Viloxazine (±)-2-[(2-ethoxyphenoxy)methyl]morpholine hydrochloride; C13H20NO3Cl) (SPN-812) has been approved in the USA since April 2021 for the treatment of ADHD in children aged 6 to 17 and depression. It was approved as an antidepressant in Europe from 1976 to 2006 and was used off-label for enuresis and narcolepsy.
Brand names: Viloxazin, Emovit, Viloxazina, Viloxazinum, Vivarint, Vicilan, Vivalan, Catatrol
Viloxazine modulates serotonin and noradrenaline activity. Viloxazine increases the serotonin level in the prefrontal cortex, but does not increase the release of noradrenaline. It has a weak effect on dopamine and shows a slight increase in drive compared to other ADHD medications.
Viloxazine is well tolerated and has side effects such as drowsiness, reduced appetite and headaches.
It should not be taken in the case of epilepsy, severe hepatic insufficiency or during pregnancy.
1. Mechanisms of action of viloxazine¶
Viloxazine acts as
- strong:
- selective serotonin 5-HT2B receptor antagonist
- Serotonin 5-HT2C receptor agonist
- moderate:
- selective noradrenaline reuptake inhibitor (Ki: 0.63 μM)
- thereby increasing dopamine and noradrenaline in the PFC
- no additional release of noradrenaline
- weak:
- Serotonin 5-HT7 receptor antagonist
- α1B-adrenoceptor antagonist
- β2-adrenoceptor antagonist
- very weak:
- competitive and reversible inhibitor of monoamine oxidase A and B.
Viloxazine has been shown to increase dopamine levels, noradrenaline levels and serotonin levels in the PFC. However, it does not appear to act as a serotonin reuptake inhibitor.
It does not increase the release of noradrenaline.
Viloxazine increases the dopamine level in the nucleus accumbens significantly less than stimulants. We consider the authors’ assertion that non-stimulants have fewer side effects to be misguided. Non-stimulants (atomoxetine, guanfacine) have significantly higher side effects with a significantly lower effect strength than stimulants.
Other in vitro studies found no dopamine release in the striatum and only a small 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 to be a consequence of NET reuptake inhibition. The minimal effect of viloxazine on dopamine in the nucleus accumbens could indicate a low susceptibility to abuse. We therefore suspect a lower increase in drive than stimulants.
Viloxazine significantly increases the plasma level of the adenosine A1 and A2 antagonist theophylline. It is conceivable that part of the effect of viloxazine in ADHD could be due to the dopamine-increasing effect of the adenosine antagonist theophylline.
Contrary to almost all widely used ADHD medications to date, viloxazine does not alter histamine levels. Viloxazine appears to exert a weak competitive inhibition at the histamine receptors H1 and H2 (< 25 %).
Pharmacological data
- Bioavailability approx. 88 %
- Tmax (time to maximum plasma concentration): approx. 5 hours at 200 mg
- Active ingredient is highly protein-bound (76-82 %)
- Average half-life of viloxazine ER is 7 hours (2.25 to 11.75 hours).
2. Viloxazine for ADHD¶
Viloxazine extended-release (viloxazine ER; SPN-812) has been shown to be an effective and well-tolerated alternative for some children with ADHD in several Phase 2 and Phase 3 studies at 200 to 400 mg/day. The mechanism of action of viloxazine is unique in that it modulates both serotonin and norepinephrine activity.
The effect size of viloxazine was determined to be between 0.46 and 0.63 in various studies and is therefore considerably weaker than the effect size of stimulants (1.1 to 1.5).
Various phase II and phase III studies found a good effect of viloxazine on ADHD in
- 100 and 200 mg / day
- 100, 200 and 400 mg / day
- 200 to 400 g / day
- 400 or 600 mg / day
The various publications on Phase III originate from an identical group of authors.
Symptom reduction after 2 weeks predicted treatment success after 6 weeks quite well.
A comparative study found clear advantages of viloxazine ER over atomoxetine.
Dosage
- Age from 6 to 11 years
- recommended starting dose 100 mg orally once daily
- Increased dosage in steps of 100 mg per week
- recommended maximum dose 400 mg once daily
- Age from 12 to 17 years
- recommended starting dose 200 mg orally once a day for the first week
- Dose up to the maximum daily dose of 400 mg.
In adults with ADHD, one study found a symptom reduction of more than 50% compared to the AISRS baseline in 40.2% of subjects.
A combination with methylphenidate is possible.
3. Side effects and contraindications¶
3.1. Side effects of viloxazine¶
The most common adverse effects of viloxazine ER include
- Drowsiness
- reduced appetite
- Headache
- Tiredness
- Upper abdominal pain
- Nausea
- Vomiting
- Irritability
3.2. Contraindications for viloxazine¶
Viloxazine should not be taken if
- Tendency to epilepsy
- severe hepatic insufficiency
- during or if pregnancy is intended. Viloxazine can damage the fetus.
- before the end 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. Degradation of viloxazine¶
Viloxazine is metabolized by CYP2D6, UGT1A9 and UGT2B15, possibly also by CYP1A2
Viloxazine is a potent CYP1A2 inhibitor.
If drugs metabolized by CYP1A2 are taken at the same time, it may be necessary to reduce the dose of these drugs.
