This document summarizes key aspects of pharmacovigilance in pediatrics. It notes that drug safety profiles in children are often less well known than in adults due to limited clinical trials. Off-label use is also common in pediatrics due to a lack of approved formulations and dosing recommendations for children. Certain adverse drug reactions are specific to pediatric patients and can be related to developmental factors. Spontaneous reporting and epidemiological studies are important for monitoring drug safety in children but underreporting remains an issue. The incidence of adverse drug reactions in children varies depending on factors like treatment setting and country.

1. Accepted Manuscript
Title: Pharmacovigilance in pediatrics
Author: ´Emilie Bouquet Kristina Star Annie Pierre
Jonville-B´era Genevi`eve Durrieu
PII: S0040-5957(18)30017-9
DOI: https://doi.org/doi:10.1016/j.therap.2017.11.012
Reference: THERAP 247
To appear in:
Received date: 15-10-2017
Accepted date: 15-11-2017
Please cite this article as: ´Emilie BouquetKristina StarAnnie Pierre
Jonville-B´eraGenevi`eve Durrieu Pharmacovigilance in pediatrics (2018),
https://doi.org/10.1016/j.therap.2017.11.012
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Therapie
Rubrique : Pediatric pharmacology/Drugs and children
Numéro 2 mars avril 2018
Pharmacovigilance in pediatrics
Pharmacovigilance in pediatrics
Émilie Bouquet a
, Kristina Star b,c
, Annie Pierre Jonville-Béra a
, Geneviève Durrieu d,*
a
Department of clinical pharmacology and regional pharmacovigilance center, university hospital, CHRU
Tours, 37044 Tours, France
b
Uppsala monitoring centre, 75140 Uppsala, Sweden
c
Department of public health and caring sciences, Uppsala university, 75105 Uppsala, Sweden
d
Department of medical and clinical pharmacology, Toulouse university hospital, faculty of medicine, 31000
Toulouse, France
Received 15 October 2017; accepted 15 November 2017
*Corresponding author. Department of medical and clinical pharmacology, Toulouse university hospital,
faculty of medicine, 37 allées Jules Guesde, 31000 Toulouse, France.
E-mail adress: genevieve.durrieu@univ-tlse3.fr (G. Durrieu)
Summary
The characteristics of pharmacology and drug evaluation in the pediatric age group highlight the
necessity for the pharmacovigilance community to adjust to the specific features of children. At the
time of marketing a medicinal product intended for children, the product’s safety profile is

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sometimes less well known than for adults due to fewer or small sample clinical trials. Furthermore,
the frequent off-labeled drug use, the use of unsuitable dosage forms and the need for continuous
dose adjustments increase the risk of medication errors and thus lead to avoidable adverse drug
reactions (ADRs). The occurrence of child-specific ADRs (such as growth disorders) or ADRs
more commonly occurring in children than in adults make it necessary to monitor the safety of
child-specific drugs. Pediatric pharmacovigilance includes also the consequences of in utero
exposure, whether manifestations are present from birth or occur in early childhood (such as
neurodevelopmental disorders). The incidence of ADRs varies with age, setting of medical care (in
or out-patients, pediatric specialties) and by country in which the study was carried out. The drugs
most frequently reported with ADRs are those most commonly used in the pediatric age group
i.e.antibiotics and vaccines. The ADRs most often reported are skin, neurological and general
disorders. As in adults, spontaneous notification is essential to generate alerts and child-specific
pharmaco-epidemiological studies are necessary and should be developed.
KEYWORDS
Pharmacovigilance; Children; Adverse drug reactions; Pharmacoepidemiology
Abbreviations
ADDUCE: attention deficit hyperactivity disorder drugs use chronic effects
ADHD: attention deficit hyperactivity disorders
ADRs: adverse drug reactions
EMA: European medicines agency
EUADR: European adverse drug reaction (project)
GRIP: Global research in paediatrics – network of excellence
ICSRs: individual case safety reports
MEDRA: medical dictionary for regulatory activities
PV: pharmacovigilance
SOC: system organ class
SRS: spontaneous reporting systems
TNF: tumor necrosis factor
WHO: World health organization
Introduction

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The unique features of the continuously developing pediatric patient requires much consideration
within drug safety. Newborns are at a particularly high risk of harm from medicines because of their
organ immaturity and rapid developmental changes that occur after birth. Many available drugs
used in pediatrics have not formally been evaluated in pediatric clinical trials, hence evidence for
efficacy and safety is lacking and optimal dosing is rarely known for the individual pediatric
patient. Drug formulations that were not originally produced for the pediatric population make dose
optimization even more difficult, exposing pediatric patients to medication errors such as
overdosing resulting in adverse drug reactions (ADRs). Harm from drugs can be distinct to a
pediatric age because some drugs are targeted for a specific age-population. Other age specific
ADRs can be explained by the maturation phenomena during growth and organ development.
Against this background, post-marketing drug safety surveillance is particularly important in
children. Prospective studies on pediatric patients provide information on incidence rates of ADRs
and retrospective reviews of pharmacovigilance (PV) databases provide information on type of
reported ADRs and drugs. However, underreporting remains a major problem in children probably
because the diagnosing of ADRs are difficult to establish or require a long time to be detected,
particularly in chronic diseases.
The characteristics of the pediatric population relevant for drug safety
Lack of drug evaluation in neonates, infants, children and adolescents
Data on safety for medicinal products in the pediatric population remain scarce compared with
those available in adults [1]. Unlike for the adults, few clinical trials are performed in the pediatric
population except for some therapeutic areas (oncology, infectious diseases and neuropsychiatric
disorders). This lack of drug evaluation can be explained by less frequent pediatric specific
indications, smaller population to treat and greater difficulties in conducting studies in this
population compared with adults. Recruitment difficulties for clinical trials are numerous, notably
related to the fear of side effects and over-medicalization [2]. However, drug evaluation is crucial in
the pediatric population because of pharmacokinetic and pharmacodynamic modifications
throughout organ development, which makes it especially risky to extrapolate data obtained in
adults to children [3]. In 2007, European legislation introduced the evaluation of the safety of
medicinal products specifically in the pediatric population by requiring pharmaceutical companies
to carry out a pediatric investigation plan for any dossier on new substances, new indications or
changes of pharmaceutical forms. Furthermore, when pediatric trials are conducted, serious ADRs
are usually not detected most likely because they are too rare to be observed (lack of power) among
the limited number of patients included in a clinical trial [4-6]. The ADRs which are delayed or
which affect only one age group not included in the trial are not known at the time of marketing
authorization [7]. This background enhances the importance of monitoring drug safety in the
pediatric population.

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Necessity of off-label drug use
The lack of drug evaluation in children restricts the availability of licensed medicines and thereby
information on recommended doses and risks of their use specific to the pediatric population.
However, pediatric patients still need to be treated with medicines. For example, no step 2
analgesics are currently licensed in France for ages below 18 months of age, but still infants need to
be treated for cancer pain. Pediatric patients, especially the neonates, commonly receive off-label
drug prescriptions (ranging from 3.3% to 47% in children and from 46.5% to 50.5% in neonates
depending on the studies) [8], i.e. a prescription for an indication, age or with a dosage which is
different from the licensed terms. Some studies have shown that off-label medications increase the
risk of ADRs [9]. Moreover, the lack of dose recommendations for specific pediatric ages result in
prescriptions of doses that are extrapolated on the basis of body weight, which can lead to
overdosage and the lack of adapted galenic forms can lead to prescribing, dispensing or
administering errors [10]. Furthermore, the benefits of drug treatment in children may not always be
the same as in adults [11]. A recent randomized controlled trial evaluating the effect of metformin
versus placebo on glycated hemoglobin in overweight type 1 diabetic teenagers did not show
benefit from metformin and revealed a higher risk of ADRs [12]. In summary, off-label prescribing
is often based on a supposed benefit while the knowledge on the risks is limited potentially leading
to severe side effects.
Characteristics of some adverse drug reactions in the pediatric population
The maturation phenomena (especially the growth) illustrate that some adverse reactions are
specificto pediatric patients, e.g. corticosteroid-induced growth retardation, long bone thickening
and premature ossification induced by retinoid or dental dyschromia associated with cyclins [13-
18]. Other ADRs are not specific to children but seems more frequent than in adults as
hypoglycemia with b-blockers [19], psychiatric disorders with montelukast [20-22] or intracranial
hypertension with vitamin A [23-24]. Furthermore, children like elderly, may be more sensitive
than adults to some metabolic ADRs such as hyponatremia with desmopressin [25]. Conversely,
due to lack of other risk factors, some ADRs are more rarely observed in children than in adults,
e.g. gastrointestinal bleeding [26] or kidney failure secondary to non-steroidal anti-inflammatory
drugs [27].
When children are the unique target population of some drugs the adverse reactions are not
described in adults. For instance, for measles-mumps-rubella vaccine the first cases of
thrombopenic purpura was published in the pediatric population [28] and intestinal invaginations
with rotavirus vaccineswere exclusively reportedin infants [29].
Pediatric pharmacokinetic characteristics

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The broad range of physiological developmental stages, from the fetal period to adolescence, makes
the pediatric population vulnerable to certain ADRs. There are pharmacokinetic characteristics in
children according to each stage of development. Neonates may present a higher risk of adverse
drug effects than other age groups because of their organ immaturity and rapid developmental
changes that occur after birth. Pharmacokinetic characteristics concern primarily newborns and
infants. The volume of distribution is higher in infants and children with consequently higher
weight-based doses than in adults. Binding to plasma proteins is reduced at birth, which may
account for increased sensitivity to some drugs. This requires caution with regard to certain drugs
with high affinity for albumin as exemplified by kernicterus in neonates treated with sulfonamides
[30-31]. The immaturity of phase I (cytochrome P450, 3A, 2C, 2D or 1A) and phase II
(glucuronidation, conjugation to glutathione, acetylation, methylation) reduces the clearance and the
rate of elimination of many drugs (e.g. acetaminophen, caffeine or even chloramphenicol whose
increased serum concentrations have been associated with baby grey syndrome) [30-31]. On the
contrary, sulfoconjugation is mature at birth which makes it possible to eliminate acetaminophen.
The metabolic immaturity results in a reduced clearance and a prolonged half-life explaining the
need to space unit doses of some drugs during the neonatal period. The maturation of metabolism is
acquired at a variable age according to the cytochromes: methylation of caffeine towards the 4th
month, acetylation of caffeine in the 2nd year, glycuroconjugation of acetaminophen in the older
children. After the first month of life, metabolic activity increases progressively in the infant to
exceed that in adults. Thus, metabolic clearance is higher and half-life is shorter in infants and
young children explaining the need to reduce time between each dose. The glomerular filtration,
reduced in the newborn to 30% of the adult capacities, reaches the adult values at the end of the
second week of life [7]. Another peculiarity met with skin thinness which increases drug resorption
(such as local anesthetics and ethanol) explaining the occurrence of ADR after dermal application
as methemoglibemia with lidocaine [32]. Finally, pediatric doses need to be prepared at much lower
doses than for adults, which increase the risk of medication errors [33].
Consequences of “in utero” exposure
A child could also have been exposed to a drug taken by its mother during pregnancy resulting in
secondary ADRs. Withdrawal syndromes (secondary to benzodiazepines, morphine, etc.) are
observed within a few days after birth and are easily attributed to drugs taken by the mother in late
pregnancy [34]. On the other hand, to establish a causal relationship for these secondary ADRs with
in utero drug exposure is more difficult, especially when the manifestations are atypical such as for
autism spectrum disorders and valproate use during pregnancy [35], or are non-specific such as for
infections after in utero exposure to tumor necrosis factor (TNF) alpha biotherapy [36], or are
transgenerational as hypospadias, cryptorchidism, or testicular hypotrophy in boys whose
grandmothers were treated with distilbene [37-38].

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Avoidability of adverse drug reactions in the pediatric population
In children, the frequent off-label drug use, the need for dose adjustment and the use of unsuitable
dosage forms increase the risk of avoidable ADRs. Avoidability, or preventability, is an important
concept in the study of ADRs. Avoidable ADRs may result from several levels of errors during the
process of drug treatment, i.e. prescribing, transcription/interpretation, dispensing and administering
errors, with the last three of these types of errors considered distribution errors. ADRs are avoidable
or preventable if the prescription did not meet the recommendations (indications, contraindications,
dose, route of administration, precautions for use, etc) given in the summary of product
characteristics or if there was an alternative therapy at least as effective as the prescribed
medication but with lower toxicity [39]. There are two aspects of avoidability: whether in principle
an event is avoidable in the absence of error and whether we can in fact prevent it [40]. Different
Anglo-Saxon and French scales are used for measuring avoidability [41-42]. However, these scales
are not always optimal for pediatrics, which conducted to the recent development of a specific scale
for children: the Liverpool scale [43]. The evaluation of avoidability allows for obtaining
quantitative data and qualitative information to know the circumstances that might have rendered an
adverse reaction preventable, in order to propose suitable preventive measures for a direct impact
on the safety [44]. According to a systematic review of fourteen studies of ADRs in children, the
rate of ADRs being either definitely or possibly avoidable was ranging from 7 to 98% [45].
Incidence rates and characteristics of adverse drug reactions in the pediatric population
Incidence rates of ADRs
The incidence rates of ADRs in children during inpatient hospital stay were 9.53% (95% confidence
interval 6.81% to 12.26%) and 10.9% (4.8% to 17.0%), respectively, described in two systematic
literature reviews [46,47]. ADR incidence rates were higher in hospitalized children than ADR rates
causing hospital admission or in outpatient settings. Admissions to hospital due to ADRs were
estimated to be 1.8% to 2.1%. In the review of Impicciatore [46], 39.3% of the pediatric admissions
due to ADRs were considered life-threatening. Fewer data was reported in out-patient children from
studies performed in ambulatory emergency care. In these patients, the ADR incidence rate ranged
from 0.5% to 1.5% [46-51].
In agreement with these previous studies, Smyth et al. also [45] reported, in a large systematic
literature review, that ADR incidence rates were generally higher in hospitalized children than ADR
rates causing hospital admission or in an outpatient setting. The higher rate of ADRs for
hospitalized children may be explained by that more drugs are used per patient; that high risk drugs
are used more often related to ADRs (off-label or unlicensed drugs or patients in oncology or
infection wards); or that closer ADR monitoring is possible in hospital [52,53]. Smyth et al. [45]
also underlined that one of the main difficulties of comparing ADR incidence rates from
observational studies, is that the studies differ in several ways, such as geographical area, clinical

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setting, population characteristics and study duration. This may explain the large amount of
heterogeneity in the incidence rates reported.
Due to the characteristics of pediatrics, the pediatric population ought to be more vulnerable to experiencing
ADRs [54]. However, the incidence rate of ADRs remains lower than in adults. A French study, conducted
in 2008, showed that the incidence rate of ADR-related hospitalizations increased with age: <15 years: 1.4%
(95% confidence interval: 0.5% to 2.8%), 16-64 years: 3.3% (2.4% to 4.2%), >65 years: 4.9% (3.8 to 6.0%)
[55]. More recently in the USA, the National electronic injury surveillance system–cooperative adverse drug
event surveillance project [56] found similar results. But considerable variation may exist depending on the
pediatric specialty involved, such as oncology patients or the age of children [57,58].
Moreover, the likelihood of a child being admitted in hospital with an ADR increased with the
number of medicines taken (OR 1.24, 95% CI 1.19, 1.29, p <0.05). For each additional medicine
taken, the risk of an ADR occurring increased by almost 25% [57,59]. In patients who took four
medicines or more, the prevalence was increased by a factor of 7 compared with patients taking
only one drug. This means that polypharmacy and drug interactions constitute a known and relevant
risk for increased ADRs in pediatrics as well as in adult medicine [60].
Types of reported ADRs
Skin reactions were the most frequently reported suspected ADRs in children in VigiBase, the
World health organization (WHO) global database of individual case safety reports (ICSRs) [61],
whilst general disorders (including administration site conditions) such as pyrexia/fever were the
most frequently reported suspected ADR in the EudraVigilance web-based system of ICSRs [1]. In
the EudraVigilance review, reports on vaccines dominated the pediatric dataset, which presumably
influenced the type of ADRs that were most frequently reported in this analysis. Reports on
vaccines were excluded from the VigiBase analysis, and anti-infective agents, such as amoxicillin,
were most frequently reported, and thereby most likely influencing the high reporting of skin
reactions, since allergic reactions are well known to be induced by antibiotic use [62]. In a recent
systematic literature review of studies on pediatric ADRs from national and international PV
databases, Cliff Eribo et al. [63] described that skin disorders (rash and urticaria) were the most
frequently reported ADRs in most of the studies [61,64-67]. In this review, other common ADRs
were nervous system disorders (headache, dizziness, and drowsiness) and pyrexia/fever. The
majority of the studies which ranked the frequency of ADRs described them in system organ class
(SOC), the highest level of SOC according to the medical dictionary for regulatory activities
(MedDRA) classification [65], whilst a few studies described ADRs with lowest level terms. These
differences in presentation made comparison of the studies difficult.
A “serious” ADR has been defined as ‘‘any untoward medical occurrence that at any dose results in
death, requires hospital admission or prolongation of existing hospital stay, results in persistent or
significant disability/incapacity, or is life threatening’’ [69]. In the review by Smyth et al. [45] only
a third of the studies (34/102) assessed ADRs for seriousness. Rates of reported ADRs considered
to be “serious” ranged from 0%–66.7%. The proportion of ADRs occurring in hospital assessed as
serious ranged from 0% to 66.7%, compared with 0% to 45.5% of ADRs causing admission, and
0% to 32.6% of ADRs occurring in the community. Twenty studies provided a reference to indicate
the seriousness tools used, however tools differed widely. Some studies have moreover

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demonstrated the existence of an association between unlicensed and off-label drug use and a higher
risk of developing serious ADRs [70,71]. There was also variation between age groups with regards
to seriousness, with suggestions of that neonates may be particularly vulnerable for serious ADRs.
In the French PV database, the majority of neonatal ADR reports were classified as serious [72].
However, the seriousness was essentially related to hospitalizations (admission or prolonged stay)
rather than the occurrence of disability or fatalities, 3.7% of neonates deceased as a consequence of
an ADR. In this population, special mention should be given to the difficulty of neonatologists in
diagnosing ADRs in the context of multiple comorbidities.
Few studies focused on fatal reports. One study [73] described only fatal reports, and the most
frequent fatal ADR in this study was hepatic failure. The systemic review performed by Cliff Eribo
et al. indicated that the proportions of deaths in the reports were higher in North America compared
with those in Europe, Asia, and Latin America [63]. These results must be interpreted with caution.
It may reflect differences in the use of medicines and also differences in attitudes toward child care
and ADR reporting.
Reports of “drug ineffectiveness” in children, most commonly in association with drugs used for
attention deficit hyperactivity disorders (ADHD), such as methylphenidate seems to increase in
recent years [61]. They could be related to inappropriate dose or indication.
Types of suspected drugs reported
Antibiotics and vaccines were the most frequently reported drugs in almost all the studies identified
in Europe, Latin America, and Asia, according to the studies from PV databases [63]. Amoxicillin
was the most frequently reported individual antibiotic (where this was stated) apart from in one
Italian study where it was second after amoxicillin/clavulanic acid [64] and in one Chinese study
where cefuroxime was the most frequent [74]. In contrast, in North America, drugs used for treating
ADHD (methylphenidate was named in one study) and isotretinoin were most frequently associated
with ADRs [59]. In VigiBase, the WHO global database of ICSRs, reactions with drugs used for
ADHD dominated reports received during recent years for children and adolescents [61].
Reviews published on international datasets of spontaneous reports commonly present the most
frequently reported suspected drugs and ADRs, which reflect drugs commonly used in the pediatric
population (e.g. antibiotics, vaccines and drugs used for ADHD). These reviews give an overall
pattern of safety concerns for the pediatric population. Serious ADRs, often identified from drugs
used in small sub-populations reported with rare ADRs (e.g. hepatic failure and Stevens-Johnson
syndrome), are not well-captured in these analyses. In addition, reviews on national PV datasets are
limited in the presentation of rare ADRs in the pediatric population, particularly for the youngest
ages where drug use is scarce.
Medications that have been established for many years can give cause foralarmin children, such as
first generation H1 antihistamines with coma and deaths in infants and toddlers, codeine for
analgesia and opiate toxicity (respiratory depression) in CYP2D6 ultra-rapid metabolisers or
domperidone and cardiac risk [56,75,76]. Moreover, a recent study [77] on the safety profile ofH1

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antihistamines (including first generation) in pediatrics highlighted association with serious and
unexpected ADRs such as toxic epidermal necrolysis and chlorphenamine.
Issues related to pediatricdrug safety
Risks vary by age
Some age specific ADRs may be explained by the fact that children’s organ systems under go a
process of maturation during growth [78]. The process of growth itself is not linear but
characterized by dynamic age-specific changes that affect the pharmacokinetic and
pharmacodynamic capacity. An example of pharmacodynamic differences during development is
the immunosuppressive effect of cyclosporin. In fact, infants presented an enhanced sensitivity to
cyclosporin when compared to older children and adults [79,80].
Diseases in neonates, infants, children, and adolescents may be qualitatively and quantitatively
different for each age group, and both benefits and risks of drug therapies may be unique in each
group defined European medicines agency (EMA) pediatric age classification [81]. The risk/benefit
balance of drug treatments during infancy and childhood should be considered as a continuously
changeable variable, which should be periodically subjected to re-evaluation, especially in chronic
diseases. The hepatic metabolizing enzyme activity varies considerably during puberty: for
example, doses of drugs used for chronic illnesses such as depression or epilepsy before puberty
might become too high or too low when the patient enters puberty, resulting in toxicity or lack of
effect [82].
Diagnosis of ADRs
To recognise that a sign or symptom in a patient is related to the administration of a drug can be
challenging and to relate a symptom to an ADR in a child is perhaps even more difficult and
requires consideration. However, it is not known whether patient characteristics (age, body mass
index, sex, number of drugs and clinical conditions) might influence ADR identification and
reporting by physicians. Young and mentally disabled children are not always able to articulate
what it is wrong, in addition health professionals might assume that their symptoms are part of
childhood diseases [54]. The child is therefore dependent on observant caregivers to acknowledge
any unexpected changes, such as changes of skin or behaviour, inconsolable crying, drowsiness or
sleeplessness to possibly be caused by a drug [83]. In older children, for instance in adolescents
with chronic disease such as asthma or diabetes mellitus, disease refusal behavior may lead to
suspect drugs wrongly. In contrast, an ADR can be missed because the symptom is related to an
expected behavioral disorder instead of considering the possibility of it being drug induced [84].

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In primary care where the caregiver is most likely the parent, clear information on how to monitor
the child following medicine use is needed for ADRs to be acknowledged, treated and reported. The
challenge of detecting ADRs in the home might be part of the explanation of why the incidence and
reporting of ADRs in the community is scarce [47,85].
Chronic disease and long term safety
Long-term drug use during childhood is of importance because of possible effects on growth and
development. Clinical studies lack sufficient time of follow-up and ADRs occurring long after
initiating therapy are not easily recognized. Especially for drugs being used chronically or for
ADRs that require a long duration of exposure (such as cancer, and certain types of infections),
studies investigating long-term safety are necessary [86,78].
EMA requested long-term safety measures in certain therapeutic areas, i.e. most frequently for
cardiovascular disease (88%), immunology-rheumatology (83%), and oncology (80%) [5]. For
instance, the attention deficit hyperactivity disorder drugs use chronic effects (ADDUCE) study has
been developed in response to the EMA 2010 priorities for drug safety research. This study is
investigating the long-term safety of methylphenidate used for the treatment of ADHD in children
and adolescents [87]. These initiatives are very important; however, the project is dependent on
financial support to continue the long-term follow-up and the investigation is restricted to areas pre-
determined by the current knowledge of safety issues and for only one of the drugs used for ADHD.
To capture emerging safety issues for previously unknown ADRs, including long-term harms, we
are still dependent on spontaneous reports/notifications.
In addition, medicine registries have the potential to provide a long-lasting active surveillance of
populations with a specific diagnosis or exposed to a specific drug [88].However, evidence is
needed to support whether registry surveillance covers a large enough population to detect
unexpected and rare ADRs. Another option to long surveillance could be the linkage of databases,
such as health insurance or hospitalization databases, already used to conduct post-authorization
safety studies [89].
Medication errors
The scope of pharmacovigilance has widened in recent years [90]. The collection of individual case
safety reports encompass events associated with improper use of medications, any medication error
that may have caused harm to a patient should be reported. Dosing errors are the most common type
of error in pediatric care and can lead to serious consequences [91]. There are many opportunities
for mistakes when calculating individualised doses in the prescribing, transcribing, preparing and
administering medicine delivery process in pediatric care.

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A large amount of data on medication errors in pediatric hospitals are available, less well assessed
are the out-patient situations where parents and family medicate young children and where studies
performed in pediatric emergency departments indicate that errors occur frequently [92].Over-the-
counter medicines can be involved in medication errors. In the USA, cough and cold medicines for
children <2 years old were withdrawn from the market because these medicines were related to a
high number of emergency visits following unsupervised ingestions and these medicines did not
demonstrate a favourable benefit– risk profile [93]. To reduce systematic errors, improvements in
medication packaging, easier to use dosing measures and educational campaigns have been
achieved [94].
Conclusions - Proposals to improve PV in the pediatric population
The increasing number of published studies and safety warnings from regulatory agencies [95]
within pediatrics demonstrate how awareness about pediatric pharmacovigilance has been raised.
Post-marketing surveillance through spontaneous reporting systems is sensitive and capable of
quickly identifying rare, unpredictable or serious ADRs after market launch. However, there is still
work to be done. We discuss here some proposals to improve pharmacovigilance in the pediatric
population.
Increase ADR reporting
Spontaneous reports still constitute the basis for the majority of regulatory decisions during the
post-marketing phase of a drug [95]. The spontaneous reporting systems encompass safety
information for any population and care setting. The system reflects both real-life events and real-
life drug use. The information from these individual reports can be used to identify hypotheses of
new previously unknown risks and to learn more about the unique features of ADRs in the pediatric
population in order to eventually be able to minimize the risk in the future.
An international collaboration to ease the sharing of standardized information on suspected ADRs,
which would be particularly important for the identification of rare and unpredictable ADRs, was
initiated already in 1968 when the WHO programme for international drug monitoring was
established. The thalidomide tragedy affecting newborns with malformations led up to the initiation
of this programme providing the opportunity for the identification of drug safety issues also in small
sub-populations.
However, underreporting of ADRs remains a major obstacle. The main reasons for such
underreporting include lack of awareness of the problem, difficulties in correct diagnosis of ADRs,
lack of time and fear of potential legal consequences from off-label uses and medication errors
resulting in adverse drug reactions [96].
Several studies have shown the positive effect of providing education/training to staff (physicians
and nurses) and/or patients or their parents on reporting ADR rate [97]. Parents are the key

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individuals in the detection of ADRs in their children [98]. Parental reporting of ADRs has been
demonstrated to be feasible. For example, Tobaiqy et al. found that the ADR reports by parents
were clear, concise and relevant to pediatric pharmacovigilance [99]. Reporting of ADRs by parents
will be valuable not only for the earlier signal detection of symptomatic reactions to new medicines,
but also for the detection of unexpected ADRs in special populations such as children.
Another strategy to improve ADR notification is computer detection in health care databases. The
principle is to look for signals suggesting the possible presence of an ADR from hospital
information systems. The databases more often used are pharmacy and laboratory sources but also
medical administrative databases such as hospital medical information system databases [100].
Moreover, the development of trigger tools in pediatric population will improve the detection of
ADRs [101].
Improving quality of reports
The need for an improved quality information of ADR reports in children is frequently mentioned
in the literature. Poor information quality has long been identified as an important factor hampering
the usefulness of individual ADR reports. In pediatrics, the specification of age is crucial in order to
identify that the report refers to this population, also in order to consider the distinct features
described for the different pediatric age groups. In agreement with Star et al., two other information
important in the assessment of pediatric reports include weight and height [90].Height, in addition
to weight, is important to establish if the dose recorded on the report is feasible. Since dosing is a
major obstacle in pediatrics and too low or higher doses can result in ADRs or lack of effect, details
on dose and formulation would additionally be especially important to record.
Moreover, in addition to the data collected on standardized fields, descriptive free-text fields on
reports can give important information for the case. These data might be crucial to the knowledge of
an ADR and can help regulatory decisions [102]. These free-text fields can provide descriptions on
the context of which the ADR occurred, how the ADR evolved, as well as information on severity
and how the ADR impacted the life of the child and family.
However, as Star et al. [90] pointed out, these free-text fields are often not shared between countries
because of confidentiality regulations, showing the limits of the monitoring and evaluation of
reactions in children on an international level, but in contrast the importance of the national/regional
level in capturing targeted information.
Different methodological approaches
There are a number of approaches that have been taken to improve drug safety in children.
Pharmacoepidemiology studies are an essential part of strategies for drug safety, notably for signal

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validation. Better evidence regarding drug safety in the pediatric population might be generated by
linking data sources such as spontaneous reporting systems (SRS) and electronic healthcare records.
Safety signal detection using SRS databases may be complemented by mining longitudinal data in
electronic health report databases, as described by the European adverse drug reaction (EUADR)
project [103]. In addition, longitudinal electronic medical records may provide useful clinical data
for potential signals, which have been highlighted by individual ADR reports [104], although the
data was scarce for rare ADRs. It is less likely that a subset of national electronic medical records,
as was used by Star et al [104], could be used in the identification of rare and unpredictable ADRs
in the pediatric subpopulation.
The Global research in pediatrics (GRiP) – network of excellence [105] was also set up with
specific objectives to apply innovative approaches and standardized methodologies, as well as
better utilization of existing healthcare and spontaneous reporting databases. Despite these
initiatives, a recent review concluded that the number of pediatric pharmacoepidemiological safety
studies remains low [106].
Recently, an update of North American pediatric post-marketing safety systems (databases,
networks, and research consortiums) only identified nine pediatric-focused systems. Important
criteria have been brought out: 1) Large enough systems to detect rare adverse events 2) Enough
clinical detail to understand the outcome 3) Presence of exposure data (a denominator for the
adverse event data). All three of those criteria are rarely present in one pediatric-focused system
[107].
Finally, to meet its multifaceted challenges, pediatric drug safety should utilize multiple approaches
to take advantage of their individual characteristics.
Disclosure of interest
Authors have no competing interest to declare

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