Trends in the Prescribing and Adverse Drug Reactions Patterns of Psychostimulants Among Danish Children and Adolescents

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).


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 andDrug 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 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.

Design
We conducted a retrospective analysis of all spontaneous ADR reports for 0-17-year old children from 2000 to 2009. Data were obtained from the Danish ADR database and placed at the disposal of this study in anonymous form with encrypted person identification. The unit of analysis was one ADR. Data on medicine use from each of the stimulants were extracted on individual level from the national Danish medicines registry as defined daily doses (DDD) per 1000 inhabitants per day and users (number of treated persons per 1000 inhabitants).

Danish registry of medicine use
In only a few countries information about medicine use at the individual level is available, Denmark being one of these countries. The Registry of Medicinal Product Statistics is a national database covering all outpatient pharmacy-dispensed prescriptions in Denmark.
The registry was established in 1994 to provide complete statistics on the use of medicines in Denmark. Data on prescriptions are registered for each patient via the civil registration number. Each prescription record contains the date of purchase, the dispensing pharmacy, the prescribing physician and detailed information on the drug dispensed, including product name, anatomical therapeutic classification (ATC) system name, dosage, package size and formulation. Medicine use is recorded in different ways. In this study we apply the defined daily doses (DDD) per 1000 inhabitants and number of users per 1000 inhabitants for our analysis. The DDD is defined at the assumed average maintenance dose per day for a drug used for its main indication in adults (WHO, 2011).

Definition of psychostimulants
A psychostimulants is an agent that causes an increase in functional activity, usually of the central nervous system (Howard et al., 2010). Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others. Due to their effects typically having an "up" quality to them, stimulants are also occasionally referred to as "uppers". Stimulants (analeptics) produce a variety of different kinds of effects by enhancing the activity of the central and peripheral nervous systems (Howard et al, 2010).
In this study we focus on the type of stimulants most frequently prescribed in Denmark, i.e. methylphenidate, atoxometine, modafinil and amphetamine derivates in the paediatric population. According to the official summary of product information methylphenidate and atomoxetine are licensed for treatment of ADHD in children and adolescents from 6 and 8 years of age respectively. Modafinil and amphetamine derivates are not licensed for use in children (Danish Medicines Agency, 2011).

ADR reporting system
The reporting of ADRs has been obligatory in Denmark since 1 May 1968. Initially, only physicians were covered by the obligation; however, in 1972, dentists and veterinary surgeons were also required to report ADRs (Aagaard et al., 2008b). Since 1995, drug manufacturers have been obliged to keep registers of suspected and demonstrated ADRs and to make these available to the regulatory authorities. Since July 2003, consumers and other health care professionals have been able to report ADRs directly to the authorities (Aagaard et al., 2008b). 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 medicine(s); (iii) the presumed ADR(s); and (iv) information about the person making the report. An ADR report may contain one or more ADR terms (Aagaard et al., 2008b).
After receiving the ADR reports, professional staff at the DKMA code and categorize the ADRs by degree of seriousness and type of reaction according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology (Aagaard et al., 2008b).
ADR reports are forwarded electronically to the respective pharmaceutical companies, which periodically assess the ADR reports received. The results of their assessments are reported to the DKMA via periodic safety update reports (PSURs). The Danish ADR database contains all spontaneous ADR reports in Denmark, including those reported directly to the pharmaceutical companies (Aagaard et al., 2008b).

Adverse drug reaction (ADR)
An ADR is defined as "any noxious and unintended response to medicines that occurs at doses normally used in humans for the prophylaxis, diagnosis or therapy of diseases" (Volume 9, 2009).

Criteria for seriousness
Severity of reported ADRs was classified according to the criteria defined in volume 9 of the rules governing medicinal products in the European Union guideline (Volume 9, 2009).
Here serious ADRs are divided into: resulting in death, life-threatening, requiring hospitalization or prolongation of existing hospitalization, resulting in persistent or www.intechopen.com significant disability/incapacity in the reporter's opinion, a congenital anomaly/birth defect and other medically important conditions (Volume 9, 2009).
Other reactions were classified as being non-serious.

Anatomical therapeutic chemical (ATC) classification groups
The ATC system classifies medicinal products according to the primary constituent, organ or system on which they act and their chemical, pharmacological and therapeutic properties. Medicines are divided into 14 main groups (first level), with one therapeutic subgroup (second level). The third and fourth levels are chemical/pharmacological/therapeutic subgroups and the fifth level is the chemical substance (WHO ATC index, 2011).
The extract from the ADR database only provides information according to the trade name of those medicinal products that have been reported as causing ADRs. Therefore it was necessary to translate manually trade names into generic names at ATC level 5 in the national medicines register, and then run the generic form of the medicine name against the ADRs reported.

Data extraction
Prescription data were extracted from the Danish registry of dispensed medicine. We extracted information about DDDs per 1000 inhabitants per day and number of persons per 1000 inhabitants prescribed for psychostimulants among children from 0 to 17-years of age. Information about gender was also extracted from the registry. ADR reports submitted to the DKMA were placed at the disposal of this study in anonymous form with encrypted identification of the medicine user. Data were extracted from the ADR database on Microsoft Excel files and the material comprised all ADR reports on children from birth to 17 years of age reported to the Danish Medicines Agency from 2000 to 2009 for the psychostimulants. The unit of analysis was one ADR.
The Danish ADR database defines five categories of persons who may submit data to the database. This article applies this official designation for category of person submitting reports: • Lawyer: patient injury insurers and/or law firms

Prescribed psychostimulants, 2000-2009
Figure 1 displays the annual number of DDD/1000 inhabitant/day and no. of persons/1000 inhabitants/day for all types of psychostimulants prescribed for children from 0 to 17-years of age.

Reported adverse drug reactions for psychostimulants, 2000-2009
From 2000 to 2009 a total of 130 ADR reports including 329 ADRs were reported for psychostimulants for individuals from birth to 17 years of age. One half of ADRs were serious (N = 165), and no fatal cases were reported. Figure 3 displays the annual number of reported ADRs by type of psychostimulant. The majority of the ADRs were reported for methylphenidate (N = 251) and atomoxetine (N = 69). Only few ADRs were reported for amphetamine derivates (N = 2) and modafinil (N = 7).

Adverse drug reactions by type of reporter
The distribution of ADRs reported for psychostimulants by seriousness and type of reporter is displayed in table 2.
Seventy-six percent of ADRs were reported by physicians, 13% of ADRs by consumers and 10% of ADRs were reported by other health care professionals.   Table 3 shows the distribution of ADRs reported for psychostimulants by age, gender and seriousness in the paediatric population, 2000-2009.

Adverse drug reactions by age and gender
Totally, 80 % of ADRs were reported for boys and 20 % of ADRs for girls.
The largest number of ADRs (N = 75) were reported in 9 to 10-year-olds, followed by 16 to 17-year olds ( N = 33) and 15 to 16-year olds (N = 32). Less than one percent of ADRs was reported in children up to 4 years of age.
The largest number of ADRs was reported in 9 to 10-year old boys (N = 68). In 16-17 -year olds girls, a larger number of ADRs (N = 20) were reported than in boys. In the age group a number of ADR reports were submitted without information about gender.
Approximately 50% of ADRs reported for both boys and girls were serious, however large variations were observed within age groups.  Approximately 85% of ADRs were reported in boys, the majority for methylphenidate and atomoxetine. All ADRs reported for modafinil occurred in boys and they were all serious.
For amphemine derivates one out of 2 reported ADRs occurred in boys.
Approximately 45% of ADRs occurring in boys reported for atomoxetine and methylphenidate were serious.
www.intechopen.com Table 5 displays the characteristics of ADRs reported for psychostimulants by type, system organ class, seriousness and medication.

Adverse drug reactions by type and seriousness
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.

Adverse drug reaction (ADR) (alphabetical order)
Amphetamine derivates  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.

Methylphenidate Atomoxetine Modafinil Total
Within this SOC approximately 90% of ADRs were reported for methylphenidate, the majority of reactions being dizziness, headache and dyskinesia.
www.intechopen.com  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 third of ADRs were reported by physicians, and approximately 80 % of all ADRs were reported for boys from above 5 years of age. The www.intechopen.com  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.