Pediatric Drug Safety Surveillance: A 10-Year Analysis of Adverse Drug Reaction Reporting Data in Calabria, Southern Italy

Proportion of Pediatric ICSRs in the Calabrian Pharmacovigilance Database

During the 10-year period covered by our analysis, after exclusion of duplicates, vaccines, and ICSRs containing missing age data, reporting of suspected ADRs in the pediatric population of the Calabria region represented about 6% of all ICSRs collected in the Calabrian Pharmacovigilance database. This proportion was lower than that reported in the EudraVigilance database (11.2%) [34] and the Portuguese pharmacovigilance database (9.7%) [35], but it was similar to the percentage of pediatric ICSRs reported in the whole RNF database (6.8%) [25], in the Spanish pharmacovigilance database (7%) [36], and in VigiBase (7.7%) [37]: similar to our study, the RNF database and VigiBase analyses excluded vaccine-related reports.

The low proportion of ICSRs on suspected pediatric ADRs in the Calabria region may be partially explained considering that the regional pediatric population significantly decreased in the same period [38], as well as the Italian pediatric population [39]: these demographic data are consistent with the similar percentages of pediatric ICSRs reported in the Calabrian and the Italian pharmacovigilance databases. However, the well-known under-reporting of pediatric ADRs in SRSs [40] could also have contributed to the low proportion of ICSRs concerning the pediatric population of the Calabria region. Indeed, pediatric ADRs can be difficult to characterize as many of the tools available are unsuitable for use in pediatrics [40]. Furthermore, reporting of ADRs in children is more challenging than in adults as it generally involves the parent as an essential intermediary and because children may not be as able as adults to describe their symptoms [34]. Therefore, a greater engagement of parents in their child’s treatment and a better communication between clinicians and parents about any potential risks associated with medicines may help with early detection and reporting of pediatric ADRs.

Brief Overview of the Regional Pediatric ICSRs

This descriptive analysis identified the characteristics of suspected ICSRs concerning the pediatric population from the Calabrian RNF database across a 10-year period. First, we observed a decline in the number of pediatric ICSRs after 2015. A greater number of ICSRs was found in male subjects aged 28 days up to 17 years. Only 15.2% of the total ICSRs were classified as serious and most of them required hospitalization, with over two thirds of serious cases involving children (aged 2–11 years) and adolescents (aged 12–17 years). However, around 80% of the ADRs completely recovered or improved. The majority of pediatric ICSRs were issued by physicians.

Interestingly, the ADR outcome was reported to be unknown in 20% of ICSRs. This is in line with the 22% of pediatric ICSRs without a known outcome previously reported in the whole RNF database [25]. Such a proportion of ICSRs indicates a need to improve the reporting of patients’ outcomes and, more generally, the follow-up of the cases (by the local individuals responsible for pharmacovigilance) to obtain supplementary detailed information significant for their scientific evaluation. For this reason, since 22 June 2022, the new RNF has been operational, including a new international standard format (ISO ICSR format) for reporting suspected ADRs, which, as from 30 June, 2022, must be used in all EU countries to send and receive ICSRs to and from EudraVigilance [41]. The updated data structure of the new reporting form aims at improving the quality of ICSR content by adding specific data fields for each single suspected ADR: onset and end dates, seriousness, seriousness criteria, and outcome are provided at the ADR level and no longer at the case level [41, 42].

Pediatric ICSRs by Age Category and Sex

Our findings are largely consistent with several previous studies investigating pediatric reporting patterns in other national and international SRSs [25, 35,36,37, 43, 44]. In accordance with findings from VigiBase [37] and the Italian SRS database [25], most child ICSRs corresponded to children aged 2 up to 17 years and about 52% of all ICSRs concerned boys, mainly from 28 days to 17 years of age. The higher proportion of ICSRs that we found in the 2–11 and 12–17 years of age groups could be owing to the greater prevalence of drug use among older children [45], but it might be also related to the increasing demographic drop of the Calabria region [46]. However, the sex pattern might in part reflect the greater prevalence and incidence of some childhood diseases (e.g., asthma, certain infections, and epileptic syndromes) in the male sex [47, 48]. However, it is unclear whether boys are more likely to require medication or to be involved in an ICSR. Our data regarding sex differences across the age groups are inconsistent with previous findings showing prevalence rates for drug use as higher in adolescent girls than in adolescent boys, whereas an opposite trend had been reported for younger age categories [45]. Accordingly, male prevalence reversed in adolescents when examining the Italian SRS database [25] and other nationwide and supranational pharmacovigilance networks [35,36,37, 43]. The changeability of reporting habits (including under-reporting) between different drugs and patient age categories may partially justify the different sex pattern reported in our analysis [44, 49].

Who Did Report Pediatric ADRs? What About the Seriousness of Reported Pediatric ADRs?

In line with national [25] and VigiBase data [37], physicians were the main reporters among healthcare workers, being actively involved in over 64% of pediatric ICSRs and over 80% of serious ICSRs. In fact, it has been reported that seriousness is a pivotal factor driving physicians’ reporting [50]: this attitude may probably justify the small number of pediatric cases retrieved and analyzed in the study period. With rising age groups, the proportion of ICSRs decreased for physicians while increased for the other healthcare workers. Such an outcome does not offer an easy explanation. Moreover, our dataset did not include any information about the type of reporting physicians that it would have been diriment in this setting. However, we might speculate a gradual decreased involvement of pediatricians and a greater engagement of nurses and other healthcare workers in drug safety monitoring from infant to adolescence age. Indeed, Italian pediatricians are entrusted with children’s medical care up to the age of 14 years, thus all pediatric clinical information (including specialist and hospital care) is stored in their medical records [45]. Similar to the Spanish pharmacovigilance system [36], physicians were more likely to report serious ADRs than other notifiers in our study, disagreeing with findings from the Danish ADR database [43].

Regional Healthcare Facilities Submitting Pediatric ICSRs to the RNF

During the study period, most child ICSRs submitted to the RNF database were issued from the “Mater Domini” University Hospital (Catanzaro), where a Regional Center of Drug Information was institutionalized by the end of 2010 thanks to the pharmacovigilance funding program during 2008–9. This center is carrying out active pharmacovigilance projects with the aim of improving regional spontaneous reporting and promoting a more rational use of medicines in clinical practice [21, 26]. Such an activity of disseminating pharmacovigilance knowledge and training for healthcare professionals could explain the increasing pediatric reporting rate observed in the early study period. Conversely, the recent declining reporting rate is worrying from a public health viewpoint because it might reflect a decreasing awareness of iatrogenic disease among reporters. It is also important to note that the large majority of child ICSRs (~67%) came from the area of Catanzaro where one Pediatric University Unit, four Pediatric Hospital Units, and one Neonatal Intensive Care Unit have been operational for many years.

Anatomical Main Groups (ATC First Level) and SOCs Involved in ADRs

Following stratification by drug group and SOC, ICSRs involving anti-infective, nervous system, and respiratory system drugs as suspected medicines and skin disorders as ADRs were proportionally higher in the child group compared with the adult group. Of note, the distribution of the ICSRs in terms of suspected drugs and ADRs is in accordance with several other SRSs. The greater proportion of ICSRs relating to anti-infectives (excluding vaccines) and respiratory tract medicines for children than for adults supports the fact that asthma and infections are common childhood diseases [47]. In fact, these drug classes have been reported as the most commonly prescribed medicines in all pediatric age categories in Italy and other European countries [45]. Similarly, the higher proportion of ICSRs involving nervous system drugs in children as compared with adults is likely to reflect that some neurologic disorders (e.g., epilepsy) are common in childhood [51]. Moreover, children show an increased susceptibility to convulsions because their brain is still immature and continues to develop [52]. In addition, drug utilization research in children has proven a moderate prevalence of prescriptions for nervous system agents in European countries [45].

Congruent with previous studies excluding vaccine-related ICSRs [25, 37], skin adverse reactions were the most commonly notified ADRs for both children and adults, but they were reported more frequently in the child group than in the adult group. This could be owing to a greater susceptibility of children to cutaneous ADRs, based on their different skin physiology compared with adults [53]. Additionally, as previously confirmed [25], our findings corroborate that antibiotic use is well known to induce allergic reactions, especially in children [54]: antibiotics were the most frequently used drugs in relation to pediatric skin disorders in our study. Moreover, antibiotics were involved in over half of pediatric ICSRs reporting allergic skin reactions (see also Sect. 4.7). With regard to these findings, it should be considered that changeable patterns of disease, pharmacokinetics, and pharmacodynamics associated with pathophysiological changes could justify the differences in relation to drugs and ADRs observed across age. Consistent with results from the Spanish ADR database [36], urticaria was the most common PT described in pediatric ICSRs.

Single Suspected Drugs (Active Substances) Involved in Pediatric ADRs and Most Recurrent Pediatric Drug-ADR Pairs

At the level of a single suspected drug, amoxicillin/clavulanic acid was primarily involved in terms of the absolute number of pediatric ICSRs, ADRs, and serious ADRs. At the drug-ADR pair level, amoxicillin/clavulanic acid was the mostly implicated drug in skin disorders in the pediatric population. In particular, amoxicillin/clavulanic acid was involved in one-third of pediatric ICSRs related to allergic skin reactions from antibiotic use. Overall, antibiotics were associated with the highest number of ICSRs and serious ADRs in the pediatric population.

The involvement of antibiotics in the highest number of pediatric ICSRs reflects previous national and European results showing that this therapeutic group was the most commonly prescribed in children [45]. Among the most reported antibiotics, amoxicillin/clavulanic acid, ceftriaxone, and cefaclor were primarily associated with serious ADR occurrences. Moreover, in step with the RNF database [25], amoxicillin/clavulanic acid-skin reactions were the most recurrent pediatric drug-ADR pair. This trend is relatively predictable if considering that broad-spectrum penicillins and third-generation cephalosporins represent, respectively, the largest subgroup of systemic antibiotics and the most common cephalosporins prescribed to children in Italy [55]. Furthermore, a pediatric cohort study in five European countries has recently reported the highest prescription rate for amoxicillin plus an enzyme inhibitor in Italy [55]. Unsurprisingly, the outpatient pediatric prescription patterns seem to also support our ranking of amoxicillin/clavulanic acid, paracetamol, and ibuprofen as the top three most frequently reported active substances [45, 55].

Noteworthy, a possible pharmacokinetic drug–drug interaction was suspected in one pediatric case of hyperammonemia involving the combination of lamotrigine and valproic acid. Consistently, it has been previously reported that the combined use of lamotrigine with valproic acid might potentiate the risk of an elevated blood ammonia level and/or valproic acid-induced hyperammonemic encephalopathy [56]. This may be justified by the competition between lamotrigine and valproic acid for the UDP-glucuronosyltransferase metabolic pathway [57]. However, other studies showed opposite findings in relation to the aforementioned drug interaction [58, 59].

Off-Label/Unlicensed Drug Prescribing and ADR Occurrence in Pediatric Patients: Which Evidence?

Off-label/unlicensed drug use was recognized in 3.5% of pediatric ICSRs included in our analysis, suggesting that ADR occurrence was not significantly related to off-label prescribing. This evidence is in line with previous results of a French survey on pediatric drug prescribing [60]. However, off-label prescription in pediatric practice has been shown to be common among drugs reported as possible cause of ADRs in different pediatric patient settings [15, 61]. Such data inconsistency could be explained considering that pediatric ADRs are notably under-reported in SRSs [40], especially after off-label use [61]. Our ICSRs mostly concerned children and adolescents, although newborns had been identified as the most exposed group to off-label use in a previous literature review [7]. In contrast to the findings from a Swedish observational analysis of spontaneous ADR reports [15], in our study, off-label drug prescribing was more frequently associated with non-serious ICSRs, but it mainly involved an age not labeled in both investigations. Consistent with our findings, drugs for the treatment of nervous system disorders ranked first among off-label ICSRs in a recent descriptive analysis of ADR notifications in the pediatric population from Germany [62]. Further, a previous prospective study in a pediatric hospital population in Germany had reported anti-infectives to be suspected more frequently in ADRs, especially those related to off-label drug use [63]. In addition, results from a very recent multicenter trial showed that off-label use of antidepressants and antipsychotics in children and adolescents was not a risk factor for the occurrence of serious ADRs [64]. However, off-label prescribing mainly involved an unapproved indication in previous French surveys investigating the relationship between off-label drug use and an increased risk of ADRs in pediatric patients [14, 60]. We also found skin disorders to be the most frequently reported pediatric ADRs associated with prescriptions outside the specifications of product license, while psychiatric disorders and mucocutaneous inflammatory reactions were the most common clinical conditions identified in the Swedish study [15]. With reference to serious ADRs linked to off-label drug use, the metoclopramide-hypertonia and seizures pair deserves a special consideration, based on previous regulatory actions in children. Noteworthy, in 2004, AIFA contraindicated the prescription of metoclopramide in patients aged younger than 16 years, according to the increasing number of neurological adverse events (including extrapyramidal disorders) reported in the RNF for this age group population [25]. After a formal re-assessment of safety and efficacy data, in October 2013, the European Medicines Agency restricted the use of metoclopramide in pediatric patients > 1 year of age as a second choice to prevent delayed nausea and vomiting after chemotherapy and to treat postoperative nausea and vomiting [65].

Among non-serious ICSRs, one case (submitted to the RNF in 2013) involved retigabine, which was voluntarily withdrawn from the market in 2017 because of its limited usage [66].

Drug Use Outside the Marketing Authorization and ADR Occurrence in Pediatric Patients. What About Misuse, Abuse, and Medication Error Cases?

Only two inappropriate self-medication cases were identified in the children category (aged 2–11 years), involving over-the-counter medicines. This confirms that self-medication bears the risk of misuse, further supporting the well-known link between over-the-counter use and ADRs. The risks of inappropriate self-medication also include incorrect self-diagnosis, delay in consulting a physician, use of excessive dosages, prolonged drug-use duration, drug interactions, polypharmacy, and drug abuse [67, 68]. In our study, a serious case of vasculitis involved ibuprofen, which represents one of the most common self-medication drugs [69]. Based on patients’ ages in Table 5, their parents (or relatives) were probably responsible for the inappropriate use of nonprescription drugs, potentially owing to a lack of knowledge of anti-inflammatory and analgesic drug use. Indeed, inappropriate nonprescription use is often associated with limited information and low medication literacy in adults, resulting in a higher risk of hospitalization and serious adverse drug events [67].

Regarding drug abuse, five out of seven cases concerned intentional self-injury in adolescent girls and mainly involved nervous system drugs. Sixty percent (n = 3) of intentional self-injury episodes were classified as serious. An opposite sex pattern has been reported in a previous 10-year analysis of psychiatric ADRs in a Swedish pediatric population where boys were over-represented, particularly among serious cases [70]. Remarkably, we noted that two serious cases of intentional self-injury were not associated with any symptoms/suspected adverse events (e.g., asymptomatic abuse): these cases were improperly submitted to the RNF database because they were not reportable as valid ICSRs in accordance with GVP, Module VI [32].

Almost 2% of pediatric ICSRs were related to medication errors, half of which were serious and occurred mainly in children (aged 2–11 years). Medication errors represent an important concern both in hospital and outpatient settings. However, ADRs associated with medication errors are highly under-reported because of several barriers, including fear of potential disciplinary actions, fear of a lack of confidentiality, lack of time, and a lack of awareness that an error has occurred [71]. Therefore, it is essential to improve pediatric patient safety by fostering pharmacovigilance knowledge, by strengthening the continuous training of healthcare professionals, and by educating families in the prevention of medication error problems in the pediatric population. This last goal seems to be particularly important in our study context, considering that most medication error cases (accidental exposure) occurred in very young children probably because of their parents’ carelessness. Moreover, a young boy experienced tachycardia related to an accidental overdose with respiratory drugs because of improper use of an inhalation device by his father. In EudraVigilance, pediatric ADR errors were mainly associated with inappropriate dose and indication [34] whereas errors related to accidental overdoses were prevalent in VigiBase [37].

A careful analysis of regional pediatric ADR errors showed that two cases were not associated with suspected clinical consequences/ADRs (e.g., asymptomatic medication errors) and, thus, they were not required to be submitted as ICSRs: medication errors without suspected ADRs do not fall in the definition of a valid reportable ICSR in line with GVP, Module VI [32].

Comparing Calabrian Spontaneous Reporting Database with the RNF and Other Nationwide and Worldwide Pharmacovigilance Networks

Taken together, the characteristics of pediatric ICSRs stored in the Calabrian ADR database agree with those from the RNF and the other European and worldwide spontaneous reporting databases. This could reflect a relatively harmonized implementation of the new European pharmacovigilance legislation across countries [26]. Nevertheless, we observed small discrepancies with the RNF database, probably reflecting regional differences in drug exposure, reporting habits and/or region-specific active pharmacovigilance projects. We also reported small variations compared with other nationwide SRSs, which could be interpreted in a similar way.

Implications for Pharmacovigilance Activities

Of note, our analysis highlights some differences within child age groups and between children and adults, emphasizing the need for an age-specific approach when investigating epidemiological data on ADRs. This could help to target specific patient age groups that are more likely to have an increased risk for particular ADRs. Notably, in further supporting previous national and supranational findings [25, 34,

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