Adverse Drug Reactions In Children Research Articles

Identifying genomic and developmental causes of adverse drug reactions in children.

Adverse drug reactions are a concern for all clinicians who utilize medications to treat adults and children; however, the frequency of adult and pediatric adverse drug reactions is likely to be under-reported. In this age of genomics and personalized medicine, identifying genetic variation that results in differences in drug biotransformation and response has contributed to significant advances in the utilization of several commonly used medications in adults. In order to better understand the variability of drug response in children however, we must not only consider differences in genotype, but also variation in gene expression during growth and development, namely ontogeny. In this article, recommendations for systematically approaching pharmacogenomic studies in children are discussed, and several examples of studies that investigate the genomic and developmental contribution to adverse drug reactions in children are reviewed.

1253 Adverse Drug Reactions in Children Admitted to a Tertiary Care Center

Background and aims: Knowledge of adverse drug reactions (ADR) is scant in the pediatric population compared to adults. Our goul was to determine the incidence of ADR in hospitalized patients, identify the drugs involved, the most frequent clinical manifestations and their follow-up. Methods: Retrospective study of clinical records of patients hospitalized in a tertiary care hospital, in which an ADR was reported, over a 16 years period. Results: We identified 188 ADR, 0.46% of total admissions. The ADR was the reason for admission in 20,2%. The most common diagnoses were infectious diseases. Children had a mean age of 4.0±3.8 years, 57,4% were male and a past history of allergy or immunodeficiency was reported in 26.7%. The most frequent clinical manifestations were mucocutaneous (51.6%), followed by cardiovascular (14.4%) and gastrointestinal (12.2%). The drugs most often implicated were antibiotics (40.3%), especially vancomycin (19.7%) and amoxicillin-clavulanate (18.4%), followed by chemotherapeutic agents (8.0%), vaccines (6.9%) and steroids (5.9%). Intravenous administration was associated with 54,3% of ADR and the time from first drug administration to ADR was > 48 hours in 51.6%. The reactions were mild in 83.5%, but 3 cases required admission to ICU, with one fatality. Only 14 children (7.4%) were referred to a consultation for follow-up. Conclusions: Our data showed a low incidence of ADR compared to recent prospective studies, but the type of reactions and drugs involved were similar. It is necessary to alert health professionals to occurrence of ADR in order to implement their coding and reporting to the authorities.

Information about adverse drug reactions reported in children: a qualitative review of empirical studies

To review the literature on adverse drug reactions (ADRs) in children with respect to occurrence, seriousness, type, therapeutic group, age and gender of the child and category of reporter. Medline and Embase databases were searched from origin and updated until February 2010. We included empirically based articles on ADRs in populations aged 0 to 17 years. Studies monitoring ADRs in patients with particular conditions or drug exposure were excluded. We extracted information about types and seriousness of ADRs, therapeutic groups, age and gender of the child and category of reporter. ADR occurrence was calculated as incidence rate and prevalence. We included 33 studies monitoring ADRs in general paediatric populations. The highest numbers of ADRs were reported in national ADR databases where data were collected over a longer period than in studies monitoring inpatients and outpatients. However, prevalence and incidence were much lower in the national databases. Types of reported ADRs, seriousness of ADRs and types of medicines differed substantially between studies due to differences in time periods and patient populations. Information about ADRs was mainly provided by health care professionals, although parents also contributed reports. We found a higher incidence rate of ADRs in hospitalized children and outpatients than in national databases. There seems to be considerable potential for increasing the knowledge of ADRs by advocating the submission of reports to the spontaneous reporting systems. Our study underscores that ADRs in children constitute a significant public health problem.

Pharmacogenomics and Active Surveillance for Serious Adverse Drug Reactions in Children

Juxtaposing clinical pharmacology with human genetics, pharmacogenomics utilizes a patient's genetic information to identify genetic variants that have the potential to provide clinically relevant predictions of toxicity and efficacy. The goal is to develop personalized and genetic-based predictions of an individual's drug response and likelihood of experiencing an adverse drug reaction. The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) has implemented active adverse drug reaction surveillance to monitor and discover genetic markers related to serious adverse drug reactions in the pediatric population. Evidence-based pharmacogenomics research will inform public policy and influence drug benefit-risk decision-making. Regulatory processes and future challenges in pharmacogenomics research will be discussed.

Adverse drug reactions causing admission to a paediatric hospital: a pilot study

It is known that adverse drug reactions (ADRs) cause admission to hospital in adults and children. A recent adult study showed that ADRs are an important and frequent cause of hospital admission. The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital. Prospective observational study over a 2-week period. There were 19 admissions to the main hospital wards related to an ADR, giving an estimated incidence of 4%, with the ADR directly leading to the admission in 71% of cases. There were no deaths attributable to ADR. 33% of the reactions were possibly avoidable. The drugs most commonly implicated in causing admissions were anti-neoplastic agents. The most common reactions were neutropenia, vomiting and diarrhoea. The health burden of ADRs in the paediatric population is likely to be significant. This pilot study will be used to inform a much larger prospective study providing more detailed evidence of the burden of ill-health from ADRs in children. This larger study will add to a body of research aiming to identify drug-related problems within children to aid paediatric pharmacovigilance. This study provides knowledge regarding the methodology to be used for a larger study investigating ADRs in children. The study will allow authors who wish to replicate the study in their own populations (internationally) to avoid some of the pitfalls in planning a large epidemiological study of paediatric ADRs. The study also provides an estimate of the incidence and problem of admissions caused by ADRs in a UK paediatric population.

Drug‐induced hepatic injury in children: a case/non‐case study of suspected adverse drug reactions in VigiBase

To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents. Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding. Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12-17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known. Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children.

The Canadian Pharmacogenomics Network for Drug Safety: A Model for Safety Pharmacology

Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death in the developed world, and the direct medical costs of ADRs exceed $100 billion annually in the United States alone. Pharmacogenomics research seeks to identify genetic factors that are responsible for individual differences in drug efficacy and susceptibility to ADRs. This has led to several genetic tests that are currently being used to provide clinical recommendations. The Canadian Pharmacogenomics Network for Drug Safety is a nation-wide effort established in Canada to identify novel predictive genomic markers of severe ADRs in children and adults. A surveillance network has been established in 17 of Canada's major hospitals to identify patients experiencing specific ADRs and to collect biological samples and relevant clinical history for genetic association studies. To identify ADR-associated genetic markers that could be incorporated into predictive tests that will reduce the occurrence of serious ADRs, high-throughput genomic analyses are conducted with samples from patients that have suffered serious ADRs and matched control patients. ADRs represent a significant unmet medical problem with significant morbidity and mortality, and Canadian Pharmacogenomics Network for Drug Safety is a nation-wide network in Canada that seeks to identify genetic factors responsible for interindividual differences in susceptibility to serious ADRs. Active ADR surveillance is necessary to identify and recruit patients who suffer from serious ADRs. National and international collaborations are required to recruit sufficient patients for these studies. Several pharmacogenomics tests are currently in clinical use to provide dosing recommendations, and the number of pharmacogenomics tests is expected to significantly increase in the future.

Adverse drug reactions reported for systemic antibacterials in Danish children over a decade

Adverse drug reactions reported for systemic antibacterials in Danish children over a decade

Adverse drug reactions in children in Camagüey Province, Cuba

ObjectiveTo determine the incidence of adverse drug reactions (ADRs) in children in Camagüey Province, Cuba.MethodsA national pharmacovigilance programme has been established in Cuba and involves suspected ADRs being reported to...

The use of electronic reporting to aid surveillance of ADRs in children: a proof of concept study

ObjectiveTo investigate: (1) the feasibility of establishing active paediatric surveillance for adverse drug reactions (ADRs), (2) whether electronic reporting is effective and (3) whether such a system could complement the...

Adverse Drug Reactions in the Paediatric Population in Denmark

The potential risk of adverse drug reactions (ADRs) in the paediatric population has become a public health concern and regulatory agencies in Europe and the US have acknowledged that there is a need for more research in this area. Spontaneous reporting systems can provide important new information about ADRs. To characterize ADRs in children reported in Denmark over a period of one decade. We analysed ADRs reported to the Danish Medicines Agency from 1998 to 2007 for individuals aged from birth to 17 years. Data were analysed with respect to time, age and sex, category of ADR (System Organ Class [SOC]), seriousness, suspected medicines (level 2 of the Anatomical Therapeutic Chemical [ATC] Classification System) and type of reporter. 2437 ADR reports corresponding to 4500 ADRs were analysed. On average, 234 ADR reports were submitted annually, corresponding to approximately two ADRs per report. From 2003 to 2005, an increasing number of ADRs submitted per report were observed, but after 2005 the reporting rate decreased. One-half of ADRs were reported for infants from birth to 2 years of age. Similar total numbers of ADRs were reported for boys and girls. The majority of ADRs reported were from the following SOCs: general disorders and administration site conditions (31%), skin and subcutaneous tissue disorders (18%) and nervous system disorders (15%). Reports encompassed medicines from ATC group J: vaccines and anti-infectives for systemic use (65%); and ATC group N: nervous system (17%). On average, 42% of ADRs were classified as serious. ATC group N had the highest proportion of ADRs that were classified as serious. Although physicians reported approximately 90% of the ADRs, a relatively large proportion of serious ADRs were reported by other sources. In Denmark, the ADR reporting rate in the paediatric population has declined since 2005. The majority of ADRs reported in young children were reported for vaccines and anti-infectives, but also a high number of serious ADRs were reported for medicines from ATC group N. The Danish Medicines Agency should monitor prescribing patterns more tightly to identify potential risks in the paediatric population in relation to the evolving pattern of medicine use among children.

Medical Students’ Knowledge Of Risk Factors For Adverse Drug Reactions In Children

Adverse drug reaction (ADR) is a global problem that affects all age groups. Poor perceptions of doctors about ADRs and risk management have contributed to high rate of ADR under-reporting in Nigeria. The focus of this study was to assess the knowledge of medical students on the risk factors for ADRs in children and to identify the classes of medicines most likely be involved. Assessment was done before and after a didactic lecture on ADRs and pharmacovigilance. Forty four medical students in their fourth year, comprising of 25 males and 19 females, were assessed with a structured questionnaire for their knowledge of possible risk factors for ADRs in children, knowledge of pre-existing diseases that may predispose a child to having ADRs, and their ability to identify the classes of medicines that are most likely involved. Before the lectures on ADRs and pharmacovigilance, the risk factors were well identified except medication dose error, age and gender of a child that were wrongly perceived. The perception was much improved in the post lecture assessment. In both the preand postlecture assessments, atopy, asthma, immunodeficiency, malignancy, sickle cell anaemia, and tuberculosis were all considered diseases that may likely be associated with adverse reactions. However, the proportions of students with correct perceptions of these diseases were significantly higher in the post –lecture assessment (P< 0.05 in all cases). Medicines with potentials for ADRs that were highly ranked in the preand postlecture assessments include antibiotics (88.6% vs 100%), antimalarials (84.1% vs 100%) and immunosuppressive drugs (84.1% vs 100%), respectively. It was concluded that teaching ADRs and pharmacovigilance in pharmacology enhanced the previously acquired knowledge in junior clinical postings.

Association between Drug and Vaccine Use and Acute Immune Thrombocytopenia in Childhood

Immune thrombocytopenic purpura (ITP) is an immunomediated disease characterized by a decrease in platelet count and, in its more severe forms, by bleeding symptoms. Many drugs have been implicated in the pathogenesis of drug-induced thrombocytopenia in adults; only limited data on drug-related ITP in children have been published. Our study was set up to evaluate the consistency of the association between drug and vaccine use and ITP in children. This study is part of an Italian multicentre study on adverse drug reactions in children, coordinated by the Italian National Institute of Health, which was started in November 1999 and is ongoing. The study was conducted by enrolling all children aged more than 1 month who were hospitalized through the paediatric emergency department for the following conditions: thrombocytopenia (platelet count <100 x 103/L); acute neurological disorders; non-infectious mucocutaneous diseases and vasculitis; and endoscopically confirmed gastroduodenal lesions and/or clinically defined haematemesis and melaena. Children with chronic pathologies or concomitant diagnoses of cancer or immunodeficiency were not included in our study. During hospital admission, a physician interviewed parents using a structured questionnaire. The main aim of the interview was to collect information on drug exposure in a time period of 3 weeks and vaccine exposure in a period of 6 weeks preceding hospitalization. Using a case-control study design, exposure of children with thrombocytopenia (cases) to drugs and vaccines was compared with similar exposure of children with gastroduodenal lesions and neurological disorders (controls); this allowed us to estimate the odds ratios (ORs) of the occurrence of thrombocytopenia associated with the use of drugs or vaccines. Up to December 2007, the study population included 387 cases of thrombocytopenia and 1924 controls. Despite the low platelet count, ITP was generally a mild disease, without serious bleeding in the majority of cases and associated with a short length of hospital stay. After adjusting for concurrent use of other drugs, use of the antibacterials was associated with a more than 2-fold increase in the risk of developing ITP (OR 2.4; 95% CI 1.8, 3.1). Mucolytics and NSAIDs were associated with an OR of 1.9; 95% CI 1.2, 2.9 and 1.5; 95% CI 1.0, 2.1 respectively, while paracetamol (acetaminophen) was associated with an OR of 1.5; 95% CI 1.2, 2.0. MMR vaccination was associated with an increased risk of developing ITP (OR 2.4; 95% CI 1.2, 4.7). The results of this study provide evidence for an association between ITP and exposure to selected antibacterials, NSAIDs, paracetamol, mucolytics and MMR vaccination.

Reazioni allergiche a farmaci nel piccolo paziente

Adverse drug reactions are an important public health issue. Maculopapular rashes are the most common cutaneous reactions to drug in children and most of them occur during beta-lactam therapies. The diagnosis is a relatively complex and subtle art. This article describes an approach to recognize and manage adverse drug reactions in children.

Adverse drug reaction active surveillance: developing a national network in Canada's children's hospitals

Adverse drug reactions (ADRs) rank as the fifth leading cause of death in the western world. The nature and scope of these ADRs in children are not predictable based on post market surveillance reports that rely heavily on adult drug experience. The genotype-specific approaches to therapy in childhood (GATC) national ADR network was established to identify specific ADRs and to improve drug safety through identification of predictive genomic biomarkers of drug risk. GATC set out to establish a national network of trained surveillance clinicians in pediatric hospitals across Canada. Surveillance clinicians identified, enrolled, and collected clinical data and biological samples from ADR cases and controls. Surveillance was targeted to three ADRs: anthracycline-induced cardiotoxicity, cisplatin-induced hearing impairment, and codeine-induced mortality in breastfed infants. The initial surveillance site was established in September 2005, with 10 sites fully operational by 2008. In 3 years, GATC enrolled 1836 ADR cases and 13188 controls. Target numbers were achieved for anthracycline-induced cardiotoxicity. Modified target numbers were nearly attained for cisplatin-induced hearing impairment. Codeine-induced infant mortality in a breastfed infant was discovered by GATC investigators. A case-control study was subsequently conducted. GATC has demonstrated a model of active and targeted surveillance that builds an important step toward the goal of personalized medicine for children. Effective communication, site-specific solutions and long-term sustainability across the network are critical to maintain participation and productivity. GATC may provide a framework of ADR surveillance that can be adapted by other countries and healthcare systems.

Parental reporting of suspected adverse drug reactions in children in Lagos, Nigeria

Objectives:To determine the feasibility of parental reporting of suspected adverse drug reactions (ADRs) to community pharmacies in Nigeria.Methods:Fifteen registered pharmacies were randomly selected in Lagos, Nigeria. Caregivers who procured antibiotics,...

Recueil systématique et actif des évènements indésirables médicamenteux chez les enfants admis aux urgences pédiatriques

The aim of this study was to systematically evaluate adverse drug reactions (ADRs) in children consulting at the pediatric emergency unit during a 6-month period. The regional pharmacovigilance center (CRPV) and the department of clinical pharmacology prospectively and systematically recorded all potential ADRs among patients younger than 18 years of age in the pediatric emergency unit reported at the daily staff meetings. All cases were then screened and validated by the CRPV. For validated cases, preventability, seriousness, and off-label use were evaluated. During the study period, from 1 March to 1 September 2005, 90 children presented potential adverse drug events. ADRs were confirmed in 43 patients, 19 females and 24 males. Thirty-four patients (79%) were under the age of 5. According to the European definition, 14 patients (33%) had serious ADRs. One anaphylactic shock after amoxicillin injection; antimalarial prophylaxis misuse leading to convulsive status epilepticus, convulsion, and coma after hepatitis B and MMR vaccines were deemed life-threatening. Three ADRs were considered avoidable. Antibiotics and vaccines were the most common possible cause of ADRs (76%). Skin reactions (n=27), fever (n=8), and gastric disorders (n=5) were the most common clinical manifestations. Because ADRs were reported by clinicians on a voluntary basis, serious ADRs were probably reported more systematically. Compared to a similar period without active monitoring, active drug monitoring of ADRs doubled the number of confirmed cases 43 vs 17, p<0.001. Close collaboration between the pharmacovigilance center, pharmacologists, and clinicians is necessary and seems feasible for improving the monitoring of ADRs in children.

Psychiatric adverse drug reactions to glucocorticoids in children and adolescents: a much higher risk with elevated doses

Psychiatric and behavioural adverse drug reactions (ADRs) to glucocorticoids, especially when used at high dose, are multiple, unforeseeable and extend to a large spectrum of psychopathological disturbances [1–4]. Such high-dose glucocorticoids are frequently prescribed for children with chronic diseases such as asthma, nephrotic syndrome or following organ transplantation. The present study to evaluate the occurrence of psychiatric and/or behavioural ADRs in children was performed using data obtained from the French Pharmacovigilance Database (FPD) to identify spontaneous reports containing such ADRs induced by glucocorticoids in children and adolescents (age < 18 years). The French Pharmacovigilance System was first established in 1973 and consists of a network of 31 Regional Centres. The FPD was established in 1985 to record spontaneous reporting of ADRs. Furthermore, reporting ‘serious’ or ‘unlabelled’ ADRs to the French Regional Centres has been mandatory for any drug prescriber, physician, dentist or midwife in France since 1995 [5]. Despite this obligation, the reporting rate of ADRs in France remains very low. It is estimated at about 5–10% for ‘serious’ ADRs [6]. Spontaneous reports submitted to the FPD, in which glucocorticoids were suspected for psychiatric and/or behavioural ADRs in patients <18 years old, were extracted from 1 January 1985 to 30 March 2007. All spontaneous reports were reviewed and information concerning age, gender, different types of psychiatric ADRs, types of suspected glucocorticoid, dose and route of administration, indication, duration of treatment, time to onset, seriousness and evolution of ADRs was analysed. Among the 455 spontaneous reports containing psychiatric and/or behavioural ADRs reported with glucocorticoids in the FPD from 1 January 1985 to 30 March 2007 (in both adults and children), 95 (20.9%) occurred in patients <18 years old, including 136 ADRs (Table 1). Fifteen cases were classified as ‘serious’ (one death and 14 hospitalizations). Mean age of the patients was 5.9 years and 57 were <6 years old. Glucocorticoid dose was unknown in 16 cases. ADRs occurred in 29 cases (30.5%) after prescription or administration errors [overdose (n = 16) or high dose (n = 13)]. They were observed in 13 other children (13.7%) after use of high (n = 8) or supratherapeutic (n = 5) doses for different therapeutic indications (i.e. serious asthma, nephrotic syndrome or leukaemia) (Figure 1). In four cases the indications were out of the recommendations of Summary Product Characteristics. So, off-label prescription or administration was present in 25 (26.3%) cases (21 overdose and four off-label indications). The most frequent ADRs were agitation or excitation and sleep disturbances. ADRs occurred most often by oral forms (n = 72), but were also reported after administration of intravenous or inhaled forms. In 75% of cases, the time to onset was <7 days. The majority of the ADRs (82 cases, 86.3%) recovered completely after glucocorticoid withdrawal. Glucocorticoids more frequently involved were betamethasone (38 cases), prednisolone (21 cases) and prednisone (17 cases). Table 1 Characteristics of psychological and/or behavioural ADR cases related to glucocorticoids, recorded in FPD, in patients <18 years old, from 1 January 1985 to 30 March 2007 Figure 1 Psychiatric and/or behavioural adverse drug reactions (ADRs) recorded in the French Pharmacovigilance Database from 1985 to March 2007 according to the dose of glucocorticoids. Overdose, (); High dose, (□); Normal dose, (); Unknown dose, () Our data show that psychiatric and/or behavioural ADRs of glucocorticoids could also occur in children and adolescents and are frequently due to glucocorticoid overdose (22.1%) or high dosage (22.1%). The level of off-label prescription or administration associated with these ADRs is 26.3% (25 cases), which could be considered relatively high. However, the present results should be interpreted with caution because of the low reporting rate of ADRs in France [6]. Our study has also shown that the ADRs appear most often in the first week of glucocorticoid introduction. The main psychological ADRs are agitation and sleep disturbances. It appears to be necessary to inform health professionals about such ADRs, which are difficult to recognize because of their complex and heterogeneous clinical symptoms.

Adverse drug reactions in children: Types, incidence and risk factors

Adverse drug reactions in children: Types, incidence and risk factors

Review Article: Adverse drug reactions in children: Types, incidence and risk factors

Review Article: Adverse drug reactions in children: Types, incidence and risk factors