Paediatric clinical pharmacology in the UK

Paediatric clinical pharmacology is the scientific study of medicines in children and is a relatively new subspecialty in paediatrics in the UK. Training encompasses both the study of the effectiveness of drugs in children (clinical trials) and aspects of drug toxicity (pharmacovigilance). Ethical issues in relation to clinical trials and also studies of the pharmacokinetics and drug metabolism in children are crucial. Paediatric patients require formulations that young children in particular are able to take. The scientific evidence generated from clinical trials, pharmacokinetic studies and studies of drug toxicity all need to be applied in order to ensure that medicines are used rationally in children

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

Substandard and counterfeit medicines: a systematic review of the literature

Objective: To explore the evidence available of poor quality (counterfeit and substandard) medicines in the literature. Design: Systematic review. Data sources: Databases used were EMBASE, MEDLINE, PubMed and the International Pharmaceutical Abstracts, including articles published till January 2013. Eligibility criteria: Prevalence studies containing original data. WHO definitions (1992) used for counterfeit and substandard medicines. Study appraisal and synthesis: Two reviewers independently scored study methodology against recommendations from the MEDQUARG Checklist. Studies were classified according to the World Bank classification of countries by income. Data extraction: Data extracted: place of study; type of drugs sampled; sample size; percentage of substandard/counterfeit medicines; formulations included; origin of the drugs; chemical analysis and stated issues of counterfeit/substandard medicines. Results: 44 prevalence studies were identified, 15 had good methodological quality. They were conducted in 25 different countries; the majority were in low-income countries (11) and/or lower middle-income countries (10). The median prevalence of substandard/counterfeit medicines was 28.5% (range 11–48%). Only two studies differentiated between substandard and counterfeit medicines. Prevalence data were limited to antimicrobial drugs (all 15 studies). 13 studies involved antimalarials, 6 antibiotics and 2 other medications. The majority of studies (93%) contained samples with inadequate amounts of active ingredients. The prevalence of substandard/counterfeit antimicrobials was significantly higher when purchased from unlicensed outlets (p<0.000; 95% CI 0.21 to 0.32). No individual data about the prevalence in upper middle-income countries and high-income countries were available. Limitations: Studies with strong methodology were few. The majority did not differentiate between substandard and counterfeit medicines. Most studies assessed only a single therapeutic class of antimicrobials. Conclusions: The prevalence of poor-quality antimicrobial medicines is widespread throughout Africa and Asia in lower income countries and lower middle-income countries . The main problem identified was inadequate amounts of the active ingredients

Substandard and falsified medicines in the UK: a retrospective review of drug alerts (2001-2011)

Objective: To determine the extent of substandard and falsified medicines in the UK. Design: A retrospective review of drug alerts and company-led recalls. Setting: The Medicines and Healthcare Products Regulatory Agency (MHRA) website search for drug alerts issued between 2001 and 2011. Eligibility criteria: Drug alerts related to quality defect in medicinal products. Main outcome measure: Relevant data about defective medicines reported in drug alerts and company-led recalls, including description of the defect, type of formulation, year of the alert and category of the alert. Results: There were 280 substandard medicines of which 222 were recalled. The two most frequent problems were contamination (74 incidents) and issues related to packaging (98 incidents). Formulations for parenteral administration (117 incidents) were the formulation most frequently affected. There were 11 falsified medicines, as defined by the MHRA, reported over the 11-year period. The number of defective medicines reported by the MHRA increased 10-fold from 5 in 2001 to 50 in 2011. Conclusions: Substandard medicines are a significant problem in the UK. It is uncertain whether the increasing number of reports relates to improved detection or an increase in the number of substandard medicine

Safety of fluconazole in paediatrics: a systematic review

Purpose: To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment. Methods: A search of EMBASE (1950–January 2012), MEDLINE (1946–January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982–2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years) was performed. Only articles with sufficient quality of safety reporting after patients’ exposure to fluconazole were included. Results: We identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6 %) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95 % confidence interval (CI) 0.87–2.14, P = 0.175 and RR 1.43, 95 % CI 0.67–3.03, P = 0.352, respectively]. Complete resolution of hepatoxicity was achieved by 84 % of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95 % CI 0.12–5.60, P = 0.831 and RR 1.23, 95 %CI 0.87–1.71, P = 0.235, respectively). There were 41 drug withdrawals, 17 (42 %) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children. Conclusion: Fluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity

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

Protocol for a prospective observational study of adverse drug reactions of antiepileptic 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

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

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

Why do young children die in the UK?: a comparison with Sweden

Background The UK has a high child mortality rate, whereas Sweden’s is lower (under-five mortality rates of five and three, respectively, in 2011).We therefore wished to compare causes of death in young children aged <5 years in the two countries. Methods Under-five mortality data were obtained from the Office of National Statistics for each of the individual countries within the UK for 3 years (2006–2008). Data for Sweden for the same period were obtained from the National Board of Health and Welfare. Causes of death were compared statistically using χ2 test. Results There were a total of 14 104 and 1036 deaths aged <5 years in the UK and Sweden, respectively, between 2006 and 2008. The total numbers of live births during the same period were 2 295 964 and 315 884, respectively. The overall mortality rate in the UK was 614 per 100 000 children which was significantly higher than that in Sweden (328; p<0.001). The mortality rates for the three main causes of death in the UK ( prematurity, congenital malformations and infections) were 138.5, 112.1 and 63.9, respectively, per 100 000 children. The mortality rates for the same three conditions in Sweden were 10.1, 88.6 and 34.8, respectively. They were all significantly more frequent in the UK than in Sweden (p<0.001), as were the majority of the disorders. Treatable infections, such as pneumonia, meningitis and septicaemia, in both neonates and young children had significantly higher mortality rates in the UK than in Sweden ( p<0.001). Conclusions In order to reduce the mortality rate in the UK, we need to try and reduce the causes of prematurity. Additionally, the care of children with treatable infections should be reviewed to understand ways in which to reduce the differences in mortality seen