Viloxazine, sold under the brand name Qelbree among others, is a selective norepinephrine reuptake inhibitor medication that is indicated in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It was marketed for almost 30 years as an antidepressant for the treatment of depression before being discontinued and subsequently repurposed as a treatment for ADHD. Viloxazine is taken orally. It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form, although current evidence indicates that it is significantly less effective at reducing ADHD symptoms compared to stimulant medications like methylphenidate. Side effects of viloxazine include insomnia, headache, somnolence, fatigue, nausea, vomiting, decreased appetite, dry mouth, constipation, irritability, increased heart rate, and increased blood pressure. Rarely, the medication may cause suicidal thoughts and behaviors. It can also activate mania or hypomania in people with bipolar disorder. Viloxazine acts as a selective norepinephrine reuptake inhibitor (sNRI). The immediate-release form has an elimination half-life of 2.5 hours while the half-life of the extended-release form is 7 hours. Viloxazine was first described by 1972 and was marketed as an antidepressant in Europe in 1974. It was not marketed in the United States at this time. The medication was discontinued in 2002 for commercial reasons. However, it was repurposed for the treatment of ADHD and was reintroduced, in the United States, in April 2021. Viloxazine is a non-stimulant medication; it has no known misuse liability and is not a controlled substance.
Medical uses
Attention deficit hyperactivity disorder Viloxazine is indicated to treat attention deficit hyperactivity disorder (ADHD) in children age 6 to 12 years, adolescents age 13 to 17 years, and adults. Analyses of clinical trial data suggest that viloxazine produces moderate reductions in symptoms; it is about as effective as atomoxetine and methylphenidate but with fewer side effects.
Depression Viloxazine was previously marketed as an antidepressant for the treatment of major depressive disorder. It was considered to be effective in mild to moderate as well as severe depression with or without co-morbid symptoms. The typical dose range for depression was 100 to 400 mg per day in divided doses administered generally two to three times per day.
Available forms Viloxazine is available for ADHD in the form of 100, 150, and 200 mg extended-release capsules. These capsules can be opened and sprinkled into food for easier administration.
Side effects The most common side effects include drowsiness, headache, and loss of appetite. Psychiatric side effects occur in about 20% of cases; the most common of these is irritability (>5%). Other common side effects include nausea, vomiting, epigastric pain, insomnia, and increased libido. Incidence of some side effects, including headache and drowsiness, appear to be dose-dependent. In the treatment of depression, viloxazine is more tolerable than tricyclic antidepressants such as imipramine and amitriptyline. There were three cases of seizure worldwide, and most animal studies (and clinical trials that included epilepsy patients) indicated the presence of anticonvulsant properties, so viloxazine is not completely contraindicated in patients with epilepsy.
Interactions Viloxazine increased plasma levels of phenytoin by an average of 37%. It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body, sometimes resulting in accidental overdose of theophylline.
Pharmacology
Pharmacodynamics Viloxazine acts as a selective norepinephrine reuptake inhibitor (sNRI) and this is believed to be responsible for its therapeutic effectiveness in the treatment of conditions like ADHD and depression. The affinities (KD) of viloxazine at the human monoamine transporters are 155 to 630 nM for the norepinephrine transporter (NET), 17,300 nM for the serotonin transporter (SERT), and >100,000 nM for the dopamine transporter (DAT). Viloxazine has negligible affinity for a variety of assessed receptors, including the serotonin 5-HT1A and 5-HT2A receptors, the dopamine D2 receptor, the α1- and α2-adrenergic receptors, the histamine H1 receptor, and the muscarinic acetylcholine receptors (all >10,000 nM). More recent research has found that the pharmacodynamics of viloxazine may be more complex than previously assumed. In 2020, viloxazine was reported to have significant affinity for the serotonin 5-HT2B and 5-HT2C receptors (Ki = 3,900 nM and 6,400 nM) and to act as an antagonist and agonist of these receptors, respectively. It also showed weak antagonistic activity at the serotonin 5-HT7 receptor and the α1B- and β2-adrenergic receptors. These actions, although relatively weak, might be involved in its effects and possibly its therapeutic effectiveness in the treatment of ADHD.
Pharmacokinetics
Absorption The bioavailability of extended-release viloxazine relative to an instant-release formulation was about 88%. Peak and AUCTooltip area-under-the-curve (pharmacokinetics) levels of extended-release viloxazine are proportional over a dosage range of 100 to 400 mg once daily. The time to peak levels is 5 hours with a range of 3 to 9 hours after a single 200 mg dose. A high-fat meal modestly decreases levels of viloxazine and delays the time to peak by about 2 hours. Steady-state levels of viloxazine are reached after 2 days of once-daily administration and no accumulation occurs. Levels of viloxazine are approximately 40 to 50% higher in children age 6 to 11 years compared to children age 12 to 17 years.
Distribution The plasma protein binding of viloxazine is 76 to 82% over a concentration range of 0.5 to 10 μg/mL.
Metabolism The metabolism of viloxazine is primarily via the cytochrome P450 enzyme CYP2D6 and the UDP-glucuronosyltransferases UGT1A9 and UGT2B15. The major metabolite of viloxazine is 5-hydroxyviloxazine glucuronide. Viloxazine levels are slightly higher in CYP2D6 poor metabolizers relative to CYP2D6 extensive metabolizers.
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