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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