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Accepted manuscript version, licensed CC BY-NC-ND 4.0. Published version available at https://doi.org/10.1136/ejhpharm-2018-001562. Objectives: The main objective was to investigate Y-site compatibility of intravenous drugs with one standard total parenteral nutrition (TPN) admixture for preterm infants. Since micro-precipitation was observed in the water phase after addition of trace elements, the concentration effect on micro-precipitation formation developed as a sub-goal. Methods: Seven drugs (ampicillin, ceftazidime, fluconazole, fosphenytoin, furosemide, metronidazole and paracetamol) were mixed in three mixing ratios with one preterm TPN admixture. Samples were investigated within 1 hour and again after 4 hours. Precipitation was studied in a lipid-free version called TPNaq by light obscuration, turbidimetry and visual examination. Emulsion stability data were assessed by light obscuration and laser diffraction. pH was measured to assess the theoretical risk of precipitation and emulsion destabilisation. The influence of different concentrations of trace elements on precipitation was investigated by visual examination, turbidimetry and light obscuration. Results: Ampicillin, ceftazidime, fosphenytoin and furosemide led to precipitation after mixing with TPNaq. In some samples of TPN and fluconazole, metronidazole and paracetamol, the emulsion droplet size was above the acceptance limit, although this might also be inherent to the TPN admixture. An unexpected formation of micro-precipitate correlating with increasing amounts of added trace elements might be caused by an interaction of cysteine and copper, and complicated the compatibility assessment with drugs. Conclusions: The micro-precipitate resulting from the addition of trace elements should be investigated further. This study did not provide sufficient evidence to recommend Y-site infusion of the tested drugs and the preterm admixture; however, it might offer some additional support to other compatibility data.

ObjectiveThe aim of this study was to assess the marketing status of the new paediatric medicinal products listed in the 10-year report as initially authorised between 2007 and 2016, reflecting the product availability in four Nordic countries.DesignThis is a cross-sectional study.SettingAnalysis of the national medicine agency’s databases in Denmark, Finland, Norway and Sweden.Data sourceNew medicinal products with paediatric indications and new paediatric formulations listed in the Annex of European Medicines Agency’s EU Paediatric Regulation 10-year report.Data analysisThe products were classified according to national marketing status between January 2019 and March 2019, whether a product was authorised and whether the product was marketed.Main outcome measuresThe percentages of the new medicinal products with paediatric indications and new paediatric formulations having a valid marketing authorisation and being marketed, both in terms of the sums of all countries and separately for each country.ResultsAcross the four countries, 21%–32% (16/76–24/76) of the new medicinal products were not marketed. Of the new formulations relevant to children, 29%–50% (16/56–28/56) were not marketed, and a significant proportion of these products had never been marketed.ConclusionsThis study reflects the reality of the implementation of the Paediatric Regulation. The results show that several new paediatric medicines and new formulations are not marketed. This affects the product availability. Similar data from other countries are needed to evaluate the overall European status to find remedies to current situation and increase the availability of the medicines for children.

Background It is generally not recommended to give two drugs together or drugs in addition to total parenteral nutrition in parallel infusion unless compatibility has been documented. The possibility of performing simple compatibility testing in the hospital pharmacy has attracted attention, and visual examination using a focused light source (Tyndall beam) has been suggested as a simple tool for this purpose1. Purpose To investigate the validity and reliability of the Tyndall method using two different light sources, to determine the visual detection limit in terms of particle size and concentration and to evaluate the suitability of the method for simple compatibility testing in a hospital pharmacy setting. Materials and methods A panel of 20 inspectors examined 20 samples, with and without particles, using two different light sources. The samples contained particles of different origin, varying size and concentrations. Light obscuration measurements were used as reference. The samples were classed as accept, grey or reject and the validity (sensitivity, specificity and likelihood ratios (LR)) and reliability (Fleiss’Kappa and Gwets’AC1) of the classifications were calculated. Results Gross particles and massive precipitations were easily detected, but for smaller particles in low concentrations, the inspectors were more uncertain. The LR + ratios were high, indicating that if a sample is rejected, there is a high probability that the samples actually contain particles. The LR- ratios were not low enough, meaning that if a sample is accepted there is still a considerable chance that the sample contains particles. The Fleiss9 Kappa and AC1 indicated only fair to moderate agreement between the inspectors. Conclusions The validity and reliability were not satisfactory using either of the light sources. The visual detection limit seemed to be around 5 µm, but a more data is required. The visual examination method cannot be recommended as the only method for determining compatibility, and it is not suitable for simple compatibility testing at the hospital pharmacies. Acknowledgements Vigdis Staven is a PhD student of Hospital Pharmacy North, Norway, and Dept. of Pharmacy, University of Tromso, Norway, sponsored by Helse Nord RHF. We gratefully acknowledge the financial support from the Norwegian Medicines for Children Network, Bergen, Norway. Thank you to Frode Skjold, Dept. of Pharmacy, University of Tromso, for valuable discussions on the statistical issues, to Margaret Aarag Antonsen, Hospital Pharmacy North and the employees of the Hospital Pharmacy of Tromso, Norway, for discussions, help and practical support. Reference Veggeland, T. & Brandl, M. Evaluation of a Simple Method for Visual Detection of Microprecipitates in Blends of Parenteral Drug Solutions Using a Focused (Tyndall) Light Beam. International Journal of Pharmaceutical Compounding 2010;14:78-81. No conflict of interest.