Paediatric formulations—Getting to the heart of the problem

https://doi.org/10.1016/j.ijpharm.2005.05.006Get rights and content

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 formulation 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 paediatric hospital and classified them according to licensed status and available formulations. 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 formulations 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 paediatric therapeutic areas. There is currently a large, unmet need to improve formulations of commonly used paediatric medicines, both through licensing and standardising the production of extemporaneous and ‘special’ formulations. It is expected that the awaited European regulation will help to meet some of those needs.

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, 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, 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, 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, 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.

Section snippets

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

Results

Table 1 lists oral cardiovascular drugs commonly used in children for which a licensed liquid is available in UK. Table 2 lists the medicines for which there is no licensed liquid available in UK. Fig. 1 summarises the options available to administer oral medicines to children.

The majority of medicines used for children, which act on the cardiovascular system, were unlicensed. There was no licensed liquid form for most medicines although ‘special’ preparations were available for almost all.

Discussion

There is evidence suggesting that adverse drug reactions are more likely with UL/OL medicines (Turner et al., 1999, Choonara and Conroy, 2002). Dosing errors are thought to be a major route by which children are exposed to medication errors (Wong et al., 2004), and many of these could be linked to the use of high-strength adult formulations.

Acknowledgements

The Centre for Paediatric Pharmacy Research (CPPR) was established in April 2002 as a collaboration between the School of Pharmacy, the Institute of Child Health and Great Ormond Street Hospital for Children. CPPR owes a large debt of gratitude to Professor A.T. Florence, whose effort and commitment to actively bridge research and practice has made a huge contribution to its foundation and continuing success. Bonne retraite! The authors would like to thank the pharmacists Jodi New for collating

References (42)

  • Anonymous, 2000. Boots pharmacist and trainee cleared of baby's manslaughter. Pharm. J. 264,...
  • Anonymous, 2003. Checking paediatric dosing. Pharm. J. 271,...
  • J. Breitkreutz et al.

    Dosage forms for peroral drug administration to children

    Paediatr. Perinatal Drug Ther.

    (1999)
  • British National Formulary (BNF), number 49, 2005. British Medical Association/Royal Pharmaceutical Society of Great...
  • British National Formulary for children (BNF-C), 2005. http://www.bnf.org/bnf/extra/current/noframes/450055.htm, last...
  • M.N. Carrier et al.

    Stability and compatibility of tegaserod from crushed tablets mixed in beverages and foods

    Am. J. Health Syst. Pharm.

    (2004)
  • I. Choonara et al.

    Unlicensed and off-label drug use in children: implications for safety

    Drug Saf.

    (2002)
  • S. Conroy et al.

    Survey of unlicensed and off label drug use in paediatric wards in European countriesEuropean Network for Drug Investigation in Children

    BMJ

    (2002)
  • D.I. Czyzewski et al.

    Teaching and maintaining pill swallowing in HIV-infected children

    AIDS Reader

    (2000)
  • J.T. Flynn

    Nifedipine in the treatment of hypertension in children

    J. Pediatr.

    (2002)
  • Imatinib SPC (Summary of Product Characteristics) (Glivec tablets), 2004. Novartis Pharmaceuticals UK Ltd. Last updated...
  • Cited by (0)

    View full text