Paediatric Rational Prescribing: A Systematic Review of Assessment Tools.

Rational prescribing criteria have been well established in adult medicine for both research and quality improvement in the appropriate use of medicines. Paediatric rational prescribing has not been as widely investigated. The aims of this review were to identify and provide an overview of all paediatric rational prescribing tools that have been developed for use in paediatric settings. A systematic literature search was made of MEDLINE, Embase, CINAHL and IPA from their earliest records until July 2019 for all published paediatric rational prescribing tools. The characteristics of the tools were recorded including method of development, types of criteria, aspects of rational prescribing assessed, and intended practice setting. The search identified three paediatric rational prescribing tools: the POPI (Pediatrics: Omissions of Prescriptions and Inappropriate Prescriptions) tool, the modified POPI (UK) tool, and indicators of potentially inappropriate prescribing in children (PIPc). PIPc comprises explicit criteria, whereas POPI and the modified POPI (UK) use a mixed approach. PIPc is designed for use in primary care in the UK and Ireland, POPI is designed for use in all paediatric practice settings and is based on French practice standards, and the modified POPI (UK) is based on UK practice standards and is designed for use in all paediatric practice settings. This review describes three paediatric rational prescribing tools and details their characteristics. This will provide readers with information for the use of the tools in quality improvement or research and support further work in the field of paediatric rational prescribing.

Modifying a Paediatric Rational Prescribing Tool (POPI) for Use in the UK.

Rational prescribing tools can be used by individual prescribers, organisations, and researchers to evaluate the quality of prescribing for research and quality improvement purposes. A literature search showed that there is only one tool for evaluating rational prescribing for paediatric patients in hospital and outpatient settings. The Pediatrics: Omission of Prescriptions and Inappropriate Prescriptions (POPI) tool was developed in France and comprises 105 criteria. The aim of this study was to modify this tool to facilitate its use in paediatric practice in the United Kingdom (UK). POPI criteria were compared to relevant UK clinical guidelines from the National Institute for Health and Care Excellence, the Scottish Intercollegiate Guideline Network and the British National Formulary for Children. Where guidelines differed, criteria were modified to reflect UK guidance. If there were no relevant guidelines or directly contradictory guidelines, criteria were removed. Overall, no change was made to 49 criteria. There were 29 modified to concord with UK guidelines. Four criteria were reduced to two criteria due to being linked in single guidelines. Twenty-three criteria were omitted, due to the absence of relevant UK guidance or directly conflicting UK practice, including one entire clinical category (mosquitos). One category title was amended to parallel UK terminology. The modified POPI (UK) tool comprises of eighty criteria and is the first rational prescribing tool for the evaluation of prescribing for children in hospital and outpatient settings in the UK.

Safety of antiepileptic drugs in children and young people: A prospective cohort study.

PURPOSE: This study aims to describe the incidence of adverse drug reactions (ADRs) in children receiving antiepileptic drugs (AEDs) and compare ADRs to the individual drugs when given as monotherapy. METHOD: Paediatric patients (≤18 years old) were enrolled for this prospective observational study over a 6-month period, between September 2015 and March 2016. Adverse reactions to antiepileptic drugs (AEDs) were elicited at the time of enrolment and after 3 months using the Paediatric Epilepsy Side Effects Questionnaire. RESULTS: A total of 1139 suspected ADRs were reported in 124 participants. Eighteen different AEDs were prescribed. Sixty-six children (53%) were receiving AED monotherapy at the time of recruitment; 34/66 (52%) of whom received new generation AEDs. Levetiracetam was the most frequently prescribed AED (62/124, 50%). When only children receiving AED monotherapy were considered, fatigue, drowsiness, weight gain, dizziness were less likely with levetiracetam (p < .01). Slow thinking and decreased concentration were less likely with levetiracetam or carbamazepine than valproic acid (p < .05). Five patients (four on polytherapy) discontinued AED treatment due to ADRs and 2 had a dose reduction. CONCLUSIONS: Levetiracetam and carbamazepine were better tolerated than sodium valproate.

Retrospective review of paediatric case reports of Stevens-Johnson syndrome and toxic epidermal necrolysis with lamotrigine from an international pharmacovigilance database.

OBJECTIVES: This study aims to characterise paediatric reports with lamotrigine (LTG) and Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN), and to explore whether potential risk factors can be identified. DESIGN: This is a retrospective review of suspected adverse drug reaction (ADR) reports. Reported time from LTG start to SJS/TEN onset, indication for use and dose was explored. To identify potential risk groups, report features (eg, ages, patient sex, co-reported drugs) for LTG and SJS/TEN were contrasted with two reference groups in the same database, using shrinkage logOR. SETTING: Reports were retrieved from VigiBase, the WHO global database of individual case safety reports, in January 2015. PATIENTS: Data for patients aged ≤17 years old were extracted. RESULTS: There were 486 reports of SJS/TEN in LTG-treated paediatric patients. Ninety-seven per cent of the cases with complete information on time to onset of SJS/TEN occurred within 8 weeks of initiation of LTG therapy. The median time to onset was 15 days (IQR: 10-22 days). The proportion of SJS/TEN with LTG and valproic acid (VPA) co-reporting was significantly more than non-cutaneous ADRs (43% vs 19%, (logOR: 1.60 (99% CI: 1.33 to 1.84)). CONCLUSIONS: The results suggest that VPA co-medication with LTG therapy is a risk factor for SJS/TEN in the paediatric population. Although this relationship has been identified from individual case reports, this is the first supportive study from a large compilation of cases. SJS/TEN risk is highest in first 8 weeks of treatment with LTG in children and clinicians should be aware of this risk during this period.

Anti-epileptic drug utilisation in paediatrics: a systematic review.

OBJECTIVES: This study aims to determine global anti-epileptic drug (AED) utilisation prevalence and describe utilisation trends in different countries. METHODS: Databases Embase (1980-May 2017), Medline (1946-May 2017) and PubMed were searched for original research on AED utilisation. All paediatric national or regional database studies and surveys were included. RESULTS: Twenty-one studies were identified. Five were excluded from the analysis as the data were collected before 2005, leaving 16 studies. Monotherapy regimen varied between 58% and 94% in different countries. In several of the studies, sodium valproate was the most frequently prescribed AED. However, there is a trend towards increasing utilisation of new-generation AEDs, particularly levetiracetam, in some countries. CONCLUSION: Monotherapy was used in 58%-94%of patients. There is increasing utilisation of the new-generation AEDs, in particular lamotrigine, levetiracetam and topiramate. Old-generation AEDs are still used in the majority of patients. There is a need for up-to-date studies to determine the prevalence of AEDs in children.

Protocol for a prospective observational study of adverse drug reactions of anti-epileptic drugs in children in the UK.

BACKGROUND: Epilepsy is a common chronic disease of children that can be treated with anti-epileptic drugs (AEDs). AEDs, however, have significant side effects. Newer AEDs are thought to have fewer side effects. There have, however, been few comparative studies of AED toxicity. The aim is to compare the safety profile of the most frequently used AEDs by performing a multicentre prospective cohort study. This protocol describes the planned study. DESIGN: A multicentre prospective cohort study of children on AED treatment in hospitals across the UK. Ethical approval will be obtained. SAMPLE SIZE: Three thousand children on treatment for epilepsy will be recruited from paediatric clinics. It is expected that this sample size will have the potential to compare toxicity between the most frequently used AEDs. DURATION OF STUDY: 24 months. OUTCOME MEASURE: Adverse drug reactions (ADRs) to AEDs. These will be identified by the use of a validated questionnaire, the Paediatric Epilepsy Side Effect Questionnaire. They will be evaluated using the Naranjo algorithm. Preventability will be assessed using the Schumock and Thornton scale. DISCUSSION: Toxicity of individual AEDs when given as monotherapy and polytherapy will be determined. Additionally, discontinuation rates due to ADRs will be determined. The data will assist clinicians in choosing AEDs with the least toxicity.

INTER-INDIVIDUAL VARIATION IN THEOPHYLLINE CLEARANCE IN CHILDREN.

BACKGROUND: Inter-individual variation in pharmacokinetics in children is an area where there has been little research. We wished to determine the extent of inter-individual variation in the clearance of theophylline in paediatric patients of different ages. METHODS: A systematic literature review was performed using the following databases; Embase (1974 to January 2013), Medline (1946 to January 2013), CINAHL (1937 to January 2013), International Pharmaceutical Abstracts (1970 to January 2013) and the Cochrane Library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined. RESULTS: A total of 56 articles reporting on 1,315 patients met our inclusion criteria. Twenty six studies gave individual data. The majority of the studies were in critically ill patients. Inter-individual variation was a major problem in all age groups. The CV was 9-93% in preterm neonates, 20-97% in term neonates, 18-52% in infants, 2-72% in children and 4.5-43% in adolescents. The mean clearance was higher in children (0.85 to 2 ml/min/kg) than in neonates (0.24 to 0.6 ml/min/kg). CONCLUSIONS: Large inter-individual variation was seen, especially in critically ill patients. Inter-individual variation was higher in neonates than children and adolescents.

INTERVENTIONS MADE BY UK PHARMACISTS TO MINIMISE RISK FROM PAEDIATRIC PRESCRIBING ERRORS.

BACKGROUND: Prescribing errors have the potential to adversely affect the safe pharmacological treatment of patients of all ages. The multi-centre General Medical Council commissioned 'EQUIP' study assessed the prevalence and nature of prescribing errors and found a mean rate of errors in 8.9% of medication orders.1 Paediatric data was not however analysed separately. Errors have been estimated to cause harm in paediatric patients three times more often than in adults.2 Clinical pharmacists play a role in identifying prescribing errors and minimising harm but this role has not been explored in detail in children in the UK. OBJECTIVES: To evaluate the prevalence and nature of prescribing errors and the role of hospital pharmacists in identifying and reducing risk in neonatal and paediatric patients. METHODS: Data collection sites were identified through the Neonatal and Paediatric Pharmacists Group by an email asking for volunteer centres. Clinical pharmacists working in these hospitals were asked to document prescribing errors in inpatient medication orders identified as part of their routine practice using a data collection form adapted from the EQUIP study1. A variety of hospital settings were aimed for.Data was collected monthly on six separate weekdays in most of the participating hospitals in 2013. Data was entered on to a SPSS database for collation and analysis.Classification of error type and potential severity was done using the EQUIP study categories1. Drugs were categorised according to the British National Formulary for Children3 and patient's ages were grouped according to the International Conference of Harmonisation guidelines.4 RESULTS: Thirteen hospitals (eight specialist children's and five general teaching hospitals) from across the UK agreed to participate. Pharmacists checked 11,941 prescriptions written for 3,330 patients and identified 1,039 errors: an overall rate of 8.7% of medication orders with 20.6% of all patients having a prescribing error.Overdose was found to be the most common error followed by incorrect or missing administration times and underdose. This was in contrast to the EQUIP study where omission errors were most common. Specialist trainees/trust grade fixed term specialty training appointments (FTSTAs) made the majority of errors; however this was in proportion with the number of prescriptions which they wrote. Antibacterial and analgesic drugs were the most common classes associated with errors and the oral route was the most common route involved.70% errors were classified as minor, though 25% were considered significant, 5.4% serious and 0.22% (two errors) potentially lethal. Five patients were stated to have experienced harm.39.6% of errors occurred during the patient's hospital stay followed by 35% errors occurring on admission. CONCLUSION: Prescribing errors occurred at a similar rate as in adult patients 1 but the most common type of errors was different with dosing errors most common in children. Clinical pharmacists' interventions play an important role in identifying and minimising harm from prescribing errors.

Systematic review of paediatric studies of adverse drug reactions from pharmacovigilance databases.

OBJECTIVE: To perform a systematic review of studies describing paediatric adverse drug reactions (ADRs) conducted from national pharmacovigilance databases. METHODS: A systematic literature search of studies describing results for paediatric ADRs from national pharmacovigilance databases was performed. PubMed database, Embase and MEDLINE were searched up to March 2015. The descriptive studies included were analysed for country of origin, reporters, and ADR reporting rate, drugs, ADRs and number of fatalities. RESULTS: 20 studies were identified. Doctors were the largest group of reporters in all the studies, and with more consumer reports seen in USA. The studies ranged from 3 - 37 years. The highest ADR reporting rate was 1458 reports per year per million children in Cuba. Antibiotics and vaccines were the most frequently reported drugs, in almost all the studies. The most frequent ADRs were skin and nervous system disorders. The highest proportion of fatalities and serious reports was from North America. Drugs used for treating attention deficit hyperactivity disorders (ADHD) and isotretinoin were the most frequently reported drugs for ADRs in North America. CONCLUSIONS: There were geographical differences in drugs responsible for ADRs and their seriousness, especially in North America. Very few studies were conducted in Asia and Latin America, none were found from Africa.

Invasiveness of pharmacokinetic studies in children: a systematic review.

OBJECTIVES: To explore whether pharmacokinetic (PK) studies in paediatric patients are becoming less invasive. This will be evaluated by analysing the number of samples and volume of blood collected for each study within four different decades. METHODS: A systematic literature review was performed to identify PK papers describing number of samples and volume of blood collected in studies of children aged 0-18 years. The following databases were searched: MEDLINE (1946 to December 2015), EMBASE (1974 to December 2015), International Pharmaceutical Abstracts (1970 to December 2015), CINAHL and Cochrane Library. RESULTS: A total of 549 studies were identified between 1974 and 2015. There were 52 studies between 1976 and 1985, 105 between 1986 and 1995, 201 between 1996 and 2005 and 191 between 2006 and 2015. The number of blood samples collected per participant increased between the first two decades (p=0.013), but there was a decrease in the number of samples in the subsequent two decades (p=0.044 and p<0.001, respectively). Comparing the first and last decades, there has been no change in the number of blood samples collected. There were no significant differences in volume collected per sample or total volume per child in any of the age groups. There was however a significant difference in the frequency of blood sampling between population PK studies (median 5 (IQR 3-7)) and non-population PK studies (median 8 (IQR 6-10); p=<0.001). CONCLUSIONS: The number of blood samples collected for PK studies in children rose in 1985-1995 and subsequently declined. There was no overall change in the volume of blood collected over the 4 decades. The usage of population PK methods reduces the frequency of blood sampling in children.

Learning Lessons from Adverse Drug Reactions in Children.

Drug toxicity is, unfortunately, a significant problem in children both in the hospital and in the community. Drug toxicity in children is different to that seen in adults. At least one in 500 children will experience an adverse drug reaction each year. For children in hospital, the risk is far greater (one in ten). Additionally, different and sometimes unique adverse drug reactions are seen in the paediatric age groups. Some of the major cases of drug toxicity historically have occurred in neonates. It is important that we understand the mechanism of action of adverse drug reactions. Greater understanding alongside rational prescribing should hopefully reduce drug toxicity in children in the future.

Herbal medicines: challenges in the modern world. Part 2. European Union and Russia.

INTRODUCTION: Herbal medicines (HMs) have been well known to people of the European Union (EU) and Russia for centuries. Currently, Western HMs can be classified into two categories, plant-derived conventional medicines and dietary supplements. Interest to HMs has grown rapidly in all countries during the past two decades. AREAS COVERED: The main goal of this review article is to present the history of HMs in the EU and Russia, forms of modern HMs, including Oriental Medicines that are popular among consumers of both countries. Additional discussion points comprise safety and adulteration issues associated with HMs, including regulatory changes and new legislative measures undertaken by the authorities. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: Due to cultural diversities in the EU and Russia, traditional HMs of other regions, particularly Chinese Traditional and Ayurvedic medicines, are also popular. Recently, dietary supplements containing multiple herbal and other natural products have flooded the EU and Russian markets. Pharmacovigilance in these markets is challenging in terms of establishing quality and safety of ingredients, determining efficacy, and defining risks of herb-herb and herb-drug interactions. Both the EU and Russia have introduced new legislation aimed to overcome these deficiencies.

Safety of Levetiracetam in Paediatrics: A Systematic Review.

OBJECTIVE: To identify adverse events (AEs) associated with Levetiracetam (LEV) in children. METHODS: Databases EMBASE (1974-February 2015) and Medline (1946-February 2015) were searched for articles in which paediatric patients (≤18 years) received LEV treatment for epilepsy. All studies with reports on safety were included. Studies involving adults, mixed age population (i.e. children and adults) in which the paediatric subpopulation was not sufficiently described, were excluded. A meta-analysis of the RCTs was carried out and association between the commonly reported AEs or treatment discontinuation and the type of regimen (polytherapy or monotherapy) was determined using Chi2 analysis. RESULTS: Sixty seven articles involving 3,174 paediatric patients were identified. A total of 1,913 AEs were reported across studies. The most common AEs were behavioural problems and somnolence, which accounted for 10.9% and 8.4% of all AEs in prospective studies. 21 prospective studies involving 1120 children stated the number of children experiencing AEs. 47% of these children experienced AEs. Significantly more children experienced AEs with polytherapy (64%) than monotherapy (22%) (p<0.001). Levetiracetam was discontinued in 4.5% of all children on polytherapy and 0.9% on monotherapy (p<0.001), the majority were due to behavioural problems. CONCLUSION: Behavioural problems and somnolence were the most prevalent adverse events to LEV and the most common causes of treatment discontinuation. Children on polytherapy have a greater risk of adverse events than those receiving monotherapy.

Adverse drug reactions in Nigerian children: a retrospective review of reports submitted to the Nigerian Pharmacovigilance Centre from 2005 to 2012.

BACKGROUND: Adverse drug reactions (ADRs) in children recorded in national pharmacovigilance databases in high-income countries have been analysed. Nigeria has a population of 31 million children and became a member of the WHO Programme for International Drug Monitoring in 2004 since when it has been submitting reports of suspected ADRs to the WHO Global Individual Case Safety Report database, VigiBase. OBJECTIVE: To gain information on reported ADRs in Nigerian children aged 0-17 years in VigiBase from 2005 to 2012. METHODS: The data were analysed for annual reports, age and sex of patients, type of reporters, suspected drugs and adverse reactions. The most commonly reported ADRs and suspected drugs were ranked, and drugs associated with the fatalities were evaluated. RESULTS: A total of 297 reports of 473 ADRs in 297 children were received from doctors, pharmacists, other health-care professionals and consumers during the period. ADRs were most frequently reported for anti-retrovirals (74, 24%), antibiotics (71, 23%) and anti-malarials (60, 20%). The most frequently reported ADRs were rash (15.2%), fever (10.3%) and pruritus (6.8%). Anti-infective agents were responsible for more than half of the reports. Twenty-one children (7%) died, eight from acute renal failure. Seven of the cases of acute renal failure were associated with contaminated paracetamol/diphenhydramine hydrochloride and herbal medicines used for teething problems. In the majority of cases, the products were contaminated with diethylene glycol. There were 14 cases of Stevens-Johnson syndrome, three of which were fatal. CONCLUSION: Anti-infective agents (antibiotics, anti-malarials and anti-retrovirals) were associated with a majority of the ADRs. Stevens-Johnson syndrome was the most frequent severe ADR. Some of the fatalities were associated with sub-standard and herbal medications.

Use and safety of azithromycin in neonates: a systematic review.

OBJECTIVES: To identify the use and adverse drug reactions associated with azithromycin in neonates. SETTING: Databases MEDLINE (1948-August 2015), EMBASE (1980-August 2015) and Pubmed (August 2015) were searched for studies on azithromycin in neonates. PARTICIPANTS: All studies involving neonates (<28 days old) who have received at least a single dose of azithromycin for which safety was evaluated. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was adverse event (AE) associated with use of azithromycin. Use of azithromycin in neonates was the secondary outcome. RESULTS: A total of 11 articles involving 473 neonates were identified. 371 AEs were reported. Adverse events were mainly respiratory (358/1000 neonate), neurological (273/1000 neonates) and gastrointestinal (196/1000 neonates) in origin. Azithromycin significantly reduced the risk of bronchopulmonary dysplasia (BPD) in extremely premature neonates (RR=0.83, 95% CI 0.71 to 0.98, p=0.02). There was no significant difference in the incidence of elevated liver enzymes between the azithromycin and placebo group (p=0.76). There were four cases of infantile hypertrophic pyloric stenosis (IHPS). CONCLUSIONS: Azithromycin significantly reduces the risk of BPD in preterm neonates. The relationship between azithromycin and IHPS requires further investigation.

Adverse drug reactions in Ghanaian children: review of reports from 2000 to 2012 in VigiBase.

OBJECTIVE: The aim of this article is to describe adverse drug reactions (ADRs) reported for children aged 0 - 17 years in Ghana. METHODS: Paediatric reports submitted by the Ghana National Centre for Pharmacovigilance to the World Health Organisation (WHO) Global ADR database, VigiBase up to December 2012 were extracted. The data were analysed for number of reports per year, types of reporters and suspected ADRs and drugs. RESULTS: A total of 343 reports for children were received during the period. The drug classes most frequently reported were vaccines (115, 31%), antimalarials (106, 28%) and antibiotics (57, 15%). Of the top 20 individual drugs, 19 were anti-infectives. The most frequently reported ADRs were injection site infection, fever and rash. There were 23 deaths reported, and antimalarials were implicated in 12 cases. CONCLUSIONS: Vaccines, antimalarials and antibiotics are the leading medicines reported to cause ADRs in Ghanaian children. There was a high mortality rate, with many of the deaths due to causes explained in the individual case safety reports.