21st WHO Expert Committee on the Selection and Use of ...

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)

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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



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



10.5 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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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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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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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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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)


7.1.1 Proposed therapeutic dosage regimen and duration of treatment

A single oral dose of 200g/kg body weight in tablet form, taken in fasting state, with

one glass of water.

7.1.2 Reference to current WHO guidelines

http://www.whocc.no/atc_ddd_index/?code=P&showdescription=yes

http://www.whocc.no/atc_ddd_index/?code=P02

http://www.whocc.no/atc_ddd_index/?code=P02C

http://www.whocc.no/atc_ddd_index/?code=P02CF


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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

http://www.merckmanuals.com/professional/infectious-diseases/nematodes-roundworms/strongyloidiasis

http://www.merckmanuals.com/professional/infectious-diseases/nematodes-roundworms/strongyloidiasis

http://www.cdc.gov/parasites/strongyloides/health_professionals


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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.


7.2.1 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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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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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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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


8.1.1 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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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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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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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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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


9.1.1 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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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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Zaha (2004) involved two cohorts of patients 312 patients in the period 1990-1999 who

were given 110g/kg of ivermectin and 97 patients who received 200g/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 200g/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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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):


19

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

200g/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.


20


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.


21

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.

Study ALB + IVM ALB alone

(or with placebo)

IVM alone (or with placebo)

Studied parasites

Jadad score

Belizario et al., 2003 X X X T. trichiura

A. lumbricoides 2

Ismail et al., 1999 X X T. trichiura 1

Knopp et al., 2010 X X T. trichiura

A. lumbricoides hookworm

4

Speich et al., 2015 X T. trichiura


3

Marti et al., 1996 X T. trichiura


2

Wen et al., 2003 X X T. trichiura hookworm

2

Wen et al., 2008 X T. trichiura


3

Xia et al., 1992 X T. trichiura


1

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)


22

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.


23

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

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

First author, year

Country Main drug(s)

(dosage)

# treated

main drug

# cured main drug

Comparator drug 1

(CD1)

# treat

ed CD1

# cured CD1

Comparator drug 2

(CD2)

# treat

ed CD2

# cured CD2

Main drug

CD1 CD2

CR (%)

ERR (%)

CR (%)

ERR

(%)

CR (%)

ERR

(%)

Belizario 2003

Philippines IVM (200

µg/kg) + ALB (400mg)

149 97 ALB

(400mg) + placebo

149 47 IVM

(200µg/kg) + placebo

154 54 65.1

99.7

31.5

97.2

35.1

98.2

Ismail 1999

Sri Lanka IVM (200 µg

/kg) + ALB (400mg)

53 43 ALB

(400mg) 55 24

81.1

94.9

43.6

70.3

Knopp 2010

Tanzania IVM (200 µg

/kg) + ALB (400mg)

140 53 ALB

(400mg) + placebo

132 13 37.9

91.3

9.8 40.3

Wen 2003

China IVM

(200µg/kg) 34 23

ALB (400mg)

34 16 67.6

47.1

Marti 1996


/kg) NR NR

11.3

58.9*

Speich 2015


/kg) + ALB (400mg)

109 30 27.5

94.5

Wen 2008

China IVM (200 µg

/kg) 102 68

66.7

86.2*

Xia 1992

China IVM (200 µg

/kg) 34 26

76.5


24

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


ivermectin; ALB, albendazole; CR, cure rate; ERR, egg reduction rate; NR, not reported.

First author,

year Country

Main drug(s) (dosage)

# treated main

drug

# cured main drug

Comparator drug 1

(CD1)

# treat

ed CD1

# cured CD1

Comparator drug 2

(CD2)

# treat

ed CD2

# cured CD2

Main drug

CD1 CD2

CR (%)

ERR

(%)

CR (%)

ERR

(%)

CR (%)

ERR

(%)

Belizario 2003

Philippines

IVM (200 µg /kg)

+ ALB (400mg) 105 82

ALB (400mg) +

placebo 99 69

IVM (200 µg/kg) + placebo

102 80 78.1

100 69.7

99.9

78.4

100

Knopp 2010

Tanzania

IVM (200 µg /kg)

+ ALB (400mg) 14 13

ALB (400mg) +

placebo 14 14

92.9

99.9

100 100

Marti 1996

Tanzania

IVM (200 µg /kg)

NR NR 100 100

*

Speich 2015

Tanzania

IVM (200 µg /kg)

+ ALB (400mg) 50 49 98 100

Wen 2008

China IVM (200 µg

/kg) 102 102 100

100*

Xia 1992

China IVM (200µg

/kg) 44 42

95.5


25

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


ivermectin; ALB, albendazole; CR, cure rate; ERR, egg reduction rate; NR, not reported.

First author, year Country Main drug (dosage)

# treated main

drug

# cured main drug

Comparator drug 1

(CD1)

# treat

ed CD1

# cured CD1

Main drug

CD1

CR (%)

ERR

(%)

CR (%)

ERR

(%)

Knopp 2010

Tanzania

IVM (200 µg /kg)

+ ALB (400mg) 30 20

ALB (400mg) +

placebo 39 16

66.7

95.9

59 94

Wen 2003

China IVM (200µg/kg) 34 6 ALB

(400mg) 34 26

17.6

76.5

Marti 1996

Tanzania

IVM (200µg/kg) NR NR 0 0

Speich 2015

Tanzania

IVM (200 µg /kg)

+ ALB (400mg) 42 21 50

95.4

Wen 2008

China IVM (200 µg

/kg) 102 34

33.3

80*

Xia 1992

China IVM (200 µg

/kg) 53 37

11.8


26

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).

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%,

Overall (I-squared = 80.7%, p = 0.006)

Ismail

First author

Knopp

Belizario

81.1

CR of

IVM+ALB

37.8

65.1

43.6

CR of ALB

9.8

31.5 37.57

0.53 (0.37, 0.76)

0.33 (0.18, 0.61)

RR (95% CI)

0.69 (0.60, 0.79)

0.51 (0.40, 0.65)

100.00

19.90

Weight (%)

42.52

IVM+ALB ALB

1 .1 10


27

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


28

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).

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

10.1 Summary of methods

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.


29

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-


30

administered with albendazole have been provided between 2005 and 2015 in the

onchocerciasis programme, some of which is also counted in the number of administrations

for the LF programme; therefore, a sum of the two numbers is not possible. However,

between the two programmes, well over one billion treatments have been provided over the

last 10 years.


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.


31

Table 6. Adverse events associated with ivermectin treatment in strongyloidiasis patients (actively collected)

Side Effects3 Occurrence (%)

Adenusi 2003

Bisoffi 2011

Datry 1994

Gann 1994

Marti4

1996

Suputtamongkol 2008

Suputtamongkol 2011

Naquira 2004

Heukelbach 2004b

Ordoñez 2004

Toma 2000

Zaha 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 pain/discomfort

0 (0%) NR NR 0 (0%) 7 (4%) NR NR 1 (2%) 23 (5%) NR NR NR

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 pain/tightness

NR NR NR NR 7 (4%) NR NR NR NR NR NR NR

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’


32

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 aminotransferase)

NR NR NR NR NR 1 (6%) 1(2%) NR NR NR NR NR

NR = not reccorded

6 Side effects actively collected using standardised questionnaires

7 reported as ‘skin rash or itching’


33

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 110g/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 200g/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.



34

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).


35

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,


36

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.

Study IVM+ALB IVM ALB

# 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.


37

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

/kg

height 150-200 µg

/kg

2x6mg

tablets

150-200 µg

/kg

400 µg /kg 200 µg /kg 200 µg /kg 150 µg /kg 200 µg /kg height 200 µg /kg 150 µg /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

48h

11x within

5 days

48h Every 6h

during 48h

8 days passive during first

24h

48h

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

pain/discomfort

NR 11 (0.07%) pre-treat NR 4 (1.1%) NR NR 21 (14.6%) NR 0 (0.0%) 4 (2%) 13 (12%) NR

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


38

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

pressure/syncope

NR NR NR NR NR NR 0 (0%) NR NR 0 (0.0%) NR NR NR

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


39

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

reaction (SCAR) (e.g. SJS,

TEN, AGEP, DRESS)

NR NR NR NR NR NR NR NR NR NR NR NR NR

any allergic reaction NR NR NR NR NR NR NR NR NR NR NR NS NR

Long term side effects

liver function

abnormalities

NR NR NR NR NR 5 (38.5%) NR NR NR NR NR NR NR

leukopenia NR NR NR NR NR NR NR NR 0 (0.0%) 0 (0.0%) NR NR NR

ALT (alanine

aminotransferase)

NR NR NR NR NR NR NR NR 0 (0.0%) 0 (0.0%) NR NR NR

AST (aspartate

aminotransferase)

NR NR NR NR NR NR NR NR 0 (0.0%) 0 (0.0%) NR NR NR

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

eyes/conjunctivitis

NR 8 (0.05%) NR NR NR NR NR NR NR NR NR NR NR

Mazzotti-type toxicity

(swelling of limbs, face or

NR NR NR 2 (13.3%) NR NR NR NR NR NR NR NR NR


40

groin)

eye pain and lacrimation NR NR NR 2 (13.3%) NR NR NR NR NR NR NR NR NR

tender or swollen lymph

nodes/adenitis

NR 2 (0.01%) NR NR NR NR NR NR 1 3.7%) NR NR NR NR

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

(clinical examination) x x x x x x x x x x x x x

lab events

x

x

x x

day 0 data

x x

x x#

x x

x x

AE significantly associated

to infection status /

intensity (parasite)

x (lf)

x (onc) x (lf)

x (lf)

x (lf)

* 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)


41

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).

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

Overall (I-squared = 75.2%, p = 0.007)

First author

Dunyo

Knopp

Makunde

Addis

0.65 (0.40, 1.06)

RR (95% CI)

0.70 (0.46, 1.07)

0.99 (0.76, 1.29)

0.70 (0.32, 1.55)

0.29 (0.15, 0.57)

100.00

Weight (%)

28.00

32.23

18.40

21.37

ALB+IV

M ALB

1 .1 10


42

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


43

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


44

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/


45

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.

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

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.


46

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

Administration

Edenbridge Pharmaceuticals

(Ivermectin)

24/10/2014 http://www.accessdata.fda.gov/scripts/

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)


47

ocess&ApplNo=204154

European Medicines

Agency

N/A (approval for human use

as a cream for rosacea

treatment only)

N/A N/A

Australian Government,

Department of Health

Merck Sharpe & Dohme Pty

Ltd (Stromectol ®)

13/05/2011 https://www.ebs.tga.gov.au/servlet/xm

lmillr6?dbid=ebs/PublicHTML/pdfStore.

nsf&docid=0572793A4C651000CA257F

8E00421437&agid=%28PrintDetailsPubl

ic%29&actionid=1

Japanese Pharmaceuticals

and Medical Devices

Agency

Banyu Pharmaceutical Co.,

Ltd (Stromectol ®)

12/2002 http://www.pmda.go.jp/files/00015317

8.pdf#page=8

Health Canada N/A (approval for human use

as a cream for rosacea

treatment only)

N/A N/A

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


48

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


49

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',

PLoS Negl Trop Dis, 2: e126.

Albonico, M., S. L. Becker, P. Odermatt, et al. 2016. 'StrongNet: An International Network to Improve

Diagnostics and Access to Treatment for Strongyloidiasis Control', PLoS Negl Trop Dis, 10:

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