The Expert Committee recommended listing of sulfadoxine + pyrimethamine
250 mg + 12.5 mg fixed-dose combination tablet on the core list of the EMLc
for the new indication of intermittent preventive treatment (of malaria) in
infancy (IPTi) on the basis of demonstrated efficacy and acceptable safety, and
in alignment with WHO malaria guideline recommendations.
The Expert Committee noted the lack of evidence of the impact of the
use of SP-IPTi on antimicrobial resistance, and encouraged further assessment
and monitoring in this regard within programme delivery.
The application requested listing of sulfadoxine + pyrimethamine fixed-dose
combination tablet on the core list of the EMLc for the new indication of
intermittent preventive treatment (of malaria) in infancy (IPTi).
Sulfadoxine + pyrimethamine 500 mg + 25 mg tablets are currently included on
the EML and EMLc for use in combination with artesunate 50 mg for the curative
treatment of malaria.
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.
The application presented the findings of a pooled analysis of six randomized,
placebo-controlled trials in 7930 infants that investigated the efficacy and safety
of IPTi with sulfadoxine + pyrimethamine (IPTi-SP) in four African countries
with moderate to high transmission of malaria, when administered to infants at
the time of routine vaccination according to the WHO Expanded Programme
on Immunization (EPI) (2).
From the pooled analysis, the combined estimate of protective efficacy
of IPTi-SP against clinical malaria in infants aged up to 1 year of age was 30.3%
(95%CI 19.8% to 39.4%, p<0.0001).
IPTi-SP was also associated with protective efficacy in infants up to 1 year
of age for anaemia (21.3% (95%CI 8.3% to 32.5%, p=0.002)), all-cause hospital
admissions (22.9% (95%CI 10.0% to 34.0%, p=0.001)), and hospital admissions
associated with malaria parasitaemia (38.1% (95%CI 12.5% to 56.2%, p=0.007)).
SP for intermittent preventive treatment in infancy is generally well tolerated.
Studies showed no evidence of any adverse effects of SP-IPTi on infants’
serological responses to vaccines (e.g. DTP, polio, hepatitis B, Haemophilus
influenzae B, yellow fever or measles). A rebound effect in terms of greater
susceptibility to malaria after termination of SP-IPTi, although reported in some
studies, was not found in the pooled analysis, where the pooled estimate of
protective efficacy of IPTi-SP against clinical malaria for the potential rebound
period was 9.5% (95%CI 0.3% to 17.8%, p=0.044) (2).
Surveillance of molecular markers of SP resistance should accompany
SP-IPTi, in particular the distribution and prevalence of Pfdhps 540 mutations,
which is a surrogate measure of SP efficacy.
Use pf IPTi-SP is contraindicated in individuals with known
hypersensitivity to pyrimethamine, sulfonamides and related compounds and
infants receiving a sulfa-based medication for treatment or prophylaxis, including
co-trimoxazole (trimethoprim–sulfamethoxazole), which is widely used as
prophylaxis against opportunistic infections in HIV-infected infants.
A 2011 systematic review of the cost and the cost-effectiveness of malaria
interventions found that the median financial cost of IPTi-SP for protecting one
person for one year was US$ 0.60 (range US$ 0.48 to US$ 1.08) (3).
A study by Conteh et al of the cost-effectiveness of IPTi in sub-Saharan
Africa found the cost per malaria episode averted for IPTi-SP was very low,
US$ 1.36 to US$ 4.03 based on trial specific data (US$ 0.68 to US$ 2.27 on pooled
analysis). The authors concluded that IPTi delivered with the EPI was a highly
cost-effective intervention against clinical malaria (4).
Cost / cost effectiveness
No information was provided in the application.
A 2010 WHO policy recommendation on IPTi-SP recommends the coadministration
of SP-IPTi with DTP2, DTP3 and measles immunization to
infants, through routine EPI in countries in sub-Saharan Africa, in areas with
moderate-to-high malaria transmission (i.e. annual entomological inoculation
rates ≥10), and where parasite resistance to SP is not high – defined as a
prevalence of the pfdhps 540 mutation of ≤50% (5).
This recommendation was not re-evaluated during the guideline
development process for the 2015 WHO Guidelines for the treatment of malaria
(3rd edition). The same recommendation is included in the 2015 Guidelines,
however the quality of evidence was not formally assessed (6).
A paediatric formulation of sulfadoxine + pyrimethamine 250 mg + 12.5 mg is
currently under assessment by the WHO Prequalification Programme.
The administered dose of IPTi-SP depends on the weight of the child:
■ Children weighing less than 5 kg should be given 125 mg sulfadoxine
and 6.25 mg pyrimethamine.
■ Children weighing 5 kg or more should be given 250 mg sulfadoxine
and 12.5 mg pyrimethamine.
The successful implementation of SP-IPTi requires that national malaria control
and EPI programmes work together. WHO, working with UNICEF developed an
implementation guide which provides the necessary technical and operational
information and tools for country-level policy-makers and programme managers
to decide on how to include SP-IPTi with immunization services (7). In areas
where SP-IPTi is implemented each child will be given SP three times in their
first year of life when they receive routine vaccinations as follows:
■■ First SP-IPTi dose (SP-IPTi1) when DTP2/Penta2 (or combo)
vaccination is given (i.e. 8-10 weeks of age)
■ Second SP-IPTi dose (SP-IPTi2) when DTP3/Penta3 (or combo)
vaccination is given (12-14 weeks of age)
■ Third SP-IPTi dose (SP-IPTi3) at the time of measles vaccination
The exact timing of the doses may vary according to the national
immunization schedule for DTP and measles vaccination.
1. World Malaria Report 2018. Geneva: World Health Organization; 2018. Available from https://
apps.who.int/iris/bitstream/handle/10665/275867/9789241565653-eng.pdf?ua=1, accessed 29
2. Aponte JJ, Schellenberg D, Egan A, Breckenridge A, Carneiro I, Critchley J et al. Efficacy and safety of
intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants:
a pooled analysis of six randomised, placebo-controlled trials. Lancet. 2009;374(9700):1533–42.
3. White MT, Conteh L, Cibulskis R, Ghani AC. Costs and cost-effectiveness of malaria control
interventions--a systematic review. Malar J. 2011;10:337.
4. Conteh L, Sicuri E, Manzi F, Hutton G, Obonyo B, Tediosi F et al. The cost-effectiveness of
intermittent preventive treatment for malaria in infants in Sub-Saharan Africa. PLoS One. 2010;
5. WHO Policy recommendation on Intermittent Preventive Treatment during infancy with
sulphadoxine-pyrimethamine (SP-IPTi) for Plasmodium falciparum malaria control in Africa.
Geneva: World Health Organization; 2010. Available from https://www.who.int/malaria/news/
WHO_policy_recommendation_IPTi_032010.pdf, accessed 29 September 2019.
6. 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?ua
=1&ua=1, accessed 29 September 2019.
7. Intermittent preventive treatment for infants using sulfadoxine-pyrimethamine (SP-IPTi) for
malaria control in Africa: Implementation Field Guide. Geneva: World Health Organization; 2011.
Available from https://apps.who.int/iris/bitstream/handle/10665/70736/WHO_IVB_11.07_eng.
pdf, accessed 29 September 2019.