Value of a web-based pediatric drug information system to prevent serious adverse drug reactions in child and adolescent psychiatry.

Psychotropic drugs are frequently prescribed 'off-label' to children and adolescents and carry the risk of serious adverse drug reactions (sADR). We examined the frequency of sADRs of psychotropic drugs in pediatric inpatients and explored their potential preventability through following the recommendations of a web-based pediatric drug information system (PDIS). The potential socio-economic impacts of using this online system is also addressed. Routine clinical data from all inpatients treated in a child and adolescent psychiatry department between January 2017 and December 2018 were retrospectively examined for the occurrence of sADRs as defined by the European Medicines Agency. The preventability of the sADRs was assessed based on the information of the PDIS. Furthermore, the expected prolongation of the hospital stay due to sADRs was calculated as well as the associated treatment costs. The study was supported by the Innovation Fund of the Joint Federal Committee, grant number 01NVF16021. In total, 1036 patients were screened of whom 658 (63.5%) received psychopharmacological treatment. In 53 (8.1%) of these patients 54 sADRs were documented, of which 37 sADRs were identified as potentially preventable through PDIS. Mitigating sADR through PDIS would likely have prevented prolonged hospital stays and conferred considerable savings for health insurance companies. PDIS provides systematic and evidence-based information about pediatric psychopharmacotherapy and helps to prevent prescribing errors. Therefore, PDIS is a useful tool to increase drug therapy safety in child and adolescent psychiatry. Further prospective studies are needed to confirm the results.

Safety of clonidine used for long-term sedation in paediatric intensive care: A systematic review.

AIM: Although not approved, the α-adrenoceptor agonist clonidine is considered an option for long-term sedation protocols in paediatric intensive care. We reviewed adverse effects of clonidine occurring in this indication. METHODS: Relevant literature was systematically identified from PubMed and Embase. We included interventional and observational studies on paediatric patients admitted to intensive care units and systemically long-term sedated with clonidine-containing regimes. In duplicates, we conducted standardised and independent full-text assessment and extraction of safety data. RESULTS: Data from 11 studies with 909 patients were analysed. The studies were heterogeneous regarding patient characteristics (age groups, comorbidity, or comedication) and sedation regimes (dosage, route, duration, or concomitant sedatives). Just four randomised controlled trials (RCTs) and one observational study had comparison groups, using placebo or midazolam. For safety outcomes, our validity evaluation showed low risk of bias only in three studies. All studies focused on haemodynamic problems, particularly bradycardia and hypotension. Observed incidences or subsequent interventions never caused concerns. However, only two RCTs allowed meaningful comparisons with control groups. Odds ratios showed no significant difference between the groups, but small sample sizes (50 and 125 patients) must be considered; pooled analyses were not reasonable. CONCLUSION: All evaluated studies concluded that the use of clonidine in paediatric intensive care units is safe. However, a valid characterisation of the safety profile remains challenging due to limited, biased and heterogeneous data and missing investigation of long-term effects. This evaluation demonstrates the lack of data, which prevents reliable conclusions on the safety of clonidine for long-term sedation in critically ill children. For an evidence-based use, further studies are needed.

[Improving the Safety of Drug Therapy through a Hospital-Internal Reporting System - Analysis of Reports over 15 Years from a Children's Hospital]. / Verbesserung der Arzneimitteltherapiesicherheit durch ein klinikinternes Meldesystem ­ Analyse der Meldungen über 15 Jahre einer Kinderklinik.

BACKGROUND: Patient safety is a major challenge and has high priority in the inpatient care. Notably, drug therapy is considered critical after surgery. The medication process is particularly difficult and problematic in newborns and children. METHOD: In a retrospective analysis, hospital-internal spontaneous reports on Drug-related Problems (DRP) from a children's hospital were analysed, which were reported between 2000 and 2014. RESULTS: 229 spontaneous reports on DRP were considered for analysis. 72.5% of these were due to a Medication Error. Nearly half of the DRP occurred during drug dispensing (44.5%), followed by problems during administration (38.0%) and prescribing (11.4%). 61.4% of Medication Errors were dispensing errors (esp. confusion of patients, wrong dose). Almost all Other Incidents happened during drug administration (mainly extravasations). 40.6% of DRP reports were associated with clinically relevant patient harm and occurred particularly during drug administration. CONCLUSION: These results show that drug therapy in paediatrics is a complex and hazardous process. The system of hospital-internal spontaneous reports has led to regular training and raising awareness of the employees for critical situations. In addition, it fosters a safety culture to report mistakes. Spontaneous reporting is suitable for increasing the safety of drug therapy in paediatrics.

The Use of Cannabinoids in Pediatric Palliative Care-A Retrospective Single-Center Analysis.

This data analysis aimed to systematically analyze a pediatric patient population with a life-limiting disease who were administered cannabinoids. It was a retrospective single-center analysis of patients under supervision of the specialized outpatient pediatric palliative care (SOPPC) team at the Department of Pediatrics and Adolescent Medicine of the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU). Thirty-one patients with a primary diagnosis of neuropediatric, oncologic, metabolic, and cardiologic categories were included. The indications we identified were spasticity, pain, restlessness, anxiety, loss of appetite, epilepsy, and paresis. Certain aspects of quality of life were improved for 20 of 31 patients (64.5%). For nine patients (29%), no improvement was detected. No conclusions could be drawn for two patients (6.5%). Adverse events were reported for six of the thirty-one patients (19.4%). These were graded as mild, including symptoms such as restlessness, nausea, and behavioral issues. We detected no clinically relevant interactions with other medications. We collected fundamental data on the use of cannabinoids by pediatric palliative patients. Cannabinoids are now frequently administered in pediatric palliative care. They seem to be safe to use and should be considered an add-on therapy for other drug regimens.

The epidemiology of drug-related hospital admissions in paediatrics - a systematic review.

BACKGROUND: Despite previous efforts, medication safety in paediatrics remains a major concern. To inform improvement strategies and further research especially in outpatient care, we systematically reviewed the literature on the frequency and nature of drug-related hospital admissions in children. METHODS: Searches covered Embase, Medline, Web of Science, grey literature sources and relevant article citations. Studies reporting epidemiological data on paediatric drug-related hospital admissions published between 01/2000 and 01/2024 were eligible. Study identification, data extraction, and critical appraisal were conducted independently in duplicate using templates based on the 'Joanna Briggs Institute' recommendations. RESULTS: The review included data from 45 studies reporting > 24,000 hospitalisations for adverse drug events (ADEs) or adverse drug reactions (ADRs). Due to different reference groups, a total of 52 relative frequency values were provided. We stratified these results by study characteristics. As a percentage of inpatients, the highest frequency of drug-related hospitalisation was found with 'intensive ADE monitoring', ranging from 3.1% to 5.8% (5 values), whereas with 'routine ADE monitoring', it ranged from 0.2% to 1.0% (3 values). The relative frequencies of 'ADR-related hospitalisations' ranged from 0.2% to 6.9% for 'intensive monitoring' (23 values) and from 0.04% to 3.8% for 'routine monitoring' (8 values). Per emergency department visits, five relative frequency values ranged from 0.1% to 3.8% in studies with 'intensive ADE monitoring', while all other eight values were ≤ 0.1%. Heterogeneity prevented pooled estimates. Studies rarely reported on the nature of the problems, or studies with broader objectives lacked disaggregated data. Limited data indicated that one in three (median) drug-related admissions could have been prevented, especially by more attentive prescribing. Besides polypharmacy and oncological therapy, no other risk factors could be clearly identified. Insufficient information and a high risk of bias, especially in retrospective and routine observational studies, hampered the assessment. CONCLUSION: Given the high frequency of drug-related hospitalisations, medication safety in paediatrics needs to be further improved. As routine identification appears unreliable, clinical awareness needs to be raised. To gain more profound insights especially for generating improvement strategies, we have to address under-reporting and methodological issues in future research. TRIAL REGISTRATION: PROSPERO (CRD42021296986).

Creating a Medication Therapy Observational Research Database from an Electronic Medical Record: Challenges and Data Curation.

BACKGROUND: Observational research has shown its potential to complement experimental research and clinical trials by secondary use of treatment data from hospital care processes. It can also be applied to better understand pediatric drug utilization for establishing safer drug therapy. Clinical documentation processes often limit data quality in pediatric medical records requiring data curation steps, which are mostly underestimated. OBJECTIVES: The objectives of this study were to transform and curate data from a departmental electronic medical record into an observational research database. We particularly aim at identifying data quality problems, illustrating reasons for such problems and describing the systematic data curation process established to create high-quality data for observational research. METHODS: Data were extracted from an electronic medical record used by four wards of a German university children's hospital from April 2012 to June 2020. A four-step data preparation, mapping, and curation process was established. Data quality of the generated dataset was firstly assessed following an established 3 × 3 Data Quality Assessment guideline and secondly by comparing a sample subset of the database with an existing gold standard. RESULTS: The generated dataset consists of 770,158 medication dispensations associated with 89,955 different drug exposures from 21,285 clinical encounters. A total of 6,840 different narrative drug therapy descriptions were mapped to 1,139 standard terms for drug exposures. Regarding the quality criterion correctness, the database was consistent and had overall a high agreement with our gold standard. CONCLUSION: Despite large amounts of freetext descriptions and contextual knowledge implicitly included in the electronic medical record, we were able to identify relevant data quality issues and to establish a semi-automated data curation process leading to a high-quality observational research database. Because of inconsistent dosage information in the original documentation this database is limited to a drug utilization database without detailed dosage information.

Impact of a computerized physician order entry system on medication safety in pediatrics-The AVOID study.

BACKGROUND: One of the most critical steps in the medication process on pediatric wards is the medical prescription. This study aims to investigate the impact of a computerized physician order entry (CPOE) system on Adverse Drug Events (ADEs) and potentially harmful ADEs (pot ADEs) in comparison with paper-based documentation in a general pediatric ward at a German University hospital. METHODS: A prospective pre-post study was conducted. All patients aged 17 years or younger were observed during the study periods (5 months pre- and postimplementation). Issues Regarding Medication (IRM) were identified by intensive chart review. Events were assessed regarding causality (WHO), severity (WHO; Dean & Barber for MEs), and preventability (Shumock) and classified into (pot) ADEs, (pot) Medication errors (ME), Adverse drug Reactions (ADR), and Other incidents (OI) accordingly. RESULTS: Total of 333 patients with medication were included in the paper-based prescribing cohort (phase I) and 320 patients with medication in the electronic prescribing cohort (phase II). In each cohort, patients received a median number of four different drugs (IQR 5 and IQR 4). A total of 3966 IRM was observed. During the hospitalization, 2.7% (n = 9) patients in phase I and 2.8% (n = 9) in phase II experienced an ADE. Potentially harmful MEs were less often observed in the cohort with electronic prescribing (n = 228 vs. n = 562). The mean number per patient significantly decreased from 1.69 to 0.71 (p < .01). CONCLUSION: The implementation of a CPOE system resulted in a reduction of issues regarding medication, particularly MEs with the potential to harm patients decreased significantly.

Adverse Drug Reactions in Children: Comparison of Reports Collected in a Pharmacovigilance Project Versus Spontaneously Collected ADR Reports.

BACKGROUND: Adverse drug reactions (ADRs) and medication errors in children may result from a lack of appropriate drugs, dosages, and pharmaceutical forms. In addition, children may respond differently to drugs than adults. Reporting of ADRs in the pediatric population is therefore of importance in order to increase the amount of safety data. However, different methodological approaches are used to collect ADRs. OBJECTIVE: The aim of the present study was to analyze whether there were differences in the ADRs collected in the KiDSafe project (845 ADR reports) compared with the spontaneous ADR reports sent to EudraVigilance (697 reports) in the same time period. The strengths and limitations of these two different approaches should be discussed. METHODS: The same inclusion criteria were applied for the systematically collected ADRs in the KiDSafe project and the spontaneous reports from EudraVigilance, and only reports of ADRs coded with hospitalization were considered. In both datasets, the number of reports (related to number of hospitals), their documentation quality (VigiGrade), causal relationship (World Health Organization-Uppsala Monitoring Centre [WHO-UMC] criteria), most frequently reported drugs and ADRs, demographical parameters of the patients, reported medical histories, and the seriousness of ADR reports were analyzed descriptively. The results of the two analyses were compared. RESULTS: There was considerable underreporting of ADRs via the spontaneous reports (0.4 reports per hospital; 697/1902) compared with 70.4 reports per hospital (845/12) in the systematically collected KiDSafe reports. Documentation quality assessment yielded similar results in both datasets. Among the 10 most frequently reported drugs, anticonvulsants such as levetiracetam (6.6%), valproic acid (5.6%), oxcarbazepine (3.6%), and lamotrigine (3.4%) were mainly reported in the KiDSafe reports, while in the EudraVigilance reports, mite allergen extract (4.4%) and allergens (3.6%) were preferentially reported. Seizures were the most frequently reported clinically specific ADRs in the KiDSafe reports, whereas anaphylactic reactions and urticaria were prominent in the spontaneous reports from EudraVigilance. Notably, the proportion of reports referring to medication errors and other medication safety related issues were more prominent in KiDSafe than in the spontaneous reports (27.8% vs. 12.6% and 46.0% vs. 29.0%, respectively). CONCLUSION: In general, reports from both data sources contributed to the identification of ADRs and dedicated issues related to drug therapy. However, these differed by nature and strength of the signal, likely due to the characteristics of the individual method. A combined approach could likely compensate for limitations inherent to the single approaches, but will most likely only be applied to dedicated pharmacovigilance topics or research objectives.

"Multisystem Inflammatory Syndrome in Children" (MIS-C) after COVID-19 Infection in the Metropolitan Area of Nuremberg-Erlangen, Germany-Expectations and Results of a Two-Year Period.

BACKGROUND: Multisystemic Inflammatory Syndrome in children (MIS-C) is a rare autoimmune disorder occurring after a latency period following acute SARS-CoV-2 infection. The therapeutic regime of MIS-C is adapted to the therapy of the Kawasaki disease, as clinical symptoms are similar. Since the Kawasaki disease can potentially result in severe symptoms, which may even affect long-term health, it is essential to gain further knowledge about MIS-C. Thus, we aimed to investigate the incidence, symptoms, therapeutical procedure and outcome of MIS-C patients in the metropolitan area of Nuremberg-Erlangen during the SARS-CoV2 pandemic. MATERIAL AND METHODS: Retrospective analysis of clinical charts of MIS-C patients was carried out at three children's hospitals covering the medical care of the metropolitan area of Nuremberg-Erlangen in Germany. Demographic characteristics and symptoms at first visit, their clinical course, therapeutic regime and outcome were recorded within the time period January 2021-December 2022. RESULTS: Analysis of 10 patients (5 male, 5 female) with MIS-C resulting in an incidence of 2.14/100.000 children. The median time between COVID-19 infection and admission to hospital was 5 weeks. The median age was 7 years. Symptoms comprised fever (100%), rash (70%), bilateral non-purulent conjunctivitis (70%) and urticaria (20%). At the time of presentation, diagnosis-defining inflammation parameters were increased and the range for C-reactive protein was 4.13 mg/dL to 28 mg/dL, with a median of 24.7 mg/dL. Procalcitonin was initially determined in six patients (1.92 ng/mL to 21.5 ng/mL) with a median value of 5.5 pg/mL. Two patients displayed leukocytosis and two displayed leukopenia. None of the patients presented coronary pathologies. Nine of the ten patients received intravenous immunoglobulin (IVIG) therapy. In addition, patients received intravenous steroids (80%) and acetylsalicylic acid (80%). CONCLUSION: SARS-CoV virus may rarely exert multiorgan manifestations due to hyperinflammatory immunological processes. Within two years of the COVID-19 pandemic, we identified ten patients with COVID-induced MIS-C in the metropolitan area Nuremberg-Erlangen. In the description of the patient collective, we can confirm that MIS-C is distinguished from the Kawasaki disease by the lack of coronary manifestations. Interestingly, although having monitored all pediatric facilities in the investigated area, we find lower incidences of MIS-C compared to findings in the literature. In conclusion, an overestimation of incidences in the upcoming MIS-C during the pandemic needs to be considered.

A Complex Intervention to Prevent Medication-Related Hospital Admissions.

BACKGROUND: Children are often treated off-label and are at a disadvantage in pharmacotherapy. The aim of this study was to implement and evaluate a quality assurance measure (PaedPharm) for pediatric pharmacotherapy whose purpose is to reduce medication-related hospitalizations among children and adolescents. METHODS: PaedPharm consisted of the digital pediatric drug information system PaedAMIS, pediatric pharmaceutical quality circles (PaedZirk), and an adverse drug event (ADE) reporting system (PaedReport). The intervention was implemented in a cluster-randomized trial (DRKS 00013924) in 12 regions, with a pediatric and adolescent medicine clinic in each and a total of 152 surrounding private practitioners, in 6 sequences over 8 quarters. In addition to the proportion of ADE-related hospital admissions (primary endpoint), comprehensive process evaluation included other endpoints such as coverage, user acceptance, and relevance to practice. RESULTS: 41 829 inpatient admissions were recorded, of which 5101 were patients of physicians who participated in our study. 4.1% of admissions were ADE-related under control conditions, and 3.1% under intervention conditions (95% CI: [2.3; 5.9] and [1.8; 4.5], respectively). A model-based comparison yielded an intervention effect of 0.73 (population-based odds ratio; [0.39; 1.37]; p = 0.33). PaedAMIS achieved moderate user acceptance and PaedZirk achieved high user acceptance. CONCLUSION: The introduction of PaedPharm was associated with a decrease in medication-related hospitalizations that did not reach statistical significance. The process evaluation revealed broad acceptance of the intervention in outpatient pediatrics and adolescent medicine.

Development and Adjustment of an Algorithm for Identifying Drug-Related Hospital Admissions in Pediatrics.

OBJECTIVE: Adverse drug events (ADEs) in the outpatient pediatric pharmacotherapy can be serious and lead to inpatient admissions. Recent research only focused on ADE identification during hospitalization. The aim of the present study was to develop an algorithm to identify drug-related hospital admissions in pediatrics. METHODS: A systematic literature research was performed, and a pediatric trigger tool for identifying drug-related inpatient admissions was built. The initial version was tested in a sample of 292 patients admitted to a German university children's hospital. Subsequently, the tool was further improved by combining different modules as a novel approach. RESULTS: The obtained algorithm with 39 triggers in 5 modules identified drug-related inpatient admissions at a sensitivity of 95.5% (95% confidence interval [CI], 89.3%-100%) and a specificity of 16.5% (95% CI, 11.9%-21.2%), respectively. After modifications including trigger activation requiring a combination of different modules, specificity increased to 56.9% (95% CI, 50.7%-63.0%). Identifying 36 of 44 ADEs leading to admission, sensitivity remained high (81.8% [95% CI, 70.4%-93.2%]). The overall positive predictive value was 25.2% (95% CI, 18.1%-32.3%). CONCLUSIONS: The algorithm is the first trigger tool to identify ambulant acquired ADEs leading to hospital admission in pediatrics. However, the underlying patient sample is small.Using a larger population for refinement will allow further specifications and reduction in the total amount of triggers and thus signals.

Metamizole Use in Children: Analysis of Drug Utilisation and Adverse Drug Reactions at a German University Hospital between 2015 and 2020.

BACKGROUND: Metamizole use is controversially discussed due to its potentially serious adverse drug reactions (ADRs). In Germany, however, it remains a popular analgesic and antipyretic drug. OBJECTIVE: The aim of this study was to discuss the safety profile of metamizole in children by analysing the inpatient prescription patterns and presenting the metamizole-related ADRs at a paediatric hospital between 2015 and 2020. METHODS: Metamizole utilisation data were retrospectively analysed from electronic medical records. ADRs were prospectively recorded via the hospital's stimulated reporting system and analysed accordingly. Patients aged < 18 years admitted to one of the general wards of the department of paediatrics and adolescent medicine of a German university hospital between June 2015 and May 2020 who received at least one drug therapy within their inpatient stay were included in the analysis. Causality of ADRs was rated according to the World Health Organisation causality assessment. RESULTS: In 31.7% (3759/11,857) of the inpatient stays of 7809 patients, metamizole was administered. Metamizole exposure was highest in adolescents (37.9%) and lowest in newborns (9.9%). Overall, metamizole was administered parenterally in about 90%. Three cases of agranulocytosis, one allergic shock and one rash with possible or higher causality to metamizole treatment were reported. Three of these occurred prior to hospitalisation. All patients recovered without remaining harm. DISCUSSION: Metamizole is commonly used in paediatric inpatients in Germany. Serious ADRs occur but rarely. Continuous monitoring of drug therapy through, for example, stimulated reporting systems ensures that serious ADRs are detected, and appropriate interventions can be introduced.

Repeated Use of Prescription Drugs in Pediatrics: Comprehensive Overview Based on German Claims Data.

Background: Investigating drug utilization in large and unselected samples of children and adolescents is an important component of public health monitoring. Most existing studies in this field focused on any drug use (i.e., ≥1 prescription of a certain drug) although chronic drug use may be more relevant. This study aimed to provide a comprehensive overview of prevalence and types of prescription drugs used repeatedly in children and adolescents in Germany in 2016. Methods: We used the German Pharmacoepidemiological Research Database (GePaRD)-a claims database covering ∼20% of the German population. We included children and adolescents aged 0-17 years and assessed repeated use of prescription drugs (≥3 prescriptions in 2016) on two levels: therapeutic subgroups (ATC 2nd level) and chemical substances (ATC 5th level). Analyses were stratified by sex and age groups (<2, 2-5, 6-12, and 13-17 years). Results: Overall, 2.5 million children and adolescents were included. In the age groups below 13 years, the prevalence rates of repeated use of prescription drugs (ATC 2nd level) were higher in boys than in girls (113-152 vs. 83-130 per 1,000 person-years), whereas in the age group 13-17 years, they were twice as high in girls than in boys (236 vs. 118 per 1,000 person-years). In boys and girls aged below six years, systemic antibiotics, topical ocular antibiotics, and drugs for constipation were among the most common drugs used repeatedly. For higher ages, methylphenidate, levothyroxine, and combined hormonal contraceptives, were among the most common drugs used repeatedly. Conclusions: Overall, about one in ten children in Germany repeatedly used prescription drugs. This proportion as well as the type of drugs used repeatedly markedly varied by sex and age. For certain drugs, our findings raise concerns regarding appropriateness of prescribing that should be addressed in future studies.

Development and Evaluation of a Web-Based Paediatric Drug Information System for Germany.

Background: Off-label use is frequent in paediatrics but that does not necessarily mean that the risk-benefit ratio is negative. Nevertheless, evidence-based data is essential for safe drug therapy. In Germany, there is no publicly available compendium providing transparent, evidence-based information for paediatric pharmacotherapy to date. This work describes the development of a web-based paediatric drug information system (PDIS) for Germany and its evaluation by health care professionals (HCP). Methods: Since 2012, a PDIS is being developed by the authors and is supported by the Federal Ministry of Health since 2016. Dosing recommendations were established based on systematic literature reviews and subsequent evaluation by clinical experts. The prototype was evaluated by HCP. Based on the results, the further development was concluded. Results: 92% of HCP believed that the PDIS could improve the quality of prescribing, as currently available information is deficient. Besides the license and formulations, dosing recommendations were the most relevant modules. A dosage calculator was the most wanted improvement. To facilitate sustainability of future development, a collaboration with the Dutch Kinderformularium was established. As of 2021, the database will be available to German HCP. Conclusion: The fundamentals for a German PDIS were established, and vital steps were taken towards successful continuation.

Descriptive analysis of adverse drug reaction reports in children and adolescents from Germany: frequently reported reactions and suspected drugs.

BACKGROUND: Adverse drug reactions (ADRs) in the pediatric population may differ in types and frequencies compared to other populations. Respective studies analyzing ADR reports referring to children have already been performed for certain countries. However, differences in drug prescriptions, among others, complicate the transferability of the results from other countries to Germany or were rarely considered. Hence, the first aim of our study was to analyze the drugs and ADRs reported most frequently in ADR reports from Germany referring to children contained in the European ADR database (EudraVigilance). The second aim was to set the number of ADR reports in relation to the number of drug prescriptions. These were provided by the Research Institute for Ambulatory Health Care in Germany. METHODS: For patients aged 0-17 years 20,854 spontaneous ADR reports were received between 01/01/2000-28/2/2019. The drugs and ADRs reported most frequently were identified. Stratified analyses with regard to age, sex and drugs used "off-label" were performed. Reporting rates (number of ADR reports/number of drug prescriptions) were calculated. RESULTS: Methylphenidate (5.5%), ibuprofen (2.3%), and palivizumab (2.0%) were most frequently reported as suspected. If related to the number of drug prescriptions, the ranking changed (palivizumab, methylphenidate, ibuprofen). Irrespective of the applied drugs, vomiting (5.4%), urticaria (4.6%) and dyspnea (4.2%) were the ADRs reported most frequently. For children aged 0-1 year, drugs for the treatment of nervous system disorders and foetal exposure during pregnancy were most commonly reported. In contrast, methylphenidate ranked first in children older than 6 years and referred 3.5 times more often to males compared to females. If age- and sex-specific exposure was considered, more ADR reports for methylphenidate referred to children 4-6 years and females 13-17 years. Drugs for the treatment of nervous system disorders ranked first among "off-label" ADR reports. CONCLUSIONS: Our analysis underlines the importance of putting the number of ADR reports of a drug in context with its prescriptions. Additionally, differences in age- and sex-stratified analysis were observed which may be associated with age- and sex-specific diseases and, thus, drug exposure. The drugs most frequently included in "off-label" ADR reports differed from those most often used according to literature.

Analysis of the reporting of adverse drug reactions in children and adolescents in Germany in the time period from 2000 to 2019.

The objective of this study was to analyse reports on adverse drug reactions (ADRs) from Germany in the particularly vulnerable patient group of children and adolescents. Reporting characteristics, demographic parameters and off-label use were examined among others. The ratio of ADR reports per number of German inhabitants and the ratio of ADR reports per number of German inhabitants exposed to drugs were calculated and compared. These parameters were examined to derive trends in reporting of ADRs. 20,854 spontaneous ADR reports for the age group 0-17 years were identified in the European ADR database EudraVigilance for the time period 01.01.2000-28.02.2019 and analysed with regard to the aforementioned criteria. 86.5% (18,036/20,854) of the ADR reports originated from Healthcare Professionals and 12.2% (2,546/20,854) from non-Healthcare Professionals. 74.4% (15,522/20,854) of the ADR reports were classified as serious. The proportion of ADR reports per age group was 11.8% (0-1 month), 11.0% (2 months-1 year), 7.4% (2-3 years), 9.3% (4-6 years), 25.8% (7-12 years), and 34.8% (13-17 years) years, respectively. Male sex slightly dominated (51.2% vs. 44.8% females). Only 3.5% of the ADR reports reported off-label use. The annual number of ADR reports increased since 2000, even if set in context with the number of inhabitants and assumed drug-exposed inhabitants. The pediatric population declined in the study period which argues against its prominent role for the increase in the total number of ADR reports. Instead, among others, changes in reporting obligations may apply. The high proportion of serious ADR reports underlines the importance of pediatric drug safety.

A mini-review of non-parenteral clonidine preparations for paediatric sedation.

OBJECTIVE: To provide an overview of non-parenteral clonidine formulations and assess the feasibility of their use for paediatric sedation. METHODS: A literature search was conducted using electronic databases and a combination of search terms. Forty articles met the inclusion criteria. Publications were grouped into different dosage forms and assessed for their potential application for sedation of children in intensive care. KEY FINDINGS: Several routes of clonidine administration have been investigated for numerous indications in children, including perioperative sedation and analgesia. These include oral liquids, tablets, oral transmucosal systems, nasal sprays and rectal suspensions. Conflicting studies on oral transmucosal clonidine formulations suggest that further research is required to fully establish efficacy. Nasal sprays and rectal suspensions have the advantages of rapid onset of action and potential for dose flexibility, but predictable absorption is difficult to obtain. CONCLUSIONS: Provided age-appropriate strengths are available, intravenous formulations remain the most predictable in terms of bioavailability and flexible in terms of dose adjustment. However, as with all routes, down-titration is difficult given the long half-life of clonidine. Oral transmucosal systems, nasal sprays and rectal suspensions have potential in a less acute setting, but significant clinical work is required to elucidate a full pharmacokinetic and pharmacodynamic profile.