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Subject: WHO prequalifies artesunate for malaria
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E-DRUG: WHO prequalifies artesunate for malaria
--------------------------------------------

On 18 March WHO prequalified a second product for malaria: artusenate 50mg
tablets from Sanofi (France), made by Guilin Pharmaceutical Co. Ltd, Guangx,
China. See
http://mednet3.who.int/prequal/mal/mal_suppliers_(second-edition).pdf
Artesunate was already being sold for >10 years, but as there was no
"originator" (the product is known in China for more than 2000 years; as
there was no possibility to patent it, few drug companies were interested to
do all the preclinical safety and tox studies), it was difficult for WHO to
apply its stringent prequalification criteria (see
http://mednet3.who.int/prequal/default.shtml).

The prequalification of artesunate tablets now opens Global Fund receivers
to order an alternative product from the previously registered Co-artem
(artemether + lumefantrine, made by Novartis). Artesunate should however be
used in COMBINATION with another anti-malarial. See WHO/Roll Back Malaria
guidelines:

-------
Position of WHO's Roll Back Malaria Department on malaria treatment policy

Background

Global malaria control is being threatened on an unprecedented scale by
rapidly growing resistance of Plasmodium falciparum to conventional
monotherapies such as chloroquine, sulfadoxine-pyrimethamine (SP) and
amodiaquine. Multi-drug resistant falciparum malaria is widely prevalent in
South-East Asia and South America. Now Africa, the continent with highest
burden of malaria is also being seriously affected by drug resistance.

WHO recommendations

As a response to the antimalarial drug resistance situation, WHO recommends
that treatment policies for falciparum malaria in all countries experiencing
resistance to monotherapies should be combination therapies, preferably
those containing an artemisinin derivative (ACT - artemisinin-based
combination therapy).

Following are the therapeutic options currently recommended by WHO:

artemether/lumefantrine
artesunate plus amodiaquine
artesunate plus sulfadoxine/pyrimethamine (in areas where SP efficacy
remains high)
amodiaquine plus sulfadoxine/pyrimethamine, in areas where efficacy of both
amodiaquine and sulfadoxine/pyrimethamine remains high (mainly limited to
West Africa).
artesunate plus mefloquine, an additional recommended combination treatment
which is reserved for areas of low transmission.
The current WHO policy on antimalarial treatment is based on the
recommendations and conclusions of two consultations of international
experts on malaria chemotherapy, held in November 2000 and April 2001 (see
ANNEX I).

WHO strategic position on expanding access to ACT

Over the last three years around 20 countries (7 in Africa) have updated
their treatment policies to include ACTs as 1st-line or 2nd-line treatment
of malaria. This was based on WHO advice, and was made possible with the
participation of RBM partners and increased mobilization of international
funding.

In 2002 the Global Fund to fight AIDS, Tuberculosis and Malaria (GFATM) was
established, and it has become one of the main international funding
mechanism to support the implementation of highly effective interventions
for the control of these three diseases in endemic developing countries. The
GFATM has become the largest financial supporter of ACTs in countries. A
total of US$30 million has been committed over the full 5-year life of GFATM
Board-approved proposals from African countries for the purchase of ACTs in
three proposal rounds. Moreover, as a result of flexibility in the use of
funds committed to these programmes, even more funds may be allocated to
purchase ACTs as countries continuously evaluate their drug policies and how
to best utilize grants from the GFATM. Indeed a number of recipient
countries in Africa, which originally requested funding for chloroquine, are
already in the process of re-evaluating their drug policies towards the use
of ACTs, examples being Senegal, Ghana, Benin, Mali, Chad, and The Gambia.
In addition to the GFATM, national Governments and RBM partners, such as UN
Organizations, Bilateral Agencies and NGOs (MSF in particular) have
contributed to the sourcing and financing of ACTs.

The single non artemisinin-based combination therapy (amodiaquine plus SP),
listed among WHO recommended options is reserved for countries which, for
whatever reason, are unable to move into ACTs. However, the following
limitations of this option should be noted:

The number of countries where efficacy is high of both amodiaquine and SP is
limited and mainly restricted to West Africa.
As both amodiaquine and SP are currently in wide usage as monotherapies it
is unlikely that the adoption of this combination therapy will significantly
delay the spread of resistance to either drug. Therefore, the adoption of CT
with amodiaquine plus SP is likely to be a short-term solution.
Even in areas where the efficacy of both amodiaquine and SP remain high,
their combined use will compromise the useful therapeutic life of both, and
thus endanger their potential use as partner drugs for artesunatein ACTs.
There is currently no replacement for SP as a drug for Intermittent
Preventive Treatment (IPT) in pregnancy. Rather than compromise its
therapeutic life by using it as a component of a CT, SP should be reserved
for IPT.
As the process of drug policy change and implementation is resource- and
time-intensive (experience shows it to take from one to three years), all
efforts for improving access to treatment should be directed towards
implementing the most effective and durable treatment policy.
One of the principal reasons for countries wishing to adopt non artemisinin
based combinations (CTs) is their lower price. However, multiple financial
mechanisms are now available in countries, and international support is
being mobilised to help countries adopt ACTs, and an increasing number of
countries are now replacing ineffective monotherapies with ACTs.
To facilitate access to ACTs, WHO has, in collaboration with UNICEF,
established a system for pre-qualification of manufacturers of artemisinin
derivatives, negotiated price agreements with manufacturers, engaged in
international procurement, and set up systems of pharmacovigilance. A
service for malaria medicines and supplies is now being established by WHO
and RBM partners to facilitate access to ACTs. This will be a component of a
larger facility for improving access to medicines and supplies for HIV-AIDS,
TB and Malaria.

Conclusions

Consistent with WHO recommendations, malaria endemic countries which are
experiencing resistance to currently used antimalarial drug monotherapies
(chloroquine, sulphadoxine/pyrimethamine or amodiaquine) should change
treatment policies to the highly effective artemisinin-based combination
treatments (ACTs).

We call on all RBM partners to unite in a global coalition to mobilise
expertise and resources to support countries to access ACTs and to make
these drugs affordable to the people in need.

* * *

ANNEX I

WHO Informal Consultation on the Use of Antimalarial Drugs (13-17 November
2000)

The meeting reviewed and updated recommendations on the use of antimalarial
drugs for malaria prevention and treatment of uncomplicated malaria, and to
assess the implications of latest drug developments for national treatment
policies. The experts elaborated a specific definition of antimalarial
combination therapy, and highlighted the strategic value of drug
combinations for national malaria control programmes and those involved in
implementing antimalarial treatment policies.

In particular, the experts recognized and widely accepted:

"the potential value of drug combinations, notably those containing an
artemisinin derivative, to improve efficacy, delay development and selection
of drug-resistant parasites and thus prolong the therapeutic life of
existing antimalarial drugs. Combinations that do not contain an artemisinin
derivative could be a preferred option for reasons of cost and accessibility
in some countries."
WHO Technical Consultation on Antimalarial Combination Therapy (4-5 April
2001)

In view of the recognition of the role of combination therapy, WHO convened
a technical consultation to review existing evidence on combination therapy
for malaria and to make specific choices on appropriate combinations for
use.

The Technical Consultation strongly endorsed the potential of combination
therapy for use in Africa. It recommended the following four combination
therapies with potential for deployment, on the basis of the available
safety and efficacy data, which are listed below in prioritized order, if
costs were not an issue:

artemether/lumefantrine;
artesunate (3 days) plus amodiaquine;
artesunate (3 days) plus sulfadoxine/pyrimethamine (SP), in areas where SP
efficacy is high;
amodiaquine plus SP, in areas where efficacy of both drugs remains high -
mainly limited to countries in West Africa.
The consultation recognized that increased funding would be required to
facilitate the appropriate exploration of use and purchase of optimal
antimalarial drugs. Failure to assure funding for antimalarial drugs will
provide a major obstacle for many countries in Africa in moving to
combination therapy.

Options that were not recommended for policy included:

chloroquine-based combinations (CQ + SP and CQ + artesunate)
one-day treatment of artesunate + SP
mefloquine-based combinations (e.g. mefloquine plus artesunate) in areas of
high malaria transmission
one-day treatment of artesunate plus mefloquine in the acute phase of a
complex emergency or malaria epidemics
The committee also recommended the accelerated development of other
artemisinin-based combination therapies which are in the pipeline, in
particular of:

piperaquine/dihydroartemisinin,
chlorproguanil/dapsone/artesunate and
pyronaridine/artesunate.

------
MSF

MSF also recommends combination products or co-blisters, NOT to use
artesunate in isolation.
See
http://www.accessmed-msf.org/prod/publications.asp?scntid=2442003111212&cont
enttype=PARA&
Or full report (3.5MByte!)
http://www.accessmed-msf.org/documents/malariaACTNOWlow.pdf

-----
[MEDLINE on artusenate & SANOFI]

Med Trop (Mars). 1998;58(3 Suppl):70-2.

Positioning, labelling and control of medical information: artesunate
strategy and Arsumax development story.

Moneton P, Ducret JP.

Sanofi Winthrop AMO, Gentilly, France. philippe.moneton@sanofi.com

Sanofi decided, some years ago, to help developing a molecule of a new type
called artesunate, a semisynthetic derivative from Qinghaosu, or
artemisinine, a sesquiterpenic lactone extracted from the leaves of a world
wide spread plant: Artemisia annua. After having signed a secrecy agreement
with a local pharmaceutical company in China manufacturing artesunate,
Sanofi started, in 1993, the assessment of all the data transmitted as well
as the plant involved in the artesunate tablet manufacturing. As conclusions
of the whole audit performed on this project were judged satisfactory,
Sanofi signed a cooperation agreement with this Chinese pharmaceutical firm
in order to be allowed to start further development work required to
guarantee quality and safety of artesunate 50 mg tablets called Arsumax, and
to complete a registration dossier acceptable for Health Authorities in
French-speaking Africa. Pharmaceutical, pharmacotoxicological and clinical
documentation were widely completed, and entirely reformated according to
European guidelines. The registration dossier was submitted in all French
speaking African countries. The approval has been obtained in 13 countries.
Due to its fast efficacy, its absence of undesirable effects, its
presentation in tablets, its quite simple dosage (one box for a treatment),
Arsumax positioned itself as an accurate second line antimalaric treatment.

PMID: 10212905 [PubMed - indexed for MEDLINE]

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