Academic journal article Bulletin of the World Health Organization

Ascertainment of Risk of Serious Adverse Reactions Associated with Chemoprophylactic Antimalarial Drugs

Academic journal article Bulletin of the World Health Organization

Ascertainment of Risk of Serious Adverse Reactions Associated with Chemoprophylactic Antimalarial Drugs

Article excerpt

Ascertainment of risk of serious adverse reactions associated with chemoprophylactic antimalarial drugs


Because of chloroquine-resistance in Plasmodium falciparum, other potentially more toxic drugs were introduced for the prevention and treatment of malaria infections. When resistance to chloroquine was first reported, there was nothing to indicate that the new drugs could be hazardous and guidelines for treatment and prophylaxis were soon changed to include them. When adverse reactions to these new drugs were first published in the early 1980s, malaria specialists were largely unprepared and unable to determine the significance of these alerts. Measurements of the rates of serious drug reactions to pyrimethamine/sulfadoxine varied widely between 1:5000 to 1:8000 in the USA [1] and 1:150 000 in Switzerland [2], and it was unclear whether these data reflected a true difference or resulted from incompatible study designs and other flaws. WHO therefore called a series of meetings to resolve the conflict arising from ambiguous results, and to propose a rational procedure for formulating malaria prevention guidelines (89). While the differences in rates between countries could not be explained, the meetings promoted greater awareness of the need to quantify risks and benefits associated with malaria and its prevention [3] and it was realized that more refined epidemiological studies were required to determine the risks. (a)

As a result of all this experience, drugs which may cause serious reactions are now reserved for those at highest risk of severe infection. However, since the degree and intensity of transmission of resistant strains will increase, there will be continued interests to explore the differences of potentially toxic drugs [4-6]. Furthermore, data generated from studies of risk will be integrated more frequently into modelled analyses [7]. We here report the main serious adverse reactions associated with recently used antimalarial drugs, taking into account the scientific criteria and methodological issues that influence risk ascertainment, and suggest how morbidity and mortality associated with the use of potentially toxic chemoprophylactic drugs can be minimized.


Adverse drug reactions

An adverse drug reaction is defined as any drug action that is not of diagnostic, therapeutic, or prophylactic benefit to the user.

Seriousness. Reactions associated with chemoprophylactic drugs must be differentiated into nonserious and serious reactions. The former may cause transient impairment and may compromise compliance with chemoprophylaxis. Such reactions which are particularly associated with proguanil, include nausea and vomiting, mouth ulcers [8-11], and loss of hair [12]. They deserve study to help avert poor compliance which may lead to an increased risk of malaria infection. This paper, however, focuses on serious reactions--defined as fatal, life-threatening, disabling or incapacitating. A list of adverse reactions defined as serious by the Committee on Safety of Medicines (in the United Kingdom) has recently been published [13]. The chemoprophylactic drugs associated most frequently with serious reactions are pyrimethamine/sulfadoxine, pyrimethamine/dapsone and amodiaquine. Drugs recently employed (mefloquine, doxycycline) have not yet been comprehensively monitored.


Adverse reactions may be classified according to a number of clinical and biological criteria [14]. reactions are more frequently subdivided as dose-dependent, dose-independent and pseudo-allergic. The majority of serious reactions associated with antimalarial drugs are dose-independent hypersensitivity reactions. Dose-dependent reactions may, however, occur in the following situations:

(i) Changes in the drug formulation of either the active ingredient or the excipients.

(ii) Route of administration--influencing the uptake and distribution of the drug. …

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