Viloxazine for ADHD

Viloxazine ((±)-2-[(2-ethoxyphenoxy)methyl]morpholine hydrochloride; C13H20NO3Cl) (SPN-812) has been approved in the U.S. since April 2021 for the treatment of ADHD in children aged 6 to 17 and for depression. It was approved in Europe as an antidepressant from 1976 to 2006 and was used off-label to treat enuresis and narcolepsy.¹
Brand names: Viloxazin, Emovit, Viloxazina, Viloxazinum, Vivarint, Vicilan, Vivalan, Catatrol
Extended-release viloxazine capsules: Qelbree®, Supernus

Viloxazine modulates serotonin and norepinephrine activity.² Viloxazine increases serotonin levels in the prefrontal cortex but does not increase norepinephrine release. It has a weak effect on dopamine and shows a slight increase in motivation compared to other ADHD medications.
Viloxazine is well tolerated and has side effects such as drowsiness, loss of appetite, and headaches.
It should not be taken by individuals with a predisposition to epilepsy, severe liver failure, or during pregnancy.

1. Mechanisms of Action of Viloxazine¶

Viloxazine differs from other ADHD medications that target norepinephrine reuptake and is better described as a serotonin and norepinephrine modulator. It exhibits antagonistic activity at 5-HT-2B receptors and agonistic activity at 5-HT-2C receptors, and increases serotonin levels in the prefrontal cortex (PFC). It has a moderate inhibitory effect on the norepinephrine transporter and a moderate effect on the noradrenergic and dopaminergic systems. This finding is consistent with the low incidence of cardiac effects in clinical practice.

Viloxazine has no binding affinity for the dopamine transporter (DAT) and does not interact directly with the D1 and D2 dopamine receptors. Given its minimal effect on dopamine in the nucleus accumbens, it is believed to pose a low risk of substance abuse. The immediate-release viloxazine formulation was initially marketed as an antidepressant in Europe and was later withdrawn for reasons unrelated to safety or efficacy. Data from more than two decades of research in adults have shown that viloxazine is safe and well-tolerated compared to TCAs, with fewer cardiovascular effects and minimal impact on blood pressure.

Viloxazine acts as³⁴⁵

• strong:
  • selective serotonin 5-HT2B receptor antagonist
  • Serotonin 5-HT2C receptor agonist
• moderate:
  • selective norepinephrine reuptake inhibitor (Ki: 0.63 μM)
    • resulting in increased levels of dopamine and norepinephrine in the PFC
    • no additional release of norepinephrine¹
• weak:
  • Serotonin 5-HT7 receptor antagonist
  • α1B-adrenergic receptor antagonist
  • β2-adrenoreceptor antagonist
• very weak:
  • A competitive and reversible inhibitor of monoamine oxidase A and B.¹

Viloxazine does not interact with the DAT or dopamine receptors.⁶

Viloxazine has been shown to increase dopamine levels⁷, norepinephrine levels⁷, and serotonin levels^{89 6} in the PFC. However, it does not appear to act as a serotonin reuptake inhibitor.⁸⁷
It does not increase norepinephrine release.

Viloxazine increases dopamine levels in the nucleus accumbens to a significantly lesser extent than stimulants.¹⁰ We consider the authors’ claim that non-stimulants have fewer side effects to be misguided. Compared to stimulants, non-stimulants (atomoxetine, guanfacine) have significantly more side effects while having a significantly lower effect size.

Other in vitro studies found no dopamine release in the striatum and only a minor effect on dopamine receptors or DAT. In rodents, viloxazine significantly increased dopamine levels in vivo in the PFC, moderately in the amygdala, and minimally in the nucleus accumbens. The increase in dopamine in the PFC is likely a consequence of NET reuptake inhibition. The minimal effect of viloxazine on dopamine in the nucleus accumbens could indicate a low potential for abuse.¹ We therefore suspect that it produces a lesser increase in drive than stimulants.
Viloxazine significantly increases plasma levels of the adenosine A1 and A2 antagonist theophylline.¹¹¹² It is conceivable that part of the effect of viloxazine in ADHD could be attributed to the dopamine-increasing effect of the adenosine antagonist theophylline.

Unlike almost all ADHD medications that have been widely used to date, viloxazine does not alter histamine levels. Viloxazine appears to exert weak competitive inhibition (< 25%) at the H1 and H2 histamine receptors.¹

Pharmacological data:

• Bioavailability: approximately 88%⁵
• Tmax (time to maximum plasma concentration): approximately 5 hours for 200 mg⁵; 6 to 9 hours⁶
• The active ingredient is highly protein-bound (76–82%)⁵
• The mean half-life of Viloxazin ER is 7 hours (2.25 to 11.75 hours)⁵⁶¹³
• Metabolized primarily by the enzymes CYP2D6, UGT1A9, and UGT2B15⁶
• 90% of the drug is excreted by the kidneys. Of this, 12–15% is excreted unchanged, and the remainder as inactive metabolites⁶
• The estimated Cmax and AUC of viloxazine and its metabolites at steady state were approximately 40 to 50 percent higher in children aged 6 to 11 years than in children aged 12 to 17 years.¹³

2. Viloxazine for ADHD¶

Extended-release viloxazine (Viloxazine ER; SPN-812) has been shown in several Phase 2 and Phase 3 studies at doses of 200 to 400 mg/day to be an effective and well-tolerated alternative for some children with ADHD. The mechanism of action of viloxazine is unique because it modulates the activity of both serotonin and norepinephrine.¹⁴⁵
Viloxazine improved emotional, behavioral, and executive function symptoms in children and, to a lesser extent, in adolescents as well.¹⁵

The effect size of viloxazine has been determined in various studies to range from 0.46 to 0.63¹⁶, making it significantly weaker than the effect size of stimulants (1.1 to 1.5).¹⁷
Various Phase II and Phase III studies found that viloxazine was effective in treating ADHD in

• 100 and 200 mg per day¹⁸
• 100, 200, and 400 mg per day¹⁹
• 200 to 400 g per day^20212223
• 400 or 600 mg per day²⁴

The various publications on Phase III come from the same group of authors.

In 5 dose-response studies involving 1,560 participants, viloxazine outperformed placebo in terms of ADHD (mean difference 5.47 points; 95% CI 4.03 to 6.91). The dose-response curve follows a bell-shaped pattern. Doses above 400 mg or 7 mg/kg do not result in greater efficacy but do increase side effects. The effect levels off in weeks 4 through 6. The discontinuation rate due to side effects was 4.15%; the risk of discontinuation was 2.48 times higher than with placebo (95% CI 1.26 to 4.88). Doses of 200 to 400 mg or 6 to 8 mg/kg are recommended.²³

A long-term study of viloxazine involving 1,080 evaluable people with ADHD showed a mean duration of treatment of 428 days. A total of 641 (58.3%) remained on treatment for at least 6 months, 447 (40.6%) for at least 12 months, and 275 (25.0%) for at least 24 months. Fewer than 10% of children and fewer than 20% of adolescents remained on the initial doses of 100 and 200 mg daily, respectively. Side effects were predominantly mild (26.5%) or moderate (26.9%); 3.9% reported severe side effects, including suicidal thoughts in 0.6% and drowsiness in 0.4%. Additional treatment was required in 15.3% of cases, and discontinuation occurred in 1.9%.²⁵

The reduction in symptoms after 2 weeks was a fairly good predictor of treatment success after 6 weeks.⁵
A comparative study found clear advantages of Viloxazine ER over atomoxetine.²⁶

Dosage:⁵²

• Ages 6 to 11
  • Recommended starting dose: 100 mg orally once daily
  • Up-dosing in 100-mg increments weekly
  • Recommended maximum dose: 400 mg once daily
• Ages 12 to 17
  • Recommended starting dose: 200 mg orally once daily during the first week
  • Up-dosing up to the maximum daily dose of 400 mg
    • 73% of the participants in a study used 400 mg²⁷

A study of 646 children and 454 adolescents (66.5% male/33.5% female) conducted over a period of up to 72 months found that²⁸

• Median of the most commonly used dose per day with free dose titration
  • 300 mg for children (starting dose 100 mg, max. 400 mg)
  • 400 mg for adolescents (Sart 300 mg, max. 600 mg)
• Improvement compared to the double-blind baseline in the ADHD-RS IV/5 total score
  • in month 3: -24.3 ± 12.0
  • in month 12: in month 3, -26.1 ± 11.5
  • in the last month of the study (up to 72 months): -22.4 ± 13.6

A placebo-controlled study involving n = 384 adults with open-label dose titration resulted in an average dose of 500 mg.²⁹
In adults with ADHD, a study found that 40.2% of participants experienced a reduction in symptoms of more than 50% compared to their baseline AISRS score.³⁰

Viloxazine can be combined with

• Methylphenidate³¹⁶
• Lisdexamfetamine⁶.

3. Side Effects and Contraindications¶

3.1. Side Effects of Viloxazine¶

The most common side effects of Viloxazin ER include:²

• Drowsiness¹⁵
• loss of appetite¹⁵
  • The reduction in appetite caused by viloxazine appears to be significantly greater than that caused by atomoxetine (meta-analysis, n = 26)³²
• Headaches
• Fatigue¹⁵
• Upper abdominal pain
• Nausea
• Vomiting
• Irritability
• increased heart rate³³
  • by more than 20 beats per minute in 30% of the children, compared with 15% of those treated with a placebo
  • The increase was dose-dependent
• high blood pressure³³
  • At doses below 400 mg/day, 25% of adolescents experienced an increase in diastolic blood pressure of ≥ 15 mmHg at some point during the clinical trial, compared with 13% in the placebo group

A study of 646 children and 454 adolescents (66.5% male/33.5% female) found²⁸

• Side effects with an incidence of ≥ 5% were
  • Nasopharyngitis: 9.7%
  • Somnolence: 9.5%
  • Headaches: 8.9%
  • decreased appetite: 6.0%
  • Fatigue: 5.7%
• 3.9% reported severe side effects
• 8.2% discontinued their participation in the study due to side effects

A placebo-controlled study involving n = 384 adults with open-label dose titration resulted in an average dose of 500 mg. The most common treatment-related adverse effects were:²⁹

• Insomnia: 14.8%
• Fatigue: 11.6%
• Nausea: 10.1%
• Loss of appetite: 10.1%
• Dry mouth: 9.0%
• Headaches: 9.0%

The discontinuation rate due to side effects was 9.0%, compared with 4.9% in the placebo group.

An analysis of reports submitted to the WHO VigiAccess database revealed the following relative frequency of adverse event reports for viloxazine (the percentages do not indicate the frequency of occurrence during treatment):³⁴

Report Rate %	Side Effects
4.27%	Nausea
3.96%	Vomiting
3.64%	-induced headaches
2.91%	Drowsiness
2.46%	Fatigue
2.27%	Insomnia
2.00%	Suicidal Thoughts
1.86%	Migraine
1.68%	Confusion
1.55%	Seizures
1.46%	Hepatitis
1.27%	Anxiety
1.05%	Withdrawal Syndrome
1.05%	Elevated alanine aminotransferase
1.05%	Dizziness
1.05%	Skin rash
1.00%	Unruhe
1.00%	Irritability
0.95%	Loss of appetite

0.95% of the reports concerned the drug’s lack of efficacy.

3.2. Contraindications for Viloxazine¶

Viloxazine should not be taken if

• Predisposition to epilepsy
• severe liver failure
• during pregnancy or when planning to become pregnant. Viloxazine may harm the fetus.
• before fourteen days have elapsed since the last dose of a monoamine oxidase inhibitor (MAOI).

Elevated suicidal tendencies were reported in a small proportion of child participants.

4. Degradation of Viloxazine¶

Viloxazine is metabolized by CYP2D6, UGT1A9, and UGT2B15, and possibly also by CYP1A2.³⁵⁵

Viloxazine is a potent CYP1A2 inhibitor.¹³
If taken concurrently with medications metabolized by CYP1A2, a reduction in the dose of those medications may be necessary.

Viloxazine is a weak inhibitor of CYP2D6 and CYP3A4, which increases the risk of side effects and may require dose adjustments for medications metabolized by CYP2D6 and CYP3A4.¹³