Guanfacine extended release (GXR) is a non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD).

To separate efficacy and sedative treatment-emergent adverse events (TEAEs) associated with GXR in four randomized, controlled trials in children (6–12 years) and adolescents (13–17 years) with ADHD.

SPD503-301 (n=345) and SPD503-304 (n=324) were 8 and 9 week studies of fixed-dose GXR (≤4mg/day). SPD503-312 (n=314; adolescents only) and SPD503-316 (n=338) were 10–13 week studies of dose-optimized GXR (1–7mg/day).

In fixed-dose studies, pooled incidences of sedative TEAEs with GXR were highest at week 1 (GXR, 13.9–18.7%; placebo, 8.7%) and decreased to placebo levels at week 8 (0–1.4%; placebo, 0%). In contrast, proportions of responders (≥30% reduction from baseline in ADHD Rating Scale IV [ADHD-RS-IV] total score) increased from week 1 (GXR, 29.6–34.8%; placebo, 25.0%) through endpoint (GXR, 66.7–72.2%; placebo, 42.6%). Incidences of sedative TEAEs, but not proportions of responders, increased with GXR dosing. GXR was associated with a statistically significant reduction in ADHD-RS-IV total score from baseline to endpoint in patients without sedative TEAEs in both fixed-dose and dose-optimized studies (GXR versus placebo, effect size=0.49 and 0.67, respectively; P<0.001). GXR was associated with statistically significant improvements compared with placebo in both ADHD-RS-IV Hyperactivity/Impulsivity and Inattentiveness subscale scores (P<0.001).

These data from pooled GXR clinical trials indicate that incident sedative TEAEs do not contribute to increased treatment response over time, and that sedation and symptomatic improvement are distinct effects of GXR.