Viloxazine was first described by 1972[9] and was marketed as an antidepressant in Europe in 1974.[6][10] It was not marketed in the United States at this time.[11] The medication was discontinued in 2002 for commercial reasons.[6][12][13] However, it was repurposed for the treatment of ADHD and was reintroduced, in the United States, in April 2021.[6][14][15] Viloxazine is anon-stimulant medication; it has no knownmisuse liability and is not acontrolled substance.[1]
Analyses of clinical trial data suggest that viloxazine produces moderate reductions in symptoms; it is about as effective asatomoxetine andmethylphenidate but with fewer side effects.[7][8][16]
Viloxazine was previously marketed as anantidepressant for the treatment ofmajor depressive disorder.[6][5] It was considered to be effective in mild to moderate as well as severe depression with or without co-morbid symptoms.[6] The typical dose range for depression was 100 to 400mg per day in divided doses administered generally two to three times per day.[6]
Viloxazine is available for ADHD in the form of 100, 150, and 200 mgextended-releasecapsules.[1] These capsules can be opened and sprinkled into food for easier administration.[1]
There were three cases ofseizure worldwide, and most animal studies (and clinical trials that includedepilepsy patients) indicated the presence ofanticonvulsant properties, so viloxazine is not completely contraindicated in patients with epilepsy.[20]
Viloxazine increasedplasma levels ofphenytoin by an average of 37%.[21] It also was known to significantly increase plasma levels oftheophylline and decrease its clearance from the body,[22] sometimes resulting in accidentaloverdose oftheophylline.[23]
More recent research has found that thepharmacodynamics of viloxazine may be more complex than previously assumed.[6][25] In 2020, viloxazine was reported to have significant affinity for the serotonin5-HT2B and5-HT2C receptors (Ki = 3,900 nM and 6,400 nM) and to act as anantagonist andagonist of these receptors, respectively.[25][5][28] It also showed weak antagonistic activity at the serotonin5-HT7 receptor and theα1B- andβ2-adrenergic receptors.[25][5][28] These actions, although relatively weak, might be involved in its effects and possibly its therapeutic effectiveness in the treatment of ADHD.[6][25][28]
Thebioavailability of extended-release viloxazine relative to an instant-release formulation was about 88%.[1]Peak andAUCTooltip area-under-the-curve (pharmacokinetics) levels of extended-release viloxazine are proportional over a dosage range of 100 to 400 mg once daily.[1] Thetime to peak levels is 5 hours with a range of 3 to 9 hours after a single 200 mg dose.[1] A high-fat meal modestly decreases levels of viloxazine and delays the time to peak by about 2 hours.[1]Steady-state levels of viloxazine are reached after 2 days of once-daily administration and no accumulation occurs.[1] Levels of viloxazine are approximately 40 to 50% higher in children age 6 to 11 years compared to children age 12 to 17 years.[1]
Theelimination of viloxazine is mainlyrenal.[1] Approximately 90% of the dose isexcreted inurine within 24 hours and less than 1% of the dose is recovered infeces.[1]
Theelimination half-life of instant-release viloxazine is 2 to 5 hours (2–3 hours in the most reliable studies)[2] and the half-life of extended-release viloxazine is 7.02 ± 4.74 hours.[1]
The medication was first marketed in 1974.[6][10] Viloxazine was not approved for medical use by the FDA.[11] In 1984, the FDA granted the medication an orphan designation for treatment ofcataplexy andnarcolepsy with the tentative brand name Catatrol.[31] For unknown reasons however, it was never approved or introduced for these uses in the United States.[6] Viloxazine was withdrawn from markets worldwide in 2002 for commercial reasons unrelated to efficacy or safety.[6][12][13]
As of 2015, Supernus Pharmaceuticals was developing extended release formulations of viloxazine as a treatment forADHD andmajor depressive disorder under the names SPN-809 and SPN-812.[32][33] Viloxazine was approved for the treatment of ADHD in the United States in April 2021.[14][15]
The benefit of viloxazine was evaluated in three clinical studies, including two in children (ages 6 to 11 years) and one in adolescents (ages 12 to 17 years) with ADHD.[34] In each study, pediatric participants were randomly assigned to receive one of two doses of viloxazine or placebo once daily for 6 to 8 weeks.[34] None of the participants, their parent(s)/caregiver(s), the study sponsor, or the study doctors knew which treatment the participant received during the study.[34] The severity of ADHD symptoms observed at the last week of treatment was significantly greater in participants who received placebo compared with participants who received viloxazine.[34] The severity of ADHD symptoms was assessed using the Attention-Deficit Hyperactivity Disorder Rating Scale 5th Edition (ADHD-RS-5).[34] A fourth study provided information about the safety of viloxazine in adolescents 12 to 17 years of age with ADHD.[34] The FDA approved viloxazine based on evidence from several clinical trial(s) of 1289 participants with attention deficit hyperactivity disorder (ADHD).[34] The trials were conducted at 59 sites in the United States.[34]
Viloxazine has undergone two randomized controlled trials fornocturnal enuresis (bedwetting) in children, both of those times versus imipramine.[36][37] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.[38]
Innarcolepsy, viloxazine has been shown to suppress auxiliary symptoms such ascataplexy and also abnormal sleep-onsetREM[39] without significantly improving daytimesomnolence.[40] In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.[13]
Viloxazine has also been studied for the treatment ofalcoholism, with some success.[41]
Viloxazine did not demonstrate efficacy in a double-blind randomized controlled trial versusamisulpride in the treatment ofdysthymia.[42]
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^Case DE, Reeves PR (February 1975). "The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans".Xenobiotica; the Fate of Foreign Compounds in Biological Systems.5 (2):113–129.doi:10.3109/00498257509056097.PMID1154799.
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^abDahmen MM, Lincoln J, Preskorn S (2010). "NARI Antidepressants". In Stolerman IP (ed.).Encyclopedia of Psychopharmacology. Berlin Heidelberg: Springer-Verlag. pp. 816–822.ISBN978-3-540-68706-1.
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^Bushe C, Day K, Reed V, Karlsdotter K, Berggren L, Pitcher A, et al. (May 2016). "A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients".Journal of Psychopharmacology.30 (5):444–458.doi:10.1177/0269881116636105.PMID27005307.S2CID104938.{{cite journal}}: CS1 maint: overridden setting (link)
^Chebili S, Abaoub A, Mezouane B, Le Goff JF (1998). "[Antidepressants and sexual stimulation: the correlation]" [Antidepressants and sexual stimulation: the correlation].L'Encephale (in French).24 (3):180–184.PMID9696909.
^Poznanski AJ, Akinyemi E (September 2022). "Recent Advances in Psychopharmacology".Advances in Psychiatry and Behavioral Health.2 (1):253–266.doi:10.1016/j.ypsc.2022.03.009.S2CID252258910.
^Perault MC, Griesemann E, Bouquet S, Lavoisy J, Vandel B (September 1989). "A study of the interaction of viloxazine with theophylline".Therapeutic Drug Monitoring.11 (5):520–522.doi:10.1097/00007691-198909000-00005.PMID2815226.
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