BackgroundGuidelines for off-label prescribing are emerging.1–6 However, these guidelines do not provide practical guidance to assess the risk benefit balance and select the right paediatric dose We, therefore, aimed to develop a practical framework to guide paediatric healthcare professionals to assess the risks and benefits of off-label use.MethodsWe have reviewed available literature on the suggested criteria for appropriate off-label use and evaluated these criteria for relevance in paediatrics. For guidance on dose-selection we searched for regulatory guidance on paediatric drug development. Next, the literature was searched for strategies that can be applied to assess the risks and benefits of off-label use. Based on literature findings a framework was proposed to provide practical guidance to physicians for off-label prescribing. Finally, the framework was applied to a case.ResultsThe following conditions for appropriate off-label use were identified based on available literature: 1. Medical need for off-label use. 2. Off-label use is based on ‘high quality evidence’. As ‘high quality evidence’ in paediatrics is often lacking-, we propose to replace the need for high quality evidence by a positive risk-benefit assessment based on available evidence. 3. Parents and patients are informed. This is not feasible for every single drug prescribed off-label, we propose a graded approach 4. The outcomes of off-label use are followed up.The PROACT-URL framework7 for decision-making as well as the FDA paediatric decision tree8 seem helpful tools to guide decisions in real-life practice.ConclusionWe identified important aspects and tools to develop a framework (ARBOP-P) to guide healthcare professionals on how to systematically assess and balance the benefits and risks for off-label use, including dose selection, to ultimately optimize efficacy and safety of paediatric off-label prescribing.ReferencesFrattarelli DA, Galinkin JL, Green TP, et al. Off-label use of drugs in children. Pediatrics 2014;133:563–7Online.Dooms M, Killick J. Off-label use of medicines: The need for good practice guidelines. Int J Risk Saf Med. 2017;29:17–23Online.Gazarian M, Kelly M, McPhee JR, Graudins LV, Ward RL, Campbell TJ. Off-label use of medicines: consensus recommendations for evaluating appropriateness. Med J Aust 2006;185:544–8Online.Largent EA, Miller FG, Pearson SD. Going off-label without venturing off-course: evidence and ethical off-label prescribing. Arch Intern Med 2009;169:1745–7Online.Ansani N, Sirio C, Smitherman T, et al. Designing a strategy to promote safe, innovative off-label use of medications. Am J Med Qual 2006;21:255–61Online.Weda M, Hoebert J, Vervloet M, et al. Study on the off-label use of medicinal products in the European Union.: www.ec.europa.com 2017.Hammond J, Keeney R, Raiffa H. Smart Choices:A practical guide to making better decisions. Boston, MA.: Harvard Business School Press.; 2002.Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric drug-development programs...
IntroductionWhile evidence on the pharmacokinetics of midazolam in children in increasing, there is only limited information on the pharmacokinetic-pharmacodynamic relation of midazolam in critically ill children. In this study, we explored the relation between midazolam concentrations and level of sedation using data from a multi-institutional clinical trial1 comparing Daily Sedation Interruption (DSI) with protocolised sedation versus protocolised sedation alone (i.e DSI + PS vs. PS) in critically-ill, mechanically ventilated paediatric ICU (P-ICU) patients.MethodsPharmacokinetic information on midazolam use along with COMFORT and NISS scores from 113 mechanically ventilated P-ICU patients (median age 3 months, range: 0 to 17 years) admitted between 2010 and 2014 were used from the original study.1 Midazolam plasma concentrations at the time of each COMFORT score were calculated using a pharmacokinetic model published on the same dataset.2 Sedation scores were categorised into under-, adequate- and over-sedated categories according to the study protocol.3 ResultsIn total, 6662 COMFORT scores were elicited (3112 and 3550 records for DSI+PS and PS arms, respectively). Patients were observed to be adequately sedated in 4232 (64%) scores, and under- and over-sedated in 720 scores (10%) and 1710 (26%) scores, respectively. For all three sedation categories, median midazolam concentrations were significantly lower in the DSI+PS arm compared to PS (P < 0.001). Generalized multivariate linear mixed-effects modelling identified previously reported over-sedation scores (P < 0.001) in combination with high log-transformed midazolam concentrations (P < 0.001) as predictors of over-sedation in patients. Prior under-sedation, but not individual predicted midazolam concentration, predicted current under-sedation (P < 0.001).ConclusionThese preliminary results suggest a role of previous sedation scores in subsequent sedation scores. Further exploration of these data using Markov modelling seems required to identity the relation between midazolam concentrations and level of sedation in mechanically ventilated P-ICU patients.ReferencesVet NJ, de Wildt SN, Verlaat CW, et al. A randomized controlled trial of daily sedation interruption in critically ill children. Intensive care medicine 2016;42(2):233–44. doi: 10.1007/s00134-015-4136-z [published Online First: 2015/11/26]Vet NJ, Brussee JM, de Hoog M, et al. Inflammation and organ failure severely affect midazolam clearance in critically ill children. American journal of respiratory and critical care medicine 2016;194(1):58–66. doi: 10.1164/rccm.201510-2114OC [published Online First: 2016/01/23]Vet NJ, de Wildt SN, Verlaat CW, et al. Daily interruption of sedation in critically ill children: study protocol for a randomized controlled trial. Trials 2014;15:55. doi: 10.1186/1745-6215-15-55 [published Online First: 2014/02/15]Disclosure(s)Conflict of interest statement: The original trial was supported by project grants from the Netherlands Organization for Health Research and Develop...
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