The Expert Committee recommends the addition of co-packaged amodiaquine
with sulfadoxine + pyrimethamine to the core list of the EMLc for seasonal
malaria chemoprevention in children on the basis of acceptable safety and
demonstrated benefits for reducing clinical malaria episodes, serious malaria
episodes and reduced rates of mortality and anaemia, and in alignment with
WHO malaria guidelines.
The Expert Committee noted the lack of evidence of the impact of the
use of amodiaquine with sulfadoxine + pyrimethamine for SMC on antimicrobial
resistance, and encouraged further assessment and monitoring in this regard
within programme delivery.
The application requested the addition of co-packaged amodiaquine with
sulfadoxine + pyrimethamine to the core list of the EMLc for seasonal malaria
chemoprevention (SMC) in children.
Amodiaquine and sulfadoxine + pyrimethamine are both listed on the EMLc for
use in combination with artesunate for the curative treatment of malaria. These
medicines have not previously been considered for use in malaria prophylaxis/
Public health relevance
Malaria is one of the leading causes of illness, death and lost economic
productivity globally. In 2017, there were an estimated 219 million malaria
cases worldwide, the majority of which occurred in the African region (92%,
200 million cases) (1). Of the 435 000 deaths due to malaria globally in 2017,
266 000 (61%) were in children under 5 years of age.
Across the Sahel sub-region in Africa, most childhood morbidity and
mortality from malaria occurs during the rainy season, which is generally
short. Giving effective antimalarial medicines – at full treatment doses and at
appropriate intervals during this period – has been shown to prevent illness and
death from malaria in children.
The interventions currently recommended by WHO for the control of
malaria are use of long-lasting insecticidal mosquito nets and/or indoor residual
spraying for vector control, prompt access to diagnostic testing of suspected
cases and treatment of confirmed cases with effective artemisinin-based
combination therapy. In addition to these, other interventions recommended
for specific high-risk groups in areas of high transmission include intermittent
preventive treatment in pregnancy (IPTp) and infancy (IPTi). With the changing
epidemiology of malaria, there has been a progressive shift from a ‘one size fits
all’ approach to targeting malaria control strategies to specific populations and/
or locations for maximal effectiveness. In line with this approach and on the
basis of new evidence, WHO recommends an additional intervention against
Plasmodium falciparum malaria: seasonal malaria chemoprevention (SMC). The
objective of preventive treatment is to prevent malarial illness by maintaining
therapeutic drug levels in the blood throughout the period of greatest risk (2).
A 2012 Cochrane systematic review of seven trials (12 589 participants) evaluated
the effects of seasonal malaria chemoprophylaxis compared with no prophylaxis
in children aged 6 years or less living in areas of West Africa with seasonal
malaria transmission (3). In three studies, amodiaquine (AQ) and sulfadoxine
+ pyrimethamine (SP) was administered monthly at full treatment doses, two
studies used SP every two months, and one study used SP and artesunate
monthly, during the malaria transmission season.
In comparison with no chemoprophylaxis, SMC was associated with
markedly reduced clinical malaria episodes (rate ratio (RR) 0.26, 95%CI 0.17
to 0.38) and serious malaria episodes (RR 0.17, 95%CI 0.1 to 0.76). SMC may
also be associated with a reduction in mortality (RR 0.66, 95%CI 0.31 to 1.39)
and a reduction in moderately severe anaemia (RR 0.71, 95%CI 0.52 to 0.98).
The findings were consistent in trials in which there was high (>90%) use of
insecticide-treated bednets (3).
AQ + SP are safe and well tolerated when used at the recommended doses and
regimens. Both drugs have been used for decades for malaria treatment, and SP
is currently used for intermittent preventive treatment of malaria in pregnancy
and in infancy.
Both AQ and SP are also used in combination with artesunate as
artemisinin-based combination therapy, which is used for the treatment of
uncomplicated malaria in many endemic countries.
In Senegal, where nearly 800 000 treatment courses of SP + AQ within
SMC have been given to children, no serious adverse events attributable to these
drugs were observed during intensive pharmacovigilance based on spontaneous
AQ + SP is generally well tolerated in children. Mild side-effects may
occur, of which the most common is vomiting associated with intake of AQ.
No serious adverse events attributable to AQ + SP have been reported in trials
involving children (5–7).
SMC with AQ + SP is contraindicated in children receiving sulfabased
medication for treatment or prophylaxis, including sulfamethoxazole
+ trimethoprim, which is widely used as prophylaxis against opportunistic
infections in HIV-infected infants.
Cost / cost effectiveness
Evaluation of the cost of delivering SMC in large field trials shows that the
greatest costs are associated with delivering the drugs and the incentives paid to
health workers. In Gambia, the cost of SMC delivery by village health workers
was estimated to be US$ 1.63 per child per year (9). In Senegal, where SMC was
delivered by community health workers paid a daily rate and supervised by the
health post nurse, the overall cost at 46 health posts was estimated to be US$ 0.5
per child per month, or approximately US$ 1.50 per child per year (10). The cost
of SMC is similar to those of other malaria control interventions (11).
The 2015 WHO Guidelines for the treatment of malaria recommend SMC with
monthly AQ + SP for all children aged less than 6 years during each transmission
season in areas with highly seasonal malaria transmission in the sub-Sahel
region of Africa (strong recommendation, high quality evidence) (8).
The guideline recommendation was informed by the Cochrane systematic
review mentioned above (3).
Co-packaged sulfadoxine + pyrimethamine and amodiaquine tablets are
currently available on the market from three manufacturers and have been
prequalified by the WHO Prequalification Programme.
1. World Malaria Report 2018. Geneva: World Health Organization; 2018. Available from https://apps.
who.int/iris/bitstream/handle/10665/275867/9789241565653-eng.pdf, accessed 29 September
2. World Health Organization. WHO Policy Recommendation: Seasonal malaria chemoprevention
(SMC) for Plasmodium flaciparum malaria control in highly seasonal transmission areas of the
Sahel sub-region in Africa. March 2012. Available from https://www.who.int/malaria/mpac/
feb2012/smc_policy_recommendation.pdf, accessed 29 September 2019.
3. Meremikwu MM, Donegan S, Sinclair D, Esu E, Oringanje C. Intermittent preventive treatment
for malaria in children living in areas with seasonal transmission. Cochrane Database Syst Rev.
4. Cisse B, Ba EH, Sokhna C, JL ND, Gomis JF, Dial Y et al. Effectiveness of Seasonal Malaria
Chemoprevention in Children under Ten Years of Age in Senegal: A Stepped-Wedge Cluster-
Randomised Trial. PLoS Med. 2016;13(11):e1002175.
5. Dicko A, Diallo AI, Tembine I, Dicko Y, Dara N, Sidibe Y et al. Intermittent preventive treatment
of malaria provides substantial protection against malaria in children already protected by an
insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial. PLoS
6. Konate AT, Yaro JB, Ouedraogo AZ, Diarra A, Gansane A, Soulama I et al. Intermittent preventive
treatment of malaria provides substantial protection against malaria in children already
protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind,
placebo-controlled trial. PLoS Med. 2011;8(2):e1000408.
7. Sokhna C, Cisse B, Ba el H, Milligan P, Hallett R, Sutherland C et al. A trial of the efficacy, safety and
impact on drug resistance of four drug regimens for seasonal intermittent preventive treatment
for malaria in Senegalese children. PLoS One. 2008;3(1):e1471.
8. Guidelines for the treatment of malaria - 3rd edition. Geneva: World Health Organization; 2015.
Available from http://apps.who.int/iris/bitstream/10665/162441/1/9789241549127_eng.pdf,
accessed 29 September 2019.
9. Bojang KA, Akor F, Conteh L, Webb E, Bittaye O, Conway DJ et al. Two strategies for the delivery
of IPTc in an area of seasonal malaria transmission in the Gambia: a randomised controlled trial.
PLoS Med. 2011;8(2):e1000409.
10. Pitt C, Ndiaye M, Conteh L, Sy O, Hadj Ba E, Cisse B et al. Large-scale delivery of seasonal malaria
chemoprevention to children under 10 in Senegal: an economic analysis. Health Policy Plan.
11. Seasonal malaria chemoprevention with sulfadoxine-pyrimethamine plus amodiaquine in
children: a field guide. Geneva: World Health Organization; 2013. Available from https://apps.
who.int/iris/bitstream/handle/10665/85726/9789241504737_eng.pdf, accessed 29 September