Roberta Richey

Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence

BackgroundA lack of age-appropriate formulations can make it difficult to administer medicines to children. A manipulation of the dosage form may be required to achieve the required dose. This study aimed to describe medicines that are manipulated to achieve the required dose in paediatric practice.MethodA structured, undisguised observational study and postal survey. The observational study investigated drug manipulations occurring in clinical practice across three sites. The questionnaire, administered to a sample of paediatric nurses throughout the UK, surveyed manipulations conducted and nurses’ experiences and views.ResultsThe observational study identified 310 manipulations, of which 62% involved tablets, 21% were intravenous drugs and 10% were sachets. Of the 54 observed manipulations 40 involved tablets with 65% of the tablets being cut and 30% dispersed to obtain a smaller dose. 188 manipulations were reported by questionnaire respondents, of these 46% involved tablets, 12% were intravenous drugs, and 12% were nebuliser solutions. Manipulations were predominantly, but not exclusively, identified in specialist clinical areas with more highly dependent patients. Questionnaire respondents were concerned about the accuracy of the dose achieved following manipulations and the lack of practice guidance.ConclusionManipulations to achieve the required dose occur throughout paediatric in-patient settings. The impact of manipulations on the efficacy of the drugs, the accuracy of the dose and any adverse effects on patients is not known. There is a need to develop evidence-based guidance for manipulations of medicines in children.

The manipulation of drugs to obtain the required dose: systematic review

AIM To describe the development of a systematic review protocol that maps the evidence relating to drug manipulations conducted to obtain the required dose. This process included defining a search strategy and methods to assess the quality and to synthesize the evidence retrieved. BACKGROUND Economic constraints mean that marketed formulations may not meet the needs of all patients. Consequently, it is sometimes necessary to manipulate marketed products with the aim of obtaining the required dose. Most clinical practice appears to be guided by ad hoc approaches and informal literature reviews. METHODS This systematic review protocol has been designed to identify the evidence available on drug manipulation. The review aims to identify what evidence is available and where the gaps appear in the current evidence. This report describes the challenges of developing a systematic review in an area that potentially involves many drugs and considers outcomes other than effectiveness. In particular, searches required the use of non-specific terms and the iterative development of a complex search strategy. The development of quality assessment criteria is also described. Funding commenced in April 2009. DISCUSSION The systematic review described here will capture a broad selection of research about drug manipulations and may also be of interest to those conducting reviews in broad remit subject areas that are not easy to define using accepted terminology.

Estimating the requirement for manipulation of medicines to provide accurate doses for children

Objective To determine the type and frequency of manipulations of drug dosage forms required to administer smaller doses for children and the drugs involved. Methods An experienced paediatric clinical pharmacist estimated the requirement to manipulate a medicine to achieve accurate dose administration from prescription data in all neonatal and paediatric inpatients collected over 5-day periods and information on drug dosage form availability in a regional childrens hospital (RCH) and regional paediatric intensive care unit (RPICU), a regional neonatal intensive care unit (RNICU) and paediatric and neonatal wards of a district general hospital (DGH) using paper-based prescribing systems. Doses were expressed by weight. Ward stock supply with some intravenous drugs ready-to-administer was provided. The main outcome measures were the estimated requirement for dosage form manipulation, nature of the manipulation and drug name. Results Of 5375 evaluated drug administrations, 542 (10.1%) were judged to require manipulation or measurement of a small volume (<0.2 ml). The most frequent manipulation was measurement of oral dose in volumes of 0.1 to <0.2 ml in the DGH. Requirement to measure doses of <0.1 ml (oral and intravenous) accounted for 25.2% of all manipulations, with the need to measure intravenous doses of <0.1 ml being most frequent in the RNICU and RPICU (60.4% and 31.9% of manipulations, respectively). Hydrocortisone was the drug most frequently judged to require manipulation with both measurement of small volumes for intravenous injection (RPICU and RNICU) and segmentation of tablets (RCH). Conclusions Manipulation of medicines (including measurement of very small volumes) to provide accurate smaller doses for children is common in the hospital setting.

Quality of care: a comparison of perceptions of health professionals in clinical areas in the United Kingdom and the United States.

A tool was developed, using the nominal group and Delphi techniques, to explore healthcare staffs perceptions of the quality of hospital care provided in the United Kingdom compared with a tool from the United States. Similarities were identified in many core areas; however, there were several differences between the UK and US tools. This article identifies the process and findings and discusses possible reasons for similarities and differences between the tools.

A systematic review of the use of dosage form manipulation to obtain required doses to inform use of manipulation in paediatric practice

This study sought to determine whether there is an evidence base for drug manipulation to obtain the required dose, a common feature of paediatric clinical practice. A systematic review of the data sources, PubMed, EMBASE, CINAHL, IPA and the Cochrane database of systematic reviews, was used. Studies that considered the dose accuracy of manipulated medicines of any dosage form, evidence of safety or harm, bioavailability, patient experience, tolerability, contamination and comparison of methods of manipulation were included. Case studies and letters were excluded. Fifty studies were eligible for inclusion, 49 of which involved tablets being cut, split, crushed or dispersed. The remaining one study involved the manipulation of suppositories of one drug. No eligible studies concerning manipulation of oral capsules or liquids, rectal enemas, nebuliser solutions, injections or transdermal patches were identified. Twenty four of the tablet studies considered dose accuracy using weight and/or drug content. In studies that considered weight using adapted pharmacopoeial specifications, the percentage of halved tablets meeting these specifications ranged from 30% to 100%. Eighteen studies investigated bioavailability, pharmacokinetics or clinical outcomes following manipulations which included nine delayed or modified release formulations. In each of these nine studies the entirety of the dosage form was administered. Only one of the 18 studies was identified where drugs were manipulated to obtain a proportion of the dosage form, and that proportion administered. The five studies that considered patient perception found that having to manipulate the tablets did not have a negative impact on adherence. Of the 49 studies only two studies reported investigating children. This review yielded limited evidence to support manipulation of medicines for children. The results cannot be extrapolated between dosage forms, methods of manipulation or between different brands of the same drug.

MODRIC - Manipulation of drugs in children.

European Medicines Agency Committee for Medicinal Products for Human Use & Paediatric Committee & Committee on Herbal Medicinal Products (concept paper only). Guideline on the pharmaceutical development of medicines for paediatric use. Concept paper, first draft, comments, revised draft and overview of comments. Available at: http://www.ema.europa.eu/ema/ index.jsp?curl=pages/regulation/general/general content 000362.jsp&mid= WC0b01ac0580028eb2 (accessed 05.01.13). European Paediatric Formulation Initiative, 2013. EUPFI 3rd conference “Formulating better medicines for children”, Available at: http://www.eupfi.org/ new%20website%20template/index1.html (accessed 01.09.12, accessed 02.01.13). International Conference on Harmonization, 2013. Guideline ICH Q8(R2) on Pharmaceutical Development, Available at: http://www. ich. org/products/guidelines/quality/article/quality-guidelines.html (accessed 02.01.13). European Commission, 2013. Directive 2001/83 of the European Parliament and of the Council of 6 November 2011 on the community code relating to medicinal products for human use, Available at: http://ec.europa. eu/health/documents/eudralex/vol-1/index en.htm (accessed 02.01.13). European Pharmacopoeia, 2013. Monograph 0478 on Tablets, Available at: http://online6.edqm.eu/ep708/#doc 15 of 532 (accessed 05.01.13). European Commission DG Sanco, 2012. A guideline on summary of product characteristics (SmPC), Available at: http://ec.europa.eu/health/files/ eudralex/vol-2/c/smpc guideline rev2 en.pdf (accessed 13.11.12). European Commission Enterprise Directorate General, 2013. Notice to Applicants, Volume 3B. Guidelines Medicinal Products for human use. Safety of environment and information. Excipients in the label and package leaflet of medicinal products for human use, Available at: http://www. ema.europa.eu/docs/ en GB/document library/Scientific guideline/2009/09/WC500003412.pdf (accessed 02.01.13).

G26 Parents’ experiences of administering and manipulating medicines for children with long term chronic conditions

Aims To explore the experiences and methods used by parents to administer long term medicines to their children. Methods Semi structured qualitative interviews with parents of children who are prescribed long term medication for a chronic condition. Interviews were audio recorded and transcribed. Analysis was inductive and informed by the principles of grounded theory and constant comparison method. Results Semi structured interviews with the parents of 13 (N = 12) children between 5 to 11 years; female (n = 5) and male (n = 8). The sample is currently being extending to include the parents of up to 20 children. Parent’s accounts were variable. Some parents reported no problems administering medicines to their child but other parents described prolonged ‘battles’. Taste was cited as the main reason for a child refusing a medicine. Some methods used by parents to encourage children to comply with medication, such as rewards and reasoning are commonly used by parents giving short term medicines but these methods needed to be regularly adapted over time as their effect wore off. Parents also described ordering medicines, giving two medicines together or missing medicine doses in order to reduce ‘battles’ and increase compliance. Parents were confident in manipulating medicines (cutting, crushing or splitting tablets etc.), but had concerns about controlling the dose their child received e.g. tablets crumbling. Similarly, parents did not favour disguising medicines in food or drink as they felt this method did not work, risked losing the trust of their child, and their child potentially refusing that particular food or drink in the future. Furthermore, parents had concerns about controlling the dose of a medicine using this method. Conclusion Some parents described ‘battles’ over administering medicine to their children that had a significant and negative impact on daily family life. Taste was the major barrier to compliance. Methods perceived as favourable by clinicians, such as disguising medicines in food and drink, were not favoured by parents who employed a range of alternative strategies, some of which involved altering medicine regimens and was not supported by evidence.

Manipulation of medicines to deliver a required dose: development of a good practice guideline

Aims The need to manipulate some dosage forms to deliver a suitable dose of a drug to infants and children is well recognised and established in paediatric practice.1 2 The aim of this project was to produce best practice guidance on how healthcare professionals, working in neonatal and paediatric in-patient clinical areas, can obtain a required dose, where no suitable formulation or alternative product exists. Methods The guidelines were informed by a number of work streams, undertaken under the umbrella of the MODRIC (Manipulating Drugs in Children) project. The evidence from a systematic review of the literature, an observational study of manipulations in clinical practice and a national survey of the experience of paediatric nurses in manipulating medicines, was reviewed and supplemented with the expertise of a guideline development group to develop an acceptable guideline. Results This guideline describes situations where medicines should not be manipulated and has recommendations on avoiding manipulation (such as by procuring the appropriate dosage forms or using dose rounding where appropriate). Where a manipulation is considered necessary, recommendations have been developed for different dosage forms. In addition recommendations to the regulator, to industry and to inform further research have been included. Conclusions The use of this guideline will raise awareness about drug manipulation in paediatric and neonatal care settings and offer guidance for undertaking manipulations if they cannot be avoided. It is intended that the guideline will be used to inform hospital Medicines Management Policy on manipulation of medicines.

1545 The Use of Drug Manipulation to Obtain Doses Required in Paediatric Practice: A Systematic Review

Background and Aims To determine whether there is an evidence base for drug manipulation to obtain the required dose, a common feature of paediatric clinical practice. Methods Systematic review, including studies that considered the dose accuracy of manipulated medicines of any dosage form, evidence of safety or harm, bioavailability, patient experience, tolerability, contamination and comparison of methods of manipulation. Results 43 studies were eligible for inclusion, 42 of which involved tablets being cut, split, crushed or dispersed. The remaining one study involved the manipulation of suppositories of one drug. No eligible studies concerning manipulation of oral capsules or liquids, rectal enemas, nebuliser solutions, injections or transdermal patches were identified. Seventeen of the tablet studies considered dose accuracy using weight and/or drug content. In studies that considered weight using adapted pharmacopoeial specifications, the percentage of halved tablets meeting these specifications ranged from 33% to 93%. Nine studies investigated bioavailability outcomes following the manipulations of five delayed release formulations. In all nine studies all of the dosage form was administered. Only one study was identified where drugs were manipulated to obtain a proportion of the dosage form, and that proportion administered. The eight studies that considered patient experience found that having to manipulate the tablets did not have a negative impact on adherence. Of the 43 studies only two studies reported investigating children. Conclusion This review yielded limited evidence to support manipulation of medicines. The results cannot be extrapolated between dosage forms, methods of manipulation or between different brands of preparation.