Hepatic Events Associated with Atomoxetine Treatment for??Attention-Deficit??Hyperactivity Disorder

Bangs, Mark E.; Jin, Ling; Zhang, Shuyu; Desaiah, Durisala; Allen, Albert J.; Read, Holly A.; Regev, Arie; Wernicke, Joachim

doi:10.2165/00002018-200831040-00008

Cited by 64 publications

(38 citation statements)

References 16 publications

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“…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%

“…The other two studies used Eli Lilly's databases containing spontaneous AEs and clinical trial data to investigate hepatic effects [30,48]. Bangs et al [48] analyzed hepatic-related events in both of these databases, and included clinical trials with short durations (up to 6 months), while Donnelly et al [30] analyzed data from long-term clinical trials (C3 years).…”

Section: Findings In the Predefined Literature Searchmentioning

confidence: 99%

Section: Findings In the Predefined Literature Searchmentioning

confidence: 99%

“…Bangs et al [48] analyzed hepatic-related events in both of these databases, and included clinical trials with short durations (up to 6 months), while Donnelly et al [30] analyzed data from long-term clinical trials (C3 years). Bangs et al [48] found that, in the spontaneous AEs database, a probable causal role for atomoxetine was identified in 3 of 351 reports of AEs related to the liver in children, adolescents, and adults. There was too little information for 146 cases to assess atomoxetine causation, 69 cases had ''explanations unrelated to atomoxetine'', and 133 cases had possible confounding factors and were deemed to be ''possibly related'' [48].…”

Section: Findings In the Predefined Literature Searchmentioning

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

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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...

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Section: Findings In the Predefined Literature Searchsupporting

confidence: 85%

Section: Findings In the Predefined Literature Searchmentioning

confidence: 99%

Section: Findings In the Predefined Literature Searchmentioning

confidence: 99%

Section: Findings In the Predefined Literature Searchmentioning

confidence: 99%

See 2 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

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“…A recent summary of clinical trial data from nearly 8000 pediatric and adult patients treated with ATMX found that increases in liver function tests are rare events (Bangs et al 2008). Albeit limited by a small sample size of short duration, adjunct MPH did not alter liver function testing.…”

Section: Hammerness Et Almentioning

confidence: 99%

An Open Study of Adjunct OROS-Methylphenidate in Children Who Are Atomoxetine Partial Responders: II. Tolerability and Pharmacokinetics

Hammerness

Georgiopoulos

Doyle

et al. 2009

Journal of Child and Adolescent Psychopharmacology

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Objective: The aim of this study was to evaluate the tolerability of adding OROS methylphenidate (MPH) to children who are partial responders to atomoxetine (ATMX) in the treatment of attention-deficit=hyperactivity disorder (ADHD). Methods: This was a two-phase, 7-week, open study in children aged 6-17 years. Phase 1 initiated ATMX for a minimum of 4 weeks. Phase 2 entered partial responders to ATMX and added OROS MPH to their regimen. Safety was assessed using blood pressure and heart rate measurements, electrocardiogram readings, AEs, laboratories, and ATMX levels. Results: Fifty subjects who were partial responders to ATMX received the combination therapy, with 41 subjects completing the entire protocol. As reported elsewhere , OROS MPH added to partial responders of ATMX was accompanied by a 40% reduction in the ADHD rating scale score and improvements in executive functioning. However, the combination of ATMX plus OROS MPH was associated with greater rates of insomnia, irritability, and loss of appetite compared to ATMX alone. A small significant increase in diastolic blood pressure was observed during adjunctive OROS MPH, with no clinically meaningful changes in electrocardiogram (ECG) parameters during the study. ATMX levels and liver function tests did not significantly change during the combination treatment. Conclusion: Adjunct OROS MPH in ATMX partial responders yielded an additive adverse effect burden in this short-term study. Further controlled research with larger samples of children is warranted.

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Noradrenaline reuptake inhibitors (NRIs) for attention deficit hyperactivity disorder (ADHD) in adults

Crescenzo

Зиганшина

Yudina

et al. 2018

Cochrane Database of Systematic Reviews

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Hepatic Events Associated with Atomoxetine Treatment for??Attention-Deficit??Hyperactivity Disorder

Abstract: Since the launch of atomoxetine therapy, three spontaneously reported cases of reversible drug-induced liver injury were deemed probably related to it. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury and should not be restarted.

Cited by 64 publications

References 16 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

An Open Study of Adjunct OROS-Methylphenidate in Children Who Are Atomoxetine Partial Responders: II. Tolerability and Pharmacokinetics

Noradrenaline reuptake inhibitors (NRIs) for attention deficit hyperactivity disorder (ADHD) in adults

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