Safety of Attention-Deficit/Hyperactivity Disorder Medications in Children: An Intensive Pharmacosurveillance Monitoring Study

Ruggiero, Simona; Rafaniello, Concetta; Bravaccio, Carmela; Grimaldi, Giampina; Granato, Rosario; Pascotto, Antonio; Sportiello, Liberata; Parretta, Elisabetta; Rinaldi, Barbara; Panei, Pietro; Rossi, Francesco; Capuano, Annalisa

doi:10.1089/cap.2012.0003

Cited by 29 publications

(31 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found four studies and two case reports that reported hepatic effects [18,30,[48][49][50][51][52]. The results are compatible with the rarity of reports of liver injury highlighted in the European SPC.…”

Section: Findings In the Predefined Literature Searchsupporting

confidence: 85%

“…Similarly, we have not discussed the extremely broad topic of overall tolerability. The manuscript was written using the seven predefined topics as headings, with all the papers selected during stages 2 and 3 [17][18][19][20][21] referred to under the appropriate heading(s) in Sect. 3.…”

Section: N=924mentioning

confidence: 99%

“…In our predefined literature search, we identified 13 studies and two case reports related to suicidality or self-harm [17,18,[25][26][27][28][29][30][31][32][33][34][35][36][37]. The nine studies with the largest atomoxetine-treated patient populations (range 421-6818) were four meta-analyses and one pooled analysis of data from atomoxetine pediatric clinical trials, two national register-based studies, and two clinical trials [17, 25-27, 29, 30, 32, 33, 36].…”

Section: Findings In the Predefined Literature Searchmentioning

confidence: 99%

“…The nine studies with the largest atomoxetine-treated patient populations (range 421-6818) were four meta-analyses and one pooled analysis of data from atomoxetine pediatric clinical trials, two national register-based studies, and two clinical trials [17, 25-27, 29, 30, 32, 33, 36]. The other four studies reported fewer (range 42-72) atomoxetine-treated patients [18,28,35] or did not specify how many atomoxetinetreated patients were included [37]. The first warnings of increased risk of suicidality included in the European SPC and US label were based on 3 The current US label states that pediatric patients treated with atomoxetine ''should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases''.…”

Section: Findings In the Predefined Literature Searchmentioning

confidence: 99%

“…An increasing number of longer-term studies, and studies with larger patient populations, are being published because of the use of epidemiological databases, healthcare registries, and meta-analyses of several clinical trials. For example, in Italy, it is mandatory to include patients treated with medication for ADHD in a national registry [17][18][19][20][21]. These registries may also be more representative of real-life patient populations than clinical trials, as patients may be excluded from the latter because of, for example, prior history of seizures or comorbid psychosis or bipolar disorder.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research

et al. 2016

View full text Add to dashboard Cite

Atomoxetine is a noradrenergic reuptake inhibitor prescribed for attention-deficit/hyperactivity disorder (ADHD) that first gained approval in the USA in 2002 and has been authorized in 97 countries worldwide. The aim of this paper is to comprehensively review publications that addressed one or more of seven major safety topics relevant to atomoxetine treatment of children and adolescents (aged ≥6 years) diagnosed with ADHD. While the review focuses on children and adolescents, publications in which data from patients aged >18 years and from 6 to 18 years were analyzed in the same dataset were included. Using a predefined search strategy, including agreement of two reviewers when selecting papers, reduced the potential for bias. Using this process, we identified 70 eligible papers (clinical trials, epidemiological studies, and case reports) across the seven topics. We also referred to the European Summary of Product Characteristics (SPC) and US label. We found 15 papers about suicidality, three about aggression/hostility, seven about psychosis/mania, six about seizures, seven about hepatic effects, 29 about cardiovascular effects, and 28 about growth and development. The main findings (i.e., those from the largest and most well-conducted studies/analyses) are as follows. A large register-based study of pediatric and adult patients (6818 received atomoxetine) calculated a hazard ratio of 0.96 for suicide-related events during treatment with atomoxetine, and a meta-analysis of 23 placebo-controlled studies (N = 3883), published in 2014, found no completed suicides and no statistically significant association between atomoxetine and suicidality. The frequency of aggression/hostility was not statistically significantly higher with atomoxetine, e.g., experienced by 1.6 % (N = 21/1308) of atomoxetine-treated patients versus 1.1 % (N = 9/806) of placebo-treated patients in one meta-analysis. Symptoms of psychosis and mania were mainly observed in patients with comorbid bipolar disorder/depression. Based on spontaneous reports, during a 2-year period when 2.233 million adult and pediatric patients were exposed to atomoxetine, the reporting rate for seizures was 8 per 100,000 patients. In the manufacturer's database, atomoxetine was a "probable cause" of three hepatic adverse events (AEs) (all reversible hepatitis), and 133 hepatic AEs had possible confounding factors and were "possibly related" to atomoxetine, during 4 years when atomoxetine exposure had reached about 4.3 million patients. Rare cases of severe liver injury are described in the US label and European SPC; a case requiring liver transplantation is described in the US label. In a comprehensive review of a clinical trials database (N = 8417 received atomoxetine), most pediatric patients experienced modest increases in heart rate and blood pressure, and 8-12 % experienced more pronounced changes (≥20 bpm, ≥15 to 20 mmHg). However, in three long-term analyses (≥2 years), blood pressure was within age norms, and few patients discontinued due to cardiovascular AE...

show abstract

Section: Findings In the Predefined Literature Searchsupporting

confidence: 85%

Section: N=924mentioning

confidence: 99%

Section: Findings In the Predefined Literature Searchmentioning

confidence: 99%

Section: Findings In the Predefined Literature Searchmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research

et al. 2016

View full text Add to dashboard Cite

show abstract

Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies

Storebø

Pedersen

Ramstad

et al. 2018

Cochrane Database of Systematic Reviews

238

161

View full text Add to dashboard Cite

Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here.Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.

show abstract

Pediatric Pharmacovigilance: Current Practice and Future Perspectives

Aagaard

2018

Methods in Pharmacology and Toxicology

View full text Add to dashboard Cite

Safety of Attention-Deficit/Hyperactivity Disorder Medications in Children: An Intensive Pharmacosurveillance Monitoring Study

Cited by 29 publications

References 26 publications

The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research

The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research

Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies

Pediatric Pharmacovigilance: Current Practice and Future Perspectives

Contact Info

Product

Resources

About