E-DRUG: Paediatric formulations for malaria drugs
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[With this posting we intend to stimulate the discussion on improving access to a range of paediatric malaria drugs, not on promoting defined producers or their products. HH, E-drug moderator].
Dear E-druggers, dear Dr Barasa Edwine,
Your remarks are correct. Paediatric formulations do not come as readily as others. And when it comes to combination therapy for malaria serious problems may occur. Artemether lumefantrine tablets for adults need to be crushed and then given to young and very sick children.
Fortunately the private sector has found answers for your problem.
The Belgian pharmaceutical company Dafra Pharma introduced a suspension for children containing artemether-lumefantrine(to be made up ex tempore). It comes as a dry powder and after adding water it is a sweet suspension that children like.
For serious and complicated malaria the same company offers artemether in oil for injection. The unit dose is 20 mg/ml and permits easy calculation.
For conditions where parenteral artemether cannot be used, e.g. in rural and remote areas where mothers have to take direct care of their children the company offers soft gel capsules containing artemether in oil for rectal application. These applications allow for rapid absorbtion from the rectum, giving peak plasma levels within 3-4 hours. When the child recovers from the initial attack therapy can then be switched to a commonly used ACT combination therapy.
It should be noted that the suspension artemether/lumefantrine and the injectable artemether 20 mg/ml is in the running to be accepted as Essential Drug (see coverage of the discussion on WHO web site). Unfortunately the decision to accept these drugs has yet not been taken.
Sincerely yours,
Dr. F.H. Jansen
Turnhout
Belgium
E-DRUG: Paediatric formulations for malaria drugs (2)
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Dear E-druggers, Dear FH Jansen
Thank you for your information. The issue of access has to be addressed
within the context of safe, efficacious and quality medicines. If my memory
serves me right, the arthemether/lumefantrine powder for reconstitution,
though a noble idea, had no stability information. At our hospital, for an
oral liquid formulation to be accepted in our formulary, it must be
accampanied by stability data (how stable is the formulation after
reconstitution?) and off-course bioequivalence studies to the originator
product. I would be glad if you would comment on that.
More information on the availability of suppositories would also be
appreciated.
Thank you
*Dr Barasa W. Edwine*
*Drug and Poison Information Pharmacist *
*Gertrudes Garden Childrens Hospital*
*Nairobi Kenya*
E-DRUG: Paediatric formulations for malaria drugs (3)
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Dear E-druggers,
Yes, there is a problem with availability of appropriate dosage forms
and strengths of antimalarials for children (as is the case for many
other products). However, in this particular case I would like to refer
you to the report of the WHO Expert Committee from October 2007
(http://mednet3.who.int/EMl/expcom/expcom16/WATERMARKED.pdf) which
reports the decision of the Expert Committee not to add this particular
combination product to the Model Essential Medicines List. The reasons
for rejection are stated in the report, but highlight the problems with
development of children's medicines in malaria. In particular, defining
the appropriate dose of components of combination products is
challenging. As noted in the Expert Committee Report, there is the
potential for under dosing (with resulting inefficacy) and overdosing
(with resulting toxicity) for products that are combinations of existing
components that have poorly defined dose response curves. What is needed
first of all is analysis of existing kinetic data for many of the single
components of ACTs in order to better define appropriate doses for
children. Although this process may highlight gaps, there may well be
published studies that are potentially useful for this purpose. These
then also have to be matched to weight or age bands of children that
allow for appropriate and easy dosing. This is part of the work that WHO
is undertaking in the Making Medicines Child Size Campaign.
Kind regards,
Suzanne Hill
Secretary
WHO Expert Committee on Selection and Use of Essential Medicines.
Scientist
Policy, Access and Rational Use
Medicines Policy and Standards
phone 41 22 7913522
fax 41 22 791 4167
email: hills@who.int
E-DRUG: Paediatric formulations for malaria drugs (5)
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Dear E-druggers,
While appreciating the improved recommendations outlined in the recent WHO Expert Committee on the list of Essential Medicines for children, I noticed with dismay that for oral liquid dosage forms (syrups and powders for reconstitution), members did not address the important issue of the presence of a safe and efficacious preservative in such a preparation. Preservation of the reconstituted dry powder from contamination by microbes should be considered as important as the dosaging of the drug itself, since available clean and potable drinking water is a major problem in resource-poor settings. Most of the artemisinin-derived dry powders on the market suggest a treatment period of 5-7 days, a sufficient time for bacterial and fungal growth, which can cause co-infection especially in a vulnerable age group like young children. In a study published recently in Malarial Journal on `Assessment of content and efficacy of preservatives in artemisinin-derived antimalarial dry suspensions (www.malariajournal.com/content/pdf/1475-2875-6-12.pdf), we found that many drug companies did not mention the type of preservative(s) used on their product label, and for those that did have this agent, there was incomplete dissolution after adding water. As expected, after challenging the suspensions with a number of micro-organisms the products failed the preservative efficacy test requirments of the Ph. Eur.
I suggest to health workers prescribing any paediatric oral formulations requiring addition of an aqueous medium to advice patients to:
1) use properly boiled and cooled drinking water for reconstitution
2) do a visual check on the powder: if powder particles stick together or cake, there will be a problem with under- or overdosaging
3) after adding water and mixing, check for sedimentation over the days as undissolved excipients (including poorly soluble actives) may settle if a suitable suspending agent was not used in the formulation
Magnus A. Atemnkeng PhD
Montreal, Canada
E-mail: magnusajong@yahoo.com
E-DRUG: Paediatric formulations for malaria drugs (6)
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Dear E-druggers,
The issue presented by Dr Atemnkeng is important indeed. A good preparation
should protect against bacterial contamination. Therefore antibacterial
substances are added to dry preparations and they are expected to be active
over the time that the pharmaceutical product is active and is being used.
This implies a limited period after reconstitution. In the Belgian
artemether-lumefantrine product discussed in earlier E-drug postings the
antibacterial products are of the so-called parabenes: methyl and propyl
parabene (methyl parabene is the methyl ester of 4-hydroxybenzoic acid).
These products are stable throughout the shelf life of the pharmaceutical
product and they ensure that in the 2 weeks after preparing the suspension
in water, bacterial contamination does not occur beyond the limits of
pharmacopoeal recommendations.
Sincerely yours,
Dr. F. Herwig Jansen
Turnhout
Belgium
E-mail: fhjansen@skynet.be