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Résumé La douleur est un problème courant chez les enfants. Des mesures pharmacologiques et non pharmacologiques sont utilisées pour la prendre en charge. Depuis quelques décennies, les opioïdes par voie orale sont populaires pour soulager la douleur modérée à grave. La codéine a longtemps été l’opioïde par voie orale le plus connu pour les enfants. Pour des raisons de sécurité, elle est désormais nettement moins accessible et moins employée. Divers autres opioïdes la remplacent, mais les données sur leur efficacité et leur sécurité sont limitées chez les enfants. L’oxycodone par voie orale emprunte les mêmes voies métaboliques que la codéine, mais sa pharmacocinétique est très variable. Les données sur la sécurité et l’efficacité de l’hydromorphone et du tramadol par voie orale chez les enfants sont également limitées. Lorsqu’on y recourt au lieu de la codéine, la morphine par voie orale est l’opiacé dont la sécurité et l’efficacité sont les mieux démontrées chez les enfants. Des recherches devront être réalisées pour explorer d’autres approches relatives aux médicaments opioïdes et non opioïdes, afin d’orienter les traitements analgésiques fondés sur des données probantes qui soulageront la douleur modérée à grave chez les enfants.

Key points Children with chronic debilitating illness and pain are increasingly using cannabis for medical purposes, particularly when conventional treatment options have limited benefit or substantial adverse effects. Caregivers are becoming aware of evidence that suggests medical cannabis provides

Background: In Canada and the United States, most families referred for pediatric weight management services do not start treatment. Of families who initiate care, many discontinue before ...

Objective Although anti-Saccharomyces cerevisiae antibodies (ASCAs) could be a useful biomarker in differentiating Crohn disease (CD) from ulcerative colitis (UC), their role as prognostic markers in children with CD has been underinvestigated. This longitudinal prospective observational study aimed to assess the prognostic value of ASCA status among children with CD managed using biologics. Methods The study population comprised children with inflammatory bowel disease diagnosed with CD from 2012 to 2018. Cox regression model with adjustment for a priori covariates was used to examine the response to anti-tumor necrosis factor (TNF) biological therapy among ASCA-positive patients in comparison to ASCA-negative patients. Results There were 273 measurements available from the study cohort comprising children with CD, who were followed up for a median duration of 14 months (interquartile range 5-42). ASCA-positive patients had a higher risk for moderate to severe clinical disease (odds ratio 2.88; 95% confidence interval [CI] 1.2-7.55) and extensive endoscopic distribution (odds ratio 3.30; CI 1.12-9.74) at baseline in comparison to ASCA-negative patients, respectively. In comparison to ASCA immunoglobulin G (IgG)-negative patients, ASCA IgG-positive patients who were treated with biologics had a significantly lower relapse rate (adjusted hazard ratio 0.12; CI 0.02-0.93). Ten (14%) patients had an unstable ASCA value with either ASCA immunoglobulin A or ASCA IgG status changing from positive to negative or vice versa. Conclusions ASCA-positive children with CD present with more extensive (endoscopic) and clinically severe disease. ASCA IgG is a useful prognostic marker among children with CD who receive biologics.

There is some evidence to date that those with asthma are overrepresented among the adult patients who have been admitted to hospital with coronavirus disease 2019 (COVID-19).[1][1],[2][2] This overrepresentation may occur because severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggers

Objective Mood and anxiety disorders (MADs) are common conditions with multiple aetiologies. Exposure to antibiotics has been proposed as a possible risk factor in animal studies. We aimed to assess maternal antibiotic use in pregnancy and child antibiotic use in the first three years of life, collectively called early life, as potential risk factors for subsequent development of MADs during childhood and adolescence. Methods A population-based retrospective cohort study was conducted including 221,139 children born in Manitoba, Canada between 1996 and 2012. Exposure was defined as having filled one or more antibiotic prescriptions during early life. Children were followed until the earliest MADs diagnoses, 19th birthday, migration, death, or end of the study period. We computed crude and adjusted hazard ratios (aHRs) with corresponding 95% confidence intervals (CIs) using Cox proportional hazard regression. Results Children born to mothers who received one or more antibiotic courses in pregnancy had significantly higher rates of MADs compared with non-exposed children (aHR 1.08, 95% CI 1.03,1.13). Overall antibiotic exposure during the first three years of life was not significantly associated with MADs (aHR 1.00, 95% CI 0.94,1.07). A significantly increased risk of MADs was observed after postnatal exposure to tetracyclines, aminoglycosides, quinolones (33%) or sulfonamides and trimethoprim (28%). Postnatal exposure to macrolides, lincosamides, and streptogramins significantly reduced the risk of MADs by 16%. Conclusion Early life exposure to antibiotics is associated with different risk effects on MADs in children. The apparent associations may have been confounded by indication and may not be clinically meaningful.

Wernicke encephalopathy (WE) and Korsakoff psychosis (KP), together termed Wernicke–Korsakoff syndrome (WKS), are distinct yet overlapping neuropsychiatric disorders associated with thiamine deficiency. Thiamine pyrophosphate, the biologically active form of thiamine, is essential for multiple biochemical pathways involved in carbohydrate utilization. Both genetic susceptibilities and acquired deficiencies as a result of alcoholic and non-alcoholic factors are associated with thiamine deficiency or its impaired utilization. WKS is underdiagnosed because of the inconsistent clinical presentation and overlapping of symptoms with other neurological conditions. The identification and individualized treatment of WE based on the etiology is vital to prevent the development of the amnestic state associated with KP in genetically predisposed individuals. Through this review, we bring together the existing data from animal and human models to expound the etiopathogenesis, diagnosis, and therapeutic interventions for WE and KP.

BACKGROUND: Inflammatory bowel disease (IBD) is a collective term for diseases involving inflammation of the gastrointestinal tract, among which Crohn’s disease (CD) and ulcerative colitis (UC) are the two main sub-categories. Although Anti-Saccharomyces cerevisiae antibodies (ASCA) could be a useful biomarker in differentiating CD from ulcerative colitis UC, their role as prognostic markers in children with CD has been under-investigated. AIMS: Our longitudinal study aimed to assess the stability of ASCA status over time and the possibility of an association between ASCA-positive childhood CD and disease relapse during clinical follow-up. We also investigated the role of ASCA status as a prognostic marker of response to Anti-TNF biological therapy among children with CD. METHODS: The study population comprised of children with inflammatory bowel disease (IBD) diagnosed with CD from 2012 to 2018. Cox-regression model with adjustment for a priori covariates was used to examine the risk of disease relapse and response to biological therapy among ASCA positive patients in comparison to ASCA negative patients. The models were adjusted for age at diagnosis, sex, history of CD in the first-degree relatives, luminal disease distribution at baseline, pharmacological therapy and baseline clinical disease activity. RESULTS: A total of 273 measurements from 72 CD patients (mean age at diagnosis of 12.17±3.17 years), who were followed up for a median duration of 14 months (IQR: 5–42) were included. ASCA positive patients had a higher risk for moderate to severe clinical disease and extensive distribution at baseline in comparison to ASCA negative patients, (odds ratio (OR): 2.88; 95% confidence interval (CI): 1.2–7.55) (OR: 3.30; 95% CI: 1.12–9.74) respectively. In comparison to ASCA IgG negative patients, ASCA IgG positive patients who were treated with biologics had a significantly lower relapse rate (aHR: 0.12; 95% CI: 0.02–0.93). Ten (14%) patients had an unstable ASCA value with either ASCA IgA or ASCA IgG status changing from positive to negative or vice versa. CONCLUSIONS: ASCA positive children with CD present with more extensive and clinically severe disease. ASCA IgG is a useful prognostic marker among children with CD who receive biologics. [Image: see text] Survival plots for disease relapse during follow-up among biological therapy naïve children with Crohn’s disease (a and c) compared to those who were treated with biological therapy (b and d). (adjusted for age at diagnosis, sex, family history of IBD, luminal disease distribution at baseline, non-biologic pharmacological therapy and baseline disease severity) FUNDING AGENCIES: Children’s Hospital Research Institute of Manitoba

Selon les donnees recueillies a ce jour, les personnes asthmatiques seraient surrepresentees parmi les adultes hospitalises pour la COVID-19 (maladie a coronavirus 2019)[1][1],[2][2]. Cette surrepresentation pourrait etre due au fait que le SRAS-CoV-2 (coronavirus du syndrome respiratoire

textabstractAims Low-dose aspirin (LDA) and non-steroidal-anti-inflammatory drugs (NSAIDs) both increase the risk of upper gastrointestinal events (UGIEs). In the Netherlands, recommendations regarding the prescription of gastroprotective agents (GPAs) in LDA users were first issued in 2009 in the HARM-Wrestling consensus. National guidelines on gastroprotective strategies (GPSs) in NSAID users were issued in the first part of the preceding. The aim of the present study was to examine time-trends in GPSs in patients initiating LDA and those initiating NSAIDs between 2000 and 2012. Methods Within a large electronic primary healthcare database, two cohorts were selected: (i) patients newly prescribed LDA and (ii) patients newly prescribed NSAIDs between 2000 and 2012. Patients who had been prescribed a GPA in the previous six months were excluded. For both cohorts, patients risk of a UGIE was classified as low, moderate or high, based on the HARM-Wrestling consensus, and the presence of an adequate GPSwas determined. Results A total of 37 578 patients were included in the LDA cohort and 352 025 patients in the NSAID cohort. In both cohorts, an increase in GPSs was observed over time, but prescription of GPAs was lower in the LDA cohort. By 2012, an adequate GPS was present in 31.8% of high-risk LDA initiators, vs. 48.0% of high-risk NSAID initiators. Conclusions Despite a comparable risk of UGIEs, GPSs are prescribed less in high-risk LDA initiators than in high-risk NSAID initiators. For both groups of patients, there is still room for improvement in guideline adherence.

Objective. To determine how often patients with musculoskeletal (MSK) complaints prescribed a non-steroidal anti-inflammatory drug (NSAID) subsequently consult their general practitioner (GP) with a non-serious adverse drug reaction (ADR). Design. Cohort study. Setting. A healthcare database containing the electronic GP medical records of over 1.5 million patients throughout the Netherlands. Patients. A total of 16 626 adult patients with MSK complaints prescribed an NSAID. Main outcome measures. The patients' medical records were manually assessed for the duration of NSAID use for a maximum of two months, and consultations for complaints predefined as potential ADRs were identified. Subsequently, the likelihood of an association with the NSAID use was assessed and these potential ADRs were categorized as likely, possible, or unlikely ADRs. Results. In total, 961 patients (6%) consulted their GP with 1227 non-serious potential ADRs. In 174 patients (1%) at least one of these was categorized as a likely ADR, and in a further 408 patients (2.5%) at least one was categorized as a possible ADR. Dyspepsia was the most frequent likely ADR, followed by diarrhoea and dyspnoea (respectively 34%, 8%, and 8% of all likely ADRs). Conclusion. Of the patients with MSK complaints prescribed an NSAID, almost one in 30 patients re-consulted their GP with a complaint likely or possibly associated with the use of this drug. The burden of such consultations for non-serious ADRs should be taken into account by GPs when deciding whether treatment with an NSAID is appropriate.

Conduct of clinical trials is perceived to be more challenging in children than in adults. This study aimed to evaluate the impact of the age of participants on completion rates of randomized controlled trials (RCTs).A cross-sectional study on RCTs registered in the ClinicalTrials.gov database. All RCTs registered up to December 31, 2016, were extracted and were classified according to their recruitment status: active, completed, or discontinued and according to the age of participants: children (17 years), adults (≥18 years), and mixed-age population. A logistic regression model was applied to assess the impact of participant's age category on trial completion while controlling for other relevant trial features.A total of 65,095 registered RCTs were identified. Among pediatric trials, 49.9% were completed and 8.5% were discontinued. Among adult and mixed age RCTs, respectively, 49.7% and 47.9% were completed whereas, 10.2% and 9.4% were discontinued. Overall, pediatric and mixed age RCTs were more likely to be registered as completed than adult RCTs (odds ratio: 1.16, 95% CI: 1.02-1.30; odds ratio: 1.15, 95% CI: 1.04-1.27, respectively). Also, funding source, type of intervention under evaluation, primary trial purpose, use of a blinding procedure, use of a placebo, and participants' assignment model were identified as independent predictors of RCT completion.Contrary to current perceptions and despite several specific challenges, recruitment of children and adolescents is not a limiting factor to completing a RCT. Other study features such as funding source, impact completeness and should be carefully considered before initiating research.

Contains fulltext : 127746.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The Dutch HARM-Wrestling (HW) Task Force issued general and drug-specific recommendations aimed at reducing hospital admissions related to medication (HARMs). This study examines if the drug-specific recommendations could be converted into indicators that could be monitored in existing databases of general practitioner (GP) or community pharmacy (CP) data. The study also assesses the performance of these indicators before and during the official release of HW recommendations. METHODS: HW recommendations were divided into sub-recommendations. We studied to what extent these were measurable as indicators based on available information in both databases. For each measurable indicator, performance between 2007 and 2010 was determined and possibilities for further improvement were estimated. RESULTS: Thirty-four drug-specific HW recommendations were divided into 69 sub-recommendations, 32 of which were measurable as indicator in at least one of the databases. Application of these indicators between 2007 and 2010 showed that many of the indicators did not change over time. Possibilities for further improvement were estimated as moderate to major for 16/31 (52%) indicators measured in the GP database and 6/15 (40%) HW indicators measured in the CP database. CONCLUSIONS: Further implementation of the HW recommendations and development of additional monitoring methods are warranted to improve drug safety in outpatients.

Background An association between PPHN and antidepressant use in pregnancy has been reported. Purpose We sought to examine this relationship. Methods A review of the literature was performed, to evaluate this association. Results Six published studies fulfilled our criteria for inclusion, with only three studies large enough to have the power to detect an association. There appears to be a small but significantly, increased risk of late pregnancy SSRI exposure associated with PPHN in one case–control study; OR 5.1 (95% CI, 1.9–13.3) and two large cohort studies; RR 2.56; (95% CI, 1.17–4.85) and OR 2.1 (95% CI, 1.5–3.0) The other three studies did not find an association. Conclusion the absolute risk cannot be determined, but it is very small, probably less than 1%. If a pregnant woman requires pharmacological treatment, this information does not support discontinuation or lowering the dose of the antidepressant.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cough and cold medicines are frequently used in children to treat upper respiratory tract infections without solid proof of benefits. • Safety issues have been raised about the use of these drugs in young children. • In 2007 international warnings were issued advising against use of these drugs in young children. WHAT THIS STUDY ADDS • Cough and cold medicines prescribing by primary care physicians has not really been influenced by international warnings in the Netherlands, where no additional national warnings were made and only partially in Italy. • A concerted action should be taken in Europe to advise strongly against the OTC use and prescription of cough and cold medicines in young children. AIM The aim of the study was to assess the influence of national and international warnings on the prescription rates of cough and cold medicines (CCMs) in the youngest children (

Aliment Pharmacol Ther 2011; 33: 77–88 Summary Background The association between myocardial infarction (MI) and co-administration of proton pump inhibitors (PPIs) and clopidogrel remains controversial. Aim To quantify the association between concomitant use of PPIs and clopidogrel and occurrence of recurrent MI. Methods We conducted a case–control study within a cohort of acute MI patients in PHARMO Record Linkage System (1999–2008). The cases were patients readmitted for MI. PPI exposure was categorized as current (3–1 days before MI), past (30–3 days before MI), or no use (>30 days before MI). We used conditional logistic regression analyses. Results Among 23 655 patients hospitalized following MI, we identified 1247 patients readmitted for MI. Among clopidogrel users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.62, 95% CI: 1.15–2.27) when compared with no PPI use, but not when compared with past PPI use (OR: 0.95, 95% CI: 0.38–2.41). Among clopidogrel non-users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.38, 95% CI: 1.18–1.61) when compared with no PPI use. Conclusions The apparent association between recurrent MI and use of PPIs with clopidogrel depends on the design, and is affected by confounding by indication. The association is not present when (un)measured confounding is addressed by design.

Asthma drugs are amongst the most frequently used drugs in childhood, but international comparisons on type and indication of use are lacking. The aim of this study was to describe asthma drug use in children with and without asthma in the Netherlands (NL), Italy (IT), and the United Kingdom (UK). We conducted a retrospective analysis of outpatient medical records of children 018 years from 1 January 2000 until 31 December 2005. For all children, prescription rates of asthma drugs were studied by country, age, asthma diagnosis, and off-label status. One-year prevalence rates were calculated per 100 children per patient-year (PY). The cohort consisted of 671,831 children of whom 49,442 had been diagnosed with asthma at any time during follow-up. beta 2-mimetics and inhaled steroids were the most frequently prescribed asthma drug classes in NL (4.9 and 4.1/100 PY), the UK (8.7 and 5.3/100 PY) and IT (7.2 and 16.2/100 PY), respectively. Xanthines, anticholinergics, leukotriene receptor antagonists, and anti-allergics were prescribed in less than one child per 100 per year. In patients without asthma, beta 2-mimetics were used most frequently. Country differences were highest for steroids, (Italy highest), and for beta 2-mimetics (the UK highest). Off-label use was low, and most pronounced for beta 2-mimetics in children

Antibiotic use during infancy alters gut microbiota and immune development and is associated with an increased risk of childhood asthma. The impact of prenatal antibiotic exposure is unclear. We sought to characterise the association between prenatal antibiotic exposure and childhood asthma.We performed a population-based cohort study using prescription records, hospitalisation records and physician billing claims from 213 661 mother–child dyads born in Manitoba, Canada between 1996 and 2012. Associations were determined using Cox regression, adjusting for maternal asthma, postnatal antibiotics and other potential confounders. Sensitivity analyses evaluated maternal antibiotic use before and after pregnancy.36.8% of children were exposed prenatally to antibiotics and 10.1% developed asthma. Prenatal antibiotic exposure was associated with an increased risk of asthma (adjusted hazard ratio (aHR) 1.23, 95% CI 1.20–1.27). There was an apparent dose response (aHR 1.15, 95% CI 1.11–1.18 for one course; aHR 1.26, 95% CI 1.21–1.32 for two courses; and aHR 1.51, 95% CI 1.44–1.59 for three or more courses). Maternal antibiotic use during 9 months before pregnancy (aHR 1.27, 95% CI 1.24–1.31) and 9 months postpartum (aHR 1.32, 95% CI 1.28–1.36) were similarly associated with asthma.Prenatal antibiotic exposure was associated with a dose-dependent increase in asthma risk. However, similar associations were observed for maternal antibiotic use before and after pregnancy, suggesting the association is either not directly causal, or not specific to pregnancy.

Non-alcoholic fatty liver (NAFL) disease (NAFLD) affects 30% of overweight adolescents and increases the risk of type 2 diabetes mellitus (T2D). Resveratrol is a naturally occurring compound with potential to reverse NAFL and its associated insulin resistance in adults. The use of resveratrol to reduce risk for T2D through its effect on NAFL has not been examined to date in youth. This paper provides a literature review and protocol for a 30 day proof of principle trial of resveratrol in a population of adolescents at risk for T2D. This randomized double-blind controlled trial is designed with the primary objective of evaluating a twice daily supplementation of 75 mg of resveratrol for safety and tolerability in overweight and obese adolescent subjects (13 to

Many respiratory drugs are not available in formulations suitable for infants and toddlers. Efficacy and safety research is mostly restricted to older children. However, respiratory drugs are frequently used in children for common diseases like asthma, upper and lower respiratory tract infections, rhinitis and sinusitis. The unlicensed and off-label use of respiratory drugs in children were studied. A population-based cohort study was conducted by using the computerised medical records in the Integrated Primary Care Information project. The study population comprised a random sample from all children aged 0-16 yrs who were registered with a general practitioner in 1998. All prescriptions for respiratory drugs during the study period were classified according to their licensing and off-label status. The study population comprised 13,426 patients (51.7% male, median age 8.7 yrs), of whom 2,502 (19%) received 5,253 prescriptions for respiratory drugs in 1998. A total of 3,306 (62.9%) prescriptions concerned licensed drugs. Of the remaining 1,947 prescriptions (37.1%), 882 (16.8%) were unlicensed for use in children, and 1,065 (20.3%) were prescribed off-label. The 1-yr cumulative risk of receiving an unlicensed or off-label prescription was 45% among children with at least one prescription for a respiratory drug. This population-based study showed that a large proportion of respiratory drugs prescribed by the general practitioner are unlicensed for use in children, or licensed but prescribed in an off-label manner. Results have to be interpreted with caution because they may unjustly suggest inaccurate prescribing, whereas it may be difficult to treat children with respiratory symptoms and diseases, because for many respiratory drugs paediatric data on safety and efficacy are insufficient. These findings underline the importance of research on suitable formulations, dosages and efficacy of respiratory drugs in children.

Objectives: In the light of the undesired effects that unlicensed and off-label drug use might have, it is necessary to study the determinants affecting the prescribing of such drugs. Prescription of drugs to children younger than the minimum licensed age may carry the highest risk of adverse reactions. To obtain insight into the factors that affect prescription of drugs to children below the minimum licensed age, we conducted a population-based case-control study. Methods: The case-control study was nested in a cohort of 13,426 children aged 0–16 years, who were registered in the Integrated Primary Care Information (IPCI) project, a longitudinal observational general practitioners' database in the Netherlands. "Cases" were children who received a drug prescription for which they were below the minimum licensed age. To each case we matched up to four controls based on GP practice and patient age. As potential risk factors we evaluated the use of health care resources, and acute and chronic morbidity. Results: We identified 447 cases who were matched to 1355 controls. The cases consulted their GPs significantly more often during the preceding half year, had more drug prescriptions, and had more specialist referrals than the controls. Respiratory diseases were the most important determinants for the prescription of drugs to children below the minimum licensed age. In adolescents, migraine and other headaches were the most important reasons. Conclusions: This study showed that children suffering from respiratory disease or migraine have the highest risk of receiving a drug prescription for which the patient is below the minimum licensed age. Regulatory authorities and the pharmaceutical industry should be stimulated to improve the evaluation of drug efficacy and safety in children.

Objectives. Many drugs used in paediatric care are not licensed for that use or are prescribed outside the terms of the product license (off-label). Studies in the UK and Europe showed a large number of unlicensed and off-label drug prescription in specialised paediatric health care centres. We determined the extent and nature of use of unlicensed drugs and off-label prescriptions in children in a general hospital in the Netherlands. Methods. We conducted a longitudinal prospective cohort study in a dynamic population consisting of patients admitted to the paediatric ward and the neonatology unit of a general hospital during a 19-week period. Drug-licensing status of all prescriptions given to these patients was determined. Results. A total of 1017 prescriptions was administered to 293 paediatric patients for 114 different drugs. The median number of prescriptions per patient was three (interquartile range 2–5). The most commonly administered drugs were acetaminophen (14%), cefotaxime (8%), amoxicillin (7%), caffeine (4%) and prednisolone (4%). Four hundred and forty-three (44%) prescriptions were off-label, and 285 (28%) were for unlicensed drugs. Ninety-two percent of patients received one or more unlicensed or off-label prescriptions, and this proportion was significantly higher in children below 6 months of age than in older children. Conclusions. This study shows that the extent of unlicensed and off-label drug prescription in a paediatric ward and neonatology unit of a general hospital is large and not smaller than in an academic paediatric setting. Lack of paediatric drug labelling is therefore not solely a problem with drugs used in university hospitals, but also in general hospitals. Efforts must be taken to change the current situation.

The Rosalind and Morris Goodman Family Paediatric For-mulations Centre of the CHU Sainte-Justine is a new non-profit organisation dedicated to supporting the development of safe and efficacious medicines that have a child-friendly formulation. One way of providing these paediatric medicines is to partner with industry to promote commercialising of a suitable paediatric formu-lation for commonly used medicines currently only avail-able in adult formulations. Working with all stakeholders including, pharmacists, paediatricians, Health Canada and the pharmaceutical industry, the Goodman Centre has identified commonly used off-label medicines that are currently compounded in pharmacies to produce pedi-atric formulations. In many cases, paediatric formulations and indications are available in other jurisdictions yet they have not been submitted by industry to Health Canada for regulatory approval. Using this novel approach, the Centre is to partnering with pharmaceutical companies to use existing data that has been submitted in other jurisdictions for Canadian approval. We will provide an overview of the Goodman Centre and outline the novel approach developed to improve access to paediatric for-mulations that we have undertaken.

Background. The treatment of pediatric patients with drugs in hospitals is being impeded by a shortage in the availability of licensed drugs in an appropriate formulation. We have studied the extent of use of drugs that are not licensed for use in children (unlicensed) and drugs that are used outside the terms of the product license (off-label). We conducted this study in a Dutch academic children's hospital. Methods. In a prospective study of 5 weeks' duration, we reviewed drug prescriptions in a pediatric ward and 3 intensive care units. We classified the prescribed drugs in 3 main categories—licensed, unlicensed, and off-label—and determined the nature of their unlicensed and off-label use. Results. Two thousand one hundred thirty-nine courses of drugs were administered to 237 patients in 442 patient-days. Of 2139 prescriptions, 725 (34%) were licensed, 1024 (48%) were unlicensed, and 390 (18%) were off-label. In 392 (90%) of 435 patient-days, children received 1 or more courses of an unlicensed or off-label drug prescription in hospital. Conclusion. With regard to the availability of drugs of proven quality and adequate license for pediatric patients in hospital, dramatic shortcomings exist. As a result, drug legislation originally designed to protect patients and prescribing physicians against unsafe drug use and unjustified claims has turned into an insurmountable threshold to make proper drugs available for a vulnerable minority of patients.

Background Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project. Methods We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0–18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children. Results The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest). Conclusions Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children.

Acute liver failure is idiopathic and drug-related in, respectively, around 50 and 15 % of children. Population-based, epidemiologic data about the pattern of disease manifestation and incidence of less severe acute liver injury, either idiopathic or potentially drug-attributed are limited in children and adolescents. (i) To assess the incidence of idiopathic acute liver injury (ALI) and its clinical features in children and adolescent outpatients; and (ii) to investigate the role of the drug as a potential cause of ALI which is considered idiopathic. A retrospective cohort study was performed during the years 2000-2008. Data were retrieved from three longitudinal electronic healthcare databases in two European countries: Pedianet and Health Search/CSD Longitudinal Patient Database from Italy and the Integrated Primary Care Information database from The Netherlands. Cases of idiopathic acute liver injury in population aged < 18 years were identified by exclusion of all competing causes of liver injury (e.g. viral, autoimmune hepatitis), according to CIOMS criteria. The potential role of drug exposure as actual underlying cause of idiopathic ALI was detected through signal detection mining techniques. Both pooled and country-specific incidence rates [IR/100,000 person-years (PYs)] of idiopathic ALI and pooled adjusted rate ratios (RR) of drugs identified as a potential cause of idiopathic ALI, plus 95 % confidence intervals (CI) were estimated using the custom-built software Jerboa. Among 785 definite cases of idiopathic ALI, the pooled IR was 62.4/100,000 PYs (95 % CI 58.1-66.8). The country-specific IR was higher in Italy (73.0/100,000 PYs, 95 % CI 67.8-78.4) than in The Netherlands (21.0/100,000 PYs, 95 % CI 16.0-27.2) and increased with age in both countries. Isolated elevations of liver enzymes were reported in around two-thirds of cases in Italy, while in The Netherlands the cases were more often identified by a combination of signs/symptoms. Among drugs detected as potential underlying cause of idiopathic ALI, clarithromycin (RR 25.9, 95 % CI 13.4-50), amoxicillin/clavulanic acid (RR 18.6, 95 % CI 11.3-30.6), and amoxicillin (RR 7.5, 95 % CI 3.4-16.8) were associated with the highest risk compared to non-use. The incidence of idiopathic ALI in paediatrics is relatively low and comparable with adults. Clinical presentations differ between the two European countries. Signal detection in healthcare databases allowed identifying antibiotics as the drugs mostly associated with ALI with apparently unknown aetiology.

Increasingly, patient information is stored in electronic medical records, which could be reused for research. Often these records comprise unstructured narrative data, which are cumbersome to analyze. The authors investigated whether text mining can make these data suitable for epidemiological studies and compared a concept recognition approach and a range of machine learning techniques that require a manually annotated training set. The authors show how this training set can be created with minimal effort by using a broad database query.The approaches were tested on two data sets: a publicly available set of English radiology reports for which International Classification of Diseases, Ninth Revision, Clinical Modification code needed to be assigned and a set of Dutch GP records that needed to be classified as either liver disorder cases or noncases. Performance was tested against a manually created gold standard.The best overall performance was achieved by a combination of a manually created filter for removing negations and speculations and rule learning algorithms such as RIPPER, with high scores on both the radiology reports (positive predictive value = 0.88, sensitivity = 0.85, specificity = 1.00) and the GP records (positive predictive value = 0.89, sensitivity =0.91, specificity =0.76).Although a training set still needs to be created manually, text mining can help reduce the amount of manual work needed to incorporate narrative data in an epidemiological study and will make the data extraction more reproducible. An advantage of machine learning is that it is able to pick up specific language use, such as abbreviations and synonyms used by physicians.

ObjectiveTo confirm that gentamicin 5 mg/kg/dose every 48 hours in neonates less than 35 weeks corrected gestational age (CGA) results in the majority of gentamicin serum trough levels within the range of 0.5–2 mg/L and peak levels within the range of 6–12 mg/L.DesignProspective pharmacokinetic (PK) analysis.SettingTwo neonatal intensive care units and one intermediate care unit in two tertiary care centres. Patients: Neonates less than 35 weeks CGA who received empiric gentamicin for sepsis between March 10 and June 10, 2014 in whom at least one gentamicin serum level was measured. Methods: PK analysis was performed following implementation of empiric dosing for gentamicin of 5 mg/kg every 48 hours in neonates.ResultsMean Cl, t1/2 and V1 were 42±10 mL/kg/h, 10.0±1.8 h, and 0.58±0.09 L/kg, respectively (n=54). A one-compartment pharmacokinetic model best represented the data. The mean Cl of gentamicin at 24 h post dose was significantly lower in neonates.ConclusionsGentamicin 5 mg/kg q48h results in serum post dose levels between 6–12 mg/L 98% of the time compared to 5% of the time for once daily doses of 2.5 or 3 mg/kg. Gentamicin doses of 5 mg/kg q48h resulted in serum pre levels less than 0.5 mg/L 82% of the time (48 h post dose) compared to 9% of the time for once daily doses (24 h post dose). Increased clearance with advanced PNA suggests the need for more frequent dosing in neonates >14 days of age.

In 1997, Beers and colleagues developed explicit criteria for potentially inappropriate drug prescribing in ambulatory older adults aged 65 years and over. Several studies have been performed to estimate the prevalence of inappropriate drug prescribing based on these criteria. In 2002, the criteria were updated.To examine the extent and trend of inappropriate drug prescribing to ambulatory older adults in the Netherlands between 1997 and 2001, according to the 1997 and the updated Beers criteria.Data were retrieved from the Integrated Primary Care Information (IPCI) project, a general practice research database with data from computer-based patient records of a group of 150 general practitioners in the Netherlands. All subjects aged 65 and over were included. Prescriptions were classified as inappropriate if they fulfilled the Beers criteria of prescriptions that generally should be avoided in older adults because of a high risk of adverse effects, while also considering dose and comorbidity.Between 1997 and 2001, the 1-year risk of receiving at least one inappropriate drug prescription for older adults ranged between 16.8% (95% CI: 16.3-17.3%) and 18.5% (18.3-18.7%) according to the 1997 criteria and between 19.1% (18.6-19.6%) and 20.0% (19.5-20.5%) according to the updated Beers criteria. According to the updated criteria, the most frequently prescribed inappropriate drugs were nitrofurantoin, long-acting benzodiazepines, amitriptyline, promethazine and cimetidine. Temazepam and zolpidem were mostly prescribed in supratherapeutic dose. Conventional NSAIDs in persons with a history of gastric/duodenal ulcer were the most frequently prescribed contra-indicated drugs.Prescribing potentially inappropriate prescriptions to ambulatory older people in the Netherlands is substantial. Compared with other studies using the 1997 Beers criteria, inappropriate prescribing to the elderly is lower than in the USA but similar to Finland. Despite a restrictive medication policy and a growing attention for medication surveillance in Europe, inappropriate drug prescribing is still a substantial problem.

Epidemiological studies suggest that certain glucose lowering drugs may increase or reduce the risks of cancer among patients with type 2 diabetes. The objective of this study was to compare different glucose lowering drugs with respect to the risk of developing adenocarcinoma.

Background: Antipsychotics have been associated with prolongation of the corrected QT interval and sudden cardiac death. Only a few epidemiological studies have investigated this association. We performed a case-control study to investigate the association between use of antipsychotics and sudden cardiac death in a well-defined community-dwelling population. Methods: We performed a population-based case-control study in the Integrated Primary Care Information (IPCI) project, a longitudinal observational database with complete medical records from 150 general practitioners. All instances of death between January 1, 1995, and April 1, 2001, were reviewed. Sudden cardiac death was classified based on time between onset of cardiovascular symptoms and death. For each case, up to 10 random controls were matched for age, sex, date of sudden death, and practice. Exposure at the index date was categorized as 3 mutually exclusive groups of current use, past use, and nonuse. Results: The study population comprised 554 cases of sudden cardiac death. Current use of antipsychotics was associated with a 3-fold increase in risk of sudden cardiac death. The risk of sudden cardiac death was highest among those using butyrophenone antipsychotics, those with a defined daily dose equivalent of more than 0.5 and short-term (≤90 days) users. The association with current antipsychotic use was higher for witnessed cases (n=334) than for unwitnessed cases. Conclusions: Current use of antipsychotics in a general population is associated with an increased risk of sudden cardiac death, even at a low dose and for indications other than schizophrenia. Risk of sudden cardiac death was highest among recent users but remained elevated during long-term use.

In May 2000 in the Netherlands, the manufacturer of terbinafine, Novartis, started a nationwide “information campaign” which included television advertisements advising people with onychomycosis to visit their general practitioner. The Dutch Society of General Practitioners objected to this campaign as an unnecessary focus on an unimportant health problem.1 In the Netherlands, terbinafine and itraconazole are available as oral treatments for onychomycosis, but the Society's guidelines recommend terbinafine.2 3 In May 2002, a Dutch court decided that Novartis's campaign did not violate laws prohibiting advertising of prescription drugs as neither Novartis nor terbinafine were specifically named1; however, Novartis stopped the campaign in July 2002. We studied the changes in rates of prescriptions of oral terbinafine and itraconazole and the consultation rate before and after the start of the campaign. We retrieved all …

Background:Neonates are commonly exposed to maternal codeine through breast milk. Central Nervous System (CNS) depression has been reported in up to 24% of nurslings following codeine exposure. In 2009, we developed guidelines to improve the safety of codeine use during breastfeeding based on previously established pharmacogenetic and clinical risk factors. The primary objective of this study was to prospectively evaluate the effectiveness of these guidelines in ensuring neonatal safety.Methods and Findings:Women taking codeine for pain following caesarean section were given safety guidelines, including advice to use the lowest codeine dose for no longer than four days and to switch to a non-opioid when possible. Mothers provided a saliva sample for analysis of genes involved in opioid disposition, metabolism and response. A total of 238 consenting women participated. Neonatal sedation was reported in 2.1% (5/238) of breastfeeding women taking codeine according to our safety guidelines. This rate was eight fold lower than that reported in previous prospective studies. Women reporting sedated infants were taking codeine for a significantly longer period of time (4.80±2.59 days vs. 2.52±1.58 days, p = 0.0018). While following the codeine safety guidelines, mothers were less likely to supplement with formula, reported lower rates of sedation in themselves and breastfed more frequently throughout the day when compared to previously reported rates. Genotyping analysis of cytochrome p450 2D6 (CYP2D6), uridine-diphosphate glucuronosyltransferase (UGT) 2B7, p-glycoprotein (ABCB1), the mu-opioid receptor (OPRM1) and catechol-o-demethyltransferase (COMT) did not predict codeine response in breastfeeding mother/infant pairs when following the safety guidelines.Conclusions:The only cases of CNS depression occurred when the length of codeine use exceeded the guideline recommendations. Neonatal safety of codeine can be improved using evidence-based guidelines, even in those deemed by genetics to be at high risk for toxicity. © 2013 Kelly et al.

Background To reduce adverse drug events (ADEs), clinical guidelines recommend cautious prescription of non-steroidal anti-inflammatory drugs (NSAIDs) in patients known to be at a high risk of developing a serious ADE. General practitioners (GPs) frequently prescribe NSAIDs in the treatment of musculoskeletal complaints (MSC). Objectives To determine the extent of prescription and of potentially harmful prescription of NSAIDs in a primary care population with MSC. Methods Data were retrieved from the Integrated Primary Care Information (IPCI) database, a longitudinal GP research database containing over one million patient records1. All new episodes of MSC occurring in adult patients (≥18 years) between 2000 and 2010 were identified based on the International Classification of Primary Care (ICPC)-coding. An episode was considered new if the patient had not consulted their GP for the same complaint in the six months prior to consultation. For all episodes, NSAID prescriptions issued on the day of consultation were subsequently identified. NSAID prescriptions were considered potentially harmful if given to patients at a high risk of adverse events at the time of NSAID prescription, defined as a high renal risk (glomerular filtration rate 70 years, or two or more of the following: age 60-70 years, history of heart failure, diabetes or severe rheumatoid arthritis, use of antithrombotics, corticosteroids, selective serotonin reuptake inhibitors or high dose NSAIDs) without adequate concomitant gastroprotection (either a cox-2 selective inhibitor or a non-selective NSAID with concomitant proton pump inhibitor, misoprostol or histamine-2 receptor antagonist). Results In total, 1,632,005 episodes of MSC occurred in 474,201 adult patients between 2000 and 2010. In 401,473 (24.6%) of these episodes, concerning 221,539 (46.7%) of all patients, an NSAID was prescribed. The percentage of NSAID prescriptions decreased over time, from 29.5% in 2000 to 21.2% in 2010 (p Conclusions Although prescription rates have decreased significantly over time, GPs still routinely treat MSC with NSAIDs. Patients’ risk profiles are not sufficiently taken into account in one tenth of prescriptions, particularly in patients at a high risk of serious gastro-intestinal ADEs. References Vlug AE, et al. Postmarketing surveillance based on electronic patient records: the IPCI project. Methods Inf Med 1999;38:339-44. Disclosure of Interest None Declared

Background The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with serious adverse drug events (ADEs)1. In many countries, including the Netherlands, NSAIDs are available over-the-counter (OTC). Objectives To determine the prevalence of OTC NSAID use in the general population and in patients with a high risk of developing a serious NSAID-related ADE. Methods We conducted a cross-sectional study among adults registered with four Dutch general practitioners (GPs). In the Netherlands, all citizens are registered with a GP. Two samples of different patient populations were selected: (i) a random sample of adults (general population), and (ii) a sample of adult patients with a high risk of developing a serious ADE in case of NSAID use (high-risk population). The patients’ risk profiles were determined using their electronic medical records. Based on Dutch clinical prescription guidelines1, patients were considered at high risk if they had a history of a peptic ulcer or ulcer complication, myocardial infarction, stroke or heart failure, were aged over 70 years, had a glomerular filtration rate Results In the general population, 120 of 456 included patients chose to participate. Of these, 35 (29%) had used an OTC NSAID in the four weeks prior to participation. In the high-risk population, 265 of 713 included patients chose to participate and 33 (13%) had used an OTC NSAID. Musculoskeletal complaints formed the most common reason for OTC NSAID use in the high-risk population, with 67% of OTC NSAID users giving this as a reason for use. In the general population, 46% of OTC NSAID users reported using these drugs because of musculoskeletal complaints. Over 20% of OTC NSAID users had used the OTC NSAID for more than seven days in the general population and over 30% in the high risk-population. OTC NSAIDs were used in a dosage exceeding the recommended daily maximum by 9% and 3% of OTC NSAID users in respectively the general and the high-risk population. Conclusions OTC NSAIDs are used by around one third of the general population and by one in eight patients with a high risk of developing a serious ADE. In this high-risk group, musculoskeletal complaints form the most common reason for OTC NSAID use. Continued efforts by healthcare professionals to inform patients of the risks of these drugs is warranted, particularly when a new diagnosis is made or medication prescribed which alters the patient’s risk profile. References Warle-Van Herwaarden MF, Kramers C, Sturkenboom MC, et al. Targeting outpatient drug safety: Recommendations of the Dutch Harm-Wrestling Task Force. Drug Saf 2012;35(3):245-59 Disclosure of Interest None Declared

Editorial by Banner and pp 1311, 1312 Drugs are subject to licensing procedures to ensure their quality, efficacy, and safety, but many drugs used to treat children in hospital are either not licensed for use in children (“unlicensed”) or are prescribed outside the terms of the product licence (“off label”).1 Little is known about such prescribing in general practice, so we conducted a cohort study in primary care in the Netherlands to investigate the subject. We retrieved data from the integrated primary care information project, a longitudinal observational database containing information from computer based patient records of 150 general practitioners in the Netherlands. The system complies with European Union guidelines on the use of medical data for medical research and has been proved valid for pharmacoepidemiological research.2 Within the dynamic population of children (0-16 years) registered in 1998, …

To the Editor: Treatment of children may be difficult because of a shortage of properly formulated or approved drugs.1 In the Netherlands and elsewhere, many drugs are not approved for use in child...

Background Better evidence regarding drug safety in the pediatric population might be generated from existing data sources such as spontaneous reporting systems and electronic healthcare records. The Global Research in Paediatrics (GRiP)–Network of Excellence aims to develop pediatric-specific methods that can be applied to these data sources. A reference set of positive and negative drug–event associations is required. Objective The aim of this study was to develop a pediatric-specific reference set of positive and negative drug–event associations. Methods Considering user patterns and expert opinion, 16 drugs that are used in individuals aged 0–18 years were selected and evaluated against 16 events, regarded as important safety outcomes. A cross-table of unique drug–event pairs was created. Each pair was classified as potential positive or negative control based on information from the drug’s Summary of Product Characteristics and Micromedex. If both information sources consistently listed the event as an adverse event, the combination was reviewed as potential positive control. If both did not, the combination was evaluated as potential negative control. Further evaluation was based on published literature. Results Selected drugs include ibuprofen, flucloxacillin, domperidone, methylphenidate, montelukast, quinine, and cyproterone/ethinylestradiol. Selected events include bullous eruption, aplastic anemia, ventricular arrhythmia, sudden death, acute kidney injury, psychosis, and seizure. Altogether, 256 unique combinations were reviewed, yielding 37 positive (17 with evidence from the pediatric population and 20 with evidence from adults only) and 90 negative control pairs, with the remainder being unclassifiable. Conclusion We propose a drug–event reference set that can be used to compare different signal detection methods in the pediatric population. Electronic supplementary material The online version of this article (doi:10.1007/s40264-015-0265-0) contains supplementary material, which is available to authorized users.

Objective: To determine the extent of use of unlicensed and off label drugs in children in hospital in five European countries. Design: Prospective study of drugs administered to children in general paediatric medical wards over four weeks. Setting: Children9s wards in five hospitals (one each in the United Kingdom, Sweden, Germany, Italy, and the Netherlands). Subjects: Children aged 4 days to 16 years admitted to general paediatric medical wards. Main outcome measure: Proportion of drugs that were used in an unlicensed or off label manner. Results: 2262 drug prescriptions were administered to 624 children in the five hospitals. Almost half of all drug prescriptions (1036; 46%) were either unlicensed or off label. Of these 1036, 872 were off label and 164 were unlicensed. Over half of the patients (421; 67%) received an unlicensed or off label drug prescription. Conclusions: Use of off label or unlicensed drugs to treat children is widespread. This problem is likely to affect children throughout Europe and requires European action. Key messages Many drugs are not tested in children, which means that they are not specifically licensed for use in children Licensed drugs are often prescribed outside the terms of the product license (off label) in relation to age, indication, dose of frequency, route of administration, or formulation Over two thirds (67%) of 624 children admitted to wards in five European hospitals received drugs prescribed in an unlicensed or off label manner 39% of the 2262 drug prescriptions given to children were off label The problem of off label and unlicensed drug prescribing in children is a European problem that requires European action