Viloxazine for ADHD

Viloxazine ¹
Brand names: Viloxazine, Emovit, Viloxazina, Viloxazinum, Vivarint, Vicilan, Vivalan, Catatrol

• 1. Mechanisms of action of viloxazine
• 2. Viloxazine for ADHD
• 3. Side effects and contraindications
  • 3.1. Viloxazine side effects
  • 3.2. Contraindications for viloxazine
• 4. Viloxazine degradation

1. Mechanisms of action of viloxazine¶

Viloxazine acts as a²³⁴

• strong:
  • selective serotonin 5-HT2B receptor antagonist
  • Serotonin 5-HT2C receptor agonist
• moderate:
  • selective norepinephrine reuptake inhibitor (Ki: 0.63 μM)
    • thereby increasing dopamine and norepinephrine in the PFC
    • no additional release of norepinephrine⁵
• weak:
  • Serotonin 5-HT7 receptor antagonist
  • α1B-adrenoceptor antagonist
  • β2-adrenoceptor antagonist

Viloxazine has been shown to increase serotonin levels in the PFC.⁶ However, it does not appear to act as a serotonin reuptake inhibitor.
It does not increase the release of norepinephrine.

Viloxazine increases dopamine levels in the nucleus accumbens significantly less than stimulants.⁷ We consider the authors’ claim that non-stimulants would show lower side effects to be erroneous.

Other in vitro studies found no dopamine release in the striatum and little effect on dopamine receptors or DAT. In rodents, viloxazine significantly increased dopamine in vivo in the PFC, moderately in the amygdala, and minimally in the nucleus accumbens. The dopamine increase in the PFC is likely a consequence of NET reuptake inhibition. The minimal effect of viloxazine on dopamine in the nucleus accumbens may indicate a low susceptibility to abuse.⁵ We therefore hypothesize a lower drive enhancement than stimulants.
Viloxazine markedly increases plasma levels of the adenosine A1 and A2 antagonist theophylline.⁸⁹

It is conceivable that part of the effect of viloxazine in ADHD may be due to the dopamine-enhancing effect of the adenosine antagonist theophylline.

Viloxazine is a very weak, competitive, and reversible inhibitor of monoamine oxidase A and B.⁵

Contrary to almost all previously heavily used ADHD medications, viloxazine does not alter histamine levels. Viloxazine appears to exert weak competitive inhibition at histamine receptors H1 and H2 (< 25%).⁵

Pharmacological data⁴

• Bioavailability approx. 88
• Tmax (time to maximum plasma concentration): about 5 hours at 200 mg
• Active substance is strongly protein-bound (76-82 %)
• Mean half-life of viloxazine ER is 7 hours (2.25 to 11.75 hours).

2. Viloxazine for ADHD¶

Extended-release viloxazine (viloxazine ER; SPN-812) was shown to be an effective and well-tolerated alternative for some children with ADHD in multiple Phase 2 and Phase 3 studies at 200 to 400 mg/day. The mechanism of action of viloxazine is unique in that it modulates the activity of both serotonin and norepinephrine.¹⁰⁴
The effect size of viloxazine was found to range from 0.46 to 0.63 in different studies.¹¹
Several phase II and phase III studies found good effect of volixazine in ADHD at 200 to 400 g/day^{1213 14} , 400 or 600 mg/day¹⁵ and at 100 and 200 mg/day.¹⁶
The different publications on phase III are from an identical group of authors.

Symptom reduction at 2 weeks predicts treatment success at 6 weeks quite well.⁴

Dosage:⁴

• Age from 6 to 11 years
  • recommended starting dose 100 mg orally once daily
  • Up-dosing in increments of 100 mg weekly
  • maximum recommended dose 400 mg once daily
• Age from 12 to 17
  • recommended starting dose 200 mg orally once daily for the first week
  • Up-dose to the maximum daily dose of 400 mg.

In adults with ADHD, one study found symptom reduction of greater than 50% from baseline AISRS in 40.2% of subjects.¹⁷

Combination with methylphenidate is possible.¹⁸

3. Side effects and contraindications¶

3.1. Viloxazine side effects¶

• Drowsiness
• reduced appetite
• Headache
• Fatigue
• Upper abdominal pain
• Nausea
• Vomiting
• Irritability

3.2. Contraindications for viloxazine¶

Viloxazine should not be taken in case of

• Epilepsy predisposition
• severe liver failure
• during or if pregnancy is intended. Viloxazine may cause harm to the fetus.
• before the expiry of fourteen days after the last intake of a monoamine oxidase inhibitor (MAOI).

Increased suicidal tendencies were reported in a small proportion of child subjects.

4. Viloxazine degradation¶

Viloxazine is metabolized by CYP2D6, UGT1A9, and UGT2B15, and possibly by CYP1A2 ¹⁹⁴

Viloxazine is a potent CYP1A2 inhibitor.
Dose reduction may be required with concomitant use of drugs metabolized by CYP1A2.