To the best of our knowledge, this is the first descriptive analysis of ADR reports originating from Germany with regard to the drugs and ADRs reported most frequently for children (0–17 years) performed in EudraVigilance. One major strength of our analysis is the consideration of the number of ADR reports in context with the number of drug prescriptions. In our study the ranking of the most frequently reported drugs in absolute numbers changed if the specific exposure of the drugs was taken into account. Differences in age. and sex-stratified analysis for the drugs and ADRs most frequently reported were observed, especially for methylphenidate. In absolute terms more ADR reports for methylphenidate referred to males. However, if drug exposure was considered, reporting rates for females aged 13–17 years were two times higher. The drugs most frequently involved in ADR reports associated with an “off-label use” differed from those reported in the whole dataset.
ADRs reported most frequently
In our analysis, the five SOCs reported most frequently were in line with those observed in other ADR database studies [11, 18, 32,33,34] except for the SOC “injury, poisoning and procedural complications”. One reason for this finding could be that all of the referenced studies [11, 18, 32, 34] had a data lock point before the definition of an ADR was widened in 2012 (except for one study  where the data lock point was June 2013). Since 2012 the definition of an ADR is no longer confined to the use within the authorized indication but also includes ADRs related to “off-label use”, suicide/self-injury behavior and medication errors . At least some of these ADRs which occurred with the use of the drug outside its authorized conditions are assigned to the SOC “injury, poisoning and procedural complications” . Although these ADRs may have been reported before 2012, it seems likely that these ADRs were more often reported afterwards.
On the more detailed PT-level our results except for dyspnea were similar to those of an analysis of pediatric ADRs published in 2014 . Further on, in a systematic review of studies performed in ADR databases, skin disorders like rash and urticaria were also most frequently observed . Others discussed differences with regard to the skin physiology for children being responsible for a higher frequency of cutaneous ADRs compared to adults [34, 36].
Drugs most often reported as suspected
Methylphenidate, ibuprofen, palivizumab, atomoxetine and etanercept were the drug substances most frequently reported as suspected in the complete data set. The ranking varied depending on age and sex, probably reflecting age- and sex-specific prevalent diseases and prescribing patterns, as also reported in other analyses [17, 34]. Additionally, the ranking changed if drug exposure was considered.
In our analysis, methylphenidate ranked first in the whole dataset and was over all ages 3.5 times more often reported for males compared to females. Methylphenidate and drugs for the treatment of attention deficit hyperactivity disorders (ADHD) ranked also 1st to 5th in a systematic analysis of ADR database studies . Methylphenidate was the ADHD medication most often prescribed in Germany in the past . In addition, regulatory actions and respective press releases may have stimulated ADR reports referring to ADHD medications [38, 39]. If our age-stratified analysis was related to the number of drug prescriptions, the reporting rates were roughly four-times higher for children 4–6 years (22.8 ADR reports) compared to the older ones (7–12 years: 5.2 ADR reports; 13–17 years: 6.0 ADR reports). Methylphenidate is approved for children older than 5 years and ranked third in our analysis of ADR reports referring to “off-label use” and first in our analysis of “off-label use” per authorized age. Furthermore, the ADRs most frequently reported differed between age groups. “Blood creatine phosphokinase increased” and “leukopenia” ranked first and second for methylphenidate in children 4–6 years. Both ADRs were more frequently reported for children 4–6 years compared to the older ones. Hence, based on our results caution is advised if younger children are treated with methylphenidate and, blood values should be monitored regularly in order to avoid these ADRs and their potential sequel.
With regard to the age- and sex-stratified analysis, the higher absolute number of ADR reports for methylphenidate referring to males may be caused by the higher prevalence of ADHD for males. Other studies estimated female/male ratios of 1:9 to 1:3 [40,41,42,43]. However, if related to the number of drug prescriptions, reporting rates were almost equal for males and females 4–12 years but almost two times higher for females 13–17 years compared to males. A more common occurrence for at least some ADRs (e.g. anxiety) for females treated with methylphenidate or ADHD medication compared to males was reported by others [44, 45]. Based on our findings female adolescents treated with methylphenidate seem to have a higher frequency of ADRs than males. In literature, a more frequent reporting of ADRs by adult females is discussed to likely impact on the number of ADR reports for females . However, it is unknown if this may also apply for female children and adolescents with regard to ADR reporting or ADR communication to their parents or doctors. Nevertheless, a higher drug use by female adolescents (14–17 years) was observed in a German study about medication use in children and adolescents which may increase the risk of ADR occurrence . Besides the exposure, ADRs in patients using drugs for the treatment of chronic diseases such as ADHD may be more likely to be recognized and reported due to a more closely monitoring of these patients than ADRs for the treatment of non-chronic diseases such as infections [46, 47].
Ibuprofen ranked second in our complete data set with the lowest reporting rate if compared to the other four drugs. Thus, the large absolute number seems to be caused by the frequent use of ibuprofen in Germany. In Germany, ibuprofen is available as prescription-only and over the counter (OTC) drug. Unfortunately, the amount of OTC use of ibuprofen was unknown. Although ibuprofen prescriptions are reimbursed in Germany for children until 12 years, OTC use cannot be excluded. Hence, the number of applications may be even higher. This would lead to an even lower reporting rate than the calculated one in our analysis. Ibuprofen ranked third in one study from North America (1 < 12 years)  and one from Italy  in a systematic ADR database analysis .
Palivizumab is a monoclonal antibody for the prevention of serious lower respiratory tract disease requiring hospitalization caused by respiratory syncytial virus (RSV). It is indicated for children at higher risk of RSV disease born at 35 weeks of gestation or less and younger than 6 months at the onset of the RSV season as well as for children younger than 2 years with bronchopulmonary dysplasia or congenital heart disease . This may explain why in our analysis palivizumab was most frequently reported for children aged 2 months-1 year, only. The ADRs most frequently reported (40.1% respiratory syncytial virus infection, 16.1% respiratory syncytial virus bronchiolitis) rather suggested reporting of a lack of efficacy which was confirmed in an individual case analysis. If drug-specific exposure was taken into account it ranked only fourth in the age group 2 month – 1 year. In the systematic analysis of ADR databases  it was mentioned in one publication only (first rank) .
Atomoxetine is authorized for the treatment of ADHD in children aged 6 years and older. It ranked second and third for males 7–12 years and 13–17 years in our analysis. In Germany, it was the second most often prescribed ADHD medication until 2013 . However, the considerably lower number of drug prescriptions compared to methylphenidate results in a higher reporting rate for atomoxetine compared to methylphenidate in our analysis, with a higher rate for males than for females aged 12–17 years. In the systematic review of ADR database analyses , atomoxetine was explicitly mentioned in one study only . However, some of these studies listed ADHD medications as summarizing term . Further on, a stimulated reporting for atomoxetine may have been caused by a Dear Doctor Letter informing about suicidality in children in 2005 . This might also have influenced the observation that “suicidal ideation” was the condition most frequently reported for atomoxetine in our analysis. In addition, atomoxetine was authorized in Europe in 2004. An increased reporting of ADRs after a new drug has entered the market (so called Weber effect) was described by others .
Etanercept ranked third in children 7–17 years, however, it ranked first if drug-specific exposure was considered. Etanercept is authorized for the treatment of juvenile idiopathic arthritis and chronic severe plaque psoriasis . Since these are severe diseases and etanercept is a biological, it may be assumed, that children taking etanercept are under regular medical surveillance. This would likely enhance the detection and reporting of ADRs. In the systematic review of ADR database analysis , etanercept was explicitly mentioned in one study only .
ADRs and drugs reported most frequently stratified by age and sex
In our age-stratified analysis, the ADRs and drugs reported most frequently differed. “Foetal exposure during pregnancy”, “atrial septal defect” and “premature baby” were the conditions, and “drugs for the treatment of nervous system disorders” (e.g. venlafaxine, lamotrigine) were the drugs most often reported in children 0–1 month. The ADRs most frequently reported seemed to be associated with drug exposure during pregnancy. Other studies also observed, among others, prematurity, poor neonatal adaption and respiratory distress in neonates of women treated with antidepressants during pregnancy [55, 56]. Our calculated reporting rates for children 2 month-1 year were considerably higher for these drugs (e.g. for lamotrigine) compared to older children. These results should be interpreted with caution since we did not exclude ADR reports that reported drug exposure via the mother during pregnancy, which was the condition most frequently reported in this age group.
Irrespective of the applied drug, “vomiting” and “urticaria” ranked first for children 2–3 and 4–12 years. Hypersensitivity-like reactions (rash, urticaria etc.) were, among others, reported in association with amoxicillin and ibuprofen for children 2–3 and 4–6 years. This finding could likely reflect that acute common infections become more frequent for children aged 3–6 years like observed in a German investigation .
“Suicide attempt” was the condition independent of the applied drugs most often reported in children 13–17 years and more often reported for females than for males. However, with regard to the drugs and their ADRs most frequently reported, hormonal contraceptives and thromboembolic events ranked first for females 13–17 years. In contrast, for males of the same age, suicide associated with methylphenidate and atomoxetine was striking. In Germany, roughly one fifth (21.5%) of girls aged 14–17 years take hormonal contraceptives  which may impact on the higher number of ADR reports. Additionally, the high media attention in the past may have led to a more frequent reporting. However, if related to the number of drug prescriptions, reporting rates were rather low compared to the other drugs.
Finally, as also stated by others [17, 18] it should be noted that very young children may not be able to communicate specific ADRs, particularly those which are subjective. Instead unspecific and/or recognizable symptoms may dominate in these age groups and may lead to differences in the most frequently reported ADRs stratified by age. In addition, reporting of ADRs at least for younger children will generally involve the parents .
The drugs substances most frequently reported in ADR reports referring to off- label use in our analysis differed from to the drugs most frequently reported in the whole dataset. Likewise they differed from the drugs most frequently used off-label according to a Germany survey . In our analysis, drugs for the treatment of nervous system disorders were commonly reported. In contrast, the drugs most often used off-label in Germany were cardiovascular drugs, antineoplastic and immunmodulating agents and drugs for the treatment of sensory organs . In this survey, drugs for the treatment of nervous system disorders played a rather minor role accounting for only 16% of off-label drugs. The potential to induce ADRs may differ between these drug classes leading to the observed differences between our study and the German survey. In addition, methodological differences in study designs have to be considered. As already mentioned, possibly not all ADR reports in which a drug was used off-label are designated with an off-label use, which may impact on our results.
With regard to the ten drugs most frequently reported overall (not restricted to off-label use) in our analysis, off-label use as per authorized age after exclusion of children aged 0–1 year was only observed for methylphenidate, risperidone and atomoxetine. All of these drugs are used for the treatment of nervous system disorders. Again, in the German study, drugs for the treatment of nervous system disorders played also a rather minor in the evaluation of drugs used off-label as per authorized age . In that study, cardiovascular drugs, antineoplastic and immunmodulating agents and drugs for the treatment of musculoskeletal and connective tissue disorders were identified as the drugs most often used off-label per authorized age. It has to be considered that we only analyzed the proportion of off-label use per authorized age in the ten most frequently reported drugs of the whole dataset. However, the proportion of identified cases for drugs used off-label as per authorized age for these ten drugs was small. Off-label use as per authorized age (3.8%) ranked only fourth as reason for the off-label use after under-dosing (17.4%), over-dosing (4.6%) and indication (4.3%) in the Germany survey .
Advantages and disadvantages of analysis using spontaneous reporting data
Strengths of our analysis include the coverage of a long period of time, the inclusion of a wide pediatric population in real life, the large number of ADR reports available for the analysis compared to many other national ADR database analyses [11, 15, 16, 33, 34] as well as the calculation of reporting rates based on the number of drug prescriptions.
One limitation of our analysis is the lack of exposure data specifically matching the individual in the ADR report. We addressed this limitation by using drug prescription data from the Central Research Institute for Ambulatory Health Care in Germany . However, our analysis only presents the reporting rates of the five drugs most frequently reported. Other drugs which are not considered might have a higher reporting rate. In addition, the drug prescription data refer only to the reimbursed drugs prescribed in outpatients while our ADR reports may also be related to drugs used in hospitals.
Another limitation is the unknown amount of underreporting which may differ, among others, per age group, particular drug and nature of the ADR [58,59,60]. Due to the missing exact exposure data and the unknown extent of underreporting no incidences can be calculated based on the results of such analyses. Additionally, due to the large number of ADR reports, an individual case assessment of all ADR reports with regard to the causal association and the quality of the ADR report was not performed. However, all submitted ADR reports are suspected cases of ADRs and 77.0% of our random sample had an at least possible causal relationship which is in line with observations of other previous analyses [21, 22, 61]. Although, the completeness score of our random sample was 0.6 [0.6–0.7] and thus below the 0.8 expected for a well-documented report , it should be noted, that certain minimal criteria have to be present to allow the submission to EudraVigilance .