Abstract
Many medicines prescribed for children are unlicensed.
Solid dosage forms present problems as children have difficulty
swallowing whole tablets or capsules. When medicines are not
licensed for children, it is unlikely that there will be a
suitable, licensed liquid l
formulationl and so
extemporaneous liquid preparations (prepared at the dispensary or
by GMP ‘special’ manufacturers) are often used. This
study looked at a list of medicines commonly prescribed for
children with cardiovascular conditions in an English
specialist l
paediatricl hospital and
classified them according to licensed status and available
l formulations.l As
expected, most medicines used for children with cardiovascular
problems were unlicensed and where this was the case, usually
only ‘special’ liquids or extemporaneous preparations
were available. Problems linked with l
formulationsl highlighted in this
therapeutic category were: problems in dosing accuracy and
unknown bioavailability of extemporaneous products, the use of
potentially toxic excipients, and lack of access to
modified release preparations for children. These problems are
likely to extend to other l
paediatricl therapeutic areas.
There is currently a large, unmet need to improve
l formulationsl of
commonly used l
paediatricl medicines, both
through licensing and standardising the production of
extemporaneous and ‘special’ l
formulations.l It is expected
that the awaited European regulation will help to meet some of
those needs.
Keywords: Cardiovascular drugs;
l Paediatricl
medicines; Licensed liquid; Special products;
Extemporaneous preparations
1. Introduction
Children are not small adults! Differences in physiology
during development mean the way in which they absorb, distribute,
metabolise and eliminate drugs cannot be predicted from adult
data (Kearns et al., 2003 and de Zwart et al., 2004). Children
represent a vulnerable group, with parental consent for treatment
relying on the evidence-base and expertise drawn upon by
professionals caring for them. Before any medicine is authorised
for use in adults, the product must have undergone clinical
testing to ensure that it is safe, of high quality and effective.
This is not the case with all medicines for hospitalised children
as, depending on speciality, between 30 and 90% are not licensed
for purpose (termed "off label" OL) or have not been licensed at
all (termed "unlicensed", UL) (Conroy et al., 2002 and Turner et
al., 1998). This is also the case in the community but possibly
to a lesser extent (Schirm et al., 2003).
Using medicines that are not licensed means there is
limited available evidence on safety, quality and efficacy and a
potentially increased risk of adverse drug reaction (Choonara and
Conroy, 2002 and Turner et al., 1999). In addition to a lack of
systematically compiled evidence for the use of unlicensed
medicines, many are available only as solid dosage forms (Schirm
et al., 2003). Depending on age many children are unable to
swallow whole tablets or capsules (Michele et al., 2002), even
when given specific training (Czyzewski et al., 2000).
Furthermore, as dosing is often based on body weight, only a
proportion of a solid dosage form has to be given which can be
difficult to achieve. Fig. 1 summarises the options available to
administer oral medicines to children who cannot swallow whole
solid dosage forms. In 2001, an audit at Great Ormond Street
Hospital (GOSH) in London (UK), one of seven specialist
paediatric hospitals in England, revealed that manipulations such
as tablet cutting, tablet crushing and opening capsules was
necessary to administer 26% of oral doses given to inpatients
(data unpublished). Splitting tablets leads to dose inaccuracy
(Breitkreutz et al., 1999, Rosenberg et al., 2002 and Teng et
al., 2002), crushing tablets can affect absorption (Breitkreutz
et al., 1999) and cause therapeutic failure (Notterman et al.,
1986).
The aim of this study was to look into the availability
of drug formulations used in a paediatric hospital within a
single therapeutic area. A recent survey including the seven
specialist paediatric hospitals in England, found that many
unlicensed chemical entities coming from the BNF "cardiovascular
system" category were extemporaneously prepared: 11.1% in terms
of the number of drugs and 14.5% of the workload
(Yeung et al.,
2004), those drugs often being potent and with a
narrow therapeutic index. The cardiothoracic unit at GOSH has
over 7000 patient attendances per year, and the vast majority of
patients will receive cardiovascular medicines. In addition,
patients with other underlying conditions may receive such drugs
(e.g. patients with hypertension secondary to renal failure).
This study aims to reflect on paediatric formulation and
licensing problems using medicines that act on the cardiovascular
system as an example.
2.
Materials and methods
A list of commonly used cardiovascular medicines
prescribed at GOSH was drawn up. The drugs were classified
according to the available formulation and their licensed status.
They were qualitatively classified into two
categories:
– If a licensed liquid dosage form was
available.
– If no licensed liquid dosage form was available. In
that case, the way the doses could be administered was further
investigated and reported as ‘special’ or
‘extemporaneous preparation’.
The term ‘special’ defined an extemporaneous
non-sterile liquid preparation produced under good manufacturing
practice (GMP) conditions by a specials manufacturer, which
includes suitably licensed hospitals units. Companies are allowed
to supply unlicensed medicinal products formulated in accordance
with the requirement of a doctor (‘named patient
supply’) if they hold a manufacturer's (specials) license
issued by the Medicine and Healthcare Products Regulatory Agency
(MHRA). Extemporaneous non-sterile liquid oral preparations are
prepared mainly from manipulated solid dosage forms; either by
the carers or hospital or community pharmacies. They can also be
prepared by dilution of an existing liquid dosage form (e.g.
injection).
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