Viloxazine
Viloxazine, sold under the brand name Qelbree and formerly as Vivalan among others, is a noradrenergic medication which is used 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 by mouth. It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form.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 (NRI). 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 due to 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.In a phase 3 regulatory randomized controlled trial of viloxazine for ADHD in adults, scores on the Attention-Deficit/Hyperactivity Disorder Investigator Symptom Rating Scale (AISRS) with viloxazine therapy decreased from 38.5 points at baseline to 23.0 points following treatment (–40%) and with placebo decreased from 37.6 points at baseline to 25.9 points (–31%). This gave a placebo-subtracted score difference (drug minus placebo), or improvement in scores attributable to the effects of viloxazine, of –3.7 points (–9%).

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
Side effects included nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, (there were three cases worldwide, and most animal studies [and clinical trials that included epilepsy patients] indicated the presence of anticonvulsant properties, so was not completely contraindicated in epilepsy) and increased libido.

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 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 AUC 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 released 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.

Elimination
The elimination of viloxazine is mainly renal. Approximately 90% of the dose is excreted in urine within 24 hours and less than 1% of the dose is recovered in feces.The elimination half-life of instant-release viloxazine is 2 to 5 hours (2–3 hours in the most reliable studies) and the half-life of extended-release viloxazine is 7.02 ± 4.74 hours.

Chemistry
Viloxazine is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.

History
Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamine side chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine.: 610 : 9  It was first described in the scientific literature as early as 1972.The medication was first marketed in 1974. Viloxazine was not approved for medical use by the FDA. In 1984, the FDA granted the medication an orphan designation for treatment of cataplexy and narcolepsy with the tentative brand name Catatrol. For unknown reasons however, it was never approved or introduced for these uses in the United States. Viloxazine was withdrawn from markets worldwide in 2002 for commercial reasons unrelated to efficacy or safety.As of 2015, Supernus Pharmaceuticals was developing extended release formulations of viloxazine as a treatment for ADHD and major depressive disorder under the names SPN-809 and SPN-812. Viloxazine was approved for the treatment of ADHD in the United States in April 2021.

Research
Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine. By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM without really improving daytime somnolence. In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.Viloxazine has also been studied for the treatment of alcoholism, with some success.While viloxazine may have been effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.

References
External links
"Viloxazine". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03247530 for "Evaluation of SPN-812 ER Low Dose in Children With ADHD" at ClinicalTrials.gov
Clinical trial number NCT03247543 for "Evaluation of SPN-812 ER High Dose in Children With ADHD" at ClinicalTrials.gov