Page 39 - 80 guidelines for the treatment of malaria_opt

7. Treatment of uncomplicated P. falciparum malaria

7.8.4 Quality assurance of antimalarial medicines
Artemisinin and its derivatives in particular have built-in chemical instability, necessary for
their biological action, which causes pharmaceutical problems both in the manufacturing
process and in their co-formulation with other compounds. The problems of instability
are accelerated under tropical conditions. The requirement to observe stringent quality
manufacturing standards is particularly important for this class of compounds.
Counterfeit antimalarial tablets and ampoules containing no or minimal amounts of
active pharmaceutical ingredients are also a major problem in some areas. These may
lead to under-dosage, and they may result in fatal delays in appropriate treatment; they
may also give rise to a mistaken impression of resistance, while also encouraging the
development of resistance, especially those delivering a low dose of the antimalarial.
The World Health Organization, in collaboration with other United Nations agencies, has
established an international mechanism to prequalify manufacturers of ACTs on the basis
of compliance with internationally recommended standards of manufacturing and quality.
Manufacturers of antimalarials with prequalified status are listed on the prequalification
12
web site. It is the responsibility of national drug and regulatory authorities to ensure
that antimalarial medicines provided through both the public and private sectors are of
acceptable quality, through regulation, inspection and law enforcement.

7.8.5 Pharmacovigilance

Rare but serious adverse drug reactions are often not detected in clinical trials, and they
can only usually be detected through pharmacovigilance systems operating in situations
of wide population use. There are few data from prospective Phase IV post-marketing
studies of antimalarials specifically designed to detect rare but potentially serious
adverse drug reactions. The safety profiles of the artemisinin derivatives, mefloquine
and sulfadoxine-pyrimethamine are supported by a reasonable evidence base (mainly
from multiple clinical trials). There have been large case-control studies with artemisinin
and its derivatives in humans with evaluation of neurology, audiometry and auditory
evoked potentials, and no evidence of neurotoxicity have been documented. Concern
remains about the risks of neutropenia and hepatotoxicity associated with amodiaquine,
whether used alone or in combination. This risk is increased by drug interactions,
e.g. with efavirenz or zidovudine. More data are needed on safety of all of the ACTs,
especially exposure in the first trimester of pregnancy, and also on interactions between
antimalarials and other commonly used medicines. It is recommended that governments
of malaria endemic countries with large-scale deployment of ACTs should consider
establishing effective pharmacovigilance systems.

12 Prequalification programme: a United Nations Programme managed by WHO. Geneva, World Health Organization,
2009 (http://apps.who.int/prequal/, accessed 24 October 2009).
25