Viloxazine

Effects

Overview

NRI that was used as an antidepressant in some European countries, and had a pronouced stimulant effect similar to amphetamines without any signs of dependence. Withdrawn in the early 2000s. TS

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.[1–5] WP

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.[1][2][3][6] WP

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.[1][3][7–13] WP

History

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. It was first described in the scientific literature as early as 1972.[7][10][14] WP

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.[3][8–11][15] WP

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.[12][13][16][17] WP

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. 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. 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. 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. The severity of ADHD symptoms was assessed using the Attention-Deficit Hyperactivity Disorder Rating Scale 5th Edition (ADHD-RS-5). A fourth study provided information about the safety of viloxazine in adolescents 12 to 17 years of age with ADHD. The FDA approved viloxazine based on evidence from several clinical trial(s) of 1289 participants with attention deficit hyperactivity disorder (ADHD). The trials were conducted at 59 sites in the United States.[18] WP

Legal status

Brand names

Viloxazine has been marketed under the brand names Emovit, Qelbree, Vicilan, Viloxazin, Viloxazina, Viloxazinum, Vivalan, and Vivarint.[3][19] WP

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).[1][3][20–23] WP

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.[2][3][21][24] WP

Absorption

The bioavailability of extended-release viloxazine relative to an instant-release formulation was about 88%. Peak and AUC (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.[1] WP

Distribution

The plasma protein binding of viloxazine is 76 to 82% over a concentration range of 0.5 to 10 μg/mL.[1] WP

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.[1] WP

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.[1] WP

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.[1][6] WP

Chemistry

Formula

C13H19NO3 PC

CAS number

46817-91-8 PC

Molar mass (g/mol)

237.29 PC

IUPAC name (computed by PubChem)

2-[(2-ethoxyphenoxy)methyl]morpholine PC

SMILES

CCOC1=CC=CC=C1OCC2CNCCO2 PC

InChIKey

YWPHCCPCQOJSGZ-UHFFFAOYSA-N PC

PubChem CID

5666

Pop culture

No references added yet.

References

1. Journal / agency Qelbree- viloxazine hydrochloride capsule, extended release
2. Journal / agency Cutler AJ, Mattingly GW, Jain R, O'Neal W. Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents. CNS Spectrums. April 2022. doi:10.1017/S1092852920001984 · PMID 33121553
3. Journal / agency Findling RL, Candler SA, Nasser AF, Schwabe S, Yu C, Garcia-Olivares J, O'Neal W, Newcorn JH. Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status. CNS Drugs. June 2021. doi:10.1007/s40263-021-00825-w · PMID 34003459 · PMC8219567
4. Journal / agency Schein J, Cloutier M, Gauthier-Loiselle M, Catillon M, Xu C, Chan D, Childress A. 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 of Managed Care & Specialty Pharmacy. June 2024. doi:10.18553/jmcp.2024.30.6.528 · PMID 38824626 · PMC11145007
5. Journal / agency Faraone SV, Gomeni R, Hull JT, Busse GD, Melyan Z, O'Neal W, Rubin J, Nasser A. 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. Psychiatry Research. February 2021. doi:10.1016/j.psychres.2020.113664 · PMID 33418457
6. Journal / agency Pinder RM, Brogden RN, Speight TM, Avery GS. Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness. Drugs. June 1977. doi:10.2165/00003495-197713060-00001 · PMID 324751
7. Journal / agency Mallion KB, Todd AH, Turner RW, Bainbridge JG, Greenwood DT, Madinaveitia J, Somerville AR, Whittle BA. 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine hydrochloride, a potential psychotropic agent. Nature. July 1972. doi:10.1038/238157a0 · PMID 4558457
8. Journal / agency Olivier B, Soudijn W, van Wijngaarden I. Progress in Drug Research. Fortschritte der Arzneimittelforschung. Progres des Recherches Pharmaceutiques. 2000. doi:10.1007/978-3-0348-8391-7_3 · PMID 10857386
9. Other Dahmen MM, Lincoln J, Preskorn S. Encyclopedia of Psychopharmacology. 2010
10. Other Williams DA. Foye's Principles of Medicinal Chemistry. 2012
11. Journal / agency Vignatelli L, D'Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. The Cochrane Database of Systematic Reviews. January 2008. doi:10.1002/14651858.CD003724.pub3 · PMID 18254030 · PMC9030766
12. Journal / agency Qelbree: FDA-Approved Drugs
13. Other Supernus Announces FDA Approval of Qelbree (SPN-812) for the Treatment of ADHD. 2 April 2021
14. Other Wermuth CG. Analogue-based Drug Discovery. 2006
15. Journal / agency Orphan Drug Designations and Approvals: Viloxazine
16. Other Supernus profile
17. Other Psychiatry portfolio
18. Journal / agency Drug Trials Snapshots: Qelbree. 13 March 2023
19. Other Swiss Pharmaceutical Society. Index Nominum 2000: International Drug Directory. 2000
20. Journal / agency Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. European Journal of Pharmacology. December 1997. doi:10.1016/s0014-2999(97)01393-9 · PMID 9537821
21. Journal / agency Yu C, Garcia-Olivares J, Candler S, Schwabe S, Maletic V. New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties. Journal of Experimental Pharmacology. 2020. doi:10.2147/JEP.S256586 · PMID 32943948 · PMC7473988
22. Journal / agency Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. The Journal of Pharmacology and Experimental Therapeutics. July 1984. doi:10.1016/S0022-3565(25)21446-X · PMID 6086881
23. Journal / agency Wander TJ, Nelson A, Okazaki H, Richelson E. Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro. European Journal of Pharmacology. December 1986. doi:10.1016/0014-2999(86)90596-0 · PMID 3816971
24. Journal / agency Garcia-Olivares J, Yegla B, Earnest J, Maletic V, Yu C. Characterization of Viloxazine Effects on Cortical Serotonin Neurotransmission at Doses Relevant for ADHD Treatment. CNS Spectrums. 2023. doi:10.1017/S1092852923001633

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