Safety of Medicines Used for ADHD in Children
Objective To assess the long-term safety of drugs for attention deficit hyperactivity disorder (ADHD).
Methods A bibliographic search was performed in the MEDLINE, EMBASE and PsycINFO databases for prospective studies evaluating the incidence of adverse events (AEs) in children and adolescents treated for ADHD.
Results A total of six prospective studies that monitored drug safety during therapy for at least 12 weeks were retrieved. The drugs studied were atomoxetine (two studies, 802 patients), osmotic-controlled released oral methylphenidate formulation (two studies, 512 patients), extended release formulation of mixed amphetamine salts (one study, 568 patients) and transdermal methylphenidate (one study, 326 patients). Heterogeneity was found in the duration of follow-up (ranging between 1 and 4 years) and in the way data were reported.
The rate of treatment-related AEs ranged from 58% to 78%, and the rate of discontinuation due to AEs ranged from 8% to 25% of the children.
Decreased appetite, insomnia, headache and abdominal pain were the most common AEs observed.
Most AEs and cases of discontinuation occurred during the first few months of treatment.
Conclusions Few studies evaluated the long-term safety of drugs for ADHD. Heterogeneity in follow-up duration and in data reporting made comparing different studies and drugs difficult. A systematic monitoring of long-term safety is needed.
Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder in children and adolescents that comprises core symptoms of developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity. Recommendations in the international guidelines on the treatment of ADHD vary. There is a general consensus on recommending psychostimulant drugs as first-line treatment, however, because of their documented efficacy in about 80% of children. In particular, methylphenidate is preferred over amphetamines, which are generally less used in Europe. Atomoxetine, although generally less effective than stimulants, is also widely available and may be recommended as an alternative to methylphenidate. Since their approval, several issues have affected the use of ADHD medications, such as tolerability, comorbidity, potential substance abuse risk and lack of efficacy.
Hundreds of clinical studies have reported that ADHD drugs are generally well tolerated and that most of their adverse effects are mild and/or temporary. Several reviews have addressed the safety of methylphenidate, amphetamines and atomoxetine in children with ADHD. However, concerns were raised by the regulatory authorities, in particular regarding cardiovascular and psychiatric adverse drug reactions. The Food and Drug Administration (FDA) requested the addition of a black box warning to the labelling of atomoxetine to alert healthcare professionals of an increased risk of suicidal thinking and behaviour. In December 2013, the FDA issued a Drug Safety Communication regarding the risk of long-lasting erection in people treated with methylphenidate. According to the FDA statement, this risk is shared also by atomoxetine and amphetamine.
In 2011 the European Network for Hyperkinetic Disorders published guidelines on managing adverse effects of ADHD medication. These covered cardiac adverse events (AEs), growth, sleep disturbance, psychotic symptoms, tics, seizures and, in particular, the risk of substance abuse.
The main findings of a 2001 meta-analysis by Schachter et al on the short-term effects of immediate-release methylphenidate (62 trials) confirmed significantly higher rates, versus placebo, of decreased appetite (Number Needed to Harm, NNH=4), insomnia (NNH=7) and stomach ache (NNH=9).
Although atomoxetine is a non-stimulant, it shares several of the stimulants' properties, such as appetite suppression and increased heart rate (HR) and blood pressure (BP). Several placebo-controlled trials on atomoxetine exist and estimated the approximate incidence of various adverse effects. Overall, these estimations were: loss of appetite, 20%, nausea and/or vomiting, 10%, dyspepsia, 10%, and fatigue and/or weakness, 10%. Compared to placebo, atomoxetine significantly decreased appetite (NNH=9) and increased somnolence (NNH=19), abdominal pain (NNH=23) and vomiting (NNH=30).
However, the main limitation of the available reviews was that most of the studies taken into account were short term. No randomised controlled trials (RCTs) with a duration of over 1 year regarding atomoxetine are available.
In the meta-analysis by Schachter et al, the average duration of intervention was 3 weeks and no studies lasted longer than 28 weeks. Aagard et al reviewed the ADRs reported in 43 studies, with a treatment duration of no longer than 32 weeks.
Multimodal treatment study of children with ADHD was the randomised clinical trial that monitored the use of stimulants for the longest time period. At the end of the 14-month follow-up 50% of children receiving stimulants reported mild, 11%, moderate and 3%, severe adverse effects. At 3-year follow-up a decreased height (on average 2 cm lower) and weight (on average 2.7 kg) were reported in children consistently medicated compared with children never medicated. No differences were found between groups concerning the incidence of substance abuse or delinquency. At 8 years psychiatric hospitalisations occurred more often for children in multimodal treatment arm than for standard care arm, but diagnoses of psychosis, mania or hypomania were uncommon for both groups. Eight children with multimodal treatment had developed one of these disorders versus only one child in control group (1.8% vs 0.4%). Tic (4.4% vs 1.7%) and elimination disorders (0.7% and 0.0%) were also infrequent for multimodal and control groups, respectively, by 8 years.
To the best of our knowledge no articles have reviewed long-term studies focused on ADRs following the use of ADHD medications in the paediatric population.
Abstract and Introduction
Abstract
Objective To assess the long-term safety of drugs for attention deficit hyperactivity disorder (ADHD).
Methods A bibliographic search was performed in the MEDLINE, EMBASE and PsycINFO databases for prospective studies evaluating the incidence of adverse events (AEs) in children and adolescents treated for ADHD.
Results A total of six prospective studies that monitored drug safety during therapy for at least 12 weeks were retrieved. The drugs studied were atomoxetine (two studies, 802 patients), osmotic-controlled released oral methylphenidate formulation (two studies, 512 patients), extended release formulation of mixed amphetamine salts (one study, 568 patients) and transdermal methylphenidate (one study, 326 patients). Heterogeneity was found in the duration of follow-up (ranging between 1 and 4 years) and in the way data were reported.
The rate of treatment-related AEs ranged from 58% to 78%, and the rate of discontinuation due to AEs ranged from 8% to 25% of the children.
Decreased appetite, insomnia, headache and abdominal pain were the most common AEs observed.
Most AEs and cases of discontinuation occurred during the first few months of treatment.
Conclusions Few studies evaluated the long-term safety of drugs for ADHD. Heterogeneity in follow-up duration and in data reporting made comparing different studies and drugs difficult. A systematic monitoring of long-term safety is needed.
Introduction
Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder in children and adolescents that comprises core symptoms of developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity. Recommendations in the international guidelines on the treatment of ADHD vary. There is a general consensus on recommending psychostimulant drugs as first-line treatment, however, because of their documented efficacy in about 80% of children. In particular, methylphenidate is preferred over amphetamines, which are generally less used in Europe. Atomoxetine, although generally less effective than stimulants, is also widely available and may be recommended as an alternative to methylphenidate. Since their approval, several issues have affected the use of ADHD medications, such as tolerability, comorbidity, potential substance abuse risk and lack of efficacy.
Hundreds of clinical studies have reported that ADHD drugs are generally well tolerated and that most of their adverse effects are mild and/or temporary. Several reviews have addressed the safety of methylphenidate, amphetamines and atomoxetine in children with ADHD. However, concerns were raised by the regulatory authorities, in particular regarding cardiovascular and psychiatric adverse drug reactions. The Food and Drug Administration (FDA) requested the addition of a black box warning to the labelling of atomoxetine to alert healthcare professionals of an increased risk of suicidal thinking and behaviour. In December 2013, the FDA issued a Drug Safety Communication regarding the risk of long-lasting erection in people treated with methylphenidate. According to the FDA statement, this risk is shared also by atomoxetine and amphetamine.
In 2011 the European Network for Hyperkinetic Disorders published guidelines on managing adverse effects of ADHD medication. These covered cardiac adverse events (AEs), growth, sleep disturbance, psychotic symptoms, tics, seizures and, in particular, the risk of substance abuse.
The main findings of a 2001 meta-analysis by Schachter et al on the short-term effects of immediate-release methylphenidate (62 trials) confirmed significantly higher rates, versus placebo, of decreased appetite (Number Needed to Harm, NNH=4), insomnia (NNH=7) and stomach ache (NNH=9).
Although atomoxetine is a non-stimulant, it shares several of the stimulants' properties, such as appetite suppression and increased heart rate (HR) and blood pressure (BP). Several placebo-controlled trials on atomoxetine exist and estimated the approximate incidence of various adverse effects. Overall, these estimations were: loss of appetite, 20%, nausea and/or vomiting, 10%, dyspepsia, 10%, and fatigue and/or weakness, 10%. Compared to placebo, atomoxetine significantly decreased appetite (NNH=9) and increased somnolence (NNH=19), abdominal pain (NNH=23) and vomiting (NNH=30).
However, the main limitation of the available reviews was that most of the studies taken into account were short term. No randomised controlled trials (RCTs) with a duration of over 1 year regarding atomoxetine are available.
In the meta-analysis by Schachter et al, the average duration of intervention was 3 weeks and no studies lasted longer than 28 weeks. Aagard et al reviewed the ADRs reported in 43 studies, with a treatment duration of no longer than 32 weeks.
Multimodal treatment study of children with ADHD was the randomised clinical trial that monitored the use of stimulants for the longest time period. At the end of the 14-month follow-up 50% of children receiving stimulants reported mild, 11%, moderate and 3%, severe adverse effects. At 3-year follow-up a decreased height (on average 2 cm lower) and weight (on average 2.7 kg) were reported in children consistently medicated compared with children never medicated. No differences were found between groups concerning the incidence of substance abuse or delinquency. At 8 years psychiatric hospitalisations occurred more often for children in multimodal treatment arm than for standard care arm, but diagnoses of psychosis, mania or hypomania were uncommon for both groups. Eight children with multimodal treatment had developed one of these disorders versus only one child in control group (1.8% vs 0.4%). Tic (4.4% vs 1.7%) and elimination disorders (0.7% and 0.0%) were also infrequent for multimodal and control groups, respectively, by 8 years.
To the best of our knowledge no articles have reviewed long-term studies focused on ADRs following the use of ADHD medications in the paediatric population.
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