On April 2 viloxazine, brand name Qelbree, received an FDA indication for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents ages 6–17 years. Viloxazine is a norepinephrine reuptake inhibitor, similar to atomoxetine (Strattera), which was approved in 2008. Atomoxetine, while approved for ADHD, has some disadvantages when compared with stimulants. It is generally less effective, with response rates only about 50%–75% of typical stimulants. And it is slow, usually taking 2–4 weeks to kick in, as opposed to a day or two for stimulants. Does viloxazine have the same disadvantages? Let’s look at the data that have been reported so far.

Viloxazine has been studied for various indications since the 1970s. It originally received an FDA orphan drug designation (less rigorous than approval) for narcolepsy and was studied for nocturnal enuresis and depression, though it did not gain approval for either indication.

For their Phase III studies of viloxazine in ADHD, Supernus Pharmaceuticals (Qelbree’s manufacturer) performed four short-term, six- to eight-week randomized controlled trials (Nasser A et al, Clin Ther 2020;42(8):1452–1466). 1,013 children and adolescents (ages 6–17) were randomly assigned to various doses of viloxazine (100–600 mg per day) or placebo. Measures included the ADHD Rating Scale-5 (ADHD-RS-5) and the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P): assessments of symptom severity and functional impairment, respectively. In one of the studies, patients taking viloxazine 400 mg daily improved significantly more than those assigned to placebo; however, the 600 mg dose did not reach statistical significance.

What about speed of response? In one study, patients assigned to viloxazine 400 mg began to show improvement over placebo by week 1—more quickly than most studies of atomoxetine, which generally separates from placebo around week 3. Viloxazine has not been compared head-to-head with stimulants or with atomoxetine, so its comparative efficacy is unknown, but it’s clearly slower than stimulants, with a clinically meaningful onset similar to atomoxetine beginning at 2–4 weeks.

The viloxazine studies have been criticized because the researchers completed the study then used a crossover mapping from the original outcome scales—the ADHD-RS-5 and WFIRS-P—to the Clinical Global Impression Scale. Such “post hoc” analyses often find positive results that may not be valid.

Side effects
Viloxazine’s side effects, like other norepinephrine reuptake inhibitors, included sedation, mania, increased blood pressure and heart rate, and suicidal ideation. Six out of the 1,013 patients reported suicidal ideation, 1 reported suicidal behavior, and 2 patients reported both suicidal ideation and behavior for a total of 9 patients (0.9%). Two control patients reported suicidal ideation (0.4%), though there were no completed suicides in either group. Irritability and insomnia were more common in the viloxazine group, with 4% reporting insomnia (vs 1% in placebo) and 3% reporting irritability (1% in placebo). Viloxazine is a potent inhibitor of CYP1A2 and is contraindicated with duloxetine, ramelteon, tasimelteon, tizanidine, and theophylline. 

Dosing
Viloxazine is supplied in dosages of 100, 150, and 200 mg extended-release capsules. It takes 2 days for this preparation to reach steady-state blood levels, and there is a ~10% reduction in absorption if viloxazine is taken with a high-fat meal or if the capsules are opened and sprinkled on applesauce. The recommended dosage for children 6–11 years old is 100 mg once daily, titrated as needed weekly by 100 mg increments to a maximum of 400 mg. For 12- to 17-year-olds, the starting dosage is 200 mg and can be titrated weekly in 100 mg increments up to 400 mg.

Any advantages over atomoxetine?
The preliminary data reported in press releases show that viloxazine may work a little bit faster than atomoxetine. But there’s no reason to expect it to be any more effective in the long run, nor do we expect it to compare favorably to stimulants.

Cost
Supernus has not released the price of Qelbree as of this writing; however, they claim that it will be competitively priced.

CCPR’s Take
Viloxazine is the second norepinephrine reuptake inhibitor to be approved for ADHD. It’s not clear if it has any advantage over atomoxetine, though if its reputed faster onset of action is better substantiated, it may be advantageous. As with atomoxetine, you should monitor patients for suicidality, mania, and drug interactions.