- Short Report
- Open Access
Adverse drug reactions from psychotropic medicines in the paediatric population: analysis of reports to the Danish Medicines Agency over a decade
- Lise Aagaard1, 2Email author and
- Ebba H Hansen1, 2
https://doi.org/10.1186/1756-0500-3-176
© Aagaard et al; licensee BioMed Central Ltd. 2010
- Received: 18 March 2010
- Accepted: 23 June 2010
- Published: 23 June 2010
Abstract
Background
The prescribing of psychotropic medicines for the paediatric population is rapidly increasing. In attempts to curb the use of psychotropic medicine in the paediatric population, regulatory authorities have issued various warnings about risks associated with use of these products in childhood. Little evidence has been reported about the adverse drug reactions (ADRs) of these medicines in practice. As spontaneous reports are the main source for information about previously unknown ADRs, we analysed data submitted to a national ADR database. The objective was to characterise ADRs reported for psychotropic medicines in the Danish paediatric population over a decade.
Findings
All spontaneous ADR reports from 1998 to 2007 for children from birth to 17 years of age were included. The unit of analysis was one ADR. We analysed the distribution of ADRs per year, seriousness, age and gender of the child, suspected medicine and type of reported ADR. A total of 429 ADRs were reported for psychotropic medicines and 56% of these were classified as serious. Almost 20% of psychotropic ADRs were reported for children from birth up to 2 years of age and one half of ADRs were reported in adolescents, especially for antidepressants and psychostimulants. Approximately 60% of ADRs were reported for boys. Forty percent of all ADRs were from the category 'nervous and psychiatric disorders'. All but one ADR reported for children below two years were serious and two of these were fatal. A number of serious ADRs reported in children from birth up to 2 years of age were presumably caused by mothers' use of psychotropic medicines during pregnancy.
Conclusion
The high number of serious ADRs reported for psychotropic medicines in the paediatric population should be a concern for health care professionals and physicians. Considering the higher number of birth defects being reported greater care has to be given while prescribing these drugs for pregnant women.
Keywords
- Atomoxetine
- Ziprasidone
- Ventricular Septal Defect
- Priapism
- Nervous System Disorder
Background
The prescribing of psychotropic medicines for the paediatric population is rapidly increasing in many countries including Denmark. In attempts to curb the use of psychotropic medicine in the paediatric population, regulatory authorities have issued various warnings about risks associated with use of these products in childhood [1–4]. A systematic review detected seventeen studies since 2000 that reported information about the occurrence of ADRs in paediatric populations [5]. Nearly one third of all ADRs reported in children were due to psychotropic medicines, especially CNS stimulants and antidepressants. However, more detailed information about the characteristics of ADRs from psychotropic medicines in the general paediatric population is lacking and little evidence has been reported about safety and long-term effects of these medicines in practice [6–8]. Lack of knowledge of adverse drug reactions (ADRs) at the point of licensing of new medicines renders spontaneous ADR reporting an important contributor to knowledge about safety of medicines [9]. As spontaneous reports are the main source for information about new and previous unknown ADRs we conducted an analysis of all spontaneous ADR reports for psychotropic medicines in Denmark from 1998 to 2007.
Methods
We used data from the national Danish ADR database, which contains information about all spontaneous reports submitted to the Danish Medicines Agency (DKMA) [10]. ADRs reported for children from 0 to 17 years of age were included. We analysed the distribution of ADRs per year, seriousness, age and gender of the child, suspected medicine and type of reported ADR (system organ class [SOC]). ADRs were classified as serious on the following criteria: death, life-threatening, requiring hospitalisation or prolongation of existing hospitalisation, resulting in persistent or significant disability/incapacity, a congenital anomaly/birth defect and other medically important conditions.
Results
ADRs over time
Annual number of adverse drug reactions (ADRs) for psychotropic medicines reported in the Danish paediatric population.
ADRs by age and seriousness
Number of adverse drug reactions reported for psychotropic medication in the paediatric population by age and seriousness (in italic) (1998 to 2007)
Age groups (years) | <1 | 1<2 | 2-10 | 11<17 | Total |
|---|---|---|---|---|---|
Antipsychotics (N05A) | |||||
Levomepromazine | 1 (1) | 0 | 0 | 1 | 2 (1) |
Zipradison | 0 | 0 | 2 | 16 (11) | 18 (11) |
Zuclopenthixol | 1 (1) | 0 | 0 | 1 (1) | 2 (2) |
Chlorprothixene | 0 | 0 | 0 | 2 | 2 |
Clozapine | 0 | 0 | 0 | 1 | 1 |
Olanzapine | 8 (8) | 5 (5) | 0 | 11 (3) | 24 (16) |
Quetiapine | 1 (1) | 0 | 1 (1) | 14 (12) | 16 (14) |
Sulpiride | 0 | 0 | 0 | 3 | 3 |
Risperidone | 1 (1) | 0 | 5 | 18 (5) | 24 (6) |
Aripiprazol | 0 | 0 | 0 | 14 (3) | 14 (3) |
Total | 12 (12) | 5 (5) | 8 (1) | 81 (35) | 106 (53) |
Hypnotics and sedatives (N05B/N05C) | |||||
Diazepam | 1 (1) | 0 | 0 | 0 | 1 (1) |
Oxazepam | 3 (3) | 0 | 0 | 0 | 3 (3) |
Buspirone | 1 (1) | 0 | 0 | 0 | 1 (1) |
Chloral hydrate | 0 | 0 | 3 (3) | 0 | 3 (3) |
Midazolam | 0 | 0 | 1 (1) | 2 (2) | 3 (3) |
Total | 5 (5) | 0 | 4 (4) | 2 (2) | 11 (11) |
Antidepressants (N06A) | |||||
Imipramine | 0 | 0 | 1 (1) | 0 | 1 (1) |
Clomipramine | 1 (1) | 0 | 0 | 0 | 1 (1) |
Amitriptyline | 2 (2) | 0 | 0 | 0 | 2 (2) |
Fluoxetine | 14 (14) | 0 | 0 | 1 (1) | 15 (15) |
Citalopram | 17 (17) | 4 (4) | 5 (2) | 10 (6) | 36 (29) |
Paroxetine | 5 (4) | 0 | 0 | 6 (2) | 11 (6) |
Sertralin | 11 (11) | 0 | 9 (3) | 25 (20) | 45 (34) |
Escitalopram | 1 (1) | 1 (1) | 0 | 0 | 2 (2) |
Oxitriptan | 0 | 0 | 0 | 3 | 3 |
Mirtazapin | 1 (1) | 0 | 0 | 12 (8) | 13 (9) |
Venlafaxin | 1 (1) | 0 | 0 | 3 | 4 (1) |
Total | 53 (52) | 5 (5) | 15 (6) | 60 (37) | 133 (100) |
Psychostimulants (N06B) | |||||
Methylphenidate | 0 | 0 | 85 (35) | 44 (17) | 129 (52) |
Modafinil | 0 | 0 | 0 | 7 (7) | 7 (7) |
Atomoxetine | 0 | 0 | 23 (7) | 20 (11) | 43 (18) |
Total | 0 | 0 | 108 (42) | 71 (35) | 179 (77) |
Total N05 and N06 | 70 (69) | 10 (10) | 135 (53) | 214 (109) | 429 (241) |
Serious ADRs from psychotropic medicines reported for children below two years of age (1998 to 2007)
ATC | Medicines | Adverse drug reaction | No | Indication of use | Age ofchild |
|---|---|---|---|---|---|
N05A | Levopromazine | Priapism | 1 | Headache | 0 |
Olanzapine | Atrial septal defects | 1 | NA | 1 | |
Blood glucose decreased | 1 | Schizophrenia | 0 | ||
Convulsion | 1 | NA | 0 | ||
Decreased appetite | 1 | Schizophrenia | 0 | ||
Drug exposure during pregnancy | 1 | NA* | 0 | ||
Failure to thrive | 1 | Schizophrenia | 0 | ||
Feeding disorder, neonatal | 1 | Schizophrenia | 0 | ||
Haemoglobin increased | 1 | NA | 1 | ||
Hypoxia | 1 | NA | 0 | ||
Pneumonia | 1 | NA | 1 | ||
Polycythaemia | 1 | NA | 1 | ||
Somnolence | 1 | Schizophrenia | 0 | ||
Tension | 1 | NA | 1 | ||
Risperidon | Drug withdrawal syndrome, neonatal | 1 | Depression | 0 | |
Sulpirid | Agitation, neonatal | 1 | Depression | 0 | |
Zuclopemthixol | Supraventricular tachycardia | 1 | Schizophrenia | 0 | |
N05B | Buspirone | Ventricular septal defect | 1 | Depression | 0 |
Diazepam | Apnoea | 1 | Convulsions | 0 | |
Oxazepam | Congenital acrochordon | 1 | Anxiety depression | 0 | |
Chondropathy | 1 | Anxiety depression | 0 | ||
Drug exposure during pregnancy | 1 | Anxiety depression | 0 | ||
N06A | Amitriptyline | Epilepsy | 1 | Depression | 0 |
Febrile convulsion | 1 | Depression | 0 | ||
Clompipramine | Psychomotor retardation | 1 | NA | 0 | |
Citalopram | Tremor, neonatal | 3 | Panic disorder | 1 | |
Drug withdrawal syndrome, neonatal | 2 | Depression/Panic disorder | 0/1 | ||
Hypotonia, neonatal | 2 | Depression | 0 | ||
Irritability | 2 | Panic disorder | 0/1 | ||
Apnoea | 1 | NA* | 0 | ||
Asthenia | 1 | NA | 0 | ||
Chorioamnionitis | 1 | Depression | 0 | ||
Convulsion, neonatal | 1 | Depression | 0 | ||
Hypertonia | 1 | Panic disorder | 1 | ||
Hypocalcaemia | 1 | Depression | 0 | ||
Neonatal asphyxia | 1 | Depression | 0 | ||
Neonatal respiratory depression | 1 | NA* | 0 | ||
Oral candidiasis | 1 | Depression | 0 | ||
Pallor | 1 | NA* | 0 | ||
Premature labour | 1 | Depression | 0 | ||
Ventricular septal defect | 1 | Depression | 0 | ||
Escitalopram | Atrial septal defect | 1 | NA | 1 | |
Drug exposure during pregnancy | 1 | NA* | 0 | ||
Fluoxetine | Drug withdrawal syndrome, neonatal | 3 | Depression | 0 | |
Tremor | 2 | Depression | 0 | ||
Agitation, neonatal | 1 | Depression | 0 | ||
Bradycardia, neonatal | 1 | Depression | 0 | ||
Deafness neurosensory | 1 | NA | 0 | ||
Drug exposure during pregnancy | 1 | NA* | 0 | ||
Dyskinesia, neonatal | 1 | Depression | 0 | ||
Feeding disorder, neonatal | 1 | Depression | 0 | ||
Hypertonia, neonatal | 1 | Depression | 0 | ||
Neonatal disorder | 1 | Depression | 0 | ||
Persistent foetal circulation | 1 | Depression | 0 | ||
Upper limb deformity | 1 | Depression | 0 | ||
Paroxetine | Klinefelter's syndrome | 1 | NA | 0 | |
Neonatal respiratory failure | 1 | NA* | 0 | ||
Psychomotor retardation | 1 | NA | 0 | ||
Sertraline | Respiration abnormal | 2 | Depression | 0 | |
Cerebral palsy | 1 | Depression | 0 | ||
Circulatory collapse | 1 | Depression | 0 | ||
Cyanosis | 1 | Depression | 0 | ||
Drug withdrawal syndrome, neonatal | 1 | Depression | 0 | ||
Drug exposure during pregnancy | 1 | Depression | 0 | ||
Muscle spasms | 1 | Anxiety | 0 | ||
Myoclonus | 1 | Anxiety | 0 | ||
Persistent foetal circulation | 1 | Depression | 0 | ||
Pulmonary hypertension | 1 | Depression | 0 | ||
Mirtazapine | Cerebral palsy | 1 | Depression | 0 | |
Venlafaxine | Agitation, neonatal | 1 | Depression | 0 |
ADRs by therapeutic subgroups
The largest share of ADRs (42%) was reported for psychostimulants (ATC group N06B), followed by 31% for antidepressants (ATC group N06A) and 24% for antipsychotics (ATC group N05A). More than one half of the ADRs reported for antipsychotics were caused by the drugs ziprasidone, olanzapine and risperidone. Although only 2.5% of ADRs were reported for anxiolytics and sedatives (ATC group N05B and N05C), predominantly in infants, all these ADRs were serious. Two-thirds of the ADRs reported for antidepressants (ATC group N06A) were reported for infants and adolescents and exclusively for the medicines sertraline, citalopram and fluoxetine and seventy-five percent of these were serious. For psychostimulants (ATC group N06B) 50% of ADRs were serious and reported for children from six to nine years of age, and 40% of the reports were associated with methylphenidate and atomoxetine. With one exception, all 70 ADRs reported for children less than one year of age were serious.
ADRs by type
Adverse drug reactions from psychotropic medicines by system organ class (descending order)
System Organ Class (SOC) | All ADRs (%) | Serious as % of all ADRs | Serious as % of ADRs |
|---|---|---|---|
N = 429 | N = 241 | ||
Psychiatric disorders | 20 | 25 | 70 |
Nervous system disorders | 19 | 26 | 77 |
General disorders and administration site conditions | 12 | 7 | 33 |
Skin and subcutaneous tissue disorders | 8 | 3 | 21 |
Gastrointestinal disorders | 8 | 6 | 41 |
Cardiac disorders | 5 | 6 | 67 |
Investigations | 5 | 6 | 67 |
Respiratory, thoracic and mediastinal breast disorders | 4 | 4 | 59 |
Metabolism and nutrition disorders | 3 | 2 | 38 |
Musculoskeletal and connective tissue disorders | 3 | 4 | 77 |
Congenital, familial and genetic disorders | 2 | 4 | 77 |
Reproductive system and breast disorders | 2 | 1 | 22 |
Vascular disorders | 2 | 2 | 56 |
Others | 7 | 4 | 33 |
Implications
There are huge gaps in the evidence on the safety of medicines in children as only few medicines prescribed for children are tested in clinical trials and licensed for use in this population. In addition, information about serious and long-term ADRs is sparse due to the limitations embedded in the design of randomised, controlled clinical trials which are used primarily to test hypotheses about efficacy rather than safety and children are usually excluded from clinical trials of medicines for ethical reasons [17]. Therefore, it is very important to systematically analyse and evaluate data reported to the spontaneous reporting programmes as these reports are the major source for new information about possibly serious and previously unknown ADRs [18]. Several of the reported ADRs were birth defects, an area where we have very limited knowledge.
Conclusions
The high number of serious ADRs reported for psychotropic medicines in the paediatric population should be a concern for health care professionals and physicians. Considering the higher number of birth defects being reported greater care has to be given while prescribing these drugs for pregnant women.
Declarations
Acknowledgements
We would like to thank the Danish Medicines Agency for placing data at our disposal.
Authors’ Affiliations
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