Utpal U. Shah

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.

Needle-free and microneedle drug delivery in children: A case for disease-modifying antirheumatic drugs (DMARDs)

Parenteral routes of drug administration have poor acceptability and tolerability in children. Advances in transdermal drug delivery provide a potential alternative for improving drug administration in this patient group. Issues with parenteral delivery in children are highlighted and thus illustrate the scope for the application of needle-free and microneedle technologies. This mini-review discusses the opportunities and challenges for providing disease-modifying antirheumatic drugs (DMARDs) currently prescribed to paediatric rheumatology patients using such technologies. The aim is to raise further awareness of the need for age-appropriate formulations and drug delivery systems and stimulate exploration of these options for DMARDs, and in particular, rapidly emerging biologics on the market. The ability of needle-free and microneedle technologies to deliver monoclonal antibodies and fusion proteins still remains largely untested. Such an understanding is crucial for future drug design opportunities. The bioavailability, safety and tolerance of delivering biologics into the viable epidermis also need to be studied.

Hospitalised neonates in Estonia commonly receive potentially harmful excipients

BackgroundInformation on the neonatal exposure to excipients is limited. Our aim was to describe the extent of excipient intake by Estonian neonates; to classify the excipients according to potential neonatal toxicity and thereby to measure the extent of exposure of neonates to potentially harmful excipients.MethodsA prospective cohort study that recorded all medicines prescribed to patients aged below 28 days admitted to Tartu University Hospital from 01.02-01.08 2008 and to Tallinn Children’s Hospital from 01.02- 01.08 2009 was conducted. Excipients were identified from Summaries of Product Characteristics and classified according to toxicity following a literature review.Results1961 prescriptions comprising 107 medicines were written for 348/490 neonates admitted. A total of 123 excipients were found in 1620 (83%) prescriptions and 93 (87%) medicines. 47 (38%) of these excipients were classified as potentially or known to be harmful to neonates. Most neonates (97%) received at least one medicine (median number 2) with potentially or known to be harmful excipient. Parabens were the most commonly used known to be harmful excipients and sodium metabisulphite the most commonly used potentially harmful excipient, received by 343 (99%) and 297 (85%) of treated neonates, respectively.ConclusionsHospitalised neonates in Estonia are commonly receiving a wide range of excipients with their medication. Quantitative information about excipients should be made available to pharmacists and neonatologists helping them to take into account excipient issues when selecting medicines and to monitor for adverse effects if administration of medicines containing excipients is unavoidable.

Risk assessment of neonatal excipient exposure: Lessons from food safety and other areas

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

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.

European Study of Neonatal Exposure to Excipients: An update

APHP – Hospital Antoine Beclere, PharmacyDepartment, Paris, FranceE-mail address: UKmark.turner@liverpool.ac.uk(M.A. Turner).TheEuropeanStudyofNeonatalExposuretoExcipients(ENSEE)aimstoprovideanevidencebasefordiscussionsaboutthesafetyofexcipients in medicines given to newborn babies. Excipients havegeneratedalotofdiscussionbuttodatethisdiscussionhasnotbeensupportedbydata.Somepeopleadvocateanextremeapplicationofthe precautionary principle and suggest that all excipients shouldbe avoided. Others advocate a balanced approach which acceptsthe use of excipients if it is impossible to formulate a medicineotherwise.Somewouldevenacceptanexcipientthatincreasesthemarketability of a product if the excipient poses a negligible risk.In order to inform this discussion ESNEE is conducting multiplestrands of research to provide an integrated source of information.ESNEE relates to the FAO/WHO model for the risk assessmentof chemicals in food. This includes hazard identification, hazardcharacterization and exposure assessment. These steps inform riskcharacterization.Hazardidentificationandcharacterisationhasbeenundertakenusingasystematicreviewofextantdatarelatingtoexcipientsafetyand kinetics. Exposure assessment involves surveys of medicinesuse and clinical studies of excipient kinetics using micro samplesandpopulationpharmacokineticmodels.Riskcharacterisationwillbe expressed in monographs about specific excipients, which willinclude information relevant to risk managers.The systematic review was developed and conducted by col-leagues in Paris (Vaconsin et al., 2012). The starting point for thesystematic review is that excipients are widely used chemicalswithsynonymsthatfeatureinmanyprimarysourcesnotrelatedtoneonates. Accordingly a selection process was required. This wasdeveloped in collaboration with EuPFI (Salunke and Tuleu, 2010).A refined search sentence was developed to account for excipientterms and neonatal terms. The first review examined propyleneglycol.Theinitialsearchesyielded35,000hits.Inordertoovercomethe challenges presented by such a wide search several steps weretaken including database exploration, sieving, and data extraction.

Inappropriate oral formulations and information in paediatric trials

Previously, quality of formulations information provided for oral medications used in paediatric clinical trials published in 10 highly cited journals between 2002 and 2004 raised concerns. This short report explores if there was any subsequent improvement on how the formulations used in trials involving children <12 years reported in the same journals. Studies published between 2004 and 2008 were hand-searched and classified as containing adequate, some or no formulation information. Those involving solid dosage forms were further analysed. Only 31% (44/140) of publications provided adequate information, 5% less compared to 2002–2004 (28/76). There was a significant 12% rise (p<0.05) of no formulation information at all (37/140) and in tablets/capsules use (53/140), of which 3/4 gave no administration details, even for those under 6 years old, but a 12% decline in suitable paediatric formulations use (52/140 compared to 37/76). Contrary to expectations, overall quality of formulation information reported markedly deteriorated, jeopardising validity of clinical outcomes. The situation may reflect continued lack of awareness among investigators and other stakeholders of the importance of using suitable age-appropriate formulations.

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.

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