Viloxazine was first described by 1972[8] and was marketed as an antidepressant in Europe in 1974.[7][9] It was not marketed in the United States at this time.[10] The medication was discontinued in 2002 for commercial reasons.[7][11][12] However, it was repurposed for the treatment of ADHD and was reintroduced, in the United States, in April 2021.[7][13][14] Viloxazine is a
non-stimulant medication; it has no known
misuse liability and is not a
controlled substance.[1]
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.[15][16][17][18][19]
Depression
Viloxazine was previously marketed as an
antidepressant for the treatment of
major depressive disorder.[7][6] It was considered to be effective in mild to moderate as well as severe depression with or without co-morbid symptoms.[7] The typical dose range for depression was 100 to 400mg per day in divided doses administered generally two to three times per day.[7]
Available forms
Viloxazine is available for ADHD in the form of 100, 150, and 200 mg
extended-releasecapsules.[1] These capsules can be opened and sprinkled into food for easier administration.[1]
Side effects
The most common side effects include drowsiness, headache, loss of appetite. Psychiatric side effects occur in about 20% of cases; the most common of these is irritability (>5%).[20] Other common side effects include
nausea, vomiting,
epigastric pain,
insomnia,[7] and increased libido.[21] Incidence of some side effects, including headache and drowsiness, appear to be dose-dependent.[22] In the treatment of depression, viloxazine is more tolerable than
tricyclic antidepressants such as imipramine and amitryptiline.[7]
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.[23]
Interactions
Viloxazine increased
plasma levels of
phenytoin by an average of 37%.[24] It also was known to significantly increase plasma levels of
theophylline and decrease its clearance from the body,[25] sometimes resulting in accidental overdose of
theophylline.[26]
More recent research has found that the
pharmacodynamics of viloxazine may be more complex than previously assumed.[7][28] 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.[28][6] It also showed weak antagonistic activity at the serotonin
5-HT7 receptor and the
α1B- and
β2-adrenergic receptors.[28][6] These actions, although relatively weak, might be involved in its effects and possibly its therapeutic effectiveness in the treatment of ADHD.[7][28]
Pharmacokinetics
Absorption
The
bioavailability of extended-release viloxazine relative to an instant-release formulation was about 88%.[1]Peak and
AUCTooltip area-under-the-curve (pharmacokinetics) levels of extended-release viloxazine are proportional over a dosage range of 100 to 400 mg once daily.[1] The
time 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]
Distribution
The
plasma protein binding of viloxazine is 76 to 82% over a concentration range of 0.5 to 10 μg/mL.[1]
The
elimination of viloxazine is mainly
renal.[1] Approximately 90% of the dose is
excreted in
urine within 24 hours and less than 1% of the dose is recovered in
feces.[1]
The
elimination 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.[7][9] Viloxazine was not approved for medical use by the FDA.[10] In 1984, the FDA granted the medication an orphan designation for treatment of
cataplexy and
narcolepsy with the tentative brand name Catatrol.[33] For unknown reasons however, it was never approved or introduced for these uses in the United States.[7] Viloxazine was withdrawn from markets worldwide in 2002 for commercial reasons unrelated to efficacy or safety.[7][11][12]
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.[34][35] Viloxazine was approved for the treatment of ADHD in the United States in April 2021.[13][14]
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.[36] 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.[36] 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.[36] 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.[36] The severity of ADHD symptoms was assessed using the Attention-Deficit Hyperactivity Disorder Rating Scale 5th Edition (ADHD-RS-5).[36] A fourth study provided information about the safety of viloxazine in adolescents 12 to 17 years of age with ADHD.[36] The FDA approved viloxazine based on evidence from several clinical trial(s) of 1289 participants with attention deficit hyperactivity disorder (ADHD).[36] The trials were conducted at 59 sites in the United States.[36]
Research
Viloxazine has undergone two randomized controlled trials for
nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.[37][38] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.[39]
In
narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as
cataplexy and also abnormal sleep-onset
REM[40] without significantly improving daytime
somnolence.[41] In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.[12]
Viloxazine has also been studied for the treatment of
alcoholism, with some success.[42]
Viloxazine did not demonstrate efficacy in a double-blind randomized controlled trial versus
amisulpride in the treatment of
dysthymia.[43]
^
abcPinder 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): 401–421.
doi:
10.2165/00003495-197713060-00001.
PMID324751.
S2CID44804763.
^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.
^"SID 180462". PubChem Substance Summary. U.S. National Library of Medicine.
Archived from the original on 14 June 2013. Retrieved 5 November 2005.
^
abOlivier B, Soudijn W, van Wijngaarden I (2000). "Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors". Progress in Drug Research. Fortschritte der Arzneimittelforschung. Progres des Recherches Pharmaceutiques. Vol. 54. pp. 59–119.
doi:
10.1007/978-3-0348-8391-7_3.
ISBN978-3-0348-9546-0.
PMID10857386.
^
abDahmen MM, Lincoln J, Preskorn S (2010). "NARI Antidepressants". In Stolerman IP (ed.). Encyclopedia of Psychopharmacology. Berlin Heidelberg: Springer-Verlag. pp. 816–822.
ISBN9783540687061.
^
abcWilliams DA (2012). "Chapter 18: Antidepressants.". In Lemke TL, Williams DA (eds.). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins.
ISBN9781609133450.
^Hazell PL, Kohn MR, Dickson R, Walton RJ, Granger RE, Wyk GW (November 2011). "Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis". Journal of Attention Disorders. 15 (8): 674–683.
doi:
10.1177/1087054710379737.
PMID20837981.
S2CID43503227.
^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.
^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.
^
abTatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". European Journal of Pharmacology. 340 (2–3): 249–258.
doi:
10.1016/s0014-2999(97)01393-9.
PMID9537821.
^Richelson E, Nelson A (July 1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". The Journal of Pharmacology and Experimental Therapeutics. 230 (1): 94–102.
PMID6086881.
^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". European Journal of Pharmacology. 132 (2–3): 115–121.
doi:
10.1016/0014-2999(86)90596-0.
PMID3816971.
^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'noi Biologii I Meditsiny (in Russian). 97 (5): 576–578.
PMID6326891.
^Wermuth CG (2006). "Chapter 1: Analogs as a Means of Discovering New Drugs.". In Fischer J, Ganellin CR (eds.). Analogue-based Drug Discovery. John Wiley & Sons.
ISBN978352760749-5.
^Attenburrow AA, Stanley TV, Holland RP (January 1984). "Nocturnal enuresis: a study". The Practitioner. 228 (1387): 99–102.
PMID6364124.
^^ Yurdakök M, Kinik E, Güvenç H, Bedük Y (1987). "Viloxazine versus imipramine in the treatment of enuresis". The Turkish Journal of Pediatrics. 29 (4): 227–230.
PMID3332732.
^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 French). 58 (1): 117–122.
PMID2371930.
^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): 293–298.
PMID2079386.