PIPs only cover a small proportion of the drugs found to be used off-label in this study. Despite waivers granted, drug substances were used nonetheless. Unmet regulatory needs are still considerable in some therapeutic areas in neonates as well as in children.

IntroductionOne in three Danish children under 3 years of age experience asthma-like symptoms, and one-third will later be diagnosed with asthma. Oral prednisolone is used in various formulations to treat acute asthma. However, the potential differences in bioequivalence between these formulations have never been examined in children despite interchangeable use in clinical practice.Methods and analysisAn open-label, randomised, two-treatment cross-over trial investigating the bioequivalence of different prednisolone formulations in children with airway disease.The included patients (6 months–11 years of age) are admitted to the Department of Paediatric and Adolescent Medicine Nordsjællands University Hospital, Hillerød, with asthma or asthma-like symptoms.The primary objective is to assess the bioequivalence between different prednisolone formulations herein area under the concentration time curve, Cmax and Tmax using saliva samples. The secondary objectives are to evaluate tolerability (five-point face scale), adverse events and severity of the disease. If the patient has an intravenous access for other purposes, the saliva samples will be validated with plasma samples.A total of 66 evaluable patients are needed according to European Medicines Agency Guideline on bioequivalence.Ethics and disseminationTraditional pharmacokinetic trials are burdensome due to the extent of blood samples necessary to capture the time-dependant drug profile. Saliva sampling is far more acceptable for paediatric patients. In addition, this trial adheres to standard dosing strategies. No additional venepunctures are performed, and no additional prednisolone doses are administered.Guidelines for paediatric bioequivalence trials are warranted.Trial registration numberThe Danish Medicines Agency EudraCT: 2017-003590-33, The Ethics Committee case no: H-17027252, and the Danish Data Protection Agency: BFH-2017–103, I-Suite no.: 05935.

IntroductionAnticipated or actual pain in neonates results in use of paracetamol for prolonged pain relief in many neonatal intensive care units. Clinical trials examining safety of paracetamol exposure in neonates have been of short duration (1–3 days) and hepatic biomarkers and paracetamol metabolism are rarely reported in the same studies.We aim to investigate the safety (hepatic tolerance) and effectiveness of prolonged paracetamol exposure in neonates by measuring hepatic biomarkers, plasma concentrations of paracetamol and its metabolites and pain scores. In addition, we study a possible interaction between ethanol and paracetamol.Methods and analysisA multicentre interventional cohort study.Neonates of any gestational age and up to 44 weeks postmenstrual age, treated with oral or intravenous paracetamol can be included.Alanine aminotransferase (ALT) and bilirubin are measured at baseline or within 24 hours after treatment initiation. P-paracetamol and metabolites are measured at steady state and every 2 days (opportunistically) together with ALT and bilirubin and lastly after discontinuation of treatment. COMFORT neo pain scores are collected longitudinally. COMFORT neo pain scores and population pharmacokinetic analysis of paracetamol samples will be analysed simultaneously using non-linear mixed effects models. One and two compartment models with first-order elimination will be tested for disposition. In addition, plasma ethanol is measured if the patient receives concomitant treatment with intravenous or oral phenobarbital containing ethanol as an excipient.Ethics and disseminationInclusion of patients can be postponed 24 hours after the first paracetamol dose. This is intended to make the inclusion process less stressful for parents. This study uses standard dosing strategies. The potential risks are additional blood samples, which are collected opportunistically to reduce additional heel pricks.Trial registrationnumberEthics Comittee: H-17027244, EudraCT no: 2017-002724-25, BFH-2017–106, 05952.

The process is time-consuming as studies are lacking and age-appropriate dosage forms and concentrations differ amongst countries. Nevertheless, the process should be somewhat similar between countries, albeit different drugs may be selected for the final formulary lists.

Treatment strategies for asthma-like symptoms are challenging with no international consensus on dose of systemic glucocorticoids. Despite, asthma-like symptoms remain one of the most common medical conditions seen in infants and preschool children. This is further complicated by limited licensed preparations and use of various extemporaneously prepared formulations in some countries. In Denmark, all extemporaneous formulations are produced according to GMP, which is different from other European countries. This retrospective cohort study examined the type and dose of extemporaneously prepared glucocorticoid formulations prescribed to infants and preschool children 0-5 years of age with acute asthma-like symptoms over a three-year period at three paediatric departments in the Capital Region of Denmark covering 1.8 mill inhabitants. In total 4877 patients were screened for eligibility. In addition, length of hospitalisation, prescribed co-medication, readmission, and adverse events were registered. Almost one in ten of the patients were treated with extemporaneous prednisolone. Eight different formulations were used interchangeably despite lack of studies supporting therapeutic equivalence between these formulations. Further, a higher dose did not result in shorter hospitalisation.