By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a new nonstimulant, nonscheduled drug to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Viloxazine is categorized as a selective norepinephrine reuptake inhibitor.1 However, in contrast to other similar agents (e.g., atomoxetine), it produces a more moderate inhibitory effect on norepinephrine uptake, selective antagonistic activity toward 5-HT2B receptors, and agonistic activity toward 5-HT2c receptors. Its psychopharmacological profile is as a serotonin norepinephrine modulating agent.2 Viloxazine is distributed as Qelbree. The drug has been marketed in Europe for more than 40 years to treat depression.
Viloxazine should be prescribed to treat ADHD in patients age 6 to 17 years.1
The recommended starting dose for ages 6 to 11 years is 100 mg once daily.1 Clinicians can titrate the dose in 100-mg increments weekly up to a maximum of 400 mg once daily. For patients age 12 to 17 years, the recommended starting dose is 200 mg, and may be titrated similarly up to 400 mg once daily. The dose should be lower for patients with severe renal impairment. The capsules may be swallowed whole or the contents may be sprinkled onto applesauce. Viloxazine is available as 100 mg, 150 mg, and 200 mg extended-release capsules.
Viloxazine provides a potentially different mechanism of action for treating ADHD. Viloxazine is not classified as a controlled substance.
The more common adverse effects compared to placebo are somnolence (16% vs. 4%) and headache (11% vs. 7%).1 Other adverse reactions include nausea, irritability, tachycardia, fatigue, and suppressed appetite.1 Slower weight gain or slight weight loss vs. placebo-treated subjects have been observed in clinical trials.1 This may be caused by drug-induced appetite suppression. There is a dose-dependent increase in heart rate and diastolic blood pressure.1 Suicidal thoughts and behavior have been reported; therefore, patients should be monitored for clinical worsening and emergence of suicidal thoughts.1 Viloxazine may activate mania or hypomania.1 Viloxazine is a strong CYP1A2 inhibitor; avoid substrates of the isoenzyme (e.g. duloxetine, ramelteon).
The efficacy of viloxazine was evaluated in three randomized, three-arm, placebo-controlled, monotherapy trials.1,3,4 Two studies (Studies 1 and 2) included subjects age 6 to 11 years and one (Study 3) included subjects age 12 to 17 years. Study 1 was a six-week study (one week titration, five weeks maintenance). Subjects (n = 477) were randomized to 100 mg, 200 mg, or placebo. The primary endpoint was the change from baseline to the end of study on the total score on the ADHD Rating Scale (ADHD-RS-5). This is an 18-question document that assesses hyperactivity, impulsivity, and inattentive symptoms, with higher score representing more severe symptoms. Study 2 was an eight-week investigation (three weeks titration, five weeks maintenance). Subjects (n = 313) were randomized to 200 mg, 400 mg, or placebo. Study 3 was a six-week examination (one week titration, five weeks maintenance). Subjects (n = 301) were randomized to 200 mg, 400 mg, or placebo. All doses produced statistically significant reduction in ADHR-RS-5 total scores vs. placebo, with a placebo-subtracted difference ranging from -12% to -14.3% (-16- to -17.7-point reduction vs. -10.9- to -11.7-point reduction for placebo). Baseline mean scores ranged from 40 to 44. Improvement was observed in inattention and hyperactivity/impulsivity subscales.3 Significant reduction was observed in the first week of treatment.3 Approximately 3% of subjects in the clinical trials discontinued treatment because of adverse reactions.1
ADHD is a common diagnosis in U.S. children, with an estimated incidence of 6.1 million in 2016, of whom 62% were taking ADHD medication.5 Of affected children, 60% had at least one other mental, emotional, or behavioral disorder, most commonly behavioral or conduct problems. Stimulants (e.g., methylphenidate, amphetamines) generally are first-line treatment for ADHD. Three nonstimulants are FDA-approved (atomoxetine, clonidine, and guanfacine). These are options for patients who cannot tolerate stimulants (e.g., agitation or sleeplessness) or who experience inadequate response. There are no published comparative studies between viloxazine and stimulants or other nonstimulants. The authors of a systematic review and network meta-analysis estimated the comparative efficacy and tolerability of oral medications (both stimulants and nonstimulants) for ADHD in children, adolescents, and adults.6 They concluded that in children and adolescents, amphetamines were superior to atomoxetine and guanfacine, and methylphenidate was superior to atomoxetine in terms of reducing ADHD core symptoms as rated by clinicians. Viloxazine offers another option with a different psychopharmacological, side effect, and drug-drug interaction profiles. The cost for viloxazine is $299 for a 30-day supply (100 mg, 150 mg, or 200 mg once daily).
- Supernus Pharmaceuticals. Qelbree prescribing information. April 2021.
- Yu C, Garcia-Olivares J, Candler S, et al. New insights into the mechanism of action of viloxazine: Serotonin and norepinephrine modulating properties. J Exp Pharmacol 2020;12:285-300.
- Nasser A, Liranso T, Adewole T, et al. A phase III, randomized, placebo-controlled trial to assess the efficacy and safety of once-daily SPN-812 (viloxazine extended-release) in the treatment of attention-deficit/hyperactivity disorder in school-age children. Clin Ther 2020;42:1452-1466.
- Nasser A, Liranso T, Adewole T, et al. Once-daily SPN-812 200 and 400 mg in the treatment of ADHD in school-aged children: A phase III randomized, controlled trial. Clin Ther 2021 Mar 6; S0149-2918(21)00054-0. doi: 10.1016/j.clinthera.2021.01.027. [Online ahead of print].
- Centers for Disease Control and Prevention. Data and statistics about ADHD. Page last reviewed Nov. 16, 2020.
- Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: A systematic review and network meta-analysis. Lancet Psychiatry 2018;5:727-738.