What medication is most similar to Qelbree (viloxazine)?

What other med is most similar to Qelbree (viloxazine)?

Comment by InpharmD Researcher

Limited data suggests that viloxazine ER is most similar to atomoxetine among FDA-approved non-stimulant ADHD medications, as both are serotonin-norepinephrine reuptake inhibitors. While direct comparisons are scarce, one small crossover trial indicated viloxazine ER may offer greater improvements in ADHD symptoms and tolerability (Table 1). Unlike atomoxetine, which is effective for anxiety disorders, viloxazine ER has demonstrated antidepressant activity, potentially benefiting patients with comorbid depression. Other non-stimulant options, such as guanfacine ER and clonidine ER, act through different mechanisms as alpha-2 adrenergic agonists and are primarily used in pediatric patients.

Background

Viloxazine (Qelbree) became only the second nonstimulant FDA-approved medication for treatment of attention-deficit/hyperactivity disorder (ADHD) in adults in 2022, following atomoxetine, another serotonin-norepinephrine reuptake inhibitor. In pediatric patients, viloxazine extended release (ER) was approved in 2021 for treatment of ADHD in patients aged 6 to 17 years; additionally, clonidine ER and guanfacine ER may also be utilized as nonstimulant options in children. While most studies have investigated the efficacy and safety of viloxazine ER compared to placebo, one open-label crossover trial compared viloxazine ER versus atomoxetine in 50 patients (35 children and 15 adults; see Table 1). The study revealed significantly greater improvement with viloxazine ER in several efficacy endpoints, including change in ADHD-Rating Scale-5 or Adult ADHD Investigator Symptom Rating Scale (AISRS) total and inattention and hyperactivity subscale scores from baseline. Fewer patients also discontinued treatment due to adverse effects when treated with viloxazine ER. The vast majority of patients (96%) preferred treatment with viloxazine ER. However, this study is hindered by its small sample size and open-label design, despite retrospective reviewers being blinded. Notably, atomoxetine has been shown to be effective in treating children and adults with anxiety disorders, while viloxazine ER has demonstrated antidepressant activity, suggesting potential additional benefits for patients with these comorbidities. [1], [2]

While direct comparisons between atomoxetine and viloxazine ER are limited to the study above, a 2023 systematic review and meta-analysis indirectly evaluated efficacy and safety of nonstimulant medications in adults with ADHD. The review encompassed 18 double-blind, randomized controlled trials (RCTs) involving 4,308 participants and included atomoxetine, guanfacine, and viloxazine ER. Hedges’ g was calculated to estimate effect sizes for efficacy, while dropout rates due to side effects and any cause were analyzed to assess tolerability and acceptability. The meta-analysis demonstrated that all three nonstimulants showed greater efficacy than placebo in reducing ADHD symptoms, with guanfacine (Hedge’s g -0.66, 95% confidence interval [CI] -0.94 to -0.38; 2 RCTs; nonsignificant heterogeneity) exhibiting the largest effect size, followed by atomoxetine (Hedge’s g -0.48, 95% CI -0.64 to -0.33; 15 RCTs; significant heterogeneity) and viloxazine ER based on its single placebo-controlled trials. Tolerability and acceptability were superior in the placebo groups compared to atomoxetine, which showed higher dropout rates due to side effects (9.3% vs. 3.6%) and overall causes (34.9% vs. 27.6%). Tolerability data for guanfacine and viloxazine ER could not be meta-analyzed due to limited studies. While guanfacine had the greatest efficacy effect size, overlapping CIs prevented definitive conclusions about comparative efficacy among the three medications. The findings underscore the need for individualized decision-making in selecting nonstimulant treatments, considering specific patient characteristics and potential side effect profiles. [3]

Additionally, a 2024 matching-adjusted indirect comparison (MAIC) was made utilizing individual patient data (IPD) from two Phase 3 trials of centanafadine (NCT03605680 and NCT03605836), an investigational drug currently being evaluated for treatment of ADHD in adolescents and children. These data were compared to aggregate data from comparator trials to assess the safety and efficacy of centanafadine sustained-release against lisdexamfetamine, atomoxetine, and viloxazine ER. Propensity score weighting matched patient characteristics across trials, standardizing variables such as age, sex, race, baseline symptom severity (AISRS or ADHD-RS), and Clinical Global Impression-Severity of Illness (CGI-S) scores. Anchored indirect comparisons were employed to reduce cross-trial heterogeneity, leveraging shared placebo arms. Safety outcomes included adverse event rates reported in both trials of a given comparison, while efficacy was measured by the mean change in AISRS or ADHD-RS scores over 4 to 10 weeks, depending on comparator trial timelines. The MAIC revealed that centanafadine demonstrated a superior short-term safety profile compared to all three comparators, with statistically significant reductions in the incidence of adverse events such as lack of appetite, dry mouth, insomnia, fatigue, and nausea (e.g., risk differences (RDs) of 23.42 and 18.64 percentage points vs. lisdexamfetamine and atomoxetine, respectively, p<0.05). Specifically compared to viloxazine ER (viloxazine ER n= 175; placebo n= 179; 1 trial), centanafadine (centanafadine n= 574; placebo n= 285; 3 trials) at Week 6 resulted in a significantly lower risk of fatigue (RD in percentage points: 11.07), insomnia (10.67), nausea (7.57), and constipation (4.63) (all p<0.05). In terms of efficacy, centanafadine showed a smaller reduction in AISRS/ADHD-RS scores relative to lisdexamfetamine (6.58-point difference; p<0.05) but comparable outcomes to atomoxetine and viloxazine ER (p> 0.05). Baseline matching achieved balanced demographic and clinical characteristics, enhancing interpretability. Despite the absence of clinically meaningful differences in AISRS reduction between centanafadine and lisdexamfetamine, the lower AE burden associated with centanafadine suggests its potential utility in optimizing ADHD symptom control while mitigating treatment-related AEs. Once again, the presented results are merely MAIC specific to centanafadine. [4]

A 2023 review article evaluated the efficacy and safety of extended-release viloxazine for treating ADHD in children and adolescents aged 6 to 17 years. The review synthesized findings from Phase III clinical trials assessing viloxazine ER's therapeutic effects. While the primary focus was viloxazine ER, the review also compared prescribing information for other FDA-approved non-stimulant medications, including atomoxetine, guanfacine ER, and clonidine ER (Table 2). The trials demonstrated that viloxazine ER significantly improved ADHD symptoms, as measured by ADHD-RS scores, compared to placebo. Pharmacokinetically, viloxazine ER achieves steady-state concentrations rapidly, within two days, even after missed doses, which may enhance adherence. Compared to atomoxetine, it has a faster onset of action (~1-2 weeks vs. ~4 weeks). A detailed comparison of the pharmacokinetic parameters of viloxazine ER with other non-stimulants is provided (Table 3). It was suggested that although direct comparative trials with other non-stimulants such as atomoxetine, guanfacine ER, and clonidine ER are limited, viloxazine ER represents a valuable option for patients who cannot tolerate stimulants or require alternative nonstimulant therapies. [5]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What other med is most similar to Qelbree (viloxazine)?

Level of evidence

A - Multiple high-quality studies with consistent results Read more→

Please see Tables 1-3 for your response.

Extended-Release Viloxazine Compared with Atomoxetine for Attention Deficit Hyperactivity Disorder
Design	Unblinded, open-label, single-arm, retrospective analysis N= 50
Objective	To assess whether pediatric and adult patients taking atomoxetine for DSM-5-TR attention deficit hyperactivity disorder (ADHD) combined type would experience improvement in ADHD symptoms following a voluntary, open-label switch to extended-release viloxazine (VER)
Study Groups	Pediatric (n = 35) Adult (n = 15)
Inclusion Criteria	Patients with a primary diagnosis of ADHD combined type according to DSM-5-TR criteria, no other concurrent psychiatric, medical, or substance-related comorbidities, and no prior exposure to either atomoxetine or VER
Exclusion Criteria	Concurrent psychiatric, medical, or substance-related comorbidities, and prior exposure to either atomoxetine or VER
Methods	Participants received atomoxetine (60 mg mean dose) followed by VER (300 mg mean dose) after a 5-day washout. Both medications were flexibly titrated according to FDA guidelines. Pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and Adult Investigator Symptom Rating Scale (AISRS) were completed before and after treatment with each medication.
Duration	4-week trial for each treatment, with weekly monitoring
Outcome Measures	Primary: Improvement in ADHD symptoms measured by ADHD-RS-5 and AISRS Secondary: Tolerability and preference between atomoxetine and VER
Baseline Characteristics		Pediatric (n = 35)	Adult (n = 15)
	Age, years	11.9 ± 2.9	29.3 ± 9.0
	Female	2 (5.7%)	4 (26.7%)
	Race White Non-white Hispanic/Latino Black Asian	33 (94.3%) 2 (5.7%) 1 (2.9%) 1 (2.9%) 0 (0%)	14 (93.3%) 1 (6.7%) 1 (6.7%) 0 (0%) 0 (0%)
	Concurrent stimulant	15 (42.9%)	11 (73.3%)
Results	Endpoint	Atomoxetine	VER	p-value
	ADHD-RS-5 Total Score; Baseline (40.3 ± 10.3) Inattention Hyperactivity/impulsivity	33.1 ± 12.1 -- --	13.9 ± 10.2 -- --	t = − 10.12, p < 0.00001 t = − 8.57, p < 0.00001 t = − 9.87, p < 0.00001
	AISRS Total Score; Baseline (37.3 ± 11.8) Inattention Hyperactivity/impulsivity	28.8 ± 14.9 -- --	11.9 ± 9.4 -- --	0.0009 t = − 3.50, p < 0.004 t = − 3.90, p < 0.002
	Positive response by 2 weeks Children Adult	14% 13%	89% 87%	-- --
	A total of 96% preferred VER over atomoxetine, with 85% (22 of 26) opting to taper psychostimulants after stabilizing on VER. This included all children (100%, 15 of 15) and 64% (7 of 11) of adults.
Adverse Events	36% discontinued atomoxetine due to side effects (GI upset [n = 6], irritability [n = 6], fatigue [n = 5], insomnia [n = 1]); 4% discontinued VER due to fatigue.
Study Author Conclusions	Pediatric and adult ADHD patients who have experienced less than optimal response to atomoxetine demonstrate rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability on extended-release viloxazine.
InpharmD Researcher Critique	Strengths include the real-world clinical setting and direct comparison of two treatments. Limitations include the unblinded, open-label design, small sample size, lack of a placebo control, and potential for placebo effect or carry-over effect. Future studies should include larger, more diverse samples and a randomized, double-blind design.

References:

Price MZ, Price RL. Extended-Release Viloxazine Compared with Atomoxetine for Attention Deficit Hyperactivity Disorder. CNS Drugs. 2023 Jul;37(7):655-660. doi: 10.1007/s40263-023-01023-6. Epub 2023 Jul 10. PMID: 37430151; PMCID: PMC10374479.

FDA-Approved Nonstimulants
	Viloxazine ER	Atomoxetine	Guanfacine ER	Clonidine ER
Brand name	Qelbree	Strattera	Intuniv XR	Kapvay
FDA approval date	2021	2002	2009	2010
Mechanism of action	Serotonin-norepinephrine modulating agent	Selective norepinephrine reuptake inhibitor	Centrally acting selective alpha-2A-adrenergic receptor agonist	Centrally acting nonselective alpha-2- adrenergic agonist
Company	Supernus Pharmaceuticals Inc.	Eli Lilly and Company LLC.	Takeda Pharmaceuticals America Inc.	Concordia Pharmaceuticals Inc.
Dosage form	Extended-release	Capsules	Extended-release tablets	Extended-release tablets
Dosages available	capsules 100, 150, and 200 mg capsules	10, 18, 25, 40, 60, 80, or 100 mg of	1 mg, 2 mg, 3 mg, 4 mg	0.1 mg and 0.2 mg
Indications	Indicated for the treatment of ADHD in pediatric patients (6-17 years) and adults	atomoxetine Indicated for the treatment of ADHD in pediatric patients (6-17 years) and adults	Indicated for the treatment of ADHD as monotherapy or as adjunctive therapy to stimulant medications in children	Indicated for the treatment of ADHD as monotherapy or as adjunctive therapy to stimulant medications in children
Oral dose	Children (6-11 years): 100-400 mg; Children (12 years) and Adolescents (<17 years): 200-400 mg; Adolescents (18 years): 200-600 mg	Children and adolescents (up to 70 kg): 0.5 mg/kg daily Children and adolescents (>70 kg): 40 mg	children (6-17 years) 1-7 mg (0.05-0.12 mg/ kg target weight-based dose range)	in children (6-17 years) 0.1-0.4 mg
Administration and discontinuation	Children (6-11 years): Recommended starting dosage is 100 mg once daily; titrate in increments of 100 mg weekly to the maximum recommended dosage of 400 mg once daily Patients (12-17 years): Recommended starting dosage is 200 mg once daily; titrate after I week, by an increment of 200 mg, to the maximum recommended dosage of 400 mg once daily	Children and adolescents (up to 70 kg): Initial daily dose: 0.5 mg/kg Target daily dose: 1.2 mg/kg Maximum total daily dose: 1.4 mg/kg Children and adolescents over 70 kg: Initial daily dose: 40 mg Target daily dose: 80 mg Maximum total daily dose: 100 mg	Begin at a dose of 1 mg once daily and adjust in increments of no more than 1 mg/week; do not crush, chew, or break tablets before swallowing; when discontinuing, taper the dose in decrements of no more than 1 mg every 3 to 7 days to avoid rebound hypertension	Start with one 0.1 mg tablet at bedtime for 1 week; increase daily dosage in increments of 0.1 mg/d at weekly intervals until the desired response is achieved. Take twice a day, with either an equal or higher split dosage being given at bedtime; when discontinuing, taper the dose in decrements of no more than 0.1 mg every 3 to 7 days to avoid rebound hypertension
Dose adjustment due to drug interactions involving the CYP450 enzymes and polymorphisms associated with CYP450 enzymes	--	Dose adjustment may be required in patients with hepatic impairment, or patients concomitantly taking strong CYP2D6 inhibitors, and in patients known to be CYP2D6 poor metabolizers	Decrease Intuniv to 50% of target dosage when coadministered with strong and moderate CYP3A4 inhibitors; based on patient response, consider titrating Intuniv dosage up to double the target dosage more than I to 2 weeks when coadministered with strong and moderate CYP3A4 inducers	--
Contraindications	Concomitant administration of monoamine oxidase inhibitors (MAOI), or dosing within 14 days after discontinuing an MAOI; concomitant administration of sensitive CYPIA2 substrates or CYPIA2 substrates with a narrow therapeutic range	Hypersensitivity to atomoxetine or other constituents of product; STRATTERA use within 2 weeks after discontinuing MAOI or other drugs that affect brain monoamine concentrations; narrow-angle glaucoma; pheochromocytoma, or history of pheochromocytoma; severe cardiovascular disorders that might deteriorate with clinically important increases in HR and BP	History of hypersensitivity to this drug, to any ingredient in the formulation, to any other product containing guanfacine, or component of the container	Known hypersensitivity to clonidine
Effect size	~0.6	~0.7	~0.6	~0.6
Abbreviations: ADHD, attention-deficit hyperactivity disorder; BP, blood pressure; ER, extended-release; HR, heart rate; FDA, Food and Drug Administration.

References:

Adapted from:
Raible H, D'Souza MS. Extended-Release Viloxazine for the Treatment of Attention-Deficit Hyperactivity Disorder in School-Age Children and Adolescents. Ann Pharmacother. 2023;57(12):1436-1448. doi:10.1177/10600280231163252

Comparison of Pharmacokinetic Parameters of Nonstimulants Used to Treat ADHD
	Viloxazine ER	Atomoxetine	Guanfacine ER	Clonidine ER
Active metabolites	No	Yes	No	No
Oral bioavailability, %	88	63	58	~89
Tmax	~5 h	1-2 h	~5 h	7 to 8 h
Half-life	7.02 + 4.74 h	5 h in extensive metabolizers 22 h in poor metabolizers	14-18 h	6.13 + 1.33 h
Effect of food	High-fat meals may increase time to peak concentration by 2 h	In children and adolescents, food reduces peak plasma concentration by 9%; high-fat meal reduces rate of absorption but not extent of absorption	Guanfacine serum concentrations may be increased when taken with grapefruit juice/ products; administration with high-fat meals may increase exposure	No effect
Protein binding, %	76 to 82	98	70	20 to 40
Metabolism	Liver	Liver	Liver	Liver
CYP 450 and other enzymes	CYP2D6, UGTIA9, and UGT2B15	CYP2D6	CYP3A4	CYP2D6
Excretion	Primarily renal; urine: 90%; feces: <1%.	Excreted mainly as metabolites in urine (80%) and in feces (<17%)	Excreted mainly as metabolites in urine; ~50% as unchanged drug	Excreted mainly as metabolites in urine; ~40% to 60% as unchanged drug

References: