- Malaria is an infectious disease caused by microorganisms of the genus Plasmodium and is prevalent in tropical and sub-tropical parts of the world.
- Humans are usually infected by four Plasmodium species namely P. falciparum, P. vivax, P. ovale and P. malariae.
- Mixed infections are not uncommon, though underestimated by routine microscopy, and occasional infections with monkey malaria parasites, such as P. knowlesi, are known to occur.
- The parasite is carried to humans through a very effective vector, the female Anopheles mosquito.
- The distribution of these mosquitoes is closely related to the ecology of an area.
- Normally, adult mosquitoes rest during the day inside human habitats and emerge to feed at night, during which feeding malaria parasites are transferred from the salivary glands of these mosquitoes to the human blood stream.
- Disease control strategies have targeted both mosquitoes and the parasite using insecticides and medicines respectively e.g. Permethrin- and alphacypermethrin-treated bed nets and curtains.
- Malaria is an important cause of death and illness in children and adults in endemic countries with mortality, estimated at about two (2) million people per year.
- Of these deaths, the overwhelming majority is among children aged 5 years or younger in rural sub-Saharan Africa,
Symptoms of malaria
- Typical symptoms of malaria include headache, lassitude, fatigue, abdominal discomfort and muscle and joint aches; followed by fever, chills, perspiration, loss of appetite, vomiting and worsening malaise. These symptoms usually appear between 10 and 15 days after an infective mosquito bite.
- The first symptoms are non-specific and similar to those of minor systemic viral illnesses. Malaria is therefore frequently over-diagnosed on the basis of symptoms alone.
- Cerebral malaria, metabolic acidosis, severe anaemia, hypoglycaemia and, in adults, acute renal failure or acute pulmonary oedema may occur as a result of malaria
- Mortality after administering treatment following cerebral malaria is 10-20%.
- Malaria is mostly diagnosed clinically based on symptoms presented by the patient. The current WHO guidelines for managing malaria strongly call for proper diagnosis using microscopy or rapid diagnostic tests, where these are available.
- Parasitological diagnosis, which is more definite, involves one of the following:
- Microscopy involving identification of species, determination of parasite density as well as stage of parasite development
- Rapid diagnostic tests (RDT) based on immunochromatographic techniques
- Molecular technique: The use of Polymerase Chain Reaction (PCR)
 Guidelines for the treatment of malaria. Geneva, World Health Organization, 2010. Available at http://www.who.int/malaria/publications/atoz/9789241547925/en/index.html(accessed on 10th January 2011).
Steady Progress against Killer. Ghana Malaria Action Alert, National Malaria Control Programme; Ghana Health Service & the Voices for Malaria-free Future Program, 2007, 1(1).
 Guidelines for the treatment of malaria. Geneva, World Health Organization, 2010.
 Skarbinski j, Ouma PO, Causer LM, Kariuki SK, Barnwell JW et al. Effect of malaria rapid diagnostic tests on the management of uncomplicated malaria with artemether-lumfantrine in Kenya: a cluster randomized trial. American Journal of Tropical Medicine and Hygiene, 2009, 80:919-926.
 Guidelines for the Treatment of Malaria, Geneva, World Health Organisation, 2010.
The Global Malaria Programme of the World Health Organization regularly publishes a comprehensive guideline for the management of malaria. The document, called Guidelines for the Treatment of Malaria, is freely available from the WHO website and can also be accessed through the link below.
The current version of the WHO Guidelines for Treating Malaria recommends the following as the first-line treatments for uncomplicated falciparum malaria: a combination of two or more antimalarial medicines with different mechanisms of action. Artemisinin Combination Therapies (ACTs) are the recommended treatments for uncomplicated falciparum malaria. The artemisinin derivative components of the combination must be given for at least three days for an optimum effect.
The following ACTs are recommended:
- artemether plus lumefantrine
- artesunate plus amodiaquine
- artesunate plus mefloquine
- artesunate plus sulfadoxine-pyrimethamine, and
- dihydrortemisinin plus piperaquine.
Fixed-dose combinations are highly preferable to the loose individual medicines co-blistered or co-dispensed.
The choice of ACT in a country or region will be based on the level of resistance of the partner medicine in the combination: in areas of multidrug resistance (east Asia), artesunate plus mefloquine, or artemether plus lumefantrine or dihydroartemisinin plus piperaquine are recommended; and in other areas without multidrug resistance (mainly Africa), any of the ACTs including those containing amodiaquine or sulfadoxine-pyrimethamine may still be effective.
Artemisinin and its derivatives should not be used as monotherapy.
The increasing resistance of the malaria parasite to established antimalarials like chloroquine and sulphadoxine-pyrimethamine (SP) led to the search for newer therapies to treat malaria. Currently, the global recommendation for the treatment of uncomplicated malaria is the use of use artemisinin-based combination therapies (ACTs). Artemisinin derivatives have been used for centuries in China and the Far East but they have only recently been deployed for use in ACTs and in several parts of the world. The information database on the safety of ACTs is quite thin and the safety profiles of artemisinins in particular and ACTs in general are not very well known in several populations and patient groups. There is little information on the safety of ACTs in pregnant women, children, the elderly and those with co-morbidities. The interactions between ACTs and medicines for HIV/AIDS and Tuberculosis are not known. The influence of genetic conditions like glucose-6-phosphate dehydrogenase (G6PD) deficiency and sickle cell disease on the disposition of ACTs is unknown. These factors make the need for safety monitoring of ACTs in all populations extremely urgent and overwhelming.
Each country or health system must have a PV system deployed to monitor the safety of all antimalarials. Pharmacovigilance systems for antimalarials may be initiated by National Malaria Control Programmes either alone or, preferably, in conjunction with national drug regulatory authorities and local hospitals. Whilst the system would be designed to focus on antimalarials, it should monitor the safety of all medicines since patients on antimalarials are likely to be taking other medicines concomitantly either to treat the other symptoms of malaria (e.g. analgesics, haematinics, antibiotics) or to treat other acute or chronic conditions. The final decision on where to locate the Pharmacovigilance for Antimalarial Programme is a matter of national priority. This Toolkit provides guidance on malaria specific issues and also links the practitioner to the wider PV Toolkit which provides detailed information on all the basic aspects of setting up and running a PV system.
For countries applying for support from the Global Fund against HIV/AIDS and TB, provision has been made for specific support towards PV. Countries therefore have the opportunity to utilise the resources of the Global Fund to establish and/or strengthen their PV systems for antimalarials.
Antimalarial medicines, like all other medicines, do have adverse events associated with their use. WHO discusses methods for collecting information related to adverse events and adverse reactions to antimalarial medicines in its publication “A practical handbook on the pharmacovigilance of antimalarial medicines”. A basic handbook for the management of adverse reactions to antimalarials has been developed by the Centre for Tropical Clinical Pharmacology & Therapeutics of the University of Ghana Medical School with financial support from the Centres Disease Control and Prevention (CDC), the Global Fund, the World Health Organization and the National Malaria Control Programme of Ghana. The handbook can be downloaded using this link. It can be adopted and amended for use by other countries provided due acknowledgement is made.
Who are potential partners and their roles in implementing pharmacovigilance of antimalarials?
The following table illustrates what could be the role of different potential Partners in PV for antimalarials:
|PotentialPartners||Category||Example of Core Activities|
|Country agencies (PV Centre, Drug regulatory authority, National Malaria Control Program) and Health Care Workers||Policy makers and implementers||Program management and implementation, running the national PV system.|
|Patients and clients alliances||Main beneficiaries||To participate in selected PV activities.|
|The Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund)||Financing Entity||To sponsor in-country PV activities within the major Global Fund supported programmes.|
|The World Health Organization (WHO)||Normative and lead technical agency||To define norms and tools (e.g. the PV toolkit, minimum PV requirements), to coordinate and to deliver technical support|
|The Uppsala Monitoring Centre, WHO-CC for PV,WHO-CC for Advocacy and Training in PV||WHO collaborating centres on PV||To provide technical expertise on drug monitoring tools; to assist WHO in delivering quality Technical Assistance (TA); to train country staff; to advocate for PV.|
|Roll Back Malaria Partnership (RBM)||Partnerships to enhance collaborations between organisations||To participate in the coordination of the fight against malaria, ensuring synergies and coherencies exist between disease specific PV efforts and transversal ones.|
|UNITAID||Financing entity||To co-fund specific PV activities.|
|U.S. President’s Emergency Plan for AIDS Relief (PEPFAR, with PMI)||Financing entity with technical Partners||To co-fund specific PV activities, to facilitate the delivery of technical assistance by its implementing partners.|
|The Bill & Melinda Gates Foundation||Financing entity||To co-fund specific PV activities, to advocate at high level about the need for PV|
|The World Bank (WB)||Financing entity||To co-fund specific PV activities|
|European Union (EU)||Financing entity||To co-fund specific PV activities (e.g. regional CEM), to facilitate delivery of technical assistance.|
|Medicines for Malaria Venture (MMV)||Technical agency interfacing with academic institutions and pharmaceutical companies||To facilitate the setting-up of active surveillance processes (e.g. CEM) in some countries in collaboration with manufacturers.|
|European Medicines Agency (EMEA),Medicines and Healthcare Regulatory Agency (MHRA), Agence française de sécurité du médicament (AFSM)||Regulators and Northern PV agencies||To accompany (twinning/mentoring) selected countries?|
|Clinton Health Access Initiative (CHAI)||Technical agency interfacing with different stakeholders||To fund and/or co-organize and/or participate in PV efforts?|
|Médecins Sans Frontières (MSF)||Technical agency with financing and direct implementation activities||To provide specific support to some countries; to participate in the global advocacy for PV enhancement.|
|Management Sciences for Health (MSH)(under USAID funded-SIAPS program)||Technical agency||To accompany (mentoring) selected countries, to propose (and potentially, to test) innovative methods of notification. To share its PV tools, to co-sponsor/co-organize the PV stakeholder workshops…|
|Universities and Scientists||Technical experts and organisations||To accompany (mentoring) countries|
|Manufacturers||Funder, Technical support||To share their ICSR and methodologies, to provide financial and/or technical resources and/or technical advice to conduct special activities (roll-out of risk management plan in a few selected countries.)|
What is the Global Fund?
The Global Fund, as an organization with the mission ‘to attract, manage and disburse additional resources through a new public/private partnership’ (hereby a ‘financing entity’), is relying on a variety of partners to successfully develop, implement and mature its strategy on PV.
In general, this Global Fund strategy on PV will be co-developed by the Global Fund and WHO with strong inputs from countries and other partners, each stakeholder taking advantage of the other’s skills. The Global Fund will propose to other Global Health Initiatives (GHI) to join and co-own this initiative, so it could become a GHI strategy on PV.
What are the objectives of national pharmacovigilance system as supporting intervention of Affordable Medicines Facility – malaria (AMFm)?
1. Overall objective: To develop or strengthen the national pharmacovigilance system to monitor, assess and improve the safety of ACT provided by the AMFm programme
2. Specific objectives:
a) To monitor the risk for adverse drug reactions associated with ACT made available through the AMFm programme and supplied by
a. The public sector,
b. The for-profit private sector or
c. The not-for-profit private sector (e.g. Non-governmental and faith-based organizations);
b) To build a strategy for communication and feedback with health-care professionals and the public about the safe use of ACT, based on information generated through the pharmacovigilance system;
c) To monitor and assess the quality of the components of the pharmacovigilance system; and
d) To monitor the safety of ACT in pregnancy by setting up or strengthening a pregnancy register at selected sites (where feasible).
Monitoring and evaluation will be required to determine the effectiveness of these interventions, to ensure that there is no under-treatment of severe malaria cases, delayed or non-referral of severe cases or misdiagnosis. Information and communication campaigns will be run to encourage the population to seek early treatment and to increase demand for high-quality, affordable, subsidized ACT.
What should be the strategy for pharmacovigilance of antimalarials?
A country’s pharmacovigilance strategy should take into consideration:
- Patient factors, such as the population at risk for the disease, potential complications of treatment and treatment-seeking behaviour for fever and suspected malaria;
- The health-care conditions in which the medicines are used, including available human and financial resources, diagnostic capacity, potential for investigating suspected adverse drug reactions, the patient referral system and existing pharmacovigilance activities;
- The epidemiology, diagnosis and clinical manifestations of malaria; and
- The effectiveness and safety of current antimalarial medicines and issues associated with an increased supply and use of act in the private sector.
Please refer to the lists of literature resources in Chapter 11.1 of the main PV Toolkit.