DANISH PERSPECTIVE - ADVERSE DRUG REACTIONS TO PSYCHOSTIMULANTS - A DANISH STUDY - Trends in the Prescribing and Adverse Drug Reactions Patterns of Psychostimulants Among Danish Children and Adolescents

Trends in the Prescribing and Adverse Drug
Reactions Patterns of Psychostimulants Among
Danish Children and Adolescents
 
Lise Aagaard and Ebba Holme Hansen
Department of Pharmacology and Pharmacotherapy, Section for Social Pharmacy,
FKL-Research Centre for Quality in Medicine Use,
Danish Pharmacovigilance Research Project (DANPREP),
Faculty of Pharmaceutical Sciences,
University of Copenhagen
Denmark
 
1. Introduction
 
The use of psychostimulants, particularly methylphenidate, to treat Attention Deficit/Hyperactivity Disorder (ADHD) symptoms in children and adolescents has increased rapidly since the 1990s (Schubert et al. 2010). In the 2000s serious reports on cardiovascular adverse drug reactions (ADRs), sudden deaths and psychiatric disorders have led the regulatory agencies in Europe and the United States (US) to warn against use of psychostimulants in the paediatric population (Schubert et al., 2010). In July 2007, class
labels were implemented in the product information to reflect more specific information about cardiovascular and psychiatric adverse events and long-term suppression of growth
(European Medicines Agency, 2007, US Food and Drug Administration, 2007). Despite these warnings, the number of children treated as well as the amount of psychostimulants
prescribed per child has steadily increased (Kalverdijk et al., 2008).
Studies have shown that the use of psychostimulants in children in the Netherlands increased 8 times from 1996 to 2006 (Trip et al., 2009) and in Germany with 96% from 2000 to
2007 (Schubert et al., 2010). From 1994 to 2004 the use of psychostimulants in children increased 5 times in Norway (Asheim et al., 2007), and from 1987 to 1996 the use of
psychostimulants increased 10 times among US children (Zuvekas et al., 2006).
Information about ADRs from psychostimulants has been reported in several clinical studies of short duration, primarily conducted in 6 to 12-year olds boys, particularly in the US
(Bloch et al., 2009). The majority of ADRs reported in these studies were of the type gastrointestinal disorders as well as nervous- and psychiatric disorders, and only few serious
ADRs were reported (Bloch et al., 2009). In spite of pharmacological treatment of children with ADHD being common, this practice has been highly debated among health care professionals due to the dilemma of treating children with substances potential for abuse, where information about long-term safety aspects is very limited (Bloch et al., 2009). The
Current Directions in ADHD and Its Treatment
concerns about safety issues from use of psychostimulants in the paediatric population are also due to the many anecdotal reports of serious psychiatric ADRs and sudden deaths that
have been submitted to the regulatory agencies over recent years (Pringsheim & Steeves, 2011). Systematic analyses of ADRs reported to national databases are necessary, as these
databases constitute an important, though underestimated, source of data, especially about new, serious and rarely occurring ADRs (Hansen, 1992; Aagaard & Hansen, 2009a). We did not locate any studies which systematically have analysed spontaneous reports for psychostimulants submitted to national databases compared to data on medicine use in the
paediatric population.
The objective of this chapter was to 1) describe trends in prescribing of psychostimulants in the Danish paediatric population and 2) characterise spontaneous ADR reports submitted to the Danish Medicines Agency (DKMA) over a decade with respect to occurrence, seriousness, type and age and gender of the child, reported for psychostimulants.
 
Adverse drug reactions by type and seriousness
Table 5 displays the characteristics of ADRs reported for psychostimulants by type, system organ class, seriousness and medication.
The largest share of reported ADRs was of the type “psychiatric disorders” (21 % of total
ADRs) followed by the SOCs “general disorders” (19% of total ADRs) and “nervous system disorders” (16% of total ADRs).
For ADRs of the type nervous- and psychiatric disorders the share of serious ADRs ranged from approximately 50 to 70 % of total ADRs. For the medications atomoxetine and
methylphenidate approximately 45% of all reported ADRs were serious, and for modafinil all reported ADRs were serious.
System Organ Class (SOC)

(alphabetical order)
Amphetamine
derivates
Methylphenidate Atomoxetine Modafinil Total
Blood and lymphatic system
disorders 0 2(2) 0 0 2(1)
Cardiac disorders 0 11(4) 6(3) 0 17(7)
Congenital, familial and genetic
disorders 0 0 1(1) 0 1(1)
Ear and labyrinth disorders 0 1 0 0 1(0)
Endocrine disorders 0 0 2(2) 0 2(2)
Eye disorders 0 6 0 0 6(0)
Gastrointestinal disorders 1 22(12) 10(2) 1(1) 34(15)
General disorders 0 55(15) 5(2) 0 60(17)
Infections and infestations 0 0 1(1) 0 1(1)
Investigations 0 13(10) 7(3) 0 20(13)
Metabolism and nutrition disorders 0 7(1) 3 0 10(1)
Musculoskeletal disorders 0 6(3) 1 0 7(3)
Nervous system disorders 0 48(33) 4(3) 3(3) 55(39)
Psychiatric disorders 1(1) 48(32) 21(12) 3(3) 73(48)
Renal and urinary disorders 0 3(1) 1 0 4(1)
Reproductive system and breast
disorders 0 1 0 0 1(0)
Respiratory disorders 0 4(2) 1 0 5(2)
Skin and subcutaneous tissue
disorders 0 19(5) 3(1) 0 22(6)
Surgical and medical procedures 0 0 1 0 1(0)
Vascular disorders 0 5(2) 2(1) 0 7(3)
Total 2(1) 251(126) 69(31) 7(7) 329(165)
Table 5. Total number of reported ADRs (N) for children distributed by System Organ Class
(SOC), medication (serious ADRs in parentheses), 2000-2009
Current Directions in ADHD and Its Treatment

Table 6 shows characteristics of ADRs reported for the SOC “psychiatric disorders” by type
of medication and seriousness.
Adverse drug reaction (ADR)
(alphabetical order)
Amphetamine
derivates
Methylphenidate Atomoxetine Modafinil Total
Affect lability 0 3(3) 0 0 3(3)
Agitation 0 2(1) 0 0 2(1)
Aggression 0 1 2 1(1) 4(1)
Anger 0 0 2(1) 0 2(1)
Animal phobia 0 1(1) 0 0 1(1)
Anxiety 0 6(2) 2(2) 0 8(4)
Asocial behaviour 0 1 0 0 1
Communication disorder 0 1(1) 0 0 1(1)
Confusional state 0 2(1) 0 0 2(1)
Depression 0 4(3) 4(1) 0 8(4)
Drug abuse 0 2(2) 0 0 2(2)
Emotional disorder 0 1 0 0 1
Euphoric mood 0 2(2) 0 0 2(2)
Food aversion 0 0 1(1) 0 1(1)
Hallucination 0 2(2) 0 1(1) 3(3)
Impulse-control disorder 0 0 1 0 1
Insomnia 0 3(2) 0 0 3(2)
Intentional self-injury 0 0 1(1) 0 1(1)
Mood swings 0 0 1(1) 0 1(1)
Nightmare 0 0 1 1(1) 2(1)
Obsessive thoughts 0 0 1(1) 0 1(1)
Psychotic disorder 1(1) 0 1(1) 0 2(2)
Personality change 0 1(1) 0 0 1(1)
Restlessness 0 1(1) 0 0 1(1)
Sleep disorder 0 7(5) 1(1) 0 8(6)
Social avoidant behaviour 0 3(3) 0 0 3(3)
Suicidal ideation 0 1(1) 3(2) 0 4(3)
Tic 0 2 0 0 2
Total 1(1) 46(33) 21(12) 3(3) 73(48)
Table 6. Total number of reported ADRs of the type “psychiatric disorders” by medication,
and seriousness (in parentheses), 2000-2009.
Two-third of ADRs was reported for amphetamine derivates and methylphenidate, and the
most frequently reported ADRs were anxiety, depression, and sleep disorders.
Table 7 displays the characteristics of ADRs reported for the SOC “nervous system
disorders” by type of medication and seriousness.
Within this SOC approximately 90% of ADRs were reported for methylphenidate, the
majority of reactions being dizziness, headache and dyskinesia.

Adverse drug reaction (ADR) Amphetamine
derivates
 
Methylphenidate Atomoxetine Modafinil Total
Akathisia 0 1(1) 0 0 1(1)
Atypical benign partial epilepsy 0 0 1(1) 0 1(1)
Burning sensation 0 2 0 0 2
Cataplexy 0 0 0 1(1) 1(1)
Crying 0 2(1) 0 0 1(1)
Demyelination 0 2(2) 0 0 2(2)
Disturbance in attention 0 1(1) 0 0 1(1)
Dizziness 0 8(5) 1(1) 1(1) 10(7)
Dyskinesia 0 2(2) 0 0 2(2)
Dystonia 0 1(1) 0 0 1(1)
Epilepsy 0 2(1) 0 0 2(1)
Headache 0 12(9) 2(1) 0 14(10)
Hemiparesis 0 2(2) 0 0 2(2)
Hypoaesthesia 0 3(2) 0 0 3(2)
Hypotonia 0 0 0 1(1) 1(1)
Loss of consciousness 0 2(1) 0 0 2(1)
Nystagmus 0 1 0 0 1
Psychomotor hyperactivity 0 2(1) 0 0 2(1)
Restless legs syndrome 0 1 0 0 1
Somnolence 0 1(1) 0 0 1(1)
Speech disorder 0 2(2) 0 0 2(2)
Syncope 0 1(1) 0 0 1(1)
Total 0 48(33) 4(3) 3(3) 55(39)
Table 7. Total reported ADRs of the type “nervous system disorders” by medication, and
seriousness (in parentheses), 2000-2009.
Table 8 shows the characteristics of ADRs reported for the SOC “general disorders and administration site conditions” by type of medication and seriousness.
Within this SOC almost all ADRs were reported for  amphetamine derivates, and no ADRs were reported for atomoxetine and modafinil. Many ADRs relating to the efficacy of the medications were reported.
A large number of ADRs within the SOC “gastrointestinal disorders” were also reported (see table 5). These reactions were predominantly reported for methylphenidate, and were
of the type’s abdominal pain, diarrhoea and dry mouth (data not shown).

Discussion
 
This is the first study from a national ADR database that has examined the characteristics and occurrence of ADRs from use of psychostimulants in the paediatric population. The study showed that over a decade the prescribing of psychostimulants in the Danish paediatric population has increased dramatically, and that methylphenidate was the predominant psychostimulant. Two thirdS of ADRs were reported by physicians, and approximately 80 % of all ADRs were reported for boys from above 5 years of age. The Current Directions in ADHD and Its Treatment  Adverse drug reaction (ADR) 
Amphetamine derivates
Methylphenidate Atomoxetine Modafinil Total
Asthenia 0 2(2) 0 0 2(2)
Chest pain 0 5(2) 0 0 5(2)
Chills 0 1 0 0 1
Drug effect decreased 0 17(1) 0 0 19(1)
Drug effect increased 0 1 0 0 1
Drug ineffective 0 14(2) 0 0 14(2)
Drug interaction 0 1(1) 1(1) 0 2(2)
Face oedema 0 1 0 0 1
Feeling hot 0 1 0 0 1
Fatigue 0 7(6) 3(1) 0 10(7)
Irritability 0 0 1 0 1
Pain 0 1(1) 0 0 1(1)
Pyrexia 0 1 0 0 1
Therapeutic response unexpected
with drug substitution 0 3 0 0 3(0)
Total 0 55(15) 5(2) 0 60(17)
Table 8. Total number of reported adverse drug reactions of the type “general disorders and administration site conditions” by medication, and seriousness (in parentheses), 2000-2009.
largest shares of reported ADRs was of the type “general disorders and administration conditions”; “psychiatric and nervous system disorders”.
From 2000 to 2009 large increases in number of prescribed dosages and users were observed, and these findings were in line with results from other countries (Asheim et al. 2007;
Kalverdijk et al., 2008; Trip et al., 2009; Schubert et al, 2010; Zuvekas et al., 2006). The majority of users were boys; but we found a large increase in use of psychostimulants among girls, and this pattern was expected (Hodgkins et al, 2011). From 2000 to 2004 the use of psychostimulants were at a stable level, however from 2005 the use has increased dramatically.
Explanations of this increase could be the marketing pressure, change in diagnostic criteria and the development of new types of psychostimulants such as atomoxetine and modafinil for
treatment of ADHD. In the same period of time the pharmaceutical companies have marketed long-term release formulations of methylphenidate for school use (van den Ban et al, 2010).
Use of psychostimulants in Danish children has increased more over the last decade than in other countries; however this may be explained by the fact that use of psychostimulants in
Denmark was lower at the beginning of the period than in other countries.
This is a descriptive study, and therefore we cannot conclude whether ADRs are reported more commonly for methylphenidate than the other products, neither whether girls
experience more ADRs than boys. The number of ADR reports does not reflect the use of psychostimulants, and the question is where in the lifecycle of medicinal products ADRs are
reported. However, since the issue is long-term treatment of children and adolescents ADR signals are extremely important. A high number of reports on decreased drug effect and/or
ineffective drugs from use of methylphenidate were reported. Whether this signal is due to problems with the quality of generic products or that real life is different from the testing
conditions (Hansen, 1992).
The majority of reports were submitted by physicians, however, we would also have expected a larger number of reports from parents, as they should be concerned about administration medications to their children, especially medications for long-term use, where information about long-term effects are limited. The explanation of the large number of reports from
physicians could be that the parents have become aware of the ADRs, and asked their physician to report them. To increase knowledge about ADRs from long term use of psychostimulants the number of reports submitted to the Danish Medicines Agency and probably other medicines agencies should be increased and the regulatory authorities must
focus on increasing ADR reporting rates from both health care professionals and consumers.
An empirical study showed that the licensing material for methylphenidate provided minimal evidence on efficacy and safety in children (Aagaard et al. 2009b), and no
information about long-term safety aspects was reported. Spontaneous reports are an important source of information about new and previously unrecognized ADRs, and the
value of spontaneous reporting schemes lies in their ability to act as hypothesis-generating signals. Due to the low number of ADRs reported for psychostimulants in Denmark it is
necessary to conduct further studies to explore data about rare and serious ADRs in larger databases, such as the EU database EudraVigilance and the international WHO-ADR
database Vigibase (Aagaard et al, 2010). These databases contain large amounts of data submitted from European and global populations, and are therefore suitable for studying
specific ADRs or new signals.
The strength of our study is that data comprised psychostimulant prescriptions and all ADRs reported in one country over a decade. The purpose was to analyse information
reported to the Danish ADR database on ADRs in the paediatric population from use of psychostimulants in the treatment of ADHD, and not to calculate the incidence of ADRs in this population as this is not feasible in material based on spontaneous reporting.
A major limitation to this study is that we do not know to which extent the causality of these ADRs can be confirmed, and this has implications for the interpretation of the results.
Spontaneous reporting systems suffer from different barriers, such as incomplete recognition of ADRs, administrative barriers to reporting, and low data quality, all of which
may result in the underreporting of important serious and rare events. Nonetheless, the study provides information on reported ADRs, and this information contributes to broadening the knowledge base on psychostimulants safety.
 
Conclusion
 
In Denmark, a large increase in the use of psychostimulants in the paediatric population has been observed. The large number of serious reported ADRs indicate that psychostimulants
should be prescribed with caution of that greater care is needed in relation to prescribing these medications for children. The Danish Medicines Agency should monitor prescribing patterns
more tightly to identify potential risks in the paediatric population in relation to the evolving utilisation of use of psychostimulants among children and adolescents and related risks.