Safety and tolerability of atomoxetine hydrochloride in a long-term, placebo-controlled randomized withdrawal study in European and Non-European adults with attention-deficit/ hyperactivity disorder

Background and Objectives: Safety and tolerability of atomoxetine were studied in the largest double-blind, placebo-controlled, randomised withdrawal trial of atomoxetine (80 or 100 mg/day) in adults with attention-deficit/hyperactivity disorder (ADHD). Methods: Patients (N = 2017), 18 to 50 years of age, with ADHD were enrolled from 18 countries. Patients who responded to atomoxetine during a 12-week open-label treatment phase and maintained that response during a 12-week double-blind maintenance phase were randomised to atomoxetine (N = 266) or placebo (N = 258) for 25 weeks of double-blind treatment. Treatment differences were compared for serious adverse events (AEs), treatment-emergent AEs (TEAEs), discontinuation due to AEs, vital signs, body weight, and electrocardiograms. Results: During the 25-week double-blind treatment phase, discontinuations due to AEs were similar between atomoxetine and placebo (3.4% vs. 1.9%; P =.418). The percentage of patients experiencing ≥1 TEAE(s) was significantly higher for atomoxetine than placebo (47.0% vs. 37.6%; P =.034), but there were no significant differences for any individual TEAE. Diastolic blood pressure (-0.1 vs.-2.3 mmHg), heart rate (-1.4 vs.-5.3 bpm), and weight (-0.2 vs. 1.1 kg) were significantly different between atomoxetine and placebo (P <.001). There were no significant differences between atomoxetine and placebo in the frequencies of patients showing an increase from baseline >30 ms in Fridericia's QT correction (QTcF; 1.4% vs. 2.6%) or Bazett's QT correction (QTcB; 2.8% vs. 2.6%). During the entire study, no patient had a QTcF or QTcB >500 ms, or an increase from baseline >60 ms. Conclusions: This study demonstrated that atomoxetine exhibited an acceptable safety profile in adults with ADHD after 1 year of treatment, and no clinically meaningful safety-related rebound effects were observed following abrupt discontinuation after 24 weeks of treatment.