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Atomoxetine (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). Atomoxetine is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. Atomoxetine is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. Atomoxetine has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. Atomoxetine has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. Atomoxetine was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data suggest that atomoxetine is unlikely to have any abuse potential. Atomoxetine appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. Atomoxetine is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers. Patients with hepatic insufficiency show an increase in atomoxetine exposure. CYP2D6 inhibitors, such as paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor CYP2D6 metabolizers. Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. Atomoxetine also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. Atomoxetine efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to atomoxetine treatment. Atomoxetine did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration. Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy. Atomoxetine was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued atomoxetine treatment because of adverse events. Atomoxetine discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. Atomoxetine appeared better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment. Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year.
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PMID:Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. 1944 48

The objective of the study was to compare the efficacy and tolerability of once-daily atomoxetine (< or =1.8 mg/(kg day) with those of placebo in children and adolescents (aged 6-16 years) with attention-deficit/hyperactivity disorder [ADHD (DSM-IV)]. This randomized, placebo-controlled, double-blind trial was conducted in Russia. The primary efficacy measure was baseline-to-end point changes in Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv) total score. Tolerability measures included treatment-emergent signs and symptoms (TESS), laboratory values and weight. Compared with patients in the placebo group (n = 33), patients treated with atomoxetine (n = 72) with a mean final dose of 1.4 mg/kg showed significantly greater improvement in ADHDRS-IV-Parent:Inv total score (least-squares mean: atomoxetine, -15.8; placebo, -11.4; p = 0.013). The most common TESS in the atomoxetine group included anorexia [atomoxetine, n = 13 (18.1%); placebo, n = 2 (6.1%)], somnolence, n = 11 versus n = 3 (15.3% vs. 9.1%, respectively), abdominal pain n = 9 versus n = 1 (12.5% vs. 3.0%, respectively) and nausea, n = 8 versus n = 1 (11.1% vs. 3.0%, respectively). Seven patients in the atomoxetine group and two in the placebo group experienced clinically important weight loss during the study (> or =7% from baseline; mean change, kg: atomoxetine, -0.6; placebo, 0.1; p = 0.032). Atomoxetine is efficacious in improving ADHD symptoms in children and adolescents. Atomoxetine treatment may be associated with a numerically higher incidence of anorexia, somnolence, abdominal pain and nausea, as well as statistically greater losses in body weight.
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PMID:Atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: a 6-week, randomized, placebo-controlled, double-blind trial in Russia. 1956 26

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioural disorders in children. It has been shown that as many as 85% of patients with ADHD have at least one psychiatric co-morbidity, and approximately 60% have at least two. Atomoxetine is a specific, noradrenergic reuptake inhibitor that provides an effective treatment option for patients with ADHD and co-morbid conditions. The efficacy of atomoxetine in treating ADHD appears to be unaffected by the presence of co-morbid conditions. Therapy with atomoxetine has been associated with statistically significant improvements in symptoms of oppositional defiant disorder in most, but not all, studies. Limited data suggest this agent may have potential in improving co-occurring symptoms of anxiety and may be useful in patients with co-morbid conditions such as tics or Tourette's syndrome. The tolerability profile of atomoxetine in patients with ADHD and co-morbid conditions was similar to that of patients with uncomplicated ADHD. Atomoxetine was well tolerated, with adverse events generally mild and transient; the most frequent adverse events in patients with ADHD included abdominal pain, decreased appetite, nausea and vomiting. The favourable safety and efficacy profile of atomoxetine makes it a promising treatment for patients with ADHD and associated co-morbidities.
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PMID:Use of atomoxetine in patients with attention-deficit hyperactivity disorder and co-morbid conditions. 1968 65

When attention deficit-hyperactivity disorder in children is truly problematic, methylphenidate, an amphetamine, can be tried as a last resort. Methylphenidate has short-term symptomatic efficacy but also many adverse effects, including a risk of sudden death. After having been evaluated, unsuccessfully, in depression, atomoxetine, a noradrenaline reuptake inhibitor, was authorised in some EU member states for use in attention-deficit/hyperactivity disorder. In France it has only received temporary authorisation for prescription on a named-patient basis. Two double-blind trials comparing atomoxetine versus methylphenidate provided somewhat different results, based on a symptom rating scale completed by the investigator after an interview with the parents. In a trial in 516 children treated for 6 weeks, the "response" rate was statistically higher than with methylphenidate (56% versus 45%). In the other trial in 330 children treated for 8 weeks, the response rate was about 80% in both groups. A meta-analysis of 9 placebo-controlled trials in a total of 1828 children showed that atomoxetine was more effective than placebo in the short term. The main adverse effects identified in clinical trials and pharmacovigilance studies conducted in the United Kingdom and the United States were gastrointestinal disorders (abdominal pain, reduced appetite, vomiting, and weight loss) and neuropsychological disorders (drowsiness, irritability, mood swings, aggressive behaviour). A meta-analysis of 12 trials and pharmacovigilance studies showed an increased risk of suicide. Atomoxetine also provokes seizures, arterial hypotension, tachycardia, and hepatic disorders. Little is known about the risk of abuse or dependence, or the long-term efficacy of treatment. Atomoxetine carries a risk of multiple drug interactions due to its metabolism by the cytochrome P450 isoenzyme 2D6 and its inhibitory effect on noradrenaline reuptake. In practice, atomoxetine has a similar safety profile to methylphenidate and is probably less effective. When drug therapy is warranted, it is better to continue to use methylphenidate, despite its adverse effects.
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PMID:Atomoxetine. Attention-deficit/hyperactivity disorder: no better than methylphenidate. 2045 29

Adverse drug reactions are common in drugs used during childhood and adolescence. Atomoxetine, a selective reuptake inhibitor, was introduced as a safe non-stimulant alternative treatment for attention deficit hyperactivity disorder. Described common side effects of atomoxetine include: headache, abdominal pain, decreased appetite, fatigue, nausea, vomiting and dizziness. In our case, we present an adolescent male who developed hypothermia under atomoxetine treatment. To our knowledge, this is the first report of a causal connection between atomoxetine intake and hypothermia. Because hypothermia is a life-threatening condition and can be treated when interfered immediately, clinicians should be aware of this adverse effect of atomoxetine.
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PMID:Atomoxetine Induced Hypothermia: A Case Report. 2773 58