Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
Pharmacotherapeutic group: Psychoanaleptics, centrally acting sympathomimetics
ATC code: N06BA09
Atomoxetine is a highly selective and potent inhibitor of the pre-synaptic noradrenaline transporter, its presumed mechanism of action, without directly affecting the serotonin or dopamine transporters. Atomoxetine has minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors. Atomoxetine has two major oxidative metabolites: 4-hydroxyatomoxetine and N-desmethylatomoxetine. 4-hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the noradrenaline transporter but, unlike atomoxetine, this metabolite also exerts some inhibitory activity at the serotonin transporter. However, any effect on this transporter is likely to be minimal, as the majority of 4-hydroxyatomoxetine is further metabolised such that it circulates in plasma at much lower concentrations (1% of atomoxetine concentration in extensive metabolisers and 0.1% of atomoxetine concentration in poor metabolisers). N-desmethylatomoxetine has substantially less pharmacological activity compared with atomoxetine. It circulates in plasma at lower concentrations in extensive metabolisers and at comparable concentrations to the parent drug in poor metabolisers at steady-state.
Atomoxetine is not a psychostimulant and is not an amphetamine derivative. In a randomised, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of atomoxetine and placebo, atomoxetine was not associated with a pattern of response that suggested stimulant or euphoriant properties.
Strattera has been studied in trials in over 5000 children and adolescents with ADHD. The acute efficacy of Strattera in the treatment of ADHD was initially established in six randomised, double-blind, placebo-controlled trials of six to nine weeks duration. Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for Strattera treated and placebo-treated patients. In each of the six trials, atomoxetine was statistically significantly superior to placebo in reducing ADHD signs and symptoms.
Additionally, the efficacy of atomoxetine in maintaining symptom response was demonstrated in a 1 year, placebo-controlled trial with over 400 children and adolescents, primarily conducted in Europe (approximately 3 months of open-label acute treatment followed by 9 months of double-blind, placebo-controlled maintenance treatment). The proportion of patients relapsing after 1 year was 18.7% and 31.4% (atomoxetine and placebo, respectively). After 1 year of atomoxetine treatment, patients who continued atomoxetine for 6 additional months were less likely to relapse or to experience partial symptom return compared with patients who discontinued active treatment and switched to placebo (2% versus 12%, respectively). For children and adolescents, periodic assessment of the value of ongoing treatment during long-term treatment should be performed.
Strattera was effective as a single daily dose and as a divided dose administered in the morning and late afternoon/early evening. Strattera administered once daily demonstrated statistically significantly greater reduction in severity of ADHD symptoms compared with placebo, as judged by teachers and parents.
In a randomised, double-blind, parallel group, 6-week paediatric study to test the noninferiority of atomoxetine to a standard extended-release methylphenidate comparator, the comparator was shown to be associated with superior response rates compared to atomoxetine. The percentage of patients classified as responders was 23.5% (placebo), 44.6% (atomoxetine) and 56.4% (methylphenidate). Both atomoxetine and the comparator were statistically superior to placebo and methylphenidate was statistically superior to atomoxetine (p=0.016). However, this study excluded patients who were stimulant nonresponders.
Strattera has been studied in trials in over 4800 adults who met DSM-IV diagnostic criteria for ADHD. The acute efficacy of Strattera in the treatment of adults was established in six randomised, double-blind, placebo-controlled trials of ten to sixteen weeks' duration. Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for atomoxetine-treated and placebo-treated patients. In each of the six trials, atomoxetine was statistically significantly superior to placebo in reducing ADHD signs and symptoms (Table X). Atomoxetine-treated patients had statistically significantly greater improvements in clinical global impression of severity (CGI-S) at endpoint compared to placebo-treated patients in all of the 6 acute studies, and statistically significantly greater improvements in ADHD-related functioning in all 3 of the acute studies in which this was assessed (Table X). Long-term efficacy was confirmed in 2 six-month placebo-controlled studies, but not demonstrated in a third (Table X).
Table X. Mean Changes in Efficacy Measures for Placebo-Controlled Studies:
In sensitivity analyses using a baseline-observation-carried-forward method for patients with no postbaseline measure (i.e. all patients treated), results were consistent with results shown in Table X.
In analyses of clinically meaningful response in all 6 acute and both successful long-term studies, using a variety of a priori and post hoc definitions, atomoxetine-treated patients consistently had statistically significantly higher rates of response than placebo-treated patients (Table Y).
Table Y. Number (n) and Percent of Patients Meeting Criteria for Response in Pooled Placebo-Controlled Studies:
| Response Defined by Improvement of at least 1 point on CGI-S | Response Defined by 40% Improvement on CAARS-Inv:SV at Endpoint | |||||
|---|---|---|---|---|---|---|
| Group Treatment | N | n (%) | p-value | N | n (%) | p-value |
| Pooled Acute Studiesa | ||||||
| ATX | 640 | 401 (62.7%) | <0.001 | 841 | 347 (41.3%) | <0.001 |
| PBO | 652 | 283 (43.4%) | 851 | 215 (25.3%) | ||
| Pooled Long-Term Studiesa | ||||||
| ATX | 758 | 482 (63.6%) | <0.001 | 663 | 292 (44.0%) | <0.001 |
| PBO | 611 | 301 (49.3%) | 557 | 175 (31.4%) | ||
a Includes all studies in Table X except: Acute CGI-S response analysis excludes 2 studies in patients with comorbid disorders (LYBY, LYDQ); Acute CAARS response analysis excludes 1 study in which the CAARS was not administered (LYBY).
In two of the acute studies, patients with ADHD and comorbid alcoholism or social anxiety disorder were studied and in both studies ADHD symptoms were improved. In the study with comorbid alcohol abuse, there were no differences between atomoxetine and placebo with respect to alcohol use behaviours. In the study with comorbid anxiety, the comorbid condition of anxiety did not deteriorate with atomoxetine treatment.
The efficacy of atomoxetine in maintaining symptom response was demonstrated in a study where after an initial active treatment period of 24 weeks, patients who met criteria for clinically meaningful response (as defined by improvement on both CAARS-Inv:SV and CGI-S scores) were randomized to receive atomoxetine or placebo for an additional 6 months of double-blind treatment. Higher proportions of atomoxetine-treated patients than placebo-treated patients met criteria for maintaining clinically meaningful response at the end of 6 months (64.3% vs. 50.0%; p=0.001). Atomoxetine-treated patients demonstrated statistically significantly better maintenance of functioning than placebo-treated patients as shown by lesser mean change on the Adult ADHD Quality of Life (AAQoL) total score at the 3-month interval (p=0.003) and at the 6-month interval (p=0.002).
A thorough QT/QTc study, conducted in healthy adult CYP2D6 poor metaboliser (PM) subjects dosed up to 60mg of atomoxetine BID, demonstrated that at maximum expected concentrations the effect of atomoxetine on QTc interval was not significantly different from placebo. There was a slight increase in QTc interval with increased atomoxetine concentration.
The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine have not been evaluated in children under six years of age.
Pharmacokinetic studies have shown that atomoxetine capsules and oral solution are bioequivalent.
Atomoxetine is rapidly and almost completely absorbed after oral administration, reaching mean maximal observed plasma concentration (Cmax) approximately 1 to 2 hours after dosing. The absolute bioavailability of atomoxetine following oral administration ranged from 63% to 94%, depending upon inter-individual differences in the modest first-pass metabolism. Atomoxetine can be administered with or without food.
Atomoxetine is widely distributed and is extensively (98%) bound to plasma proteins, primarily albumin.
Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. Individuals with reduced activity of this pathway (poor metabolisers) represent about 7% of the Caucasian population and have higher plasma concentrations of atomoxetine compared with people with normal activity (extensive metabolisers). For poor metabolisers, AUC of atomoxetine is approximately 10-fold greater and Css,max is about 5-fold greater than extensive metabolisers. The major oxidative metabolite formed is 4-hydroxyatomoxetine that is rapidly glucuronidated. 4-hydroxyatomoxetine is equipotent to atomoxetine but circulates in plasma at much lower concentrations. Although 4-hydroxyatomoxetine is primarily formed by CYP2D6, in individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine can be formed by several other cytochrome P450 enzymes, but at a slower rate. Atomoxetine does not inhibit or induce CYP2D6 at therapeutic doses.
Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.
The mean elimination half-life of atomoxetine after oral administration is 3.6 hours in extensive metabolisers and 21 hours in poor metabolisers. Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine.
Pharmacokinetics of atomoxetine are linear over the range of doses studied in both extensive and poor metabolisers.
Hepatic impairment results in a reduced atomoxetine clearance, increased atomoxetine exposure (AUC increased 2-fold in moderate impairment and 4-fold in severe impairment), and a prolonged half-life of parent drug compared to healthy controls with the same CYP2D6 extensive metaboliser genotype. In patients with moderate to severe hepatic impairment (Child-Pugh class B and C) initial and target doses should be adjusted (see section 4.2).
Atomoxetine mean plasma concentrations for end-stage renal disease (ESRD) subjects were generally higher than the mean for healthy control subjects shown by Cmax (7% difference) and AUC0-∞ (about 65% difference) increases. After adjustment for body weight, the differences between the two groups are minimised. Pharmacokinetics of atomoxetine and its metabolites in individuals with ESRD suggest that no dose adjustment would be necessary (see section 4.2).
Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, or reproduction and development. Due to the dose limitation imposed by the clinical (or exaggerated pharmacological) response of the animals to the drug combined with metabolic differences among species, maximum tolerated doses in animals used in non-clinical studies produced atomoxetine exposures similar to or slightly above those that are achieved in CYP2D6 poor metabolising patients at the maximum recommended daily dose.
A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioural and sexual development. Slight delays in onset of vaginal patency (all doses) and preputial separation (≥10mg/kg/day), and slight decreases in epididymal weight and sperm number (≥10mg/kg/day) were seen; however, there were no effects on fertility or reproductive performance. The significance of these findings to humans is unknown.
Pregnant rabbits were treated with up to 100mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 of 3 studies, decrease in live foetuses, increase in early resorption, slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The incidence of these findings is within historical control values. The no-effect dose for these findings was 30mg/kg/day. Exposure (AUC) to unbound atomoxetine in rabbits, at 100mg/kg/day, was approximately 3.3-times (CYP2D6 extensive metabolisers) and 0.4-times (CYP2D6 poor metabolisers) those in humans at the maximum daily dose of 1.4mg/kg/day. The findings in one of three rabbit studies were equivocal and the relevance to man is unknown.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
