the cure rate was 100% (42/42) for those who were HTLV-1 negative and 90% (18/20) for those who were HTLV positive.

9.1.3 Summary of available estimates of comparative effectiveness In the four trials comparing ivermectin with albendazole, the studies found parasitological cure was higher with ivermectin (RR 1.79, 95% CI 1.55 to 2.08; 478 participants, GRADE rating moderate quality evidence). Below we reproduce the tables from the Cochrane study (full study in Appendix 1):

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

In the three trials comparing ivermectin with thiabendazole, there was little or no difference in parasitological cure (RR 1.07, 95% CI 0.96 to 1.20; 467 participants, three trials, GRADE rating low quality evidence). Below we reproduce the tables from the Cochrane study (full study in Appendix 1):

In trials comparing different dosages of ivermectin, taking a second dose of 200 μg/kg of ivermectin was not associated with higher cure in a small subgroup of participants (RR 1.02, 95% CI 0.94 to 1.11; 94 participants, two trials). Below we reproduce the tables from the Cochrane study (full study in Appendix 1):

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

Other comparative studies: we found three studies that were excluded from the Cochrane study because they were either not randomised or because they compared ivermectin against other drugs. Heukelbach (2004b) was the largest of all studies we encountered enrolling 478 patients in the ivermectin arm. In addition to not being randomised, the study design involved very few patients in the comparator drug arms (albendazole, n=24; and mebendazole, n=15). The cure rate was 68% in the ivermectin arm, 79% in the albendazole arm and 53% in the mebendazole arm. Igual-Adell focused on patients with long-standing untreated strongyloidiasis of whom the majority had eosinophilia (81/88 patients). Toma (2000) compared ivermectin against both albendazole and pyrivinium palmoate. The study was conducted in Okinawa, Japan where improved sanitation makes it unlikely that the disease was transmitted from the environment. 29.4% (62/211) of the patients in the study had HTLV-1. In the ivermectin arm 16 patients had HTLV, 14 were cured (CR 87.5%); in the albendazole arm 12/19 HTLV-1 positive patients were cured (CR=63.2%), while in the pyrivinium palmoate arm 3/27 HTLV-1 positive patients were cured (CR=11.3%).

In sum, ivermectin is highly efficacious for the treatment of strongyloidiasis at the 200g/kg body weight single dose, appears to be so even in children under age 5 (more studies needed) and is comparatively more efficacious than albendazole, mebendazole and thiabendazole.

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9.2 Soil-transmitted helminthiasis 9.2.1 Identification of clinical evidence

Efficacy of albendazole-ivermectin and ivermectin against soil-transmitted helminthiasis

A meta-analysis investigated the efficacy of albendazole, mebendazole, levamisole and pyrantel pamoate against soil-transmitted helminths (STH) (Keiser and Utzinger 2008). Here we present the efficacy of ivermectin alone and co-administered with albendazole against these parasites.

A literature search without language restriction was performed using PudMed (from 1960 to November 2016) with the following search criteria: ivermect* AND (hookworm OR trichuri* OR ascari* OR soil-transmitted helminth*) AND (cure* OR trial). A total of 70 potential studies were identified of which 50 were excluded since they were either systematic reviews (Olsen 2007) or did not report on safety or efficacy of albendazole and/or ivermectin. Of the 20 studies which referred to the effect of ivermectin and/or albendazole on STHs, 12 were excluded because they were not randomized controlled trials (RCTs) (n=5), they did not use the recommended doses of ivermectin and/or albendazole (albendazole: 400mg, ivermectin: 200 µg /kg) (n=4) or drug efficacy was not assessed between two and six weeks post-treatment (n=3). Because reinfection is common, long follow-up periods may prevent a clear distinction between poor efficacy and new infection. Thus, ideally follow-up should be done between two and three weeks (WHO 2013). However, to be more inclusive we extended this period to up to 6 weeks. The diagnostic method was not part of the selection criteria.

As a result, we selected a total of eight studies, of which one compared the co- administration of albendazole-ivermectin to albendazole and ivermectin alone (Belizario et al. 2003), two compared the co-administration to albendazole alone (Ismail and Jayakody 1999; Knopp, Mohammed, Speich, et al. 2010), one compared albendazole-ivermectin to albendazole-oxantel pamoate (Speich et al. 2015), one compared ivermectin to albendazole (Wen et al. 2003) and three focused on ivermectin alone (Xia et al. 1992; Marti et al. 1996; Wen et al. 2008) (Table 1). From these eight studies we extracted the cure rates (CRs) and egg reduction rates (ERRs) (when available) of each treatment against A. lumbricoides, T. trichiura, and hookworms.

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9.2.2 Summary of available data (appraisal of quality, outcomes measures, summary of results)

Table 2 is a brief overview of the randomized controlled trials included on albendazole- ivermectin and ivermectin. Quality was evaluated using the Jadad scale for reporting RCTs (Jadad et al. 1996). Out of a total of five potential points: Knopp et al. (2010) scored four, Speich et al. (2015) and Wen et al. (2008) scored three, Belizario et al. (2003), Wen et al. (2003) and Marti et al. (1996) scored two and Ismail et al. (1999) and Xia et al. (1992) scored one.

Table 2. Treatments administered by each study and respective studied parasites.

IVM alone ALB alone Studied Jadad Study ALB + IVM (or with (or with placebo) parasites score placebo) T. trichiura Belizario et al., 2003 X X X 2 A. lumbricoides Ismail et al., 1999 X X T. trichiura 1 T. trichiura Knopp et al., 2010 X X A. lumbricoides 4 hookworm T. trichiura Speich et al., 2015 X A. lumbricoides 3 hookworm T. trichiura Marti et al., 1996 X A. lumbricoides 2 hookworm T. trichiura Wen et al., 2003 X X 2 hookworm T. trichiura Wen et al., 2008 X A. lumbricoides 3 hookworm T. trichiura Xia et al., 1992 X A. lumbricoides 1 hookworm Note ALB + IVM, co-administration of albendazole-ivermectin; ALB, albendazole; IVM, ivermectin.

Note that not all studies evaluated the efficacy of the drugs against all STHs: Ismail et al. (1999) only assessed the efficacy against T. trichiura, Belizario et al. (2003) did not evaluate the efficacy against hookworms and Wen et al. (2003) only administered the standard dose to children infected with T. trichiura and hookworms. Outcome measures were cure and egg reduction rates. Except for the case of Marti et al. (1996) and Wen et al. (2008)

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which do not mention what type of mean was used to calculate the ERR, all the other studies which provided this data used the geometric mean.

9.2.3 Summary of available estimates of comparative effectiveness

Tables 3, 4 and 5 summarize the CRs and ERRs of the six selected studies for T. trichiura, A. lumbricoides and hookworms, respectively. Summary efficacy estimates were calculated using the eight selected studies.

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Table 3. Efficacy studies of ivermectin (IVM) alone or co-administered with albendazole (ALB) against T. trichiura.

Main CD1 CD2 # # # # Comparato # Comparat # drug First author, Main drug(s) treated cured treat treat Country r drug 1 cured or drug 2 cured ER ER year (dosage) main main ed ed CR ERR CR CR (CD1) CD1 (CD2) CD2 R R drug drug CD1 CD2 (%) (%) (%) (%) (%) (%) IVM (200 ALB IVM Belizario 65. 99. 31. 97. 35. 98. Philippines µg/kg) 149 97 (400mg) + 149 47 (200µg/kg) 154 54 2003 1 7 5 2 1 2 + ALB (400mg) placebo + placebo IVM (200 µg Ismail ALB 81. 94. 43. 70. Sri Lanka /kg) 53 43 55 24 1999 (400mg) 1 9 6 3 + ALB (400mg) IVM (200 µg ALB Knopp 37. 91. 40. Tanzania /kg) 140 53 (400mg) + 132 13 9.8 2010 9 3 3 + ALB (400mg) placebo Wen IVM ALB 67. 47. China 34 23 34 16 2003 (200µg/kg) (400mg) 6 1 Marti IVM (200 µg 11. 58. Tanzania NR NR 1996 /kg) 3 9* IVM (200 µg Speich 27. 94. Tanzania /kg) 109 30 2015 5 5 + ALB (400mg) Wen IVM (200 µg 66. 86. China 102 68 2008 /kg) 7 2* Xia IVM (200 µg 76. China 34 26 1992 /kg) 5 Note All egg count means are geometric except those with a *. Marti et al. (1996) does not provide number of treated and cured individuals. IVM, ivermectin; ALB, albendazole; CR, cure rate; ERR, egg reduction rate; NR, not reported

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Table 4. Efficacy studies of ivermectin (IVM) alone or co-administered with albendazole (ALB) against A. lumbricoides.

Main CD1 CD2 # # # # First Comparato # Comparat # drug Main drug(s) treate cured treat treat author, Country r drug 1 cured or drug 2 cured ER ER ER (dosage) d main main ed ed CR CR CR year (CD1) CD1 (CD2) CD2 R R R drug drug CD1 CD2 (%) (%) (%) (%) (%) (%) IVM (200 µg ALB IVM (200 Belizario Philippi 78. 69. 99. 78. /kg) 105 82 (400mg) + 99 69 µg/kg) + 102 80 100 100 2003 nes 1 7 9 4 + ALB (400mg) placebo placebo IVM (200 µg ALB Knopp Tanzani 92. 99. /kg) 14 13 (400mg) + 14 14 100 100 2010 a 9 9 + ALB (400mg) placebo Marti Tanzani IVM (200 µg 100 NR NR 100 1996 a /kg) * IVM (200 µg Speich Tanzani /kg) 50 49 98 100 2015 a + ALB (400mg) Wen IVM (200 µg 100 China 102 102 100 2008 /kg) * Xia IVM (200µg 95. China 44 42 1992 /kg) 5

Note All egg count means are geometric except those with a *. Marti et al. (1996) does not provide number of treated and cured individuals. IVM, ivermectin; ALB, albendazole; CR, cure rate; ERR, egg reduction rate; NR, not reported.

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Table 5. Efficacy studies of ivermectin (IVM) alone or co-administered with albendazole (ALB) against hookworms.

Main CD1 # # # Comparato # drug Main drug treate cured treat First author, year Country r drug 1 cured ER CR ER (dosage) d main main ed CR (CD1) CD1 R (% R drug drug CD1 (%) (%) ) (%) IVM (200 µg ALB Knopp Tanzani 66. 95. /kg) 30 20 (400mg) + 39 16 59 94 2010 a 7 9 + ALB (400mg) placebo Wen ALB 17. 76. China IVM (200µg/kg) 34 6 34 26 2003 (400mg) 6 5 Marti Tanzani IVM (200µg/kg) NR NR 0 0 1996 a IVM (200 µg Speich Tanzani 95. /kg) 42 21 50 2015 a 4 + ALB (400mg) Wen IVM (200 µg 33. China 102 34 80* 2008 /kg) 3 Xia IVM (200 µg 11. China 53 37 1992 /kg) 8

Note All egg count means are geometric except those with a *. Marti et al. (1996) does not provide number of treated and cured individuals. IVM, ivermectin; ALB, albendazole; CR, cure rate; ERR, egg reduction rate; NR, not reported.

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Efficacy of albendazole-ivermectin against T. trichiura infections

Figure 2 shows that co-administration of albendazole-ivermectin is more effective at eliminating T. trichiura than albendazole alone (Z=3.43, p=0.001).

CR of First author IVM+ALB CR of ALB RR (95% CI) Weight (%)

Belizario 65.1 31.5 0.51 (0.40, 0.65) 37.57

Ismail 81.1 43.6 0.33 (0.18, 0.61) 19.90

Knopp 37.8 9.8 0.69 (0.60, 0.79) 42.52

Overall (I-squared = 80.7%, p = 0.006) 0.53 (0.37, 0.76) 100.00

.1 1 10 IVM+ALB ALB

Figure 2. Forest plot displaying a random-effects meta-analysis of the effect of the co- administration of albendazole-ivermectin on the number of cured T. trichiura infected patients when compared to albendazole alone.

In these three studies, which included a total of 342 patients, the co-administration of albendazole-ivermectin revealed a CR of 47%; RR: 53% (95% CI 37.2-76.4%) against T. trichiura infections (Figure 2). Bias indicators could not be calculated since there were too few strata. In the three selected studies, patients treated with the co-administration had ERRs ranging from 91.3% to 99.7% for T. trichiura which is considerably higher than those found for albendazole alone ranging from 40.3% to 97.2% (Table 2). In Tanzania, Speich et al. (2015) found a CR of 27.5% and an ERR of 94.5% using the co-administration of albendazole-ivermectin (Table 3).

Also, Belizario et al. (2003) found that the efficacy of the co-administration of albendazole- ivermectin is higher than that of ivermectin alone (CR = 65.1% versus CR = 35.1%,

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respectively) (Table 3). Furthermore, their results indicated that the decrease in egg counts obtained with the co-administration was significantly higher than the decrease obtained with the drugs on their own (P<0.001).

In summary, our results indicate that the addition of ivermectin to the standard single- dose albendazole results in higher efficacy against T. trichiura.

Efficacy of ivermectin against T. trichiura

Five studies investigated the efficacy of ivermectin alone against T. trichiura infections. Of these, four provided data on the number of cured and treated (N=324) individuals. Only one of these studies used a comparator or placebo group, hence a meta-analysis could not be conducted. For these studies we calculated an overall CR of 52.7% (Xia et al. 1992; Belizario et al. 2003; Wen et al. 2003; Wen et al. 2008). Marti et al. (1996) was not included in this calculation because they only provide the CR (no data on total and cured participants). ERR across the four studies ranged from 58.9% to 98.2% (Table 3).

Efficacy of albendazole-ivermectin against A. lumbricoides

As there were only two studies comparing the efficacy of the co-administration of albendazole-ivermectin versus albendazole and/or ivermectin alone, a meta-analysis could not be performed. However, both Belizario et al. (2003) and Knopp et al. (2010) reported that the co-administration of albendazole-ivermectin is not more effective at eliminating A. lumbricoides than albendazole alone. In these two studies the co-administration of albendazole-ivermectin revealed an overall CR of 79.8% against A. lumbricoides infections versus an overall CR of 73.5% for albendazole alone. In terms of intensity, they observed ERRs of 100% and 99.9% for the co-administration versus 99.9% and 100% for albendazole alone (Table 4).

Furthermore, Belizario et al. (2003) also found that the co-administration of albendazole- ivermectin was not more effective than ivermectin alone (CR=78.1% and ERR=100% versus CR=78.4% and ERR=99.9%, respectively) (Table 4).

Efficacy of ivermectin against A. lumbricoides

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The three studies which included a total of 248 individuals found an overall CR of 90.3% for ivermectin against A. lumbricoides infections (Table 3). Again, Marti et al. (1996) could not be included in the calculation of the overall CR due to the absence of number of treated and cured individuals. In terms of intensity of infection, ERRs were 100% in the three studies which provided this data (Table 4).

Efficacy of albendazole-ivermectin against hookworms

Only a single study evaluated the efficacy of albendazole-ivermectin against hookworm infections, thus, we could not perform a meta-analysis. The results of Knopp et al. (2010) indicate that the co-administration is more effective at curing hookworms than albendazole alone (Table 5). However, in terms of ERRs, the difference is quite small: 95.9% with the co-administration and 94% albendazole alone (2010).

Efficacy of ivermectin against hookworms

Using data from three studies (N=187), the calculated overall CR of hookworm infections using ivermectin alone was 24.6% (Xia et al. 1992; Wen et al. 2003; Wen et al. 2008). Only one study (Wen et al. 2008) calculated the ERR which was 80% (Table 5).

Overall evidence of efficacy:

 Ivermectin is highly efficacious for the treatment of strongyloidiasis and is comparatively more efficacious than albendazole, mebendazole and thiabendazole. There is evidence of increased efficacy in children under the age of five  Ivermectin co-administered with albendazole is highly efficacious for the treatment of T. trichiura and is comparatively more efficacious than albendazole alone. Efficacy of ivermectin and albendazole against A. lumbricoides and hookworms are comparable and in some cases more efficacious than albendazole alone. This is mainly due to the already high efficacy of albendazole alone against these STH species.

10. Review of harms and toxicity: summary of evidence on safety

10.1 Summary of methods

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Separate literature searchers were performed to obtain data from the published literature on safety of ivermectin use against Strongyloidiasis and soil-transmitted helminthiasis.

We used the following methodology to categorize adverse drug reactions:

Adverse drug reactions are usually graded into mild, moderate, serious, life-threatening and death related to adverse events (AEs) following standard guidelines (NCI 2009). In the Common Terminology Criteria for Adverse Events (CTCAE) and the Medical Dictionary for Medical Affairs (MedDRA), which is used as a reference system for AE reporting in clinical trials, AEs may further be classified into 3 categories: (i) laboratory-based events, (ii) measurable/observable events from clinical examination or (iii) symptomatic events (Basch et al. 2014). Symptomatic events are further considered to be more reliable if not only assessed by medical staff but also revealed from patient’s direct reports. AEs can be observed and followed in an active way by regular visits of the study subjects by medical teams or through passive reporting. The latter implies a reference centre where study participants can visit in case of adverse reactions.

To supplement the published literature, a search of the WHO Individual Case Safety Reports (ICSRs) from the VigiBase database was also performed. This is the most complete database of adverse event reports worldwide and includes information from 1945 to present. It is maintained by the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden. ICSRs with suspected adverse drug reactions (ADRs) with use of ivermectin were extracted until October 24, 2016. An overall descriptive analysis of originating countries, types of adverse reactions, patient demographics (age and sex), concomitant medications (most frequently prescribed), and most commonly reported adverse effects was performed. Reports that contained both ivermectin and albendazole were identified. Analyses were made using Stata/IC 10.0 for windows and full reports were used to summarize death cases in individuals less than 18-years of age. The complete report of adverse drug reactions for ivermectin is included in Annex 2, and a summary of findings is included below (Section 10.5).

10.2 Estimate of total patient exposure to date

Estimates of the number of people exposed to ivermectin come primarily from the WHO Preventive Chemotherapy and Transmission Control (PCT) databank. Data has been collected since 2000 for the LF programme and since 2005 for the onchocerciasis programme. The total number of ivermectin and albendazole treatments provided between 2000 and 2015 against LF is 997,297,011. A total of 916,791,269 treatments of ivermectin alone or ivermectin co-

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10.3 Strongyloidiasis 10.3.1 Description of the adverse effects/reactions and estimates of their frequency The table below (Table 6) shows the adverse effects in all studies. Most side effects were transient and mild. Loose stool, fatigue and headache were most frequently reported, and the number and among the randomised control trials (best available evidence) incidence of all side effects was highest in the studies involving children.

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Table 6. Adverse events associated with ivermectin treatment in strongyloidiasis patients (actively collected) 3 4 Side Effects Adenusi Bisoffi Datry Gann Marti Suputtamongkol Suputtamongkol Naquira Heukelbach Ordoñez Toma Zaha Occurrence (%) 2003 2011 1994 1994 1996 2008 2011 2004 2004b 2004 2000 2002 N= 122 115 29 34 163 21 60 57 458 79 367 50 Minor and transient (disappear after 1-3 days) Gastrointestinal symptoms diarrhoea NR NR NR NR 2 (1%) NR NR NR NR 2 (2.5%) 5 (1%) NR loose stool NR NR NR NR 16 (10%) NR NR NR 12 (2.6%) NR NR NR nausea 5 (4%) NR NR 1 (3%) 5 (3%) NR NR NR 15 (3%) NR 5 (1%) 1 (2%) epigastric 0 (0%) NR NR 0 (0%) 7 (4%) NR NR 1 (2%) 23 (5%) NR NR NR pain/discomfort constipation 7 (6%) 0 (0%) NR 0 (0%) 3 (2%) NR NR NR NR NR NR NR anorexia NR NR NR NR NR NR NR NR NR 2 (2.5%) NR NR vomiting 1 (2%) NR NR NR NR NR NR NR NR NR NR NR CNS Symptoms headache 11 (9%) NR NR NR 15 (9%) NR NR NR 3 (0.7%) NR NR NR dizziness NR NR NR NR 5 (3%) NR NR NR NR NR NR NR myalgia NR NR NR NR NR NR NR NR NR NR NR NR fever 8 (7%) NR NR NR 10 (6%) NR NR NR 1 (0.2%) NR NR tremors NR NR 1 (3%) NR NR NR NR NR NR NR NR NR malaise 0 (0%) NR NR NR NR NR NR NR NR NR NR NR fatigue 16 (13%) NR 1 (3%) 2 (6%) NR NR NR NR 3 (0.7%) 3 (4%)5 NR NR disorientation NR NR NR 0 (0%) NR NR NR NR NR NR NR NR chest NR NR NR NR 7 (4%) NR NR NR NR NR NR NR pain/tightness cough, not with NR NR NR NR 11(7%) NR NR NR NR NR NR NR

3 Side effects actively collected using standardised questionnaires 4 Study conducted in children 5 Reported as ‘drowsiness’

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cold common cold NR NR NR NR NR NR NR NR NR NR NR NR lumbar pain NR NR NR NR NR NR NR NR 1 (0.2%) NR NR NR Paraesthesia NR NR NR NR NR NR NR NR 1 (0.2%) NR NR NR

Side Effects6/Study Nr. 1 2 3 4 5 6 7 8 9 10 11 12 N= 122 115 29 34 163 21 60 57 458 79 367 50 Allergic phenomena oedema NR NR NR NR NR NR NR NR NR NR NR NR itching NR NR NR 4 (12%) NR NR NR NR 6 (1%)7 2 (2.5%) NR NR urticaria NR NR NR NR NR NR NR NR NR NR NR NR rashes NR NR NR NR NR NR NR NR NR NR NR NR Long term side effects Liver function abnormalities NR NR NR NR NR NR NR NR NR NR 25 (7%) NR leucopenia NR NR NR NR NR NR NR NR NR NR NR NR AGEP NR NR NR NR NR 1 (6%) NR NR NR NR NR NR ALT (alanine NR NR NR NR NR 1 (6%) 1(2%) NR NR NR NR NR aminotransferase) NR = not reccorded

6 Side effects actively collected using standardised questionnaires 7 reported as ‘skin rash or itching’

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10.3.2 Summary of available data (appraisal of quality, summary of results) Cochrane review papers: The studies involved a total of 1147 patients. Dizziness, nausea, and disorientation were the most commonly reported adverse events. There were no reports of serious adverse events or death.

Other comparative studies: Zaha (2000) recorded liver function abnormalities in 25% of patients. All these patients were HTLV-1 positive

10.3.3 Summary of comparative safety against comparators Cochrane review papers: In the four studies comparing ivermectin with albendazole, there were no statistically significant differences in adverse events (RR 0.80, 95% CI 0.59 to 1.09; 518 participants, four trials, low quality evidence). In the three trials comparing ivermectin with thiabendazole, adverse events were less common with ivermectin (RR 0.31, 95% CI 0.20 to 0.50; 507 participants; three trials, moderate quality evidence). Dizziness, nausea, and disorientation were commonly reported in all drug groups. There were no reports of serious adverse events or death related to the drug.

10.3.4 Identification of variation in safety that may relate to health systems and patient factors Zaha (2004) found significant liver abnormalities in both dosage groups (110 g/kg body weight and 200 g/kg. In the 110g/kg group, a rise in glutamic pyruvic transaminase (GPT) or glutamic oxaloacetic transaminase (GOT) was observed in 6.9% (19/274) of the patients whose liver function was normal before treatment. Sixty-eight percent (13/19) of these liver dysfunctions were observed after the first administration. GPT or GOT levels in 15 of these patients were less than 100 IU/l, but in 4 patients, they exceeded 100 IU/l. The second treatment was discontinued in 1 of these 4 patients because GPT had increased to 200 IU/l. In the 200g/kg group, liver dysfunction was observed in 6.5% (6/92) of patients. GOT and GPT levels exceeded 100 IU/l in 1 patient. The frequency of liver dysfunction was not significantly different between the two treatment groups. The abnormalities were mild, transient and not clinically important in both groups.

10.4 Soil-transmitted helminthiasis

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A literature search was performed using PubMed’s database (1960‐November 2016) with the following search criteria: ivermect* AND alben* AND combin* AND (adverse OR side effect* OR symptom*). A total of 68 studies were identified and screened for safety data after administration of albendazole-ivermectin. 47 studies were excluded since they did either not report any safety data or were reviews (n=14) or case studies (n=14), did not study the co-administration of albendazole-ivermectin (n=11), were veterinary studies (n=4) or used a third additional drug in the co-administration regimen (n=4). From the 21 references reporting adverse events after treatment with albendazole-ivermectin, 15 specified data either on the type and frequency of adverse events or reported symptoms (Table 7). Of these, those which provided the actual number of adverse events (AEs) and total number of treated individuals in the co-administration of albendazole-ivermectin group and in at least one single drug comparator (albendazole or ivermectin) group were selected for further analysis (n=4). These four studies served for comparison of risk ratios (RRs) between AEs from co-administration of albendazole-ivermectin therapy versus single drug regimens of albendazole or ivermectin.

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

Within the 13 studies reporting actual AE data (Table 8) the majority had an active case detection approach (n=11), while two studies used a passive reporting system. Actively monitoring studies mostly assessed short-term AEs occurring within the last 7 days after treatment (n=9). All studies (n=13) assessed symptom events either through AE detection questionnaires or patient’s direct reports and investigated one or the other observable (e.g. skin reaction or oedema) or measurable (e.g. fever) clinical parameters. Further, four studies (Awadzi et al. 2003; Ismail et al. 1998; Makunde et al. 2003; Na-Bangchang et al. 2006) did detailed lab analysis for assessment of haematological parameters, liver and/or heart function or urine analysis for haematuria or proteinuria. Several studies used simplified severity grading, classifying AEs into (i) 0=none, 1=mild (noticeable to the patient but not interfering with daily activities/present – not requiring any intervention), 2=moderate (some interference with daily activities/requiring medication for symptomatic relief), and 3=severe (complete interruption of daily activities/requiring medical intervention beyond symptomatic relief) (Addiss et al. 1997; Dunyo, Nkrumah, and Simonsen 2000; Knopp, Mohammed, Speich, et al. 2010; Makunde et al. 2003).

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To relate reported symptoms and adverse reactions to the intake of the drug, studies consider different methods. One way is to compare symptom reporting on day 0 of the trial with frequencies of AEs collected at a defined follow-up period after drug treatment (usually within few days after treatment). A sudden increase of symptom-reporting in one of the treatment groups may then be interpreted as drug-related. This methodology has been applied by 8 out of the 13 studies identified to report AE data.

Often studies summarize AEs reporting by creating scales and scores in order to compare frequency or severity. While some are study-specific (Addiss et al. 1997; Ismail et al. 1998), others refer to internationally accepted standard measures (Keiser et al. 2003; Na- Bangchang et al. 2006). Specific scores may be directly related to pre-treatment infection status with particular diseases such as the Mazzotti reaction score that is the result of systemic and ocular responses to the death of the microfilariae of Onchocerca volvulus (Mazzotti 1948; Ackerman et al. 1990). Within the retained literature one study (Awadzi et al. 2003) used this score in order to be able to distinguish between the reaction to the killing of microfilariae and direct drug-related reactions.

Most common adverse reactions observed

Among all included studies observed AEs for the co-administration of albendazole- ivermectin were all of mild or moderate severity (Table 8). The CTCAE categories 4 and 5 (i.e. life-threatening or death related to AE) are not reported in the scientific literature with regard to co-administration of albendazole-ivermectin therapy. Headache, fever, abdominal pain, diarrhoea and muscle/joint pain ranked among the top five symptoms assessed by the retained studies. In terms of numbers, fever and headache were the most often observed adverse reactions. Abdominal pain was prominently reported in trials of intestinal helminthiases (Anto et al. 2011; Knopp, Mohammed, Speich, et al. 2010; Ndyomugyenyi et al. 2008; Speich et al. 2015) and muscle/joint pain together with skin reactions (e.g. pruritus and rashes) more often observed in studies on filarial diseases (Addiss et al. 1997; Dunyo, Nkrumah, and Simonsen 2000; Makunde et al. 2003). Only one study assessed drug safety of the co-administration of albendazole-ivermectin in non- infected individuals (Na-Bangchang et al. 2006). Of the 23 healthy Thai subjects, none experienced any adverse events in the following 8 days after administration of albendazole together with ivermectin. Most studies (n=5) comparing frequencies of AEs between day 0 and a defined follow-up period (n=8) did not find any significant increase in the number or severity of reported adverse reactions in the albendazole-ivermectin group (Asio,

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Simonsen, and Onapa 2009; Makunde et al. 2003; Na-Bangchang et al. 2006; Speich et al. 2015; Turner et al. 2006).

10.4.2 Summary of available data (appraisal of quality, summary of results)

Out of the 14 studies which were included in the study, 11 provided either frequencies of occurrence of specific side effects or number of mild, moderate and severe AEs (Table 7). Of these, four were further considered for the comparison of safety between the co- administration of albendazole-ivermectin safety and albendazole or ivermectin alone. Two studies by Shenoy et al. (Shenoy et al. 1999; Shenoy et al. 2000) were not used for either of the above mentioned purposes because they did not present any data on frequencies of side effects and did not have comparators. Note that Ndyomugyenyi et al. (2008) studied the effect of the drugs in pregnant women (their results will be discussed in another section). Due to the limited number of studies providing safety data, we included studies using different doses of ivermectin and albendazole (details on Table 8).

Table 7. Frequencies of adverse events (AEs) reported after administration of ivermectin alone, albendazole alone and co-administration of albendazole-ivermectin.

IVM+ALB IVM ALB Study # AEs # treated # AEs # treated # AEs # treated Addis et al., 1997 20 24 11 28 7 29 Anto et al., 2011 130 15020 - - - - Asio et al., 2009 0 15 0 15 0 13 Awadzi et al., 2003 NR 14 ? 14 ? 14 Dunyo et al., 2000 47 332 36 295 31 314 Ismail et al., 1998 NR 13 - - NR 12 Keiser et al., 2003 11 40 - - - - Knopp et al., 2010* 64 144 - - 60 136 Makunde et al., 2003 11 20 - - 5 13 Na-Bangchang et al., 2006 0 23 - - - - Ndyomugyenyi et al., 2008 8 146 23 148 16 140 Shenoy et al., 1999 12 16 - - 2 3 Shenoy et al., 2000 6 12 - - - - Speich et al., 2015 27 108 - - - Turner et al., 2007 13 17 - - - - * used albendazole plus placebo; NR, the study does not report a total number of AEs.

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Table 8. Type and occurrence of AEs and additional information on AE assessment characteristics from studies (n=13) reporting side effects after treatment with the co- administration of albendazole-ivermectin.

Study Number 1 2 3** 4 5 6*** 7 8 9 10 11*** 12 13 First author Addiss Anto Asio Awadzi Dunyo Ismail Keiser Knopp Makunde Na-Bangchang Ndyomugyenyi Speich Turner Dosage Ivermectin 200-400 µg height 150-200 µg 2x6mg 150-200 µg 400 µg /kg 200 µg /kg 200 µg /kg 150 µg /kg 200 µg /kg height 200 µg /kg 150 µg /kg /kg /kg tablets /kg Albendazole 400mg ? 400mg 400mg 400mg 600mg 400mg 400mg 400mg 400mg 400mg 400mg 400mg Time span 3-5 days passive 7 days 30 days 5 days 4x/day for 11x within 48h Every 6h 8 days passive during first 48h 48h 5 days during 48h 24h Parasitic disease treated lf sh, sm mp onc lf lf lf tri lf, onc lf, sth sth tri lf, wb N = 44 15552 15 14 332 13 40 144 27 23 199 108 28 AEs (categorized) mild NR 130 (0.8%) NR NR 73 (22.0%) NR 11 (27.5%) 32 (22.2%) NR 0 (0.0%) 8 (4.0%) 17 (16%) 17 (63%) moderate NR 0 (0%) NR NR 2 (0.6%) NR 0 (0.0%) 32 (22.2%) NR 0 (0.0%) 0 (0.0%) 0 (0%) 3 (11.1%) severe NR 0 (0%) NR NR 0 (0.0%) NR 0 (0.0%) 0 (0.0%) NR 0 (0.0%) 0 (0.0%) 0 (0%) 0 (0%) Gastrointestinal symptoms diarrhoea NR 4 (0.03%) pre-treat NR 4 (1.1%) NR 1 (2.5%) 4 (2.8%) NR 0 (0.0%) NR NS NR loose stool NR NR NR NR NR NR NR NR NR NR NR NR NR nausea NR 8 (0.05%) pre-treat NR NR NR NR 11 (7.6%) NR 0 (0.0%) NR NS NR epigastric/abdominal NR 11 (0.07%) pre-treat NR 4 (1.1%) NR NR 21 (14.6%) NR 0 (0.0%) 4 (2%) 13 (12%) NR pain/discomfort blood in stool NR 5 (0.03%) NR NR NR NR NR NR NR NR NR NR NR constipation NR NR NR NR NR NR NR NR NR NR NR NR NR anorexia NR 2 (0.01%) NR NR NR NR 1 (2.5%) NR NR NR 0 (0.0%) NR NR

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vomiting NR 4 (0.03%) pre-treat NR NR NR 3 (7.5%) 3 (2.1%) NR 0 (0.0%) NS NR CNS Symptoms headache 28 (64%) 13 (0.08%) pre-treat 6 (42.9%) 17 (4.6%) NR 11 (27.5%) 5 (3.5%) 0 (0%) 0 (0.0%) NR 5 (5%) NR fever 28 (64%) 7 (0.05%) pre-treat 20 (5.4%) NR 7 (17.5%) 6 (4.2%) 5 (18.5%) 0 (0.0%) 4 (2%) NS NR dizziness NR 10 (0.06%) pre-treat NR NR NR NR NR 0 (0.0%) 0 (0.0%) NR NR NR myalgia/muscle pain 15 (34%)* 11 (0.07%) pre-treat NR 16 (4.3%) NR 2 (5%) NR 0 (0.0%) NR NR NR NR joint pain NR 8 (0.05%) NR NR NR NR NR NR NR NR NR NR tremors NR NR NR NR NR NR NR NR NR NR NR NR NR malaise NR NR NR NR NR NR NR NR NR NR NR NR NR fatigue/tiredness/lethargy NR 9 (0.06%) pre-treat NR NR NR 3 (7.5%) 4 (2.8%) 0 (0%) 0 (0.0%) NR NS NR body weakness NR 6 (0.04%) NR NR 9 (2.4%) NR NR NR NR NR NR NR NR disorientation NR NR NR NR NR NR NR NR NR NR NR NR NR chest pain/tightness NR NR NR NR NR NR NR NR NR NR NR NR NR cough, not with cold 19 (43%) NR NR NR NR NR 0 (0%) NR NR NR NR NR NR dyspnoea NR NR NR NR NR NR 2 (5%) NR NR NR NR NR NR common cold NR NR NR NR NR NR NR NR NR NR NR NR NR low blood NR NR NR NR NR NR 0 (0%) NR NR 0 (0.0%) NR NR NR pressure/syncope lumbar/lower back pain NR NR NR NR NR NR NR NR NR 0 (0.0%) NR NR NR vertigo NR NR NR NR NR NR NR 2 (1.7%) NR NR NR NS NR shivering/chills NR NR NR NR NR NR NR 3 (2.1%) 0 (0%) NR NR NR NR paraesthesia NR NR NR NR NR NR NR NR NR NR NR NR NR Allergic phenomena rashes NR 4 (0.03%) pre-treat NR 2 (0.5%) NR 1 (2.5%) NR NR NR 2 (1%) NR NR itching/pruritus NR 10 (0.06%) NR NR 3 (0.8%) NR NR 2 (1.7%) 4 (14.8%) NR NR NR urticaria NR NR NR NR NR NR NR NR NR NR NR NR

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anaphylaxis NR NR NR NR NR NR NR NR NR NR NR NR oedema NR NR pre-treat NR NR NR NR NR NR NR NR NR NR severe cutaneous adverse NR NR NR NR NR NR NR NR NR NR NR NR NR reaction (SCAR) (e.g. SJS, TEN, AGEP, DRESS) any allergic reaction NR NR NR NR NR NR NR NR NR NR NR NS NR Long term side effects liver function NR NR NR NR NR 5 (38.5%) NR NR NR NR NR NR NR abnormalities leukopenia NR NR NR NR NR NR NR NR 0 (0.0%) 0 (0.0%) NR NR NR ALT (alanine NR NR NR NR NR NR NR NR 0 (0.0%) 0 (0.0%) NR NR NR aminotransferase) AST (aspartate NR NR NR NR NR NR NR NR 0 (0.0%) 0 (0.0%) NR NR NR aminotransferase) total and direct bilirubin NR NR NR NR NR NR NR NR 0 (0.0%) 0 (0.0%) NR NR NR proteinuria NR NR NR NR NR NR NR NR NR 0 (0.0%) NR NR NR haematuria NR NR NR NR NR 1 (8%) NR NR NR NR NR NR NR abnormal ECG NR NR NR 0 (0.0%) NR 0 (0.0%) NR NR NR 0 (0.0%) Others sore throat NR 1 (0.006%) NR NR NR NR NR NR NR NR NR NR NR swelling of the limbs NR 4 (0.03%) pre-treat NR NR NR NR NR NR NR NR NR NR swelling of the face NR 3 (0.02%) pre-treat NR NR NR NR NR NR NR NR NR NR reddening of the NR 8 (0.05%) NR NR NR NR NR NR NR NR NR NR NR eyes/conjunctivitis Mazzotti-type toxicity NR NR NR 2 (13.3%) NR NR NR NR NR NR NR NR NR (swelling of limbs, face or

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

groin) eye pain and lacrimation NR NR NR 2 (13.3%) NR NR NR NR NR NR NR NR NR tender or swollen lymph NR 2 (0.01%) NR NR NR NR NR NR 1 3.7%) NR NR NR NR nodes/adenitis palpitation NR NR NR NR NR NR NR NR 4 (14.8%) 0 (0.0%) NR NR NR oedema NR NR NR NR NR NR NR NR 1 (3.7%) NR NR NR NR running nose NR NR NR NR NR NR NR NR NR 0 (0.0%) NR NR NR nasal congestion NR NR NR NR NR NR NR NR NR 0 (0.0%) NR NR NR axillary abscess NR NR NR NR NR NR NR NR NR 0 (0.0%) NR NR NR Type of assessed AE data symptom events x x x x x x x x x x x x x measurable/observable x x x x x x x x x x x x x (clinical examination) lab events x x x x day 0 data x x x x# x x x x

AE significantly associated to infection status / x (lf) x (onc) x (lf) x (lf) x (lf) intensity (parasite) * self reported; ** no AEs found/no increase in infection-related symptoms assessed pre- (pre-treat) and post treatment; *** data gained from Horton et al. (2000); **** study in pregnant women; # pre-treatment questionnaire data used to define exclusion criteria (subjects with known lf post-treatment symptoms were excluded); NR=not reported or assessed, NS=assessed but numbers not stated, abbreviations of parasites: lf=lymphatic filariasis, mp=Mansonella perstans, onc=onchocerciasis, sh=Schistosoma haematobium, sm=Schistosoma mansoni, sth=soil-transmitted helminths, tri=trichuriasis, wb=Wolbachia (endosymbiont of lf)

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10.4.3 Summary of comparative safety against comparators

Four studies compared the safety of the co-administration of albendazole-ivermectin to that of albendazole alone. Although not significant (Z=1.73, p=0.083), Figure 3 reveals that the co- administration is responsible for more AEs than albendazole alone. Similarly, but also not significant, the co-administration was associated with more AEs (67/356) than ivermectin alone (47/323) (Addiss et al. 1997; Dunyo, Nkrumah, and Simonsen 2000).

First author RR (95% CI) Weight (%)

Addis 0.29 (0.15, 0.57) 21.37

Dunyo 0.70 (0.46, 1.07) 28.00

Makunde 0.70 (0.32, 1.55) 18.40

Knopp 0.99 (0.76, 1.29) 32.23

Overall (I-squared = 75.2%, p = 0.007) 0.65 (0.40, 1.06) 100.00

.1 1 10 ALB+IV ALB M Figure 3. Forest plot displaying a random-effects meta-analysis of the number of AEs of the co- administration of albendazole-ivermectin compared to albendazole alone.

10.4.4 Identification of variation in safety that may relate to health systems and patient factors

There may be variations in safety and in the number of reported AEs dependant on several factors such as the use of different concomitant drugs, targeting pregnant versus non-pregnant women, infected versus non-infected individuals, the application of active versus passive monitoring and reporting of AEs, number of participants, etc.).

Makunde et al. (2003) found no difference in the proportion of AEs between patients infected with Wuchereria bancrofti and those co-infected with W. bancrofti and Onchocerca volvulus. Also, they did not encounter more AEs when the treatment was albendazole alone or when it

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included ivermectin as a combination. However, this four-arm treatment trial had a relatively small number of participants (N=40).

Frequency and severity of AEs have been shown to be associated with baseline infection status and intensity of infection as well as infection-related immune response parameters. We identified four studies which compared the proportion of AEs between groups infected or non- infected with W. bancrofti (Addiss et al. 1997; Dunyo, Nkrumah, and Simonsen 2000; Simonsen et al. 2004; Turner et al. 2006). Turner et al. (2006), for example, showed higher grades of AE severity in microfilaraemic subjects for W. bancrofti (a species causing lymphatic filariasis), concomitant Wolbachia bacterial infection and increased levels of proinflammatory cytokines. When comparing the safety and efficacy of ivermectin alone (150-200µg/kg) versus that of the co-administration of albendazole-ivermectin (400mg and 150-200µg/kg, respectively) against W. bancrofti, Dunyo et al. (2000) also reported that the proportion of AEs was significantly higher in microfilaria-positive patients (25.8% of microfilaria-positive patients versus 8.3% of microfilaria- negative patients in the ivermectin alone group and 36.3% of microfilaria-positive patients versus 7.1% of negative-microfilaria patients in the co-administration of albendazole-ivermectin group). Also, they found higher frequencies in AEs among microfilariae positives in the two treatment groups with ivermectin (i.e. ivermectin alone and ivermectin in co-administered with albendazole) compared to the placebo and albendazole alone regimens. This study also revealed that a higher microfilaria geometric mean intensity was associated to more AEs. Another study using the same treatment arms and the same doses of ivermectin and albendazole found similar results: headache and fever were significantly more common in microfilaria-positive than microfilaria-negative patients (Simonsen et al. 2004). Furthermore, they found that these two symptoms were also significantly more common in patients with higher levels of circulating-filarial antigen.

Of note, if ivermectin is administered to subjects with high Loa loa microfilariaemia, severe adverse reactions such as neurological signs, encephalopathy and coma have been reported (WHO/APOC 2013). These findings, dating back to 1991 and revealed during a community directed treatment with ivermectin (CDTi) campaign against onchocerciasis in Cameroon, have so far represented a major obstacle for national control programs against lymphatic filariasis and onchocerciasis, where ivermectin is used as a standard treatment (Molyneux et al. 2014). In Loa loa endemic countries, mainly countries in central and western Africa (i.e. Angola, Cameroon, Central African Republic, Chad, Congo, DRC, Equatorial Guinea, Gabon, Nigeria and Sudan) (Zouré et al. 2011), potential co-infection with this parasite thus has to be ruled out before

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starting MDAs with an co-administration of albendazole-ivermectin treatment. In case of confirmed loiasis hyper-endemicity alternative treatment schemes should be considered.

There were two studies which reported on the safety of the co-administration of albendazole- ivermectin in pregnant women (Gyapong, Chinbuah, and Gyapong 2003; Ndyomugyenyi et al. 2008). Gyapong et al. (2003) concluded that there is no evidence of a higher risk of congenital malformation or abortions in pregnant compared to non-pregnant women. Ndyomugyenyi et al. (2008) also found that the mean birth rate, the proportion of babies with low birth rate and the number of still births were not significantly associated to the different treatments (ivermectin and albendazole alone and co-administered).

In summary, it has been shown that the co-administration of albendazole-ivermectin causes some adverse effects but the vast majority is mild. Although not significant, we found a higher number of adverse effects reported when ivermectin is added to albendazole. However, it is important to mention that three of the studies evaluated another indication, whereas only one focused on STH-infected individuals. The latter study does not show any additional side effects from adding ivermectin to the standard albendazole treatment which indicates that, as previously mentioned, the adverse effects when administering ivermectin are mostly associated to W. bancrofti infections.

10.5 Reports for ivermectin in the WHO global database of reports of adverse drug reactions (VigiBase)

There were a total of 1656 reports for ivermectin in VigiBase (out of a total of over 14 million reports in the database). Reports in males and females were of similar proportions. The majority of reports were in adults aged 18 years and older. The most common indication for ivermectin was rosacea (137), filariasis (167), onchocerciasis (108), scabies (102), acarodermatitis (92), strongyloidiasis (59). For reports that contained both ivermectin and albendazole the most commonly reported indication was filariasis (117).

Reports originated from a total of 37 countries, mainly Africa and the Americas. The majority of reports originated from Sierra Leone (461), USA (460), France (198), Ghana (152) and Democratic Republic of Congo (102). Of the 1656 reports, 525 (31.7%) contained both ivermectin and albendazole, which mostly originated from Sierra Leone (397). Sierra Leone has a rigorous active pharmacovigilance component to their large-scale drug distribution programmes, which likely explains the higher proportion of reports coming from this country. Between 2007

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and 2015, there have been over 33 million tablets of ivermectin administered with albendazole in the LF programme8. This corresponds to approximately 11 adverse events per one million treatments, without taking into account drugs administered before 2007 or in 2016. All of these reported events were considered minor.

The most commonly reported ADRs for ivermectin alone and ivermectin co-administered with albendazole included pruritus, headache, dizziness, vomiting, rash, urticarial and diarrhoea. These are all known ADRs. Of the 1656 ICSRs, there were a total of 268 different ADRs reported with ivermectin that had a causality assessment. Approximately 2% of ICSRs had an ADR that was judged to have a certain likelihood of being caused by ivermectin. The most common were itching, rash and headache, which are known adverse effects. These same adverse effects were often reported as probable and possible in other reports.

Ivermectin was commonly administered concomitantly with other medications. The most common were albendazole (525), levamisole (35), praziquantel (32), doxycycline (3), paracetamol (23), acetylsalicylic acid (22), amocarzine (22), permethrin (21) and prednisone (21).

In total, 459 reports of ivermectin were reported to have a serious ADR. Sixty three resulted in death. The deaths occurred mainly in individuals aged 18-44 and those greater than 75 years of age. Concomitant medication was frequently administered and included albendazole (12), ceftriaxone (8), metronidazole (8), vancomycin (8), ciprofloxacin (7), betamethasone (6), prednisolone (6) and digoxin (5). The most frequent ADRs reported in cases that resulted in death include: Strongyloidiasis (16), drug ineffective (7), pneumonia (7), pyrexia (7), multiple organ dysfunction syndrome (5), acute respiratory distress syndrome (4), cardiac arrest (4), septic shock (4), Stevens-Johnson syndrome (4), thrombocytopenia (4), and toxic epidermal necrolysis (4).

Two deaths were in individuals under 18 years of age, both occurring in the U.S. The timing of exposure was not reported in either case. In one report, the ADR was indicated as still birth, however the age of the infant was reported to be six months. Twelve other suspected drugs were also listed in this case. A second case of death occurred in a 6-year old child. No other suspected or concomitant drugs were listed, but a number of other suspected ADRs were reported, such as abnormal behaviours, agitation, cerebral disorder. The indication was not reported and the reported date of death occurred prior to the reported date of ivermectin, indicating a possible reporting error.

8 Reference: WHO PCT databank - http://www.who.int/neglected_diseases/preventive_chemotherapy/lf/en/

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

Overall, there were mostly minor and transient ADRs associated with ivermectin use, alone or in combination with albendazole. Causality assessments were infrequently reported; however, of these reports, few were considered to have a certain likelihood of being caused by ivermectin, and all were minor events. Some reactions were consistent with those expected with treatment for onchocerciasis or LF (i.e. related to the effect on microfilariae). The use of concomitant drugs and the types of ADRs reported in cases of death indicate probable causes other than the drug itself (e.g. related to other drugs, diseases, or in the case of Strongyloidiasis, hyperinfection); however, it is clear that proper assessment of the health status of individuals before treatment to exclude sick individuals, as recommended (WHO 2006), is essential.

Overall evidence of safety:

 Over one billion treatments of ivermectin alone or co-administered with albendazole have been delivered in large-scale preventive chemotherapy programmes against lymphatic filariasis and onchocerciasis since 2000.  Adverse events associated with ivermectin treatment are primarily minor and transient and associated with the baseline infection status and intensity of infection.  Adverse event occurrence is similar with ivermectin co-administered with albendazole compared to albendazole alone.  No serious adverse events have been reported in the published literature with the exception of IVR administration in loasis patients.  As a precaution, ivermectin should not be administered to children less than 90 cm or weighing less than 15 kg, pregnant women, lactating women in the first week after birth, severely ill individuals.  The geographical distribution of Loa-Loa is well known and those areas should be excluded from large scale programme.

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

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

The cost for a package of 100 tablets of 3 mg ivermectin is $2.96 (USD 2013). The unit price is

0.0296 per tablet9.

11.2 Resource use and comparative cost-effectiveness

Large-scale treatment of soil-transmitted helminth infection is associated with low costs, as distribution of drugs can be incorporated into existing infrastructure, can be undertaken by non- health personnel, and does not require screening. Costs include those associated with training, surveys, development of health education campaigns, drug storage, etc. For distribution of albendazole or mebendazole to school-age children through school-based programmes, the mean cost of treatment per child has been calculated to be 0.30 US$ (Joseph et al. 2016). This cost increases to 0.63 US$ for treating an individual through mass drug administration with community treatment. Overall costs of programmes can vary depending on the age of the programme, the use of volunteers and non-health personnel, and the population size being treated (Goldman et al. 2007). Costs can also be reduced by integrating the delivery of drugs for multiple different diseases. Adding ivermectin to albendazole that is already being delivered on a large-scale will involve only marginally increased costs (i.e. those associated with ivermectin purchase), and will result in ancillary benefits for strongyloidiasis in co-endemic areas. In areas with LF and onchocerciasis programmes, these costs can be even further reduced. Financial unit costs for integrated treatment of NTDs is generally found to be less than 0.50 US$ when treatment is provided to at least 100,000 people (Fitzpatrick et al. 2016; WHO 2015a).

Regulatory information 12. Summary of regulatory status of the medicine

12.1 Regulatory approval

Regulatory information for 3 mg tablet of ivermectin:

Regulatory authority Company name (Product) Approval date Reference

US Food and Drug Edenbridge Pharmaceuticals 24/10/2014 http://www.accessdata.fda.gov/scripts/

Administration (Ivermectin) cder/daf/index.cfm?event=overview.pr

9Reference:http://erc.msh.org/dmpguide/resultsdetail.cfm?language=English&code=IV3T&s_year=2013&year =2013&str=3%20mg&desc=Ivermectin&pack=new&frm=TAB- CAP&rte=PO&class_code2=06.1.2.&supplement=&class_name=%2806.1.2.%29Antifilarials%3Cbr%3E)

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

ocess&ApplNo=204154

European Medicines N/A (approval for human use N/A N/A

Agency as a cream for rosacea

treatment only)

Australian Government, Merck Sharpe & Dohme Pty 13/05/2011 https://www.ebs.tga.gov.au/servlet/xm

Department of Health Ltd (Stromectol ®) lmillr6?dbid=ebs/PublicHTML/pdfStore.

nsf&docid=0572793A4C651000CA257F

8E00421437&agid=%28PrintDetailsPubl

ic%29&actionid=1

Japanese Pharmaceuticals Banyu Pharmaceutical Co., 12/2002 http://www.pmda.go.jp/files/00015317 and Medical Devices Ltd (Stromectol ®) 8.pdf#page=8

Agency

Health Canada N/A (approval for human use N/A N/A

as a cream for rosacea

treatment only)

12.2 Existing or planned listing on the WHO list of prequalified medical products

There is currently a donation programme from Merck (i.e. Mectizan donation programme) to provide ivermectin for onchocerciasis and LF elimination. There will be insufficient donated product, however, to be used to treat STH. There are no current prequalified products for ivermectin listed; however, ivermectin (3 mg tablet (unscored)) was listed in the 4th Invitation for submission of Expression of Interest (EOI) for the WHO Prequalification of Medicines Programme (July 2015). Inclusion in the EML and EMLc will assist in increasing interest in this area. Appropriate expertise and experience is already in place within the Department of Control of Neglected Tropical Diseases to work with generic pharmaceutical companies interested in producing ivermectin and to appropriately guide them through the prequalification process. This will be an essential step in order to have sufficient ivermectin

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Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

for STH control programmes, particularly for school-age children, and increase availability for clinical use.

13. Availability of pharmacopoeial standard Ivermectin is currently included in: i) The British Pharmacopoeia (https://www.pharmacopoeia.com/Catalogue/Preview?uri=%2Fcontent%2Ffile%2Fp roducts%2Fleaflets%2FBPCRS%20Leaflet_Cat%20864_BPCRS3549_2.pdf) ii) The United States Pharmacopoeia (http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/ivermectinTablets.pdf) iii) The European Pharmacopoeia

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14. Reference list

Ackerman, S. J., G. M. Kephart, H. Francis, K. Awadzi, G. J. Gleich, and E. A. Ottesen. 1990. 'Eosinophil

degranulation. An immunologic determinant in the pathogenesis of the Mazzotti reaction in

human onchocerciasis', J Immunol, 144: 3961-9.

Addiss, D. G., M. J. Beach, T. G. Streit, et al. 1997. 'Randomised placebo-controlled comparison of

ivermectin and albendazole alone and in combination for Wuchereria bancrofti

microfilaraemia in Haitian children', Lancet, 350: 480-4.

Albonico, M., H. Allen, L. Chitsulo, D. Engels, A. F. Gabrielli, and L. Savioli. 2008. 'Controlling soil-

transmitted helminthiasis in pre-school-age children through preventive chemotherapy',

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