Viloxazine

{{Short description|Medication used to treat ADHD and depression}} {{Distinguish|Vilazodone|Venlafaxine}} {{Use dmy dates|date=June 2024}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 470630208 | image = Viloxazine structure.svg | image_class = skin-invert-image | width = 175 | alt = | image2 = Viloxazine molecule spacefill.png | image_class2 = bg-transparent | width2 = 175 | alt2 = | chirality = Racemic mixture

| bioavailability = | protein_bound = 76–82%<ref name="Qelbree FDA label" /> | metabolism = Hydroxylation (CYP2D6), glucuronidation (UGT1A9, UGT2B15)<ref name="Qelbree FDA label" /> | metabolites = 5-Hydroxyviloxazine glucuronide<ref name="Qelbree FDA label" /> | elimination_half-life = {{Abbr|IR|Instant-release}}: 2–5 hours<ref name="pmid324751">{{cite journal | vauthors = Pinder RM, Brogden RN, Speight TM, Avery GS | title = Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness | journal = Drugs | volume = 13 | issue = 6 | pages = 401–421 | date = June 1977 | pmid = 324751 | doi = 10.2165/00003495-197713060-00001 | s2cid = 44804763 }}</ref> {{Abbr|ER|Extended-release}}: 7.02 ± 4.74 hours<ref name="Qelbree FDA label" /> | excretion = Urine (~90%), feces (<1%)<ref name="Qelbree FDA label" /><ref name=renal>{{cite journal | vauthors = Case DE, Reeves PR | title = The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 5 | issue = 2 | pages = 113–129 | date = February 1975 | pmid = 1154799 | doi = 10.3109/00498257509056097 }}</ref>

| index2_label = HCl | CAS_number_Ref = {{cascite|changed|??}} | CAS_number = 46817-91-8 | CAS_number2_Ref = {{cascite|correct|CAS}} | CAS_number2 = 35604-67-2 | PubChem = 5666 | IUPHAR_ligand = | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB09185 | DrugBank2 = DBSALT001262 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 5464 | ChemSpiderID2 = 64514 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 5I5Y2789ZF | UNII2_Ref = {{fdacite|correct|FDA}} | UNII2 = OQW30I1332 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08673 | KEGG2_Ref = | KEGG2 = D02572 | ChEBI_Ref = | ChEBI = 94405 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 306700 | ChEMBL2 = 2106483 | NIAID_ChemDB = | PDB_ligand = | synonyms = ICI-58834; SPN-812; SPN-809

| IUPAC_name = (''RS'')-2-[(2-ethoxyphenoxy)methyl]morpholine<ref name=iupacformula>{{cite web | url=https://pubchem.ncbi.nlm.nih.gov/substance/180462 | title=SID 180462 | work = PubChem Substance Summary | publisher = U.S. National Library of Medicine | access-date=5 November 2005 | archive-date=14 June 2013 | archive-url=https://web.archive.org/web/20130614150110/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=180462 | url-status=live }}</ref> | C = 13 | H = 19 | N = 1 | O = 3 | SMILES = CCOC1=CC=CC=C1OCC1CNCCO1 | SMILES2 = Cl.CCOC1=CC=CC=C1OCC1CNCCO1 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C13H19NO3/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11/h3-6,11,14H,2,7-10H2,1H3 | StdInChI2 = 1S/C13H19NO3.ClH/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11;/h3-6,11,14H,2,7-10H2,1H3;1H | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = YWPHCCPCQOJSGZ-UHFFFAOYSA-N | StdInChIKey2 = HJOCKFVCMLCPTP-UHFFFAOYSA-N }}

'''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.<ref name="Qelbree FDA label">{{cite web | title=Qelbree- viloxazine hydrochloride capsule, extended release | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aedf408d-0f84-418d-9416-7c39ddb0d29a | access-date=3 May 2022 | archive-date=28 October 2022 | archive-url=https://web.archive.org/web/20221028144257/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aedf408d-0f84-418d-9416-7c39ddb0d29a | url-status=live }}</ref><ref name="pmid33121553">{{cite journal | vauthors = Cutler AJ, Mattingly GW, Jain R, O'Neal W | title = Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents | journal = CNS Spectrums | volume = 27 | issue = 2 | pages = 199–207 | date = April 2022 | pmid = 33121553 | doi = 10.1017/S1092852920001984 | doi-access = free }}</ref> It was marketed for almost 30{{nbsp}}years as an antidepressant for the treatment of depression before being discontinued and subsequently repurposed as a treatment for ADHD.<ref name="Findling_2021">{{cite journal | vauthors = Findling RL, Candler SA, Nasser AF, Schwabe S, Yu C, Garcia-Olivares J, O'Neal W, Newcorn JH | display-authors = 6 | title = Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status | journal = CNS Drugs | volume = 35 | issue = 6 | pages = 643–653 | date = June 2021 | pmid = 34003459 | pmc = 8219567 | doi = 10.1007/s40263-021-00825-w }}</ref><ref name="pmid33121553" /><ref name="Qelbree FDA label" /> Viloxazine is taken orally.<ref name="Qelbree FDA label" /> It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form,<ref name="Findling_2021" /><ref name="Qelbree FDA label" /> although current evidence indicates that it is significantly less effective at reducing ADHD symptoms compared to stimulant medications like methylphenidate.<ref name="Schein_2024">{{cite journal | vauthors = Schein J, Cloutier M, Gauthier-Loiselle M, Catillon M, Xu C, Chan D, Childress A | title = Assessment of centanafadine in adults with attention-deficit/hyperactivity disorder: A matching-adjusted indirect comparison vs lisdexamfetamine dimesylate, atomoxetine hydrochloride, and viloxazine extended-release | journal = Journal of Managed Care & Specialty Pharmacy | volume = 30 | issue = 6 | pages = 528–540 | date = June 2024 | pmid = 38824626 | doi = 10.18553/jmcp.2024.30.6.528 | pmc = 11145007 }}</ref><ref name="Faraone_2021" />

Side effects of viloxazine include insomnia, headache, somnolence, fatigue, nausea, vomiting, decreased appetite, dry mouth, constipation, irritability, increased heart rate, and increased blood pressure.<ref name="Qelbree FDA label" /> Rarely, the medication may cause suicidal thoughts and behaviors.<ref name="Qelbree FDA label" /> It can also activate mania or hypomania in people with bipolar disorder.<ref name="Qelbree FDA label" /> Viloxazine acts as a selective norepinephrine reuptake inhibitor (sNRI).<ref name="Findling_2021" /><ref name="Qelbree FDA label" /><ref name="pmid33121553" /> The immediate-release form has an elimination half-life of 2.5{{nbsp}}hours<ref name="Findling_2021" /><ref name="pmid324751" /> while the half-life of the extended-release form is 7{{nbsp}}hours.<ref name="Qelbree FDA label" />

Viloxazine was first described by 1972<ref name="pmid4558457" /> and was marketed as an antidepressant in Europe in 1974.<ref name="Findling_2021" /><ref name="OlivierSoudijn2000" /> It was not marketed in the United States at this time.<ref name=Dahmen /> The medication was discontinued in 2002 for commercial reasons.<ref name="Findling_2021" /><ref name=Williams/><ref name=Cochrane2008/> However, it was repurposed for the treatment of ADHD and was reintroduced, in the United States, in April 2021.<ref name="Findling_2021" /><ref name="FDA2021">{{cite web | title=Qelbree: FDA-Approved Drugs | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=211964 | access-date=2 April 2021 | archive-date=2 April 2021 | archive-url=https://web.archive.org/web/20210402190140/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=211964 }}</ref><ref name="Supernus2021">{{cite press release | title=Supernus Announces FDA Approval of Qelbree (SPN-812) for the Treatment of ADHD | website=Supernus Pharmaceuticals | date=2 April 2021 | url=https://ir.supernus.com/news-releases/news-release-details/supernus-announces-fda-approval-qelbreetm-spn-812-treatment-adhd | access-date=3 April 2021 | archive-date=6 April 2021 | archive-url=https://web.archive.org/web/20210406133754/https://ir.supernus.com/news-releases/news-release-details/supernus-announces-fda-approval-qelbreetm-spn-812-treatment-adhd | url-status=live }}</ref> Viloxazine is a non-stimulant medication; it has no known misuse liability and is not a controlled substance.<ref name="Qelbree FDA label" />

==Medical uses==

===Attention deficit hyperactivity disorder=== Viloxazine is indicated to treat attention deficit hyperactivity disorder (ADHD) in children age 6 to 12{{nbsp}}years, adolescents age 13 to 17{{nbsp}}years, and adults.<ref name="Qelbree FDA label" />

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.<ref name="Schein_2024" /><ref name="Faraone_2021">{{cite journal | vauthors = Faraone SV, Gomeni R, Hull JT, Busse GD, Melyan Z, O'Neal W, Rubin J, Nasser A | display-authors = 6 | title = Early response to SPN-812 (viloxazine extended-release) can predict efficacy outcome in pediatric subjects with ADHD: a machine learning post-hoc analysis of four randomized clinical trials | journal = Psychiatry Research | volume = 296 | article-number = 113664 | date = February 2021 | pmid = 33418457 | doi = 10.1016/j.psychres.2020.113664 | s2cid = 230716405 | doi-access = free }}</ref><ref name="Bushe_2016">{{cite journal | vauthors = Bushe C, Day K, Reed V, Karlsdotter K, Berggren L, Pitcher A, Televantou F, Haynes V | display-authors = 6 | title = A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients | journal = Journal of Psychopharmacology | volume = 30 | issue = 5 | pages = 444–458 | date = May 2016 | pmid = 27005307 | doi = 10.1177/0269881116636105 | s2cid = 104938 }}</ref>

===Depression=== Viloxazine was previously marketed as an antidepressant for the treatment of major depressive disorder.<ref name="Findling_2021" /><ref name="pmid33121553" /> It was considered to be effective in mild to moderate as well as severe depression with or without co-morbid symptoms.<ref name="Findling_2021" /> The typical dose range for depression was 100 to 400{{nbsp}}mg per day in divided doses administered generally two to three times per day.<ref name="Findling_2021" />

===Available forms=== Viloxazine is available for ADHD in the form of 100, 150, and 200 mg extended-release capsules.<ref name="Qelbree FDA label" /> These capsules can be opened and sprinkled into food for easier administration.<ref name="Qelbree FDA label" />

==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%).<ref name="Pozzi2020">{{cite journal | vauthors = Pozzi M, Bertella S, Gatti E, Peeters GG, Carnovale C, Zambrano S, Nobile M | title = Emerging drugs for the treatment of attention-deficit hyperactivity disorder (ADHD) | journal = Expert Opinion on Emerging Drugs | volume = 25 | issue = 4 | pages = 395–407 | date = December 2020 | pmid = 32938246 | doi = 10.1080/14728214.2020.1820481 | s2cid = 221768208 | doi-access = free | hdl = 2434/851076 | hdl-access = free }}</ref> Other common side effects include nausea, vomiting, epigastric pain, insomnia,<ref name=Findling_2021/> and increased libido.<ref name=Chebili_et_al_1998>{{cite journal | vauthors = Chebili S, Abaoub A, Mezouane B, Le Goff JF | title = [Antidepressants and sexual stimulation: the correlation] | language = fr | journal = L'Encephale | volume = 24 | issue = 3 | pages = 180–184 | year = 1998 | pmid = 9696909 | trans-title = Antidepressants and sexual stimulation: the correlation }}</ref> Incidence of some side effects, including headache and drowsiness, appear to be dose-dependent.<ref name="Poznanski2022">{{cite journal | vauthors = Poznanski AJ, Akinyemi E |title=Recent Advances in Psychopharmacology |journal=Advances in Psychiatry and Behavioral Health |date=September 2022 |volume=2 |issue=1 |pages=253–266 |doi=10.1016/j.ypsc.2022.03.009|s2cid=252258910 }}</ref> In the treatment of depression, viloxazine is more tolerable than tricyclic antidepressants such as imipramine and amitriptyline.<ref name=Findling_2021/>

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.<ref name=seizure_risk>{{cite journal | vauthors = Edwards JG, Glen-Bott M | title = Does viloxazine have epileptogenic properties? | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 47 | issue = 9 | pages = 960–964 | date = September 1984 | pmid = 6434699 | pmc = 1027998 | doi = 10.1136/jnnp.47.9.960 }}</ref>

== Interactions ==

Viloxazine increased plasma levels of phenytoin by an average of 37%.<ref name=phenytoin>{{cite journal | vauthors = Pisani F, Fazio A, Artesi C, Russo M, Trio R, Oteri G, Perucca E, Di Perri R | display-authors = 6 | title = Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 55 | issue = 2 | pages = 126–127 | date = February 1992 | pmid = 1538217 | pmc = 488975 | doi = 10.1136/jnnp.55.2.126 }}</ref> It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body,<ref name=theophylline_1>{{cite journal | vauthors = Perault MC, Griesemann E, Bouquet S, Lavoisy J, Vandel B | title = A study of the interaction of viloxazine with theophylline | journal = Therapeutic Drug Monitoring | volume = 11 | issue = 5 | pages = 520–522 | date = September 1989 | pmid = 2815226 | doi = 10.1097/00007691-198909000-00005 }}</ref> sometimes resulting in accidental overdose of theophylline.<ref name=theophylline_2>{{cite journal | vauthors = Laaban JP, Dupeyron JP, Lafay M, Sofeir M, Rochemaure J, Fabiani P | title = Theophylline intoxication following viloxazine induced decrease in clearance | journal = European Journal of Clinical Pharmacology | volume = 30 | issue = 3 | pages = 351–353 | year = 1986 | pmid = 3732375 | doi = 10.1007/BF00541543 | s2cid = 10114046 | doi-access = free }}</ref>

==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.<ref name="Findling_2021" /><ref name="Qelbree FDA label" /><ref name="pmid9537821" /><ref name="YuGarcia-Olivares2020" /> 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).<ref name="pmid9537821">{{cite journal | vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = European Journal of Pharmacology | volume = 340 | issue = 2–3 | pages = 249–258 | date = December 1997 | pmid = 9537821 | doi = 10.1016/s0014-2999(97)01393-9 }}</ref><ref name="YuGarcia-Olivares2020" /> 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).<ref name="pmid6086881">{{cite journal | vauthors = Richelson E, Nelson A | title = Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 230 | issue = 1 | pages = 94–102 | date = July 1984 | pmid = 6086881 | doi = 10.1016/S0022-3565(25)21446-X}}</ref><ref name="pmid3816971">{{cite journal | vauthors = Wander TJ, Nelson A, Okazaki H, Richelson E | title = Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro | journal = European Journal of Pharmacology | volume = 132 | issue = 2–3 | pages = 115–121 | date = December 1986 | pmid = 3816971 | doi = 10.1016/0014-2999(86)90596-0 }}</ref>

More recent research has found that the pharmacodynamics of viloxazine may be more complex than previously assumed.<ref name="Findling_2021" /><ref name="YuGarcia-Olivares2020">{{cite journal | vauthors = Yu C, Garcia-Olivares J, Candler S, Schwabe S, Maletic V | title = New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties | journal = Journal of Experimental Pharmacology | volume = 12 | pages = 285–300 | year = 2020 | pmid = 32943948 | pmc = 7473988 | doi = 10.2147/JEP.S256586 | doi-access = free }}</ref> 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.<ref name="YuGarcia-Olivares2020" /><ref name="pmid33121553" /><ref name="Garcia-OlivaresYeglaEarnest2023">{{cite journal | vauthors = Garcia-Olivares J, Yegla B, Earnest J, Maletic V, Yu C | title=Characterization of Viloxazine Effects on Cortical Serotonin Neurotransmission at Doses Relevant for ADHD Treatment | journal=CNS Spectrums | volume=28 | issue=2 | date=2023 | issn=1092-8529 | doi=10.1017/S1092852923001633 | doi-access=free | page=235}}</ref> It also showed weak antagonistic activity at the serotonin 5-HT7 receptor and the α1B- and β2-adrenergic receptors.<ref name="YuGarcia-Olivares2020" /><ref name="pmid33121553" /><ref name="Garcia-OlivaresYeglaEarnest2023" /> These actions, although relatively weak, might be involved in its effects and possibly its therapeutic effectiveness in the treatment of ADHD.<ref name="Findling_2021" /><ref name="YuGarcia-Olivares2020" /><ref name="Garcia-OlivaresYeglaEarnest2023" />

===Pharmacokinetics===

====Absorption==== The bioavailability of extended-release viloxazine relative to an instant-release formulation was about 88%.<ref name="Qelbree FDA label" /> Peak and {{Abbrlink|AUC|area-under-the-curve (pharmacokinetics)}} levels of extended-release viloxazine are proportional over a dosage range of 100 to 400 mg once daily.<ref name="Qelbree FDA label" /> The time to peak levels is 5 hours with a range of 3 to 9 hours after a single 200 mg dose.<ref name="Qelbree FDA label" /> A high-fat meal modestly decreases levels of viloxazine and delays the time to peak by about 2 hours.<ref name="Qelbree FDA label" /> Steady-state levels of viloxazine are reached after 2 days of once-daily administration and no accumulation occurs.<ref name="Qelbree FDA label" /> Levels of viloxazine are approximately 40 to 50% higher in children age 6 to 11 years compared to children age 12 to 17 years.<ref name="Qelbree FDA label" />

====Distribution==== The plasma protein binding of viloxazine is 76 to 82% over a concentration range of 0.5 to 10 μg/mL.<ref name="Qelbree FDA label" />

====Metabolism==== The metabolism of viloxazine is primarily via the cytochrome P450 enzyme CYP2D6 and the UDP-glucuronosyltransferases UGT1A9 and UGT2B15.<ref name="Qelbree FDA label" /> The major metabolite of viloxazine is 5-hydroxyviloxazine glucuronide.<ref name="Qelbree FDA label" /> Viloxazine levels are slightly higher in CYP2D6 poor metabolizers relative to CYP2D6 extensive metabolizers.<ref name="Qelbree FDA label" />

====Elimination==== The elimination of viloxazine is mainly renal.<ref name="Qelbree FDA label" /> Approximately 90% of the dose is excreted in urine within 24 hours and less than 1% of the dose is recovered in feces.<ref name="Qelbree FDA label" />

The elimination half-life of instant-release viloxazine is 2 to 5 hours (2–3 hours in the most reliable studies)<ref name="pmid324751" /> and the half-life of extended-release viloxazine is 7.02 ± 4.74 hours.<ref name="Qelbree FDA label" />

==Chemistry== Viloxazine is a racemic compound with two stereoisomers, the (''S'')-(–)-isomer being five times as pharmacologically active as the (''R'')-(+)-isomer.<ref name=isomer>{{cite journal | vauthors = Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagorevskiĭ VA | title = [Behavioral and radioreceptor analysis of viloxazine stereoisomers] | language = ru | journal = Biulleten' Eksperimental'noi Biologii I Meditsiny | volume = 97 | issue = 5 | pages = 576–578 | date = May 1984 | pmid = 6326891 | trans-title = Behavioral and radioreceptor analysis of viloxazine stereoisomers }}</ref>

===Analogues=== Analogues of viloxazine include indeloxazine, reboxetine, and teniloxazine, among others.<ref name="DostertBenedettiPoggesi1997">{{cite journal | vauthors = Dostert P, Benedetti MS, Poggesi I | title = Review of the pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor | journal = Eur Neuropsychopharmacol | volume = 7 Suppl 1 | issue = | pages = S23–S35; discussion S71–S73 | date = April 1997 | pmid = 9169308 | doi = 10.1016/s0924-977x(97)00417-3 | url = }}</ref>

==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.<ref name=Williams>{{cite book | vauthors = Williams DA | chapter = Chapter 18: Antidepressants. | title = Foye's Principles of Medicinal Chemistry | veditors = Lemke TL, Williams DA | publisher = Lippincott Williams & Wilkins | date = 2012 | isbn = 978-1-60913-345-0}}</ref>{{rp|610}}<ref>{{cite book | vauthors = Wermuth CG | chapter = Chapter 1: Analogs as a Means of Discovering New Drugs. | title = Analogue-based Drug Discovery. | veditors = Fischer J, Ganellin CR | publisher = John Wiley & Sons | date = 2006 | isbn = 978-3-527-60749-5}}</ref>{{rp|9}} It was first described in the scientific literature as early as 1972.<ref name="pmid4558457">{{cite journal | vauthors = Mallion KB, Todd AH, Turner RW, Bainbridge JG, Greenwood DT, Madinaveitia J, Somerville AR, Whittle BA | display-authors = 6 | title = 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine hydrochloride, a potential psychotropic agent | journal = Nature | volume = 238 | issue = 5360 | pages = 157–158 | date = July 1972 | pmid = 4558457 | doi = 10.1038/238157a0 | s2cid = 4268001 | bibcode = 1972Natur.238..157M }}</ref>

The medication was first marketed in 1974.<ref name="Findling_2021" /><ref name="OlivierSoudijn2000">{{cite book | vauthors = Olivier B, Soudijn W, van Wijngaarden I | chapter = Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors | title = Progress in Drug Research. Fortschritte der Arzneimittelforschung. Progres des Recherches Pharmaceutiques | volume = 54 | pages = 59–119 | year = 2000 | pmid = 10857386 | doi = 10.1007/978-3-0348-8391-7_3 | isbn = 978-3-0348-9546-0 }}</ref> Viloxazine was not approved for medical use by the FDA.<ref name=Dahmen>{{cite book | vauthors = Dahmen MM, Lincoln J, Preskorn S | chapter = NARI Antidepressants | pages = 816–822 | title = Encyclopedia of Psychopharmacology | veditors = Stolerman IP | publisher = Springer-Verlag | location = Berlin Heidelberg | date = 2010 | isbn = 978-3-540-68706-1}}</ref> In 1984, the FDA granted the medication an orphan designation for treatment of cataplexy and narcolepsy with the tentative brand name Catatrol.<ref name="FDA-Orphan">{{cite web | work = U.S. Food and Drug Administration | url = https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=2384 | title = Orphan Drug Designations and Approvals: Viloxazine | archive-url = https://web.archive.org/web/20220625004326/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=2384 | archive-date=2022-06-25 | access-date = 1 August 2015 }}</ref> For unknown reasons however, it was never approved or introduced for these uses in the United States.<ref name="Findling_2021" /> Viloxazine was withdrawn from markets worldwide in 2002 for commercial reasons unrelated to efficacy or safety.<ref name="Findling_2021" /><ref name=Williams/><ref name=Cochrane2008/>

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.<ref>{{cite web | work = Bloomberg | url = https://www.bloomberg.com/research/stocks/private/snapshot.asp?privcapId=422832 | title = Supernus profile | archive-url = https://web.archive.org/web/20180311202516/https://www.bloomberg.com/research/stocks/private/snapshot.asp?privcapId=422832 | archive-date=2018-03-11 | access-date = 1 August 2015 }}</ref><ref>{{cite web | work = Supernus | url = http://www.supernus.com/psychiatry-portfolio | title = Psychiatry portfolio | archive-url = https://web.archive.org/web/20160417060946/http://www.supernus.com/psychiatry-portfolio | archive-date=2016-04-17 | access-date = 1 August 2015 }}</ref> Viloxazine was approved for the treatment of ADHD in the United States in April 2021.<ref name="FDA2021" /><ref name="Supernus2021" />

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.<ref name="Drug Trials Snapshots: Qelbree" /> 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.<ref name="Drug Trials Snapshots: Qelbree" /> 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.<ref name="Drug Trials Snapshots: Qelbree" /> 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.<ref name="Drug Trials Snapshots: Qelbree" /> The severity of ADHD symptoms was assessed using the Attention-Deficit Hyperactivity Disorder Rating Scale 5th Edition (ADHD-RS-5).<ref name="Drug Trials Snapshots: Qelbree" /> A fourth study provided information about the safety of viloxazine in adolescents 12 to 17 years of age with ADHD.<ref name="Drug Trials Snapshots: Qelbree" /> The FDA approved viloxazine based on evidence from several clinical trial(s) of 1289 participants with attention deficit hyperactivity disorder (ADHD).<ref name="Drug Trials Snapshots: Qelbree" /> The trials were conducted at 59 sites in the United States.<ref name="Drug Trials Snapshots: Qelbree">{{cite web | title=Drug Trials Snapshots: Qelbree | website=U.S. Food and Drug Administration | date=13 March 2023 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-qelbree | access-date=13 March 2023 | archive-date=14 March 2023 | archive-url=https://web.archive.org/web/20230314051311/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-qelbree }} {{PD-notice}}</ref>

== Society and culture == === Brand names === Viloxazine has been marketed under the brand names Emovit, Qelbree, Vicilan, Viloxazin, Viloxazina, Viloxazinum, Vivalan, and Vivarint.<ref name="Findling_2021" /><ref name="SwissPharmaceuticalSociety2000">{{cite book | editor = Swiss Pharmaceutical Society | author = Swiss Pharmaceutical Society | date = 2000 | title = Index Nominum 2000: International Drug Directory | publisher = Taylor & Francis | pages = 1093– | isbn = 978-3-88763-075-1 | url = https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA1093 | access-date = 2022-05-03 | archive-date = 2023-01-14 | archive-url = https://web.archive.org/web/20230114093413/https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA1093 | url-status = live }}</ref>

==Research== Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.<ref name=Attenburrow_et_al_1984>{{cite journal | vauthors = Attenburrow AA, Stanley TV, Holland RP | title = Nocturnal enuresis: a study | journal = The Practitioner | volume = 228 | issue = 1387 | pages = 99–102 | date = January 1984 | pmid = 6364124 }}</ref><ref name=Yurdakok_et_al_1987>{{note|Yurdakok_et_al_1987}} {{cite journal | vauthors = Yurdakök M, Kinik E, Güvenç H, Bedük Y | title = Viloxazine versus imipramine in the treatment of enuresis | journal = The Turkish Journal of Pediatrics | volume = 29 | issue = 4 | pages = 227–230 | year = 1987 | pmid = 3332732 }}</ref> By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.<ref name=Libert_1990>{{cite journal | vauthors = Libert MH | title = [The use of viloxazine in the treatment of primary enuresis] | language = fr | journal = Acta Urologica Belgica | volume = 58 | issue = 1 | pages = 117–122 | year = 1990 | pmid = 2371930 | trans-title = The use of viloxazine in the treatment of primary enuresis }}</ref>

In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM<ref name=narcolepsy_1>{{cite journal | vauthors = Guilleminault C, Mancuso J, Salva MA, Hayes B, Mitler M, Poirier G, Montplaisir J | title = Viloxazine hydrochloride in narcolepsy: a preliminary report | journal = Sleep | volume = 9 | issue = 1 Pt 2 | pages = 275–279 | year = 1986 | pmid = 3704453 | doi = 10.1093/sleep/9.1.275 | doi-access = free }}</ref> without significantly improving daytime somnolence.<ref name=narcolepsy_2>{{cite journal | vauthors = Mitler MM, Hajdukovic R, Erman M, Koziol JA | title = Narcolepsy | journal = Journal of Clinical Neurophysiology | volume = 7 | issue = 1 | pages = 93–118 | date = January 1990 | pmid = 1968069 | pmc = 2254143 | doi = 10.1097/00004691-199001000-00008 }}</ref> In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.<ref name=Cochrane2008>{{cite journal | vauthors = Vignatelli L, D'Alessandro R, Candelise L | title = Antidepressant drugs for narcolepsy | journal = The Cochrane Database of Systematic Reviews | volume = 2008 | issue = 1 | article-number = CD003724 | date = January 2008 | pmid = 18254030 | pmc = 9030766 | doi = 10.1002/14651858.CD003724.pub3 }}</ref>

Viloxazine has also been studied for the treatment of alcoholism, with some success.<ref name=alcoholism>{{cite journal | vauthors = Altamura AC, Mauri MC, Girardi T, Panetta B | title = Alcoholism and depression: a placebo controlled study with viloxazine | journal = International Journal of Clinical Pharmacology Research | volume = 10 | issue = 5 | pages = 293–298 | year = 1990 | pmid = 2079386 }}</ref>

Viloxazine did not demonstrate efficacy in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.<ref>{{cite journal | vauthors = Mattingly GW, Anderson RH | title = Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems | journal = CNS Spectrums | volume = 21 | issue = S1 | pages = 45–59 | date = December 2016 | pmid = 28044946 | doi = 10.1017/S1092852916000808 | url = https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=6729&context=open_access_pubs | access-date = 2019-09-24 | url-status = live | s2cid = 24310209 | archive-url = https://web.archive.org/web/20221013114453/https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=6729&context=open_access_pubs | archive-date = 2022-10-13 | url-access = subscription }}</ref>

== References == {{Reflist}}

== External links == * {{ClinicalTrialsGov|NCT03247530|Evaluation of SPN-812 ER Low Dose in Children With ADHD}} * {{ClinicalTrialsGov|NCT03247543|Evaluation of SPN-812 ER High Dose in Children With ADHD}}

{{Stimulants}} {{Antidepressants}} {{ADHD pharmacotherapies}} {{Wakefulness-promoting agents}} {{Monoamine reuptake inhibitors}} {{Serotonin receptor modulators}} {{Portal bar | Medicine}} {{Authority control}}

Category:5-HT2B antagonists Category:5-HT2C agonists Category:Antidepressants Category:Attention deficit hyperactivity disorder management Category:Drugs developed by AstraZeneca Category:Morpholines Category:Norepinephrine reuptake inhibitors Category:Phenol ethers Category:Wakefulness-promoting agents Category:Withdrawn drugs