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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

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Abstract

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 AEs. As described in the European SPC, QT interval prolongation is uncommon, e.g., in an open-label study, 1.4 % of 711 children and adolescents had prolonged QTc intervals (≥450 ms in males, ≥470 ms in females) that were not clinically significant at ≥3 years of treatment with atomoxetine. The European SPC warns about potential QT interval prolongation in patients with a personal or family history, or if atomoxetine is administered with other drugs that potentially affect the QT interval. Decreases in growth (weight and height gain) occurred and were greatest in patients of above average weight and height, but appeared to recover over 2–5 years of atomoxetine treatment. In conclusion, suicidality, aggression/hostility, psychosis, seizures, liver injuries, and prolonged QT interval are uncommon or rare in children and adolescents treated with atomoxetine, based on data from the predefined search and from the European SPC. Overall, the data that we assessed from our search do not suggest that associations exist between atomoxetine and suicidality or seizures. The data also suggest that an association may not exist between atomoxetine and aggression/hostility. While atomoxetine may affect the cardiovascular system, the data suggest these effects are not clinically significant in most patients. Reductions in growth appear to be reversible in the long term.

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Fig. 1
Fig. 2

Reproduced from Spencer et al. [84], with permission

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Notes

  1. The SPC language provided in this review article is accurate and consistent across EU member states that participate in the mutual recognition procedure for Strattera, plus Norway and Iceland. At present, this applies to 25 of the 28 EU member states, excluding France and Bulgaria, where licenses are not currently held for Strattera, and Croatia. Information about the mutual recognition procedure can be found at http://www.hma.eu/medicinesapprovalsystem.html [94].

  2. With the exception that the ‘seizures’ topic is not in the ‘warnings and precautions’ section of the US label, but is in the ‘adverse reactions’ section.

  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”. A similar statement is also in the European SPC. In addition, the US label states that “anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania” may be “precursors to emerging suicidality”.

  4. In the current European SPC and US label, for children and adolescents, the target maintenance dose is 1.2 mg/kg/day in patients up to 70 kg body weight, and 80 mg/day in patients over 70 kg body weight (as a single dose in the morning, or twice daily as an evenly divided dose in the morning and late afternoon/early evening).

  5. Of the seven safety topics reported in this review article, all the topics except “seizures” are in the “warnings and precautions” section of the US label. “Seizures” are in the “adverse reactions” section of the US label.

  6. Since October 2011, the following statement has been included in the US label, “Pulse and blood pressure should be measured at baseline, following STRATTERA dose increases, and periodically while on therapy to detect possible clinically important increases.” The European SPC states “It is recommended that heart rate and blood pressure be measured and recorded before treatment is started and, during treatment, after each adjustment of dose and then at least every 6 months to detect possible clinically important increases.”

  7. Between December 2011 and May 2013, a range of 6–12 % of patients, including adults, was shown in the European SPC.

  8. The possibility of QT interval prolongation has been reported in the European SPC since May 2006 and in the approved US label since October 2006, initially based on spontaneous reports. In the current European SPC and US label, clinical trial data about QT interval prolongation are limited to one study in healthy adult CYP2D6 poor metabolizers. The US label states, “No large changes in QTc interval (i.e., increases >60 ms from baseline, absolute QTc >480 ms) were observed in the study. However, small changes in QTc interval cannot be excluded from the current study, because the study failed to demonstrate assay sensitivity. There was a slight increase in QTc interval with increased atomoxetine concentration.” The European SPC also highlights that QT interval prolongation has been reported “very rarely” in cases of overdose; that there is “the potential for an increased risk of QT interval prolongation when atomoxetine is administered with other QT prolonging drugs (such as neuroleptics, class IA and III anti-arrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium, or cisapride), drugs that cause electrolyte imbalance (such as thiazide diuretics), and drugs that inhibit CYP2D6”; and that “atomoxetine should be used with caution in patients with congenital or acquired long QT or a family history of QT prolongation.”

  9. Atomoxetine is contraindicated in patients with “severe cardiac or vascular disorders” in the USA (between June 2012 and August 2013, the term “severe cardiovascular disorders” was used in the US label, instead of “severe cardiac or vascular disorders”). Atomoxetine has been contraindicated in patients with “severe cardiovascular or cerebrovascular disorders” in Europe since December 2011. According to the US label, atomoxetine “should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experience increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate).” Similar language was also used in the European SPC until May 2013, when the wording was changed so that atomoxetine is contraindicated for all patients with “severe cardiovascular or cerebrovascular disorders.” The European SPC states, “Severe cardiovascular disorders may include severe hypertension, heart failure, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and channelopathies (disorders caused by the dysfunction of ion channels). Severe cerebrovascular disorders may include cerebral aneurysm or stroke.”

  10. Reports of sudden deaths of atomoxetine-treated patients with structural cardiac abnormalities have been included in the European SPC since November 2008, and in the US label since October 2006. The European SPC currently states that “atomoxetine should only be used with caution in patients with known serious structural cardiac abnormalities and in consultation with a cardiac specialist”. The US label is more cautious, stating that “atomoxetine generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the noradrenergic effects of atomoxetine”.

  11. None of the studies captured using the predefined search terms were large epidemiological studies in which the goal was to analyze severe/serious cardiovascular AEs in children and adolescents treated with atomoxetine. We are aware of two large epidemiological studies that had this aim, but these studies did not fulfil the predefined search criteria, as they included patients aged <6 years and are not reported in the predefined search results in Sect. 3. Nevertheless, these two studies [92, 93] are discussed in Sect. 4.

  12. Whereas weight does not necessarily reflect growth, it can be used as an indicator of growth and development.

  13. Of 1312 patients at baseline, 61 had data at baseline and at 5 years, 926 patients discontinued during the 5 years, and it appeared that the remainder were still enrolled in the study but had not reached the 5-year time point.

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Authors and Affiliations

  1. Eli Lilly & Co., Lilly Research Centre, Windlesham, Surrey, UK

    Victoria A. Reed & Ernie Anand

  2. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands

    Jan K. Buitelaar

  3. Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, The Netherlands

    Jan K. Buitelaar

  4. Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN, USA

    Kathleen Ann Day, Himanshu P. Upadhyaya & Ludmila A. Kryzhanovskaya

  5. Eli Lilly & Co., Neuroscience Research, Budapest, Hungary

    Tamás Treuer

  6. Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, UK

    David R. Coghill

  7. Departments of Paediatrics and Psychiatry, School of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia

    David R. Coghill

  8. Eli Lilly & Co., Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL, UK

    Nicola C. Savill

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  1. Victoria A. Reed
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Correspondence to Nicola C. Savill.

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Funding

This review was funded by Eli Lilly & Company. Michael Riley, PhD, from Trilogy Writing and Consulting GmbH, Frankfurt, Germany, provided medical writing support on behalf of Eli Lilly & Co.

Conflict of interest

NC Savill, KA Day, E Anand, T Treuer, H Upadhyaya, and LA Kryzhanovskaya are full-time employees and stock holders of Eli Lilly & Co. VA Reed is a full-time employee of Eli Lilly & Co. JK Buitelaar has been a consultant, a member of an advisory board, and/or a speaker for Janssen-Cilag BV, Eli Lilly, Bristol-Myers Squibb, Organon/Schering Plough, UCB, Shire, Medice, and Servier. DR Coghill has received grants to support research from Shire and Vifor Pharma; honoraria for participation in advisory boards for Shire, Novartis, and Sandoz; speaker fees for Shire, Novartis, and Eli Lilly; royalties from Oxford University Press; and has provided expert testimony for GlaxoSmithKline.

Appendix

Appendix

1.1 Strategy Used to Search Embase, Ovid MEDLINE(R), and Ovid MEDLINE(R) In-Process and Other Non-Indexed Citations

The search was originally conducted up to July 2013, as shown below. However, it was updated to include literature published up to 16 August 2014 (not shown).

Database: Embase <1974 to 2013 July 25>, Ovid MEDLINE(R) <1946 to July week 3 2013>, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations <July 25, 2013>

1 exp atomoxetine/(3060)

2 exp attention deficit disorder/(54376)

3 1 and 2 (2079)

4 limit 3 to (human and (child <unspecified age> or preschool child <1 to 6 years> or school child <7 to 12 years> or adolescent <13 to 17 years>)) [Limit not valid in Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process; records were retained] (725)

5 limit 4 to yr = ”2001–Current” (722)

6 5 use oemezd (722)

7 atomoxetine.mp. (4248)

8 tomoxetine.mp. (146)

9 LY139603.mp. (17)

10 7 or 8 or 9 (4289)

11 exp Attention Deficit Disorder with Hyperactivity/ (54376)

12 10 and 11 (2818)

13 limit 12 to (humans and yr = ”2001–Current” and “all child (0 to 18 years)”) [Limit not valid in Embase; records were retained] (2468)

14 13 use mesz,prem (476)

15 6 or 14 (1198)

16 remove duplicates from 15 (879)

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Reed, V.A., Buitelaar, J.K., Anand, E. et al. 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. CNS Drugs 30, 603–628 (2016). https://doi.org/10.1007/s40263-016-0349-0

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