Viloxazine

Viloxazine
Names
Trade namesQelbree, Vivalan,[1] Emovit, others
Other namesICI-58834; SPN-812; SPN-809
IUPAC name
  • (RS)-2-[(2-ethoxyphenoxy)methyl]morpholine[2]
Clinical data
Drug classAntidepressant; norepinephrine reuptake inhibitor
Main usesAttention deficit hyperactivity disorder (ADHD)[3]
Side effectsTrouble sleeping, headache, sleepiness, tiredness, nausea, dry mouth, constipation, irritability, increased heart rate, increased blood pressure[3]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
Typical dose100 to 600 mg OD[3]
External links
AHFS/Drugs.comMonograph
Legal
License data
Legal status
Pharmacokinetics
Protein binding76–82%[3]
MetabolismHydroxylation (CYP2D6), glucuronidation (UGT1A9, UGT2B15)[3]
Metabolites5-Hydroxyviloxazine glucuronide[3]
Elimination half-lifeIR: 2–5 hours[4]
ER: 7.02 ± 4.74 hours[3]
ExcretionUrine (~90%), feces (<1%)[3][5]
Chemical and physical data
FormulaC13H19NO3
Molar mass237.299 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
SMILES
  • CCOC1=CC=CC=C1OCC1CNCCO1

  • HCl: Cl.CCOC1=CC=CC=C1OCC1CNCCO1
InChI
  • InChI=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 checkY
  • Key:YWPHCCPCQOJSGZ-UHFFFAOYSA-N checkY

  • HCl: InChI=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
  • Key:HJOCKFVCMLCPTP-UHFFFAOYSA-N

Viloxazine, sold under the brand name Qelbree among others, is a medication which is used to treat attention deficit hyperactivity disorder (ADHD).[3] It is taken by mouth.[3] It was used for almost 30 years for depression before being discontinued due to commercial reasons.[6] The original formulation was immediate-release while that used for ADHD in extended-release.[6]

Side effects include trouble sleeping, headache, sleepiness, tiredness, nausea, dry mouth, constipation, irritability, increased heart rate, and increased blood pressure.[3] Rarely, it may cause suicidal thoughts or behaviors or result in mania in people with bipolar.[3] There is a low risk of misuse.[6] It is a selective norepinephrine reuptake inhibitor (NRI).[3]

Viloxazine was patented in 1969 and approved for medical use in the United Kingdom in 1974.[6][7] It was not approved in the United States at this time.[8] It was repurposed and approved in the United States in 2021.[6][3] It is not a controlled substance.[9] In the United States it costs about 325 USD per month for a dose of 200 mg per day.[10]

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.[3]

In adults, scores on the Attention-Deficit/Hyperactivity Disorder Investigator Symptom Rating Scale (AISRS) 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%).[3] This gave an improvement in scores attributable to viloxazine, of –3.7 points (–9%).[3]

Depression

Viloxazine was previously used as an antidepressant in major depressive disorder.[6][11] It was considered to be effective in mild to moderate as well as severe depression with or without co-morbid symptoms.[12] The typical dose range for depression was 100 to 400 mg per day in divided doses administered generally two to three times per day.[6]

Dosage

In those 6 to 11 years old it is started at a dose of 100 mg once per day and may be increased to 400 mg once per day. In those 12 to 17 it is started at 200 mg once per day and may be increased to 400 mg once per day. In adults it may be increased to 600 mg once per day.[3]

Viloxazine is available for ADHD in the form of 100, 150, and 200 mg extended-release capsules.[3] These capsules can be opened and sprinkled into food.[3]

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[13]) and increased libido.[14]

Interactions

Viloxazine increased plasma levels of phenytoin by an average of 37%.[15] It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body,[16] sometimes resulting in accidental overdose of theophylline.[17]

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.[6][3][18][19] 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).[18][19] 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).[20][21]

More recent research has found that the pharmacodynamics of viloxazine may be more complex than previously assumed.[6][19] 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.[19][11] It also showed weak antagonistic activity at the serotonin 5-HT7 receptor and the α1B- and β2-adrenergic receptors.[19][11] These actions, although relatively weak, might be involved in its effects and possibly its therapeutic effectiveness in the treatment of ADHD.[6][19]

Pharmacokinetics

Absorption

The bioavailability of extended-release viloxazine relative to an instant-release formulation was about 88%.[3] Peak and AUC levels of extended-release viloxazine are proportional over a dosage range of 100 to 400 mg once daily.[3] The time to peak levels is 5 hours with a range of 3 to 9 hours after a single 200 mg dose.[3] A high-fat meal modestly decreases levels of viloxazine and delays the time to peak by about 2 hours.[3] Steady-state levels of viloxazine are released after 2 days of once-daily administration and no accumulation occurs.[3] Levels of viloxazine are approximately 40 to 50% higher in children age 6 to 11 years compared to children age 12 to 17 years.[3]

Distribution

The plasma protein binding of viloxazine is 76 to 82% over a concentration range of 0.5 to 10 μg/mL.[3]

Metabolism

The metabolism of viloxazine is primarily via the cytochrome P450 enzyme CYP2D6 and the UDP-glucuronosyltransferases UGT1A9 and UGT2B15.[3] The major metabolite of viloxazine is 5-hydroxyviloxazine glucuronide.[3] Viloxazine levels are slightly higher in CYP2D6 poor metabolizers relative to CYP2D6 extensive metabolizers.[3]

Elimination

The elimination of viloxazine is mainly renal.[3] Approximately 90% of the dose is excreted in urine within 24 hours and less than 1% of the dose is recovered in feces.[3]

The elimination half-life of instant-release viloxazine is 2 to 5 hours (2–3 hours in the most reliable studies)[4] and the half-life of extended-release viloxazine is 7.02 ± 4.74 hours.[3]

Chemistry

Viloxazine is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.[22]

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.[23]: 610 [24]: 9  It was first described in the scientific literature as early as 1972.[25]

The medication was first marketed in 1974.[6][26] Viloxazine was not approved for medical use by the FDA.[27] In 1984, the FDA granted the medication an orphan designation for treatment of cataplexy and narcolepsy with the tentative brand name Catatrol.[28] 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][23][29]

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.[30][31] Viloxazine was approved for the treatment of ADHD in the United States in April 2021.[32][33]

Research

Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.[34][35] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.[36]

In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM[37] without really improving daytime somnolence.[38] In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.[29]

Viloxazine has also been studied for the treatment of alcoholism, with some success.[39]

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.[40]

References

  1. ↑ Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society (ed.). Index Nominum 2000: International Drug Directory. Taylor & Francis. pp. 1093–. ISBN 978-3-88763-075-1. Archived from the original on 2022-05-03. Retrieved 2022-10-02.
  2. ↑ "SID 180462-- PubChem Substance Summary". Archived from the original on 14 June 2013. Retrieved 5 November 2005.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 "Qelbree- viloxazine hydrochloride capsule, extended release". DailyMed. Archived from the original on 28 October 2022. Retrieved 3 May 2022.
  4. 1 2 Pinder RM, Brogden RN, Speight TM, Avery GS (June 1977). "Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness". Drugs. 13 (6): 401–21. doi:10.2165/00003495-197713060-00001. PMID 324751. S2CID 44804763.
  5. ↑ Case DE, Reeves PR (February 1975). "The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans". Xenobiotica. 5 (2): 113–29. doi:10.3109/00498257509056097. PMID 1154799.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 Findling RL, Candler SA, Nasser AF, Schwabe S, Yu C, Garcia-Olivares J, O'Neal W, Newcorn JH (June 2021). "Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status". CNS Drugs. 35 (6): 643–653. doi:10.1007/s40263-021-00825-w. PMC 8219567. PMID 34003459.
  7. ↑ Sneader, Walter (31 October 2005). Drug Discovery: A History. John Wiley & Sons. p. 195. ISBN 978-0-470-01552-0. Archived from the original on 30 October 2022. Retrieved 30 October 2022.
  8. ↑ Stolerman, Ian (31 July 2010). Encyclopedia of Psychopharmacology. Springer Science & Business Media. p. 817. ISBN 978-3-540-68698-9. Archived from the original on 30 October 2022. Retrieved 30 October 2022.
  9. ↑ "Viloxazine Monograph for Professionals". Drugs.com. Retrieved 30 October 2022.
  10. ↑ "Qelbree". Archived from the original on 30 October 2022. Retrieved 30 October 2022.
  11. 1 2 3 Cutler AJ, Mattingly GW, Jain R, O'Neal W (October 2020). "Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents". CNS Spectr. 27 (2): 199–207. doi:10.1017/S1092852920001984. PMID 33121553.
  12. ↑ Findling, Robert L.; Candler, Shawn A.; Nasser, Azmi F.; Schwabe, Stefan; Yu, Chungping; Garcia-Olivares, Jennie; O'Neal, Welton; Newcorn, Jeffrey H. (2021-05-18). "Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status". CNS Drugs. Springer Science and Business Media LLC. 35 (6): 643–653. doi:10.1007/s40263-021-00825-w. ISSN 1172-7047. PMC 8219567. PMID 34003459.
  13. ↑ Edwards JG, Glen-Bott M (September 1984). "Does viloxazine have epileptogenic properties?". Journal of Neurology, Neurosurgery, and Psychiatry. 47 (9): 960–4. doi:10.1136/jnnp.47.9.960. PMC 1027998. PMID 6434699.
  14. ↑ Chebili S, Abaoub A, Mezouane B, Le Goff JF (1998). "Antidepressants and sexual stimulation: the correlation" [Antidepressants and sexual stimulation: the correlation]. L'Encéphale (in français). 24 (3): 180–4. PMID 9696909.
  15. ↑ Pisani F, Fazio A, Artesi C, et al. (February 1992). "Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction". Journal of Neurology, Neurosurgery, and Psychiatry. 55 (2): 126–7. doi:10.1136/jnnp.55.2.126. PMC 488975. PMID 1538217.
  16. ↑ 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): 520–2. doi:10.1097/00007691-198909000-00005. PMID 2815226.
  17. ↑ Laaban JP, Dupeyron JP, Lafay M, Sofeir M, Rochemaure J, Fabiani P (1986). "Theophylline intoxication following viloxazine induced decrease in clearance". European Journal of Clinical Pharmacology. 30 (3): 351–3. doi:10.1007/BF00541543. PMID 3732375. S2CID 10114046.
  18. 1 2 Tatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". Eur J Pharmacol. 340 (2–3): 249–58. doi:10.1016/s0014-2999(97)01393-9. PMID 9537821.
  19. 1 2 3 4 5 6 Yu, Chungping; Garcia-Olivares, Jennie; Candler, Shawn; Schwabe, Stefan; Maletic, Vladimir (2020). "New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties". Journal of Experimental Pharmacology. 12: 285–300. doi:10.2147/JEP.S256586. ISSN 1179-1454. PMC 7473988. PMID 32943948.
  20. ↑ Richelson E, Nelson A (July 1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". J Pharmacol Exp Ther. 230 (1): 94–102. PMID 6086881.
  21. ↑ Wander TJ, Nelson A, Okazaki H, Richelson E (December 1986). "Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro". Eur J Pharmacol. 132 (2–3): 115–21. doi:10.1016/0014-2999(86)90596-0. PMID 3816971.
  22. ↑ Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagorevskiĭ VA (May 1984). "Behavioral and radioreceptor analysis of viloxazine stereoisomers" [Behavioral and radioreceptor analysis of viloxazine stereoisomers]. Biulleten' Eksperimental'noĭ Biologii I Meditsiny (in русский). 97 (5): 576–8. PMID 6326891.
  23. 1 2 Williams DA. Antidepressants. Chapter 18 in Foye's Principles of Medicinal Chemistry, Eds. Lemke TL and Williams DA. Lippincott Williams & Wilkins, 2012. ISBN 9781609133450
  24. ↑ Wermuth, CG. Analogs as a Means of Discovering New Drugs. Chapter 1 in Analogue-based Drug Discovery. Eds.IUPAC, Fischer, J., and Ganellin CR. John Wiley & Sons, 2006. ISBN 9783527607495
  25. ↑ Mallion KB, Todd AH, Turner RW, Bainbridge JG, Greenwood DT, Madinaveitia J, Somerville AR, Whittle BA (July 1972). "2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine hydrochloride, a potential psychotropic agent". Nature. 238 (5360): 157–8. Bibcode:1972Natur.238..157M. doi:10.1038/238157a0. PMID 4558457. S2CID 4268001.
  26. ↑ Olivier B, Soudijn W, van Wijngaarden I (2000). "Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors". Prog Drug Res. 54: 59–119. doi:10.1007/978-3-0348-8391-7_3. ISBN 978-3-0348-9546-0. PMID 10857386.
  27. ↑ Dahmen, MM, Lincoln, J, and Preskorn, S. NARI Antidepressants, pp 816-822 in Encyclopedia of Psychopharmacology, Ed. Ian P. Stolerman. Springer-Verlag Berlin Heidelberg, 2010. ISBN 9783540687061
  28. ↑ FDA. Orphan Drug Designations and Approvals: Viloxazine Archived 2022-06-25 at the Wayback Machine Page accessed August 1, 2-15
  29. 1 2 Vignatelli L, D'Alessandro R, Candelise L (2008). "Antidepressant drugs for narcolepsy". Cochrane Database Syst Rev. 2010 (1): CD003724. doi:10.1002/14651858.CD003724.pub3. PMC 9030766. PMID 18254030.
  30. ↑ Bloomberg Supernus profile Archived 2018-03-11 at the Wayback Machine Page accessed August 1, 2015
  31. ↑ Supernus. Psychiatry portfolio Archived 2016-04-17 at the Wayback Machine Page accessed August 1, 2015
  32. ↑ "Qelbree: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 2 April 2021. Retrieved 2 April 2021.
  33. ↑ "Supernus Announces FDA Approval of Qelbree (SPN-812) for the Treatment of ADHD". Supernus Pharmaceuticals (Press release). 2 April 2021. Archived from the original on 6 April 2021. Retrieved 3 April 2021.
  34. ↑ Attenburrow AA, Stanley TV, Holland RP (January 1984). "Nocturnal enuresis: a study". The Practitioner. 228 (1387): 99–102. PMID 6364124.
  35. ↑ ^ Yurdakök M, Kinik E, Güvenç H, Bedük Y (1987). "Viloxazine versus imipramine in the treatment of enuresis". The Turkish Journal of Pediatrics. 29 (4): 227–30. PMID 3332732.
  36. ↑ Libert MH (1990). "The use of viloxazine in the treatment of primary enuresis" [The use of viloxazine in the treatment of primary enuresis]. Acta Urologica Belgica (in français). 58 (1): 117–22. PMID 2371930.
  37. ↑ Guilleminault C, Mancuso J, Salva MA, et al. (1986). "Viloxazine hydrochloride in narcolepsy: a preliminary report". Sleep. 9 (1 Pt 2): 275–9. doi:10.1093/sleep/9.1.275. PMID 3704453.
  38. ↑ Mitler MM, Hajdukovic R, Erman M, Koziol JA (January 1990). "Narcolepsy". Journal of Clinical Neurophysiology. 7 (1): 93–118. doi:10.1097/00004691-199001000-00008. PMC 2254143. PMID 1968069.
  39. ↑ Altamura AC, Mauri MC, Girardi T, Panetta B (1990). "Alcoholism and depression: a placebo controlled study with viloxazine". International Journal of Clinical Pharmacology Research. 10 (5): 293–8. PMID 2079386.
  40. ↑ Mattingly, GW; Anderson, RH (December 2016). "Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems". CNS Spectrums. 21 (S1): 45–59. doi:10.1017/S1092852916000808. PMID 28044946. S2CID 24310209. Archived from the original on 2022-10-13. Retrieved 2022-10-02.
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