Viloxazine ER shows sustained ADHD symptom relief and no new safety signals in long-term pediatric trial

Why it matters: ADHD is one of the most common childhood neurobehavioral conditions, affecting up to roughly 10% of US youth, and effective treatment can reduce its effects on school, relationships, and later life outcomes. Stimulants are usually first-line but are controlled substances with misuse risks, and the FDA tightened their labeling in 2023. Nonstimulants such as viloxazine ER (Qelbree), a selective norepinephrine transporter inhibitor with serotonergic activity, are an alternative. Because ADHD is chronic, long-term safety data in children and adolescents are important.

What was studied: This phase 3, open-label, flexible-dose extension trial (NCT02736656) ran at 68 US sites from 2016 to 2021. It enrolled youth who had completed one phase 2 or one of four phase 3 double-blind, placebo-controlled viloxazine ER trials. Whatever their prior assignment, participants started viloxazine ER at 100 mg/day (children) or 200 mg/day (adolescents) and were titrated weekly over a 12-week dose-optimization period, up to 400 mg/day for children or 600 mg/day for adolescents. They then entered a maintenance phase that continued until FDA approval, for up to 72 months. Safety was the primary objective, assessed through adverse events, labs, vital signs, ECGs, growth measures, and the Columbia Suicide Severity Rating Scale, with seizures treated as events of special interest. Efficacy (ADHD-RS-IV/5 and CGI-I) was measured against the double-blind baseline, using observed data without imputation.

Key results: Of 1,100 participants (646 children, 454 adolescents; 66.5% male), 58.3% stayed on treatment at least 6 months, 40.6% at least 12 months, and 25.0% at least 24 months. Median exposure was 260 days (range 1–1,896). Median modal doses were 300 mg/day in children and 400 mg/day in adolescents. Adverse events occurring in at least 5% of participants were nasopharyngitis (9.7%), somnolence (9.5%), headache (8.9%), decreased appetite (6.0%), and fatigue (5.7%). Most events were mild or moderate, 3.9% reported a severe event, and 8.2% discontinued because of adverse events. Only 15.4% completed the trial as designed, and the most frequent reasons for stopping were parent/guardian withdrawal (26.3%) and participant withdrawal (13.7%). ADHD-RS total scores improved by 24.3 ± 12.0 points at Month 3, 26.1 ± 11.5 at Month 12, and 22.4 ± 13.6 at the last OLE visit.

Implications and caveats: The authors conclude that viloxazine ER is a generally well-tolerated, effective long-term option, with no new safety concerns and the potential for further improvement beyond that seen in double-blind treatment. Several caveats apply. The study was open-label and uncontrolled, so placebo and expectancy effects cannot be separated from drug effects. Efficacy analyses used observed data only, so the apparent sustained benefit may be inflated by survivorship, since participants who did well were more likely to remain. Attrition was high, partly because the study ended administratively around FDA approval. The study was sponsored by Supernus, and several authors are employees. Findings should be weighed alongside head-to-head and controlled comparisons with other ADHD treatments.