What is the role of Quelbree (viloxazine) in treating a patient with attention deficit hyperactivity disorder (ADHD) who has not responded to first-line treatments?

Qelbree (Viloxazine) for Treatment-Resistant ADHD

Viloxazine extended-release (Qelbree) should be considered as a second-line non-stimulant option when patients with ADHD have failed or cannot tolerate both methylphenidate and amphetamine-based stimulants, or when stimulants are contraindicated due to substance abuse history or cardiovascular concerns. 1, 2, 3

Position in Treatment Algorithm

Viloxazine occupies a specific niche in the ADHD treatment hierarchy:

• Stimulants remain first-line treatment with 70-80% response rates and the largest effect sizes from over 161 randomized controlled trials 1, 2. Both methylphenidate and amphetamine formulations should be trialed before moving to non-stimulants, as approximately 40% of patients respond to both classes and 40% respond to only one 4.

• Viloxazine is positioned alongside atomoxetine and alpha-2 agonists as second-line therapy when stimulants fail, cause intolerable side effects, or are contraindicated 1, 2, 5. The American Academy of Child and Adolescent Psychiatry recommends non-stimulants specifically when: active substance abuse disorder exists, inadequate response or intolerable side effects occur with stimulants, comorbid tics or severe anxiety are present, or patient/family preference favors non-stimulants 4.

Evidence for Efficacy

Viloxazine demonstrates statistically significant efficacy in both pediatric and adult ADHD populations:

• In adults, a phase 3 trial (n=374) showed viloxazine ER (200-600 mg/day, mean dose 504 mg) produced significantly greater reduction in ADHD-RS total score (-15.5 vs -11.7 with placebo, p=0.0040) and CGI-S score (-1.4 vs -1.0, p=0.0023) at 6 weeks 6.

• Treatment effects were evident by week 2, with early response at week 2 predicting end-of-study response with 75% positive predictive power 7. This relatively rapid onset distinguishes viloxazine from atomoxetine, which requires 6-12 weeks for full effect 4, 2.

• Long-term safety data (mean exposure 265 days) demonstrates sustained efficacy with AISRS total score improvements of -18.2 points from baseline at last on-study visit 8.

• Viloxazine improved both inattention (p=0.0015) and hyperactivity/impulsivity (p=0.0380) subscales, as well as executive function measures (BRIEF-A Global Executive Composite, p=0.0468) 6.

Mechanism and Clinical Profile

Viloxazine functions as a serotonin-norepinephrine modulating agent (SNMA), moderately inhibiting norepinephrine reuptake while also acting as a selective 5-HT2B receptor antagonist and 5-HT2C receptor agonist 5, 7. This dual mechanism distinguishes it from pure norepinephrine reuptake inhibitors like atomoxetine.

Critical advantage over stimulants: Viloxazine has minimal abuse potential, no evidence of drug dependence, and elevates dopamine levels in the nucleus accumbens considerably less than traditional stimulants 5, 9. This makes it particularly valuable for patients with substance abuse history where stimulants pose significant risk 1, 5.

Dosing and Administration

FDA-approved dosing varies by age 3:

• Adults: Start 200 mg once daily, titrate in 200 mg weekly increments to maximum 600 mg/day based on response and tolerability 10, 3
• Pediatric 12-17 years: Start 200 mg once daily, may increase by 200 mg after 1 week to maximum 400 mg/day 3
• Pediatric 6-11 years: Start 100 mg once daily, titrate in 100 mg weekly increments to maximum 400 mg/day 3

In long-term adult studies, 73% of patients used maintenance doses ≥400 mg/day, with 36% requiring the maximum 600 mg/day dose 8. This suggests most adults need higher-end dosing for optimal response.

Severe renal impairment (eGFR <30): Start 100 mg once daily, titrate in 50-100 mg increments to maximum 200 mg/day 3.

Administer with or without food; capsules may be swallowed whole or opened and sprinkled on pudding/applesauce 3.

Safety Profile and Monitoring

Black Box Warning: Higher rates of suicidal thoughts and behavior were reported in ADHD patients treated with viloxazine versus placebo 3. Closely monitor all patients for clinical worsening and emergence of suicidal ideation, particularly during initial treatment and dose changes 3.

Most common adverse events (≥10% incidence) in adults: insomnia (13.8-14.8%), nausea (10.1-13.8%), fatigue (10.1-11.6%), decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0-10.7%) 6, 8.

Discontinuation rates due to adverse events: 9.0% with viloxazine ER versus 4.9% with placebo in acute trials 6, and 17.6% in long-term extension studies (most commonly insomnia 2.5%, nausea 2.5%, fatigue 1.9%) 8.

Required monitoring 3:

• Assess heart rate and blood pressure prior to initiation, following dose increases, and periodically during treatment
• Screen for personal/family history of suicide, bipolar disorder, and depression before starting
• Monitor for suicidality and clinical worsening throughout treatment

Clinical Scenarios Favoring Viloxazine

Viloxazine is particularly appropriate when:

1. Substance abuse history exists – Non-controlled substance status with minimal abuse potential makes it safer than stimulants 1, 5, 9

2. Cardiovascular contraindications to stimulants – Uncontrolled hypertension, symptomatic cardiovascular disease, or tachyarrhythmias preclude stimulant use 4

3. Comorbid depression or anxiety – Viloxazine's serotonergic activity may provide additional benefit, though SSRIs remain first-line for these conditions 1, 5

4. Stimulant side effects are intolerable – Particularly when appetite suppression, insomnia, or cardiovascular effects limit stimulant use 1, 2

5. Patient/family preference for non-stimulant – After comprehensive education about treatment options 4

Comparative Considerations

Viloxazine versus atomoxetine:

• Viloxazine shows treatment effects by week 2 6, 7 versus 6-12 weeks for atomoxetine 4, 2
• Both have medium-range effect sizes (~0.7) compared to stimulants (1.0) 4
• Atomoxetine causes more somnolence/fatigue 1, while viloxazine more commonly causes insomnia 6, 8
• Both carry FDA black box warnings for suicidality 2, 3

Viloxazine versus alpha-2 agonists (guanfacine/clonidine):

• Alpha-2 agonists require 2-4 weeks for effect 1, 2 versus 2 weeks for viloxazine 6, 7
• Alpha-2 agonists cause significant somnolence/sedation 2, making them preferable for evening dosing or when sleep disturbances exist 1, 4
• Viloxazine has more robust adult efficacy data from phase 3 trials 6, 8

Critical Limitations

Limited adult efficacy data compared to stimulants: While viloxazine has completed phase 3 trials in adults, the evidence base remains smaller than the 161+ randomized controlled trials supporting stimulants 1.

No pregnancy/breastfeeding data: There are no published studies of viloxazine in pregnancy or breastfeeding 10. The American Journal of Obstetrics and Gynecology advises caution, noting that alternative agents would be preferred 10.

Effect size smaller than stimulants: Like all non-stimulants, viloxazine's effect sizes are medium-range (~0.7) compared to stimulants (1.0) 4, 2.

Common Pitfalls to Avoid

• Do not use viloxazine as first-line therapy – Stimulants remain gold standard with superior efficacy; trial both methylphenidate and amphetamine classes before moving to non-stimulants 1, 2

• Do not underdose – 73% of adults in long-term studies required ≥400 mg/day for maintenance 8; titrate to maximum tolerated dose for optimal response

• Do not assume single antidepressant treats both ADHD and depression – While viloxazine has serotonergic activity, SSRIs remain treatment of choice for comorbid depression and should be added if mood symptoms persist 1

• Do not discontinue monitoring after initial titration – Suicidality risk requires ongoing assessment throughout treatment 3

• Do not expect immediate response comparable to stimulants – While effects appear by week 2 6, 7, this is still slower than stimulants which work within days 1