Viloxazine extended-release capsules as an emerging treatment for attention-deficit/hyperactivity disorder in children and adolescents

Figures & data

Table 1. Pharmacokinetics of viloxazine extended-release capsules.

PK parameter	Children and adolescents (6–17 years old)
Absorption
Cmax, µg/mL*	1.2–8.9
Tmax, hours*	4–5
Distribution
Plasma protein binding, %^†	76–82
Vd/F, L, range*	61.8–94.7
Metabolism
Metabolizing enzymes	CYP2D6, UGT1A9, and UGT2B15
Primary metabolite	5-hydroxyviloxazine glucuronide
Tss, days	2
Elimination
T1/2, hours, range*	7.9–10.1
CL/F, %, urine vs feces	90 vs ≤1

*Reported parameters represent the range of estimated average values at steady state, modeled separately for children and adolescents receiving viloxazine ER doses of 100, 200, 400, or 600 mg/day, based on population PK modeling.

^†Plasma protein binding is over the blood concentration range of 0.5 µg/mL to 10 µg/mL.

CL = clearance, C_max = maximum observed concentration, CYP = cytochrome P450, ER = extended-release, F = bioavailability, PK = pharmacokinetic, T_1/2 = elimination half-life, T_max = median time-to-maximum concentration, T_ss = time until steady-state, UGT = UDP-glucuronosyltransferase, V_d = volume of distribution.

Table 2. Results from the phase II trial in children (aged 6–12 years old) [86].

	NCT02633527 (Children 6–12 years old)
		Viloxazine ER
	Placebo(n = 24)	100 mg(n = 45)	200 mg(n = 46)	300 mg(n = 47)	400 mg(n = 44)
ADHD-RS-IV total score
CFB, LS mean*	−10.5	−16.7	−18.4	−18.6	−19.0
P-value^†		0.0899	0.0310	0.0268	0.0209
Hyperactivity/Impulsivity subscale
CFB, LS mean^‡	−4.7	−7.9	−9.0	−9.5	−9.8
P-value^†		0.1007	0.0254	0.0121	0.0086
Inattentional subscale
CFB, LS mean*	−5.7	−8.9	−9.0	−9.4	−9.5
P-value^†		0.1014	0.0909	0.0552	0.0533
CGI-I
LS mean*	3.0	2.6	2.6	2.2	2.4
P-value^†		0.1305	0.1376	0.0090	0.0546
CGI-S
CFB, LS mean*	−0.8	−1.4	−1.5	−1.6	−1.7
P-value^†		0.0708	0.0309	0.0148	0.0136

*Estimated from ANOVA including fixed effect for treatment.

^†Comparison between each viloxazine ER dose group and placebo; raw (unadjusted for multiplicity) P-values.

^‡Estimated using ANCOVA model with fixed effects for treatment and baseline.

ADHD = attention-deficit/hyperactivity disorder, ADHD-RS-IV = ADHD Rating Scale-IV, ANCOVA = analysis of covariance, ANOVA = analysis of variance, CFB, change from baseline, CGI = Clinical Global Impression, CGI-I = CGI-Improvement score, CGI-S = CGI-Severity score, ER = extended-release, LS = least squares.

Table 3. Results from the pivotal phase III trials in children (6–11 years old) and adolescents (12–17 years old) [87–89].

	NCT03247530			NCT03247543			NCT03247517
	(Children 6–11 years old)			(Children 6–11 years old)			(Adolescents 12–17 years old)
		Viloxazine ER			Viloxazine ER			Viloxazine ER
	Placebo(n = 155)	100 mg(n = 147)	200 mg(n = 158)	Placebo(n = 97)	200 mg(n = 107)	400 mg(n = 97)	Placebo(n = 104)	200 mg(n = 94)	400 mg(n = 103)
ADHD-RS-5 total score
CFB, LS mean ± SE	−10.9 ± 1.14	−16.6 ± 1.16	−17.7 ± 1.12	−11.7 ± 1.5	−17.6 ± 1.4	−17.5 ± 1.5	−11.4 ± 1.37	−16.0 ± 1.45	−16.5 ± 1.38
P-value		0.0004	<0.0001		0.0038	0.0063		0.0232	0.0091
Hyperactivity/ Impulsivity subscale
CFB, LS mean ± SE	−5.5 ± 0.59	−8.0 ± 0.60	−8.7 ± 0.58	−5.1 ± 0.8	−8.4 ± 0.8	−8.3 ± 0.8	−5.1 ± 0.69	−7.7 ± 0.73	−8.4 ± 0.69
P-value		0.0026	<0.0001		0.0020	0.0039		0.0069	0.0005
Inattentional subscale
CFB, LS mean ± SE	−5.7 ± 0.60	−8.6 ± 0.62	−9.2 ± 0.60	−6.2 ± 0.8	−8.9 ± 0.7	−8.6 ± 0.8	−6.6 ± 0.74	−8.7 ± 0.78	−8.7 ± 0.74
P-value		0.0006	<0.0001		0.0087	0.0248		0.0424	0.0390
CGI-I
LS mean ± SE	3.1 ± 0.10	2.7 ± 0.10	2.6 ± 0.09	3.1 ± 0.12	2.6 ± 0.12	2.6 ± 0.12	3.0 ± 0.11	2.5 ± 0.12	2.4 ± 0.12
P-value		0.0020	<0.0001		0.0028	0.0099		0.0042	0.0003

CFB LS means and P-values were obtained using a mixed model for repeated measures model with fixed effect terms for baseline ADHD-RS-5 total score, age group, treatment, visit, and treatment-by-visit interaction as independent variables; subscales and CGI were analyzed using ANCOVA with treatment as fixed effect and baseline as covariate, except for CGI-I were CGI-S score at baseline was used as a covariate.

ADHD = attention-deficit/hyperactivity disorder, ADHD-RS-5 = ADHD Rating Scale-5, ANCOVA = analysis of covariance, ANOVA = analysis of variance, CFB = change from baseline, CGI = Clinical Global Impression, CGI-I = CGI-Improvement score, CGI-S = CGI-Severity score, ER = extended-release, LS = least squares, SE = standard error.

Table 4. Adverse events (≥5% in any treatment group) from the phase II and III trials in children and adolescents (ages 6–17 years old) [86–90].

		Viloxazine ER
	Placebo	100 mg	200 mg	300 mg	400 mg	600 mg	All viloxazine ER
	(n = 487)	(n = 202)	(n = 415)	(n = 48)	(n = 354)	(n = 99)	(N = 1117)*
Somnolence	17 (3.5)	23 (11.4)	54 (13.0)	11 (22.9)	55 (15.5)	19 (19.2)	162 (14.5)
Headache	32 (6.6)	19 (9.4)	45 (10.8)	6 (12.5)	42 (11.9)	9 (9.1)	121 (10.8)
Decreased appetite	4 (0.8)	13 (6.4)	36 (8.7)	4 (8.3)	32 (9.0)	6 (6.1)	91 (8.1)
Fatigue	11 (2.3)	8 (4.0)	21 (5.1)	1 (2.1)	33 (9.3)	10 (10.1)	73 (6.5)
Nausea	13 (2.7)	4 (2.0)	17 (4.1)	5 (10.4)	22 (6.2)	9 (9.1)	57 (5.1)
Vomiting	7 (1.4)	9 (4.5)	15 (3.6)	3 (6.3)	22 (6.2)	4 (4.0)	53 (4.7)
Irritability	6 (1.2)	5 (2.5)	12 (2.9)	2 (4.2)	16 (4.5)	5 (5.1)	40 (3.6)
Diarrhea	2 (0.4)	3 (1.5)	4 (1.0)	3 (6.3)	5 (1.4)	0	15. (1.3)

Values are presented as n (%). *Two individuals participated in both the phase II and a phase III trial. One participant received viloxazine ER 100 mg/day in phase II and placebo in phase III, and AEs on each treatment are counted in their respective columns; the other participant received viloxazine ER 400 mg/day in phase II and viloxazine ER 200 mg/day in phase III and AEs from each trial are counted their respective columns; this patient is counted once for determining the total viloxazine ER sample size, with AEs from both trials considered in determining total incidence rates.

AE = adverse event, ER = extended-release.

Table 5. Common (≥5% and at least twice the rate of placebo) adverse reactions at approved doses in pediatric trials [43–45,48].

	Viloxazine ER (Qelbree®)*	Atomoxetine (Strattera®)^†	Clonidine ER (Kapvay®)^‡		Guanfacine ER (Intuniv®)^§
	Monotherapy(N = 826)	Monotherapy(N = 1597)	Monotherapy(N = 154)	Adjunct + stimulant(N = 102)	Monotherapy Fixed Dose(N = 513)	Monotherapy Flexible Dose(N = 221)	Adjunct+ stimulant(N = 302)
Somnolence	X	X	X	X	X	X	X
Fatigue	X	X	X	X	X	X	X
Lethargy					X
Insomnia			X				X
Irritability		X				X
Dizziness		X		X			X
Hypotension					X	X
Decreased appetite	X	X		X
Nausea		X			X	X
Vomiting						X
Abdominal pain						X	X

Adverse events shown here are based on those listed in the Section 6 Adverse Reactions, 6.1 Clinical Trials Experience of the FDA-approved prescribing information as occurring at ≥ 5% and at least twice the placebo rate for all doses. Specific adverse event terms related to abdominal pain, hypotension, fatigue, insomnia, or somnolence may be combined for reporting in prescribing information and therefore rates may differ from those reported in individual studies. Consult product prescribing information for specific information on adverse events for individual doses. *The somnolence term includes somnolence, lethargy, and sedation; the abdominal pain term includes abdominal discomfort, abdominal pain, abdominal pain lower, and abdominal pain upper; the insomnia term includes initial insomnia, insomnia, middle insomnia, poor quality sleep, sleep disorder, and terminal insomnia. ^†The somnolence term includes somnolence and sedation; the abdominal pain term includes abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, and epigastric discomfort. ^‡The somnolence term includes somnolence sedation; the fatigue term includes fatigue and lethargy. ^§The somnolence term includes somnolence, sedation, and hypersomnia; the abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness; the hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, and blood pressure systolic decreased.

ER = extended-release, FDA = US Food and Drug Administration.

Johnson JK, Liranso T, Saylor K, et al. A phase II double-blind, placebo-controlled, efficacy and safety study of SPN-812 (extended-release viloxazine) in children with ADHD. J Atten Disord. 2020;24(2):348–358. doi: 10.1177/1087054719836159

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Qelbree. Prescribing information. Supernus Pharmaceuticals, Inc.; 2022 [cited 2023 Feb 23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211964s003lbl.pdf

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