title: A systematic review of the use of dosage form manipulation to obtain required doses to inform use of manipulation in paediatric practice.
abstract: 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.
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool, L12 2AP, United Kingdom; The Walton Centre NHS Foundation Trust, Liverpool, L9 7LJ, United Kingdom. Electronic address: roberta.richey@thewaltoncentre.nhs.uk.
authors.forename: Roberta H
authors.initials: RH
authors.lastname: Richey
authors.affiliation: School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Hughes
authors.affiliation: Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom. Electronic address: Jean.Craig@uea.ac.uk.
authors.forename: Jean V
authors.initials: JV
authors.lastname: Craig
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool, L12 2AP, United Kingdom; School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, United Kingdom; Cheshire, Merseyside & North Wales Medicines for Children Local Research Network, Eaton Road, Liverpool, L12 2AP, United Kingdom.
authors.forename: Utpal U
authors.initials: UU
authors.lastname: Shah
authors.affiliation: School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, United Kingdom. Electronic address: j.l.ford@ljmu.ac.uk.
authors.forename: James L
authors.initials: JL
authors.lastname: Ford
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool, L12 2AP, United Kingdom; Cheshire, Merseyside & North Wales Medicines for Children Local Research Network, Eaton Road, Liverpool, L12 2AP, United Kingdom. Electronic address: catrin.barker@alderhey.nhs.uk.
authors.forename: Catrin E
authors.initials: CE
authors.lastname: Barker
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool, L12 2AP, United Kingdom; Cheshire, Merseyside & North Wales Medicines for Children Local Research Network, Eaton Road, Liverpool, L12 2AP, United Kingdom. Electronic address: Matthew.Peak@alderhey.nhs.uk.
authors.forename: Matthew
authors.initials: M
authors.lastname: Peak
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool, L12 2AP, United Kingdom; School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, United Kingdom; NIHR Medicines for Children Research Network Co-ordinating Centre, Institute of Child Health, University of Liverpool, L12 2AP, United Kingdom. Electronic address: a.j.nunn@liverpool.ac.uk.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Nunn
authors.affiliation: NIHR Medicines for Children Research Network Co-ordinating Centre, Institute of Child Health, University of Liverpool, L12 2AP, United Kingdom; Liverpool Women's Hospital NHS Foundation Trust, Crown Street, Liverpool, L8 7SS, United Kingdom. Electronic address: mark.turner@liverpool.ac.uk.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Turner
mesh_terms: D004304:Dosage Forms; D004358:Drug Therapy; D006801:Humans; D010372:Pediatrics; D004364:Pharmaceutical Preparations / Q000008:administration & dosage
chemical_list: D004304:Dosage Forms; D004364:Pharmaceutical Preparations
keywords: Drug manipulation; Hospital; Paediatric practice; Systematic review