title: Rates of spontaneous reports of adverse drug reactions for drugs reported in children: a cross-sectional study with data from the Swedish adverse drug reaction database and the Swedish Prescribed Drug Register.
abstract: BACKGROUND
  Knowledge of drug safety is limited in the paediatric population, especially for drugs not used as labelled. Spontaneous reporting of adverse drug reactions (ADRs) may be an important source for increased knowledge, but the extent of the overall rate of reporting in children is not known.
  
  
  OBJECTIVE
  The main objective of the study was to determine the extent of the spontaneous reporting of ADRs in children with a focus on drugs not used as labelled; this involved investigations of reporting rates of individual case safety reports (ICSRs) per 1000 treated individuals for drugs reported in children, to compare these between drugs labelled and not labelled for use in children, and to compare the rates for children with those of adults.
  
  
  METHODS
  ICSRs (extracted from the Swedish ADR database) and number of treated individuals (extracted from the Swedish Prescribed Drug Register) were analysed for a 2-year period (2006-7). For drugs with one or more ICSR regarding children, rates of ICSRs per 1000 treated individuals were determined and compared between children (<18 years of age) and adults (≥18 years of age). Reported drugs for which >10% of the volume was sold over-the-counter or for in-hospital use were excluded. The overall reporting ratio of aggregated ICSRs per 1000 treated individuals was calculated between drugs not labelled and drugs labelled for use in children, separately for children and adults. The overall reporting ratio was also calculated between children and adults, separately for drugs labelled and drugs not labelled for use in children.
  
  
  RESULTS
  A total of 255 (children) and 1402 (adults) ICSRs concerning 94 drugs were included in the analysis. Seventy-four (29%) and 711 (51%) ICSRs in children and adults, respectively, were registered as serious (p < 0.00001, two-sided test of proportions). For drugs reported in three or more ICSRs regarding children, the rates of ICSRs per 1000 treated individuals varied between (range) 0.01-6.45 (children) and 0.01-6.39 (adults). For 17 of the drugs (18%) the rates of ICSRs per treated individual were significantly higher for children than for adults, and for 2 of the drugs (2%) the result was the opposite. The overall comparison of aggregated ICSRs per 1000 treated children revealed a higher reporting rate for drugs not labelled than for drugs labelled for children: rate ratio 3.44 (95% CI 2.67, 4.43); p < 0.00001. The corresponding result for adults was 1.52 (95% CI 1.37, 1.68); p < 0.00001. The overall reporting rate of aggregated ICSRs per 1000 treated individuals was higher in children than adults for drugs not labelled for children: rate ratio 2.01 (95% CI 1.61, 2.51); p < 0.00001.
  
  
  CONCLUSIONS
  The results of the present study indicate that the extent of the reporting of ADRs is greater for drugs not labelled for children than for drugs labelled for children. For these drugs, the extent of the reporting is greater for children than for adults. Thus, healthcare personnel willingly report ADRs in children, especially ADRs for drugs used outside the terms of the product licence. The finding is reassuring since there are few other sources for knowledge of paediatric drug safety. Important limitations of the study are (i) only a few ICSRs were registered for most drugs, thus giving each ICSR a strong impact on the rates for individual drugs; and (ii) the results of the present study apply only to the drugs included in the analysis.
authors.affiliation: Department of Clinical Pharmacology and Regional Pharmacovigilance Centre, Sahlgrenska University Hospital, Gothenburg, Sweden. susanna.wallerstedt@pharm.gu.se
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Wallerstedt
authors.forename: Gertrud
authors.initials: G
authors.lastname: Brunlöf
authors.forename: Anders
authors.initials: A
authors.lastname: Sundström
mesh_terms: D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D016208:Databases, Factual; D004348:Drug Labeling / Q000592:standards; D011307:Drug Prescriptions / Q000706:statistics & numerical data*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D006801:Humans; D007223:Infant; D008875:Middle Aged; D012042:Registries; D013548:Sweden / Q000453:epidemiology; D013997:Time Factors; D055815:Young Adult