A. Lajoinie

Solid oral forms availability in children: a cost saving investigation

AIM To assess the suitability and potential cost savings, from both the hospital and community perspective, of prescribed oral liquid medicine substitution with acceptable solid forms for children over 2 years. METHOD Oral liquid medicines dispensed from a paediatric hospital (UK) in 1 week were assessed by screening for existence of the solid form alternative and evaluating the acceptability of the available solid form, firstly related to the prescribed dose and secondly to acceptable size depending on the childs age. Costs were calculated based on providing treatment for 28 days or prescribed duration for short term treatments. RESULTS Over 90% (440/476) of liquid formulations were available as a marketed solid form. Considering dosage acceptability (maximum of 10% deviation from prescribed dosage or 0% for narrow therapeutic range drugs, maximum tablet divisions into quarters) 80% of liquids could be substituted with a solid form. The main limitation for liquid substitution would be solid form size. However, two-thirds of prescribed liquids could have been substituted with a suitable solid form for dosage and size, with estimated savings being of £5K and £8K in 1 week, respectively based on hospital and community costs, corresponding to a projected annual saving of £238K and £410K (single institution). CONCLUSION Whilst not all children over 2 years will be able to swallow tablets, drug cost savings if oral liquid formulations were substituted with suitable solid dosage forms would be considerable. Given the numerous advantages of solid forms compared with liquids, this study may provide a theoretical basis for investing in supporting children to swallow tablets/capsules.

Different treatment benefits were estimated by clinical trials performed in adults compared with those performed in children

OBJECTIVE Our main objective was to see whether the therapeutic benefit observed in placebo controlled randomized controlled trials (RCTs) is different between adults and children. STUDY DESIGN AND SETTING We searched three electronic databases for meta-analyses that included double-blind, placebo-controlled RCTs with separate results for adults and children. The selected reviews were classified according to disease and drug used. The heterogeneity of treatment response between adults and children was measured using ratio of odds ratios (RORs). RESULTS We selected 89 meta-analyses and calculated RORs for 124 drugs. Heterogeneity in the direction of the treatment effect was observed in one drug and heterogeneity in the quantity of the treatment effect for 13 drugs, indicating significantly different treatment effect in adults when compared with children. RORs were not significantly different from 1 for 110 drugs. For 36 of these drugs, the treatment effect was confirmed in both populations. CONCLUSION We found different treatment benefits estimated by clinical trials performed in adults compared with those performed in children for 14 of 124 drugs. Data on dose adjustment and child age groups from RCTs were not adequately reported to investigate their influence on the treatment benefit dissimilarities.

Oral drug dosage forms administered to hospitalized children: Analysis of 117,665 oral administrations in a French paediatric hospital over a 1-year period.

Selecting the most appropriate dosage form, that ensures safe administration and adherence of medications, is a major issue for children. Marketed drugs, however, have rarely been tested for their use in children. There is a need for more data on drug formulations administered to children to identify unmet needs, and drive future paediatric research. We observed, over a 12-month follow-up, 117,665 oral drug administrations to 1998 hospitalized children. Nine-tenths belonged to five Anatomical Therapeutic Chemical classes: Alimentary tract & metabolism, Nervous system, Cardiovascular system, Anti-infectives for systemic use and Blood & blood forming organs, one third of drug doses administered to school-age children and adolescents were liquids, and extemporaneous capsules were commonly used in younger children. Our study shows that despite the advantages of solid dosage forms and recent evidence from randomized controlled trials showing their acceptability in infants, they are seldom used in paediatric practice.

Is the perceived placebo effect comparable between adults and children? A meta-regression analysis

Background:A potential larger perceived placebo effect in children compared with adults could influence the detection of the treatment effect and the extrapolation of the treatment benefit from adults to children. This study aims to explore this potential difference, using a meta-epidemiological approach.Methods:A systematic review of the literature was done to identify trials included in meta-analyses evaluating a drug intervention with separate data for adults and children. The standardized mean change and the proportion of responders (binary outcomes) were used to calculate the perceived placebo effect. A meta-regression analysis was conducted to test for the difference between adults and children of the perceived placebo effect.Results:For binary outcomes, the perceived placebo effect was significantly more favorable in children compared with adults (β = 0.13; P = 0.001). Parallel group trials (β = −1.83; P < 0.001), subjective outcomes (β = −0.76; P < 0.001), and the disease type significantly influenced the perceived placebo effect.Conclusion:The perceived placebo effect is different between adults and children for binary outcomes. This difference seems to be influenced by the design, the disease, and outcomes. Calibration of new studies for children should consider cautiously the placebo effect in children.

Risk of medication error administering ciprofloxacin oral suspension in children

To the Editor: Paediatrician, caregivers and medicine agencies should be advised of the risk of medication errors preparing ciprofloxacin paediatric oral suspension, as described above. Packaging of ciprofloxacin suspension (Bayer HealthCare; Ciflox®, Ciproxin®, Cipro®) consists of a small bottle of ciprofloxacin microgranules to be dissolved in a large bottle of milky white solvent (Fig. 1). Two similar medication errors occurred several months apart in two hospitalized children 20 days and 14 months of age, who were prescribed ciprofloxacin suspension, respectively, for E. coli K1 meningitis and P. aeruginosa pneumonia, on the advice of an infectious disease specialist. Nurses responsible for medicine preparation did not notice the small bottle of ciprofloxacin microgranules when opening the original packaging, and stored the bottle of unreconstituted solvent in the patient’s medicine cupboard. Subsequently, both children did not receive their ciprofloxacin regimen for several days, until a nurse accidentally discovered the forgotten bottles of microgranules. Ciprofloxacin was then effectively administered as initially prescribed. Finally, the 20-day-old child presented severe brain damage secondary to cerebral thrombophlebitis and vasculitis associated with meningitis and died. The 14-monthold child’s condition stabilized after few days, allowing the child to leave the hospital. From the healthcare team point of view, a main factor that contributed to the occurrence of those two similar medication errors was the configuration of the original ciprofloxacin suspension packaging. Firstly, caregivers are at risk of wrongly retrieving only the largest obvious bottle (containing ciprofloxacin-free solvent), forgetting the small bottle of ciprofloxacin microgranules in the packaging. Another risk factor would be the milky white aspect of the solvent, preventing any check of the presence of ciprofloxacin in the bottle. In addition, the solvent bottle is labelled with the active drug name (e.g., Ciflox®). We did not find any published report describing administration errors associated with ciprofloxacin suspension, except a brief letter posted on a US nurse website highlighting practitioners’ concerns with the risks of ciprofloxacin administration error. From this letter, the United States Pharmacopeial Convention (USP) Practitioners’ Reporting Network would have received several reports of administration errors using ciprofloxacin suspension, including one case similar to those we described [1]. USP warnings have resulted in packaging improvement (i.e., a clearer labelling of the solvent bottle using a removal label BDiluent for Cipro®^) implemented in * Audrey Lajoinie audrey.lajoinie@gmail.com

Use of available clinical evidence to extrapolate drug effects from adults to children

The extrapolation of the benefit risk ratio from adults to children is performed during drug development and often implicitly used by many paediatricians when prescribing off-label drugs in children. This is due to the specific constraints of paediatric clinical research leading to a lack of safety and efficacy data in children. Extrapolation frameworks for drug development have been proposed by several regulatory agencies. Using a meta-epidemiological approach, we explored the similarities and differences of the benefit, the benefit risk ratio and the perceived placebo effect between adults and children from meta-analyses including randomized double-blinded placebo-controlled trials evaluating a drug intervention in an indication in adults and children with separate data for both populations. We also explored the use of the effect model using adult data to predict the treatment effect in children and to calibrate future paediatric clinical trials. Our research highlights the importance of using all available evidence and quantitative methods before extrapolating the benefit risk ratio from adults to children and carrying out new studies in the context of the existing evidence. More generally, this should be applied to any research to avoid a waste of time and resources invested.

Protocol of GLUcose COntrol Safety and Efficacy in type 2 DIabetes, a NETwork meta-analysis:GLUCOSE DINET protocol - Rational and design.

The aim of this study was to propose a ranking of the currently available antidiabetic drugs, regarding vascular clinical outcomes, in patients with type 2 diabetes, through a network meta‐analysis approach. Randomized clinical trials, regardless of the blinding design, testing contemporary antidiabetic drugs, and considering clinically relevant outcomes in patients with type 2 diabetes mellitus will be included. The primary outcomes of this analysis will be overall mortality, cardiovascular mortality, and major cardiovascular events. Diabetic microangiopathy will be a secondary outcome. Adverse events, hypoglycemia, weight evolution, bariatric surgery, and discontinuation of the treatment will also be recorded. Each drug will be analyzed according to its therapeutic class: biguanide, alpha‐glucosidase inhibitors, sulfonylureas, glitazones, glinides, insulin, DPP‐4 inhibitors, GLP‐1 analogs, and gliflozins. The treatment effect of each drug class will be compared using pairwise meta‐analysis and a Bayesian random model network meta‐analysis. Sensitivity analyses will be conducted according to the quality of the studies and the glycemic control. The report will follow the PRISMA checklist for network meta‐analysis. Results of the search strategy and of the study selection will be presented in a PRISMA compliant flowchart. The treatment effects will be summarized with odds ratio (OR) estimates and their 95% credible intervals. A ranking of the drugs will be proposed. Our network meta‐analysis should allow a clinically relevant ranking of the contemporary antidiabetic drugs.

Assessing the effects of solid versus liquid dosage forms of oral medications on adherence and acceptability in children

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of solid versus liquid dosage forms on adherence to and acceptability of oral medications in children. Secondary objectives include assessment of elements of the medication risk/benefit balance influenced by the drug dosage form, such as clinical efficacy and safety, treatment costs and adverse events related to oral administration.

CP-090 Solid oral dosage forms in paediatric patients – a cost-savings investigation

Background Oral liquid drugs, commonly used in children, present numerous disadvantages. Solid oral forms have greater stability, provide higher drug compliance in children and markedly reduce costs. Two limits could explain the difficulties of solid drug use in children: swallowing difficulties and low flexibility of the solid dosage. Purpose To assess the suitability for substitution of prescribed oral liquid medicines with solid forms for children over 2 years. The cost savings that could be made if liquid medicines were substituted with an acceptable solid form were determined using NHS prices. Materials and methods Substitution suitability for dispensed liquid medicines during one week (7–13th January 2013) in Birmingham Children’s Hospital was determined (i) screening for existence of a marketed solid oral alternative then (ii) evaluating acceptability of solid forms in terms of posology and pill size depending on children’s age (EMA guidelines). Treatment costs were calculated on the basis of providing treatment for 28 days or prescribed duration for short term treatment. Results Of the 476 liquid medicines dispensed, 90% were available as a marketed solid form. Considering solid form dosage acceptability, 80% of liquid medicines could be substituted with a solid form. Only 41% of liquid formulations could be substituted when additionally considering pill size. Drug cost savings that could follow the substitution of liquid medicine with an acceptable solid form for dosage and size would be £4,951 and £8,550 in one week respectively for hospital and community, corresponding to an estimate projected annual saving of £238K and £410K (one hospital). Conclusions Surprisingly, almost all liquid medicines were available in an acceptable tablet dosage. Whilst not all children over 2 years will be able to swallow tablets, this study has shown the importance of potential drug cost savings if solid forms were used in children and may provide a theoretical basis for teaching how to swallow tablets. No conflict of interest.

SFP P-160 - Evènements indésirables médicamenteux et prescriptions hors AMM chez l’enfant

Objectifs Evaluer le risque de survenue d’evenements indesirables medicamenteux (EIM) associe a la prescription hors AMM chez l’enfant hospitalise. Methode revue systematique de la litterature (2 auteurs) extraite des bases Medline (Janv.1966- Nov.2013) et Cochrane Library. Resultat Nous avons identifie 1 etude primaire (Bellis 2013) et 3 meta-analyses incluant 30 etudes (Pandolfini 2005), 52 etudes (Cuzzolin 2006) et 14 etudes (Masson 2013). Entre 16% et 62% des prescriptions etaient hors AMM ou hors indication, parmi lesquelles 23 a 60% etaient impliquees dans un EIM. Deuxetudes ont montre que l’utilisation de medicaments hors AMM etait significativement associee a un risque superieur de survenue d’EIM(Santos 2008, risque relatif (RR) : 2,44 [2,12–2,89] ; Bellis 2013, RR : 2,25 [2,82–4,44]). L’etude prospective multicentrique EREMI (ANSM) a ete mise en place en France en novembre 2013 afin d’etudier la relation entre le risque d’EIM et la prescription hors AMM au sein de l’hopital Femme-Mere-Enfant (HCL). Conclusion La prescription hors AMM est tres repandue en pediatrie et associee a un risque accru d’EIM. Ces resultats justifient le developpement d’une pharmacovigilance proactive afin de minimiser le risque d’EIM en pediatrie.