Content uploaded by Lise Aagaard
Author content
All content in this area was uploaded by Lise Aagaard on Mar 31, 2016
Content may be subject to copyright.
Adverse Drug Reactions in the Paediatric
Population in Denmark
A Retrospective Analysis of Reports Made to the Danish
Medicines Agency from 1998 to 2007
Lise Aagaard,
1,2
Camilla Blicher Weber
1
and Ebba Holme Hansen
1,2
1 Department of Pharmacology and Pharmacotherapy, Section for Social Pharmacy, Faculty of
Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark
2 FKL-Research Centre for Quality in Medicine Use, Copenhagen, Denmark
Abstract Background: 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.
Objective: To characterize ADRs in children reported in Denmark over a
period of one decade.
Methods: 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.
Results: 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 sub-
cutaneous 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.
ORIGINAL RESEARCH ARTICLE Drug Saf 2010; 33 (4): 327-339
0114-5916/10/0004-0327/$49.95/0
ª2010 Adis Data Information BV. All rights reserved.
Conclusion: 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.
Background
The potential risk of adverse drug reactions
(ADRs) in children 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.
[1-4]
Postmarketing
surveillance of medicine safety is important be-
cause the randomized controlled clinical trials
(RCCTs) used in the clinical development process
have limited capacity to detect serious, rare and
unexpected ADRs, which are especially proble-
matic in vulnerable populations such as children,
who are rarely represented in the RCCT.
[5,6]
Therefore, it is important to survey the paediatric
population as the safety of many medicine regi-
mens prescribed for children is not well docu-
mented.
[7,8]
In a meta-analysis of 17 prospective
studies conducted in the US and Europe and
published from 1973 to 2000, the overall in-
cidence of ADRs in children was estimated to be
9.5%, with serious reactions accounting for 12%
of the total number of ADRs.
[9]
In the literature,
we identified five studies on ADRs in children
reported to national databases in the Netherlands,
Spain, the US, Sweden and Canada.
[10-14]
These
studies report ADRs in children from different
settings, time periods, patient populations of
different sizes and age groups, and different type
of reporters. Although there were wide varia-
tions in the incidence of ADRs between studies,
the studies found ADRs to be most commonly
reported in children from birth to 5 years of age
and youth from 13 to 17 years of age.
[10,12,13]
Serious ADRs comprised between 15%and 60%
of all reported ADRs in these studies.
[11-14]
The
majority of reported ADRs were from the system
organ classes (SOCs) ‘psychiatric and nervous
system disorders’ as well as ‘skin disorders’.
ADRs were most commonly reported for vac-
cines, anti-infectives, analgesics and psychotropic
medicines.
[10-14]
The need for more thorough
analysis of ADRs in children is compelling as
medicine utilization patterns among children
have changed since the beginning of the 1990s,
for example due to the launch of new types of
medicines, especially within the therapeutic
classes of antipsychotics, antidepressants and
antiepileptic medicines.
[15,16]
The objective of this study was to analyse
ADRs in children reported to the Danish Medi-
cines Agency over one decade. We analysed data
with respect to time, age and sex, category and
seriousness of ADRs, suspected medicines and
type of reporter.
Methods
Setting
During the study period the total Danish
population included approximately 5.5 million
inhabitants and 20%of these were aged from
birth to 17 years. The Danish ADR reporting
system was established by law in 1968 and
reporting of ADRs are mandatory for physi-
cians, dentists, veterinarians and pharmaceutical
companies, and voluntary for consumers and
other healthcare professionals.
[17]
The report-
ing system receives approximately 2000 ADR
reports annually, corresponding to a reporting
rate of close to 400 ADR reports per million
inhabitants. The Danish ADR database contains
328 Aagaard et al.
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
all spontaneous ADR reports in Denmark, in-
cluding those reported directly to the pharma-
ceutical companies. An ADR report is defined
by the following four criteria, which must
be included in all reports: (i) information about
the patient; (ii) the suspected medicines(s);
(iii) the presumed ADR(s); and (iv) informa-
tion about the person making the report. An
ADR report may contain one or more ADRs.
Adverse reactions due to unauthorized use are
also classified as ADRs and are included in the
database.
Data Extraction
The ADRs are assessed by the Danish Medi-
cines Agency and categorized in the ADR database
by degree of seriousness according to the CIOMS
criteria.
[18]
ADR reports are classified by criteria of
seriousness by trained staff at the Danish Medi-
cines Agency. The Danish reporting system has
been described elsewhere in more detail.
[19]
Data
were placed at the disposal of this study in anon-
ymous form with encrypted identification of the
medicine user. Data were extracted from the ADR
database on Microsoft
Excel files using the fol-
lowing criteria: Anatomical Therapeutic Chemical
(ATC) code of medications, registered tradename
and active substance of the medicines, ADRs
coded according to Medical Dictionary for Reg-
ulatory Activities
[20]
terminology at SOC level,
degree of seriousness, age of patient and type of
reporter. For the purposes of this study, in order to
present the large amount of data in a comprehen-
sive way, the medicines about which the ADRs are
reported are presented at ATC level 2. The mate-
rial comprised all ADR reports on children from
birth to 17 years of age reported to the Danish
Medicines Agency from 1998 to 2007. The unit of
analysis was one ADR.
The Danish ADR database defines five cate-
gories of people who may submit data to the da-
tabase. This study applies the following official
designation for the category of people submitting
reports:
lawyer: patient injury insurers and/or law firms;
pharmacist: community or hospital pharmacists;
physician: general practitioners, physicians
and dentists;
other healthcare professionals: nurses, phar-
maceutical companies, and social and health-
care assistants;
consumers: patients, patients’ relatives, other
members of the public.
Because consumers have had the opportunity
to report ADRs in Denmark since 2003, results in
this category only cover data from the last 5 years
of the study period.
0
100
200
300
400
500
600
700
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
Year
No. of ADRs and ADR reports
No. of ADRs per report
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Reports
ADRs
ADR/report
Fig. 1. No. of adverse drug reaction (ADR) reports and ADRs reported annually (1998–2007).
ADRs in the Paediatric Population in Denmark 329
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
Results
A total of 2437 ADR reports corresponding to
4500 ADRs were reported for individuals from
birth to 17 years of age during the study period.
The number of ADR reports per year is illustrated
in figure 1. On average, 234 ADR reports (range
157–322) were submitted per year, 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.
Adverse Drug Reactions (ADRs) by
Age and Sex
Figure 2 shows the distribution of reported
ADRs by age of the child and number of serious
ADRs. In total, 51%of all ADRs were reported for
girls and 49%for boys. Fifty-two percent of ADRs
were reported for infants from birth to 2 years of
age with almost the same number of ADRs re-
ported for boys and girls. More ADRs were re-
ported for boys than girls among the 5- to 12-year
age group, but for teenagers (13–17 years of age)
the majority of ADRs were reported for girls.
ADRs by Category and Seriousness
Table I provides an overview of the reported
ADRs classified by SOC and distributed by age
group and number of serious ADRs. Total
numbers of reported ADRs are shown for all
SOCs and age groups. ADRs were most com-
monly reported in the following SOCs: ‘general
disorders and administration site conditions’
(31%), ‘skin and subcutaneous tissue disorders’
(18%) and ‘nervous system disorders’ (15%).
Forty-two percent of all ADRs were classified as
serious and 28 of these cases were reported deaths.
Table II displays further characteristics of these
cases. The largest number of serious ADRs was
reported for the SOC ‘nervous system disorders’
(24%) followed by the SOCs ‘general disorders and
administration site conditions’ (16%) and ‘skin and
subcutaneous tissue disorders’ (11%). The distri-
bution of serious and non-serious ADRs by SOCs
variedwidely,from97%in ‘congenital, familial
and genetic disorders’ to 11%in ‘skin and sub-
cutaneous tissue disorders’.The distribution be-
tween serious and non-serious ADRs within SOCs
varied with the age of the children. More than half
oftheADRsreportedforchildrenupto2yearsof
age were in the SOCs ‘general disorders and
administration site conditions’ and ‘psychiatric
disorders’, and only 15–20%of these ADRs were
serious. Serious ADRs encompassed a wide range
of reactions, e.g. convulsion, feeding disorder
neonatal, apnoea, ventricular septal defects, cardi-
ac defects, premature labour and neonatal symp-
toms reported for medicines from ATC group N
0
200
400
600
800
1000
1200
1400
<1
1<2
2<3
3<4
4<5
5<6
6<7
7<8
8<9
9<10
10<11
11<12
12<13
13<14
14<15
15<16
16<17
17<18
Age groups (y)
No. of adverse drug reactions
Total
Serious
Fig. 2. Adverse drug reactions (ADRs) by age group and number of serious ADRs (1998-–2007).
330 Aagaard et al.
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
(nervous system disorders). For vaccines, the
majority of serious ADRs were pyrexia, febrile
convulsion, injection site reaction, thrombocyto-
penia, gait disturbance, rash and autism. For anti-
bacterials the majority of reported ADRs were skin
reactions such as rash, urticaria, erythema multi-
forme and hyperhidrosis, and gastrointestinal dis-
orders such as oesophageal ulcer haemorrhage,
abdominal pain upper and vomiting.
ADRs by Therapeutic Groups
Table III displays the number of reported
ADRs by therapeutic group (ATC level 2), age
group and number of serious ADRs. Of the re-
ported ADRs, 65%concerned anti-infectives and
vaccines (ATC group J), 17%concerned medi-
cines for nervous system disorders (ATC group
N) and 3%concerned medicines belonging to
ATC group V01 (allergens). A large proportion
of the ADRs reported in infants (birth to 2 years
of age) involved vaccines (ATC J07). Although
serious ADRs were primarily reported in the
same therapeutic groups as the majority of re-
ports, the share of serious reports varied between
therapeutic groups, e.g. 57%for anti-infectives
for systemic use (ATC J), 19%for nervous system
medications (ATC N) and 2%for respiratory
medications (ATC R). The distribution between
serious and non-serious ADRs within ATC groups
and SOCs also varied with the age of the children.
For immune sera and immunoglobulins (ATC
group J06) and vaccines (ATC group J07), the
majority of ADRs were reported for infants from
Table I. Adverse drug reactions (ADRs) distributed by System Organ Class (SOC) and age group (no. of serious ADRs in parentheses)
SOC Age group [y]
<11<22–10 11–17 Total
General disorders and administration site conditions 509 (124) 430 (86) 354 (56) 104 (35) 1397 (301)
Skin and subcutaneous tissue disorders 161 (27) 293 (74) 189 (53) 160 (52) 803 (206)
Nervous system disorders 151 (97) 224 (182) 123 (74) 172 (101) 670 (454)
Psychiatric disorders 126 (20) 23 (7) 94 (51) 108 (71) 351 (149)
Gastrointestinal disorders 50 (16) 32 (8) 100 (44) 89 (49) 271 (117)
Respiratory, thoracic and mediastinal disorders 31 (26) 15 (3) 27 (17) 76 (54) 149 (100)
Infections and infestations 26 (12) 39 (12) 23 (12) 13 (7) 101 (43)
Investigations 10 (5) 6 (5) 23 (16) 61 (42) 100 (68)
Musculoskeletal and connective tissue disorders 18 (16) 15 (10) 25 (16) 29 (16) 87 (58)
Immune system disorders 3 (3) 1 (1) 31 (18) 46 (34) 81 (56)
Blood and lymphatic system disorders 9 (8) 23 (14) 13 (12) 27 (19) 72 (53)
Cardiac disorders 19 (16) 5 (2) 15 (7) 28 (21) 67 (46)
Eye disorders 10 (4) 6 (2) 17 (8) 29 (15) 62 (29)
Vascular disorders 17 (8) 3 (2) 16 (6) 17 (16) 53 (32)
Metabolism and nutrition disorders 13 (9) 5 (4) 11 (7) 11 (8) 40 (28)
Injury, poisoning and procedural complications 17 (16) 3 (3) 11 (11) 2 (2) 33 (32)
Congenital, familial and genetic disorders 27 (26) 2 (2) 1 (1) 0 30 (29)
Reproductive system and breast disorders 3 (1) 0 9 (2) 16 (1) 28 (4)
Hepatobiliary disorders 3 (3) 4 (3) 7 (6) 12 (5) 26 (17)
Renal and urinary disorders 3 (3) 0 13 (7) 8 (4) 24 (14)
Ear and labyrinth disorders 3 (3) 2 (2) 6 (3) 9 (5) 20 (13)
Neoplasm benign, malignant and unspecified 0 0 6 (4) 5 (5) 11 (9)
Pregnancy, puerperium and perinatal conditions 8 (8) 0 0 2 (1) 10 (9)
Endocrine disorders 0 0 2 (2) 6 (2) 8 (4)
Surgical and medical procedures 0006(3)6(3)
Total 1217 (451) 1131 (422) 1116 (433) 1036 (568) 4500 (1874)
ADRs in the Paediatric Population in Denmark 331
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
birth to 2 years of age, but only 30–35%of these
ADRs were serious. A larger proportion of serious
ADRs (75–80%) was reported for children from 11
to 17 years of age. The opposite phenomenon was
observed in ATC group N (nervous system).
ADRs by Type of Reporter and Seriousness
The distribution of ADRs by seriousness and
type of reporter is displayed in table IV. Physi-
cians reported the majority of ADRs (89%),
Table II. Reported adverse drug reactions (ADRs) in children leading to death (1998–2007)
Case Year of report ATC Medicine(s) ADR(s) reported Sex Age (y)
1 1998 N03AG01 Valproic acid Cerebrovascular disorder Male 1
N03AX09 Lamotrigine Hepatic function abnormal
Purpura
2 1998 N03AX09 Lamotrigine Hepatitis Female 17
3 1998 G03AA09 Desogestrel/estrogen Pulmonary embolism Female 17
4 1999 L01BA01 Methotrexate Guillain-Barre
´syndrome Male 11
5 2000 H01AC01 Somatropin Acute leukaemia Male 14
6 2000 N01AF01 Methohexital Shock Female 1
7 2000 NA Insulin-like growth factor 1 Sudden death Male 0
8 2000 N03AX Felbamate Sudden death Female 17
9 2002 G03AA12 Drospirenon/ethinylestradiol Pulmonary embolism Female 17
10 2002 J07AG01 Ditekipol/Act-Hib vaccine Sudden infant death syndrome Male 0
11 2003 G03AA10 Norgestimate/ethinylestradiol Brain stem thrombosis Female 17
12 2003 A0 7EC02 Mesalazine Disseminated intravascular coagulation Male 16
Budesonide
Azathioprine
13 2003 J07BD52 MMR vaccine Hydrocephalus Female 12
14 2003 C02KX01 Bosentan Right ventricular failure Male 12
15 2003 L01XE02 Gefitinib Toxic epidermal necrolysis Male 15
16 2005 A10AE04 Insulin glargine Blood glucose increased Male 17
17 2005 H02AB04 Methylprednisolone Bradycardia Female 15
Cardiac arrest
Bronchospasm
18 2005 D10BA01 Isotretinoin Cardiac failure Female 15
19 2005 J01CA02 Pivampicillin Carnitine decreased Female 14
20 2005 A10AE04 Insulin glargine Vomiting Male 17
21 2005 J01CA02 Pivampicillin Vomiting Female 14
Carnitine decreased
Fatigue
Restlessness
22 2005 J01CA02 Pivampicillin Vomiting Female 14
23 2006 N06AB03 Fluoxetine Persistent fetal circulation Female 0
24 2006 G03AA09 Ethinylestradiol/desogestrel Pulmonary embolism Female 17
25 2006 B03AC02 Iron Stillbirth Male 0
26 2007 N06AB04 Citalopram Chorioamnionitis Female 0
27 2007 C01EB16 Ibuprofen Necrotizing colitis Male 0
28 2007 C01EB16 Ibuprofen Necrotizing colitis Male 0
Sepsis neonatal
ATC =Anatomical Therapeutic Chemical; MMR =measles, mumps and rubella; NA =not available.
332 Aagaard et al.
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
Table III. Adverse drug reactions (ADRs) distributed by therapeutic group, age group (no. of serious ADRs in parentheses)
ATC group Age group (y)
<11<22–10 11–17 Total
Alimentary tract and metabolism (A)
A01 Stomatological preparations 0 0 0 2 2
A02 Drugs for acid-related disorders 1 (1) 0 9 (6) 1 11 (7)
A03 Drugs for functional gastrointestinal disorders 0 0 2 (2) 14 (6) 16 (8)
A04 Antiemetics and anti-nauseants 6 (6) 0 0 0 6 (6)
A05 Bile and liver therapy 1 (1) 0 0 0 1 (1)
A06 Laxatives 0 3 6 0 9
A07 Anti-diarrheals 0 0 4 (1) 16 (11) 20 (12)
A08 Anti-obesity preparations 1 0 0 9 (9) 10 (9)
A10 Drugs used in diabetes 1 0 7 (4) 14 (11) 22 (15)
A16 Other alimentary tract and metabolism products 0 0 1 8 (8) 9 (8)
Total A 10 (8) 3 29 (13) 64 (45) 106 (66)
Blood and blood forming organs (B)
B01 Antithrombotic agents 0 0 0 3 3
B03 Anti-anaemic preparations 1 (1) 0 0 0 1 (1)
B06 Other haematological agents 0 0 0 1 (1) 1 (1)
Total B 1 (1) 0 0 4 (1) 5 (2)
Cardiovascular system (C)
C01 Cardiac therapy 5 (5) 0 1 0 6 (5)
C02 Antihypertensives 2 (2) 2 (2) 0 3 (3) 7 (7)
C03 Diuretics 1 0 0 0 1
C05 Vasoprotectives 0 0 1 (1) 0 1 (1)
C07 b-blocking agents 0 1 (1) 0 6 7 (1)
C08 Calcium channel blockers 3 0 0 0 3
C09 Agents acting on the renin-angiotensin system 3 (2) 0 0 3 6 (2)
C10 Lipid-modifying agents 2 0 0 0 2
Total C 16 (9) 3 (3) 2 (1) 12 (3) 33 (16)
Dermatological (D)
D01 Antifungal for dermatological use 0 0 1 1 (1) 2 (1)
D06 Dermatological antibiotics and chemotherapeutics 0 0 2 1 3
Continued next page
ADRs in the Paediatric Population in Denmark 333
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
Table III. Contd
ATC group Age group (y)
<11<22–10 11–17 Total
D10 Anti-acne preparations 1 0 0 63 (29) 64 (29)
D11 Other dermatological preparations 1 (1) 2 (1) 4 (1) 1 8 (3)
Total D 2 (1) 2 (1) 7 (1) 66 (30) 77 (33)
Genitourinary system and sex hormones (G)
G03 Sex hormones and modulators of the genital system 1 0 0 100 (76) 101 (76)
Total G 1 0 0 100 (76) 101 (76)
Systemic hormonal preparations (H)
H01 Pituitary and hypothalamic hormones 1 (1) 0 27 (16) 8 (5) 36 (22)
H02 Corticosteroids for systemic use 0 0 5 (5) 4 (3) 9 (8)
H03 Thyroid therapy 1 (1) 0 0 4 5 (1)
Total H 2 (2) 0 32 (21) 16 (8) 50 (31)
Anti-infectives for systemic use (J)
J01 Antibacterials for systemic use 10 (7) 7 (2) 38 (25) 57 (35) 112 (69)
J02 Antimycotics for systemic use 1 0 5 (3) 8 (3) 14 (6)
J05 Antivirals for systemic use 8 (8) 1 8 (6) 2 (2) 19 (16)
J06 Immune sera and immunoglobulins 1 (1) 2 (2) 21 (20) 8 (8) 32 (31)
J07 Vaccines 1035 (310) 1065 (384) 485 (153) 167 (96) 2752 (943)
Total J 1055 (326) 1075 (388) 557 (207) 242 (144) 2929 (1065)
Antineoplastic and immunomodulating agents (L)
L01 Antineoplastic agents 0 0 13 (13) 5 (4) 18 (17)
L02 Endocrine therapy 2 0 22 (4) 3 27 (4)
L03 Immunostimulants 2 (2) 1 7 (7) 6 (6) 16 (15)
L04 Immunosuppressants 0 0 4 (4) 21 (18) 25 (22)
Total L 4 (2) 1 46 (28) 35 (28) 86 (58)
Musculoskeletal system (M)
M01 Anti-inflammatory and rheumatic products 5 (4) 2 13 (9) 20 (16) 40 (29)
M03 Muscle relaxants 1 (1) 0 10 (5) 6 (4) 17 (10)
Total M 6 (5) 2 23 (14) 26 (20) 57 (39)
Nervous system (N)
N01 Anaesthetics 2 (1) 7 (2) 46 (6) 51 (10) 106 (19)
N02 Analgesics 3 (3) 2 (2) 18 (7) 9 (3) 32 (15)
Continued next page
334 Aagaard et al.
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
Table III. Contd
ATC group Age group (y)
<11<22–10 11–17 Total
N03 Antiepileptics 24 (17) 10 (10) 78 (33) 69 (22) 181 (82)
N04 Antiparkinson drugs 0 0 0 1 (1) 1 (1)
N05 Psycholeptics 17 (17) 5 (5) 12 (5) 83 (37) 117 (64)
N06 Psychoanaleptics 53 (52) 5 (5) 123 (48) 131 (72) 312 (177)
N07 Other nervous system drugs 0 0 0 1 1
Total N 99 (90) 29 (24) 277 (99)345 (145) 750 (358)
Antiparasitic (P)
P01 Antiprotozoals 2 0 25 (15) 9 (4) 36 (19)
P02 Anthelmintics 2 (2) 0 5 (2) 1 (1) 8 (5)
P03 Ectoparasiticides 0 0 2 5 7
Total P 4 (2) 0 32 (17) 15 (5) 51 (24)
Respiratory system (R)
R01 Nasal preparations 0 0 0 2 (1) 2 (1)
R02 Throat preparations 0 0 2 0 2
R03 Drugs for obstructive airway diseases 1 14 (5) 39 (10) 22 (11) 76 (26)
R05 Cough and cold preparations 0 0 3 1 (1) 4 (1)
R06 Antihistamines for systemic use 5 (5) 1 12 (3) 4 22 (8)
Total R 6 (5) 15 (5) 56 (13) 29 (13) 106 (36)
Sensory organs (S)
S01 Ophthalmologicals 1 0 2 0 3
S02 Otologicals 0 0 2 0 2
Total S 10405
Various (V)
V01 Allergens 7 0 45 (16) 81 (50) 133 (66)
V03 All other therapeutic products 0 1 (1) 2 (2) 0 3 (3)
V04 Diagnostic agents 2 0 0 1 3
V08 Contrast media 1 0 1 (1) 0 2 (1)
V09 Diagnostic radiopharmaceuticals 0 0 3 0 3
Total V 10 1 (1) 51 (19) 82 (50) 144 (70)
Total all therapeutic group 1217 (451) 1131 (422) 1116 (433) 1036 (568) 4500 (1874)
ATC =Anatomical Therapeutic Chemical.
ADRs in the Paediatric Population in Denmark 335
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
followed by other healthcare professionals (7%)
and consumers (4%). Lawyers and pharmacists
reported very few ADRs, and the reports
from pharmacists were all non-serious. Both
ADRs reported by lawyers were serious. Other
healthcare professionals and consumers were more
likely to report serious ADRs than physicians.
Discussion
The study showed a decline in the number of
ADR reports in the paediatric population in
Denmark over one decade. ADRs were mainly
reported in infants (birth to 2 years of age and in
adolescents from 11 to 17 years of age. ADRs
were primarily from the SOC general disorders
and administration site conditions, as well as skin
and nervous system disorders. Two-thirds of
ADRs were reported for anti-infectives and vac-
cines, followed by medicines from ATC group N.
Differences in seriousness of ADRs between age
groups and therapeutic groups were detected.
The majority of ADRs in children are reported by
physicians but a larger share of serious ADRs
was reported by other sources.
Number of Reports
The detected ADR reporting rate for the pae-
diatric population is low in Denmark compared
with other EU countries, although it is com-
paratively high for adults.
[21]
In 2004, reporting
rates of ADRs for children were estimated as
being 30 reports/million capita in Denmark, and
400, 330 and 250 reports/million capita in
Sweden, France and the Czech Republic, respec-
tively.
[21]
The number of ADR reports for the
paediatric population decreased in Denmark
from 2004 to 2007 despite the fact that the num-
ber of eligible reporters increased during the same
time period.
[17]
In contrast, the number of ADR
reports involving adults increased in the same
period in Denmark, and we had expected an in-
crease in ADR reports for children. The data does
not offer a ready explanation for the decrease,
nor for the relatively low reporting rate for chil-
dren in Denmark. The findings point to a need
for further extrapolation of this issue, not least in
view of calls from the EU and WHO to expand
the examination of medicines safety in children.
Since 2003, consumers have been allowed to re-
port ADRs in Denmark
[22]
and the extent to
which consumer reports will increase the number
or quality of ADR cases and thus increase the
data in the system is an interesting question that
cannot yet be answered. From a public health
perspective, the declining reporting rate is worry-
ing as this indicates decreasing awareness or in-
herent lack of vigilance among reporters in
monitoring drug safety.
Age and Sex of the Paediatric Population
In this study, more than 50%of the ADRs
were reported for infants (birth to 2 years of age).
Similar findings were observed in other stu-
dies.
[10-14]
This could be due to parents’ close
attention to symptoms in young children, parti-
cularly in connection with vaccinations; however,
a large number of ADRs reported in this age
group may also be due to the mother’s intake of
medicine during pregnancy, especially psycho-
tropic medicines. This is an important issue
regarding children’s health risks that has been
Table IV. Adverse drug reactions (ADRs) distributed by type of reporter and criteria of seriousness
Type of reporter Total ADRs [n (%)] Serious ADRs [n (%)] Non-serious ADRs [n (%)]
Physicians 4015 (89) 1532 (38) 2483 (62)
Pharmacists 3 (0) 0 (0) 3 (0)
Other healthcare professional 319 (7) 234 (73) 85 (27)
Lawyer 2 (0) 2 (100) 0 (0)
Consumer
a
161 (4) 106 (66) 55 (34)
Total 4500 (100) 1874 (42) 2626 (58)
a Data only reported 2003–2007.
336 Aagaard et al.
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
neglected in the ADR literature. In empirical
studies, relatively higher shares of ADRs were
reported in children up to 5 years of age and in
11- to 17-year-olds.
[10,11,14]
In this study, equal
shares of ADRs were reported for girls and
boys. In the literature, approximately 55%of
ADRs were reported for boys and 45%for girls;
in Denmark, more ADRs were reported for
boys than girls in the 5- to 12-year-old age
group.
[10-14]
System Organ Class and Anatomical
Therapeutic Classification
The reports of ADRs for the SOCs ‘nervous
system disorders’, ‘psychiatric disorders’, ‘skin and
subcutaneous disorders’ and ‘gastrointestinal dis-
orders’, were consistent with reports in other em-
pirical studies,
[10-14]
buthighersharesofADRs
from the SOC ‘general disorders and administra-
tion site conditions’ and lower shares of ADRs
from the SOC ‘skin and subcutaneous disorders’
were reported in this study. Among infants and
children aged 2–10 years a high number of ADRs
were reported for methylphenidate and atomox-
etine (both in ATC group N). This finding is
probably due to the rapid increase in the prescrib-
ing of these medications to adolescents too, in
which case one would expect an increase in this age
group too.
[23]
The high number of ADR reports
involving psychotropic medicines could also partly
be attributed to the regulatory warnings on anti-
depressants and attention-deficit hyperactivity
disorder treatments.
[24-26]
In 2005, the US FDA
and European Medicines Agency recom-
mended that antidepressants not be prescribed
for children less than 18 years of age. In 2009,
the European Medicines Agency recommended
that all patients receiving stimulants should be
screened to see if they have any problems with
their blood pressure or heart rate during treat-
ment; blood pressure, heart rate, height and
weight should also be monitored regularly.
[27]
Because of national immunization program-
mes and a high incidence of infectious disease
among children up to 2 years of age, the pre-
valence rate for the use of anti-infective medicines
(ATC J) was as high as 48%, and a high number
of ADRs reported for these medicines are ex-
pected in this study.
[28]
We found a higher share
of ADRs reported for ATC group J (65%) than in
the literature (40%).
[11,13]
The large number of
ADR reports on vaccines and anti-infectives
among young children is a concern for im-
munization coverage.
In spite of the sharp increase in psychotropic
drug prescribing in recent years, we found a similar
share of ADRs had been reported for psychotropic
medicines compared with previous studies (ap-
proximately 15%).
[10-14]
Among adolescents, more
ADRs were reported for medicines belonging to
ATC group G and ATC group N, i.e. contra-
ceptivesandSSRIs,thaninchildrenupto10years
of age, which reflects medicine use among adults.
In the literature, ADRs were not reported for
contraceptives, which probably is due to the lower
age of the studied populations compared with the
present study.
[10-14]
On the contrary, other studies
reported a larger share of ADRs for analgesics,
antihistamines and antiasthmatic drugs compared
with this present study.
[10-14]
Explanations of these
deviations could be due to time differences in stu-
dies and differences in licensing status of the med-
icines (prescription or over-the-counter status)
between various countries.
Seriousness of Reported ADRs
Data on the differences in seriousness of ADRs
between age groups provides important new in-
formation for physicians, who need to be aware of
these differences in ADR risks when prescribing
medicines for the paediatric population. We found
a higher share of serious ADRs in children (42%)
than previously reported in Danish adults
(25–30%), although the number of serious ADRs
in adults has increased since 2000.
[17]
The shares of
serious ADRs in children were in line with results
reported in the literature.
[10-14]
Who Detects the ADRs?
Although physicians were the primary reporters
of ADRs in children, they reported a relatively
lower share of serious ADRs than consumers and
other healthcare professionals. Pharmacists re-
ported almost no ADRs as expected from previous
ADRs in the Paediatric Population in Denmark 337
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
analysis of Danish ADR reports.
[22]
Physicians and
consumers reported equal shares of serious ADRs
for adults, but other healthcare professionals and
pharmacists reported higher shares. Pharmacists
have reported more ADRs in the Netherlands
and Canada, probably due to their direct contact
and dialogue with patients at the pharmacy or in
hospital.
[10,14,27,29,30]
Strategies for encouraging
Danish pharmacists to take a more active role in
ADR reporting will probably include more teach-
ing in this area during their masters’ curriculum.
We propose that pharmacists take an active role in
reporting ADRs in all countries.
Strengths and Limitations of the Study
The strength of our study is that the material
consisted of all reported ADRs in one country over
one decade. The purpose was to analyse informa-
tion reported to the Danish ADR database on
ADRs in the paediatric population, and not to
calculate the incidence of ADRs in this population
as this is not feasible in material based on sponta-
neous reporting. Spontaneous reporting of ADRs
was analysed on ATC level 2, and further analysis
of reported ADRs in different therapeutic groups,
e.g. ATC J and N, are in progress and will con-
tribute more information on the specific medica-
tions causing the ADRs, as well as information
about differences in reporting patterns betweens
boys and girls or age groups. As consumers and
pharmacists contribute a limited number of ADR
reports, qualitative studies exploring barriers
amongst these groups against reporting of ADRs
in children could be conducted.
Conclusions
In Denmark, the ADR reporting rate in the
paediatric population has declined since 2005.
The majority of ADRs reported in young chil-
dren are reported for vaccines and anti-infectives,
but also a high number of serious ADRs are re-
ported for psychotropic medicines. The Danish
Medicines Agency should monitor prescribing
patterns more tightly to identify potential risks in
the paediatric population in relation to the evol-
ving pattern of medicine use among children.
Acknowledgements
We would like to thank the Danish Medicines Agency for
placing data at our disposal.
A supplementary file containing detailed information of all
reported ADR cases can be obtained from the authors if wished.
L. Aagaard and E. Holme Hansen designed the study,
analysed data and wrote the first version of the study.
C. Blicher Weber did the sampling. All authors saw and
approved the final version of the study.
No sources of funding were used to assist in the prepa-
ration of this study. The authors have no conflicts of interest to
declare.
References
1. Le J, Nguyen T, Law AV, et al. Adverse drug reactions
among children over a 10-year period. Pediatrics 2006; 118:
555-62
2. Temple ME, Robinson RF, Miller JC, et al. Frequency and
preventability of adverse drug reactions in paediatric pa-
tients. Drug Saf 2004; 27: 819-29
3. FDA Modernization Act of 1997 [online]. Available from
URL: http://www.fda.gov/Med icalDevices/DeviceRegulation
andGuidance/Overview/MedicalDeviceProvisionsofFDA
ModernizationAct/ucm136671.htm [Accessed 2009 Oct 7]
4. RegulationEC No. 1901/2006 of the European Parliament and
the Council of 12 December 2006 on Medicinal Prod ucts for
Paediatric Use and Amending Regulation [online]. Available
from URL http://ec.europa.eu/enterprise/pharmaceuticals/
eudralex/vol- 1/reg_2006_1901/reg_2006_1901_en.pdf [As-
sessed 2009 Oct 7]
5. Hansen EH. Technology assessment in a user perspective:
experiences with drug technology. Int J Technol Assess
Health Care 1992; 8: 150-65
6. Aagaard L, Soendergaad B, Stenver DI, et al. Knowledge
creation about ADRs: turning the perspective from the
rearview mirror to the projector? Br J Clin Pharmacol
2008; 65: 364-76
7. Keinonen T, Miettinen P, Saano V, et al. Clinical trials in
children and healthy volunteers: quality and characteristics
of notifications reviewed by the regulatory agencies in
Finland. Paed Perinat Drug Ther 2003; 5: 175-82
8. Sammons HM, Choorara I. Clinical trials of medication
in children, 1996-2002. Eur J Clin Pharmacol 2005; 61:
165-7
9. Impicciatore P, Choonara I, Clarkson A, et al. Incidence of
adverse drug reactions in paediatric in/out-patients: a sys-
tematic review and meta-analysis of prospective studies. Br
J Clin Pharmacol 2001; 52: 77-83
10. Meyboom RH. Adverse reactions to drugs in children,
experiences with ‘‘spontaneous monitoring’’ in the
Netherlands. Bratisl Lek Listy 1991; 92: 554-59
11. Morales-Olivas FJ, Martinez-Mir I, Ferrer JM, et al. Adverse
drug reactions in children reported by means of the yellow
card in Spain. J Clin Epidemiol 2000; 53: 1076-80
12. Moore TJ, Weiss SR, Kaplan S, et al. Reported adverse
drug events in infants and children under 2 years of age.
Pediatrics 2002; 110: e53
338 Aagaard et al.
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
13. Kimland E, Rane A, Ufer M, et al. Paediatric adverse drug
reactions reported in Sweden from 1987 to 2001. Pharm
Drug Saf 2005; 14: 493-99
14. Carleton BC, Smith MA, Gelin MN, et al. Paediatric ad-
verse drug reaction reporting: understanding and future
directions. Can J Clin Pharmacol 2007; 14: e45-57
15. Ackers R, Murray ML, Besag FMC, et al. Prioritizing chil-
dren’s medicines for research: a pharmacoepidemiological
study of antiepileptic drugs. Br J Clin Pharmacol 2006; 63:
689-97
16. van de Vrie-Hoekstra NW, de Vries TW, van den Berg PB,
et al. Antiepileptic drug utilization in children from
1997-2005: a study from the Netherlands. Eur J Clin
Pharmacol 2008; 64: 1013-20
17. Aagaard L, Soendergaard B, Andersen E, et al. Creating
knowledge about adverse drug reactions: a critical analysis
of the Danish reporting system from 1968 to 2005. Soc Sci
Med 2007; 65: 1296-309
18. Roden S. Good case management and reporting practices.
In: Mann RD, Andrews EB, editors. CIOMS working
groups and their contribution to pharmacovigilance.
Chapter V. Middlesex: John Wiley &Sons, Ltd, 2007
19. Aagaard L, Stenver DI, Hansen EH. Structures and processes
in spontaneous reporting systems: a comparative study of
Australia and Denmark. Pharm World Sci 2008; 30: 563-70
20. Medical Dictionary for Regulatory Activities [online]. Avail-
able from URL: http://www.meddramsso.com [Accessed
2008 Aug 20]
21. Fraunhofer Institute for Systems and Innovation Research.
Assessment of the European community system of pharma-
covigilance, 2004 [online]. Avail able from URL: http://www.isi.
fraunhofer.De/t/projekte/medpharm-e-rt-eurovigilance.htm
[Accessed 2009 Dec 31]
22. Aagaard L, Nielsen LH, Hansen EH. Consumer reporting of
adverse drug reactions: a retrospective analysis of the
Danish adverse drug reaction database from 2004 to 2006.
Drug Saf 2009; 32: 1067-74
23. Aagaard L, Thirstrup S, Hansen EH. Opening the white
boxes: the licensing documentation of efficacy and safety of
psychotropic medicines for children. Pharm Drug Saf 2009;
18: 401-11
24. Cheung A, Sacks D, Dewa CS, et al. Paediatric prescribing
practices and the FDA black-box warning on anti-
depressants. J Dev Behav Pediatr 2008; 29: 213-5
25. European Medicines Agency finalises review of antidepres-
sants in children and adolescents (ref. EMEA/CHMP/
128918/2005 corr. London, 25 April 2005 [online]. Available
from URL: www.emea.europa.eu/pdfs/human/press/pr/1289
1805en.pdf [Accessed 2010 Jan 29]
26. Press release: meeting highlights from the Committee for Medi-
cinal Products for Human Use (ref. EMEA/431407/2007).
London, 19 July 2007 [online]. Available from URL: www.
emea.europa.eu/pdfs/human/press/pr/43140707en.pdf [Acces-
sed 2010 Jan 29]
27. Sanghera N, Chan PY, Khaki ZF, et al. Interventions of
hospital pharmacists in improving drug therapy in children:
a systematic literature review. Drug Saf 2006; 29: 1031-47
28. Sturkenboom CJM, Verhamme KMC, Nicolosi A, et al. Drug
use in children: cohort study in three European countries.
BMJ 2008; 24: 337: a2245
29. de Langen J, van Hunsel F, Passier A, et al. Adverse drug
reaction reporting by patients in the Netherlands: three
years of experience. Drug Saf 2008; 31: 515-24
30. Schirm E, Tobi H, van Puijenbroek EP, et al. Reported
adverse drug reactions and their determinants in Dutch
children outside the hospital. Pharm Drug Saf 2004; 13:
159-65
Correspondence: Associate Professor Lise Aagaard,
Department of Pharmacology and Pharmacotherapy,
Section for Social Pharmacy, Faculty of Pharmaceutical
Sciences, University of Copenhagen, Copenhagen, Denmark.
E-mail: laa@farma.ku.dk
ADRs in the Paediatric Population in Denmark 339
ª2010 Adis Data Information BV. All rights reserved. Drug Saf 2010; 33 (4)
