An Open-Label Extension Study Assessing the Long-Term Safety and Efficacy of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND AND OBJECTIVE: Viloxazine ER (extended-release capsules; Qelbree®) is a nonstimulant medication that has been approved by the United States Food and Drug Administration (FDA) for treatment of attention-deficit/hyperactivity disorder (ADHD) in children (> 6 years old) and adults. This phase 3 open-label extension to a pivotal phase 3, double-blind trial evaluated the long-term safety and continued efficacy of viloxazine ER in adults with ADHD. METHODS: This was a multicenter, flexible-dose, open-label extension to a phase III, double-blind, placebo-controlled trial (NCT04016779). Viloxazine ER was initiated at 200 mg/day and adjusted (between 200 and 600 mg/day) to achieve optimal efficacy and tolerability. Trial enrollment was halted temporarily (24 March 2020 to 23 July 2020) due to the coronavirus disease 2019 (COVID-19) pandemic. Participants completing double-blind treatment during that time were offered delayed enrollment upon trial requalification. Safety outcomes were the primary objectives. Secondary objectives were efficacy outcomes, including the ADHD Investigator Symptom Rating Scale (AISRS), and were assessed relative to double-blind baseline (or trial re-entry baseline for those whose enrollment was delayed by the COVID-19 pandemic). RESULTS: Overall, 159 participants (133 immediate and 26 delayed rollover) received viloxazine ER, with a mean exposure of 265 ± 254.9 days. Adverse events (AEs) included (> 10% incidence) insomnia (13.8%), nausea (13.8%), headache (10.7%), and fatigue (10.1%). AEs led to discontinuation for 17.6% of participants [most commonly insomnia (2.5%), nausea (2.5%), and fatigue (1.9%)]. AISRS total score [baseline mean ± standard deviation (SD): 37.9 ± 6.3] improved by the first follow-up visit (-11.4 ± 9.5; week 2) with continued improvement at subsequent visits (last on-study visit: -18.2 ± 11.54). Similar patterns of improvement were seen for other measures of efficacy, including quality of life and executive function. Following initial dose optimization, most participants (73%) used viloxazine ER doses ≥ 400 mg/day, with 36% using doses of 600 mg/day. CONCLUSIONS: Long-term viloxazine ER use was well tolerated, with no new long-term safety findings. Improvements in ADHD symptoms and associated measures were sustained throughout trial participation. In total, 73% percent of adult participants in this long-term study used viloxazine ER doses of 400 mg or more during maintenance treatment. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04143217.

Attention-deficit/hyperactivity disorder (ADHD) is common in children and adults and characterized by inattention, impulsivity, and hyperactivity that can substantially interfere with everyday life. On the basis of positive efficacy and safety results from clinical studies in children, adolescents, and adults, viloxazine ER (viloxazine extended-release capsules) received US Food and Drug Administration (FDA) approval as a new treatment for ADHD and is marketed under the brand name Qelbree® (Supernus Pharmaceuticals, Inc). Adults who participated in the short-term (6 weeks) double-blind study that eventually led to the FDA approval of viloxazine ER were invited to enroll in this open-label extension trial to monitor the medication's long-term safety and continued efficacy. This study also provided a pathway for study participants to continue receiving viloxazine ER until its FDA approval and commercial availability. Participants in the study received viloxazine ER at dosages between 200 and 600 mg/day on the basis of symptom response and side effects (most used at least 400 mg/day). Viloxazine ER was demonstrated to have a good safety and tolerability profile. The most common side effects were insomnia (13.8%), nausea (13.8%), headache (10.7%), and fatigue (10.1%). Long-term treatment led to continued improvement in ADHD symptoms, quality of life, and executive function (executive function includes cognitive skills such as organizing and following through with tasks). The study results further support the continued use of viloxazine ER as a long-term treatment option for adults with ADHD.

Development of fluorescence probe for spectrofluorimetric determination of viloxazine hydrochloride in pharmaceutical form and rat plasma; additional pharmacokinetic study.

Attention deficit hyperactivity disorder (ADHD) is a neurological condition frequently identified in early childhood and frequently co-occurs with other neuropsychological disorders, particularly autism. Viloxazine hydrochloride, a non-stimulant medication, has recently gained approval for treating attention-deficit hyperactivity disorder. This paper describes the first spectrofluorimetric method for precisely measuring the content of viloxazine in pharmaceutical capsules and rat plasma. This method employed NBD-Cl (4-chloro-7-nitrobenzo-2-oxa-1,3-diazole) as a fluorescent probe, which transformed viloxazine in an alkaline environment into a remarkably sensitive fluorescent adduct. Upon excitation at 476 nm, this adduct becomes detectable at a wavelength of 536 nm. The method was validated using ICH criteria, revealing acceptable linearity across a concentration range of 200-2000 ng/ml and high sensitivity with LOD and LOQ values of 46.774 ng/ml and 141.741 ng/ml, respectively. This method was adeptly applied in a pharmacokinetic study of viloxazine in rat plasma following a single oral dose (10 mg/kg), yielding a mean peak plasma concentration (Cmax) of 1721 ng/ml, achieved within 1.5 h. Furthermore, the environmental impact of the technique was assessed using two greenness assessment tools, revealing a notable level of eco-friendliness and sustainability.

Assessment of centanafadine in adults with attention-deficit/hyperactivity disorder: A matching-adjusted indirect comparison vs lisdexamfetamine dimesylate, atomoxetine hydrochloride, and viloxazine extended-release.

BACKGROUND: Head-to-head trials comparing centanafadine, an investigational therapy for adults with attention-deficit/hyperactivity disorder (ADHD), with other treatment options are lacking. OBJECTIVE: To compare safety and efficacy outcomes of centanafadine sustained-release vs lisdexamfetamine dimesylate (lisdexamfetamine), atomoxetine hydrochloride (atomoxetine), and viloxazine extended-release (viloxazine ER), respectively, using matching-adjusted indirect comparison (MAIC). METHODS: This MAIC included patient-level data pooled from 2 centanafadine trials (NCT03605680 and NCT03605836) and published aggregate data from comparable trials of 3 comparators-lisdexamfetamine (NCT00334880), atomoxetine (NCT00190736), and viloxazine ER (NCT04016779)-in adult patients with ADHD. Propensity score weighting was used to match characteristics of individual patients from the centanafadine trials to aggregate baseline characteristics from the respective comparator trials. Safety outcomes were rates of adverse events for which information was available in the centanafadine and respective comparator trials. Efficacy outcome was mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) score (ADHD Rating Scale [ADHD-RS] was used as proxy in the comparison with lisdexamfetamine). Anchored indirect comparisons were conducted across matched populations of the centanafadine and respective comparator trials. RESULTS: After matching, baseline characteristics in the centanafadine trials were the same as those in the respective comparator trials. Compared with lisdexamfetamine, centanafadine was associated with a significantly lower risk of lack of appetite (risk difference [RD] in percentage points: 23.42), dry mouth (19.27), insomnia (15.35), anxiety (5.21), nausea (4.90), feeling jittery (3.70), and diarrhea (3.47) (all P < 0.05) but a smaller reduction in the AISRS/ADHD-RS score (6.58-point difference; P < 0.05). Compared with atomoxetine, centanafadine was associated with a significantly lower risk of nausea (RD in percentage points: 18.64), dry mouth (17.44), fatigue (9.21), erectile dysfunction (6.76), lack of appetite (6.71), and urinary hesitation (5.84) (all P < 0.05) and no statistically significant difference in the change in AISRS score. Compared with viloxazine ER, centanafadine was associated with 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) and no statistically significant difference in the change in AISRS score. CONCLUSIONS: In an anchored MAIC, centanafadine showed a significantly better short-term safety profile than lisdexamfetamine, atomoxetine, and viloxazine ER; efficacy was lower than with lisdexamfetamine and comparable (ie, nondifferent) with atomoxetine and viloxazine ER. This MAIC provides important insights on the relative safety and efficacy of common treatment options to help inform treatment decisions in adults with ADHD. Safety assessment was limited to rates of adverse events reported in both trials of a given comparison. STUDY REGISTRATION NUMBERS: NCT03605680, NCT03605836, NCT00334880, NCT00190736, and NCT04016779.

Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics.

BACKGROUND AND OBJECTIVE: Viloxazine extended-release (ER) [Qelbree®] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics. METHODS: Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3-5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student's t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers. RESULTS: The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUCt), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞) was 99.11 (95.84-102.49), 436.15 (398.87-476.92), and 583.35 (262.41-1296.80), respectively; 150.76 (126.03-180.35), 185.76 (155.01-222.61), and 189.71 (160.37-224.42) for dextromethorphan Cmax, AUCt, and AUC∞, respectively; and 112.81 (104.71-121.54), 167.56 (153.05-183.45), and 168.91 (154.38-184.80) for midazolam Cmax, AUCt, and AUC∞, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were Cmax 120.70 (102.33-142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC0-24 125.66 (105.36-149.87)). CONCLUSION: Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.

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

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention and/or hyperactivity and impulsivity. Viloxazine extended-release (ER) capsules (Qelbree®) is a US Food and Drug Administration-approved nonstimulant treatment option for children, adolescents, and adults with ADHD. AREAS COVERED: This review manuscript summarizes the neurobiology of ADHD and currently available treatment options before discussing viloxazine pharmacology, efficacy, safety, and tolerability data from phase II and III trials in children and adolescents (6-17 years old). Viloxazine clinical efficacy has also been further demonstrated by post hoc analyses of pediatric clinical trial results. EXPERT OPINION: Current stimulant and nonstimulant treatments for ADHD may be suboptimal given low response rates and that tolerability issues are frequently experienced. Preclinical and clinical evidence has implicated both the role of catecholamine and serotonin signaling in the pathophysiology of ADHD and the pharmacologic effect of viloxazine on these critical neurotransmitter systems. With a relatively rapid onset of action, sustained symptom improvement, and clinical benefit in ADHD-associated impairments (functional and social), viloxazine ER represents a novel and emerging ADHD treatment option.

Comparing Pharmacotherapies for ADHD in Adults: Evidence From Outcome-Focused Analysis of Food and Drug Administration Drug Label Registration Trials.

OBJECTIVE: We appraised whether FDA registration trials for ADHD pharmacotherapy in adults provides comparable information to inform treatment expectations. METHOD: Comparison of ADHD outcome measure patterns in ADHD pharmacotherapy FDA drug label source studies. RESULTS: Among stimulants, from fixed-dose titration data, amphetamine agents had numerically higher placebo-corrected symptom improvement and symptom effect sizes than methylphenidate agents. Symptom effect sizes were lower in the flexible dosing registration studies of atomoxetine and viloxazine. Varying responder definitions were analyzable, based on ≥30% symptom improvement and/or CGI-I improvement of "much" or "very much improved." Number of exposures needed to create these responses were lower for stimulants than for viloxazine. CONCLUSION: Heterogeneity in the design and analysis of FDA drug label source trials restricts implications for clinical practice. Research conducted using replicated designs, direct comparison of available treatments, and outcome analyses that generalize to clinical care could better inform clinical decision making.

Viloxazine extended-release capsules for the treatment of attention-deficit/ hyperactivity disorder in adult patients.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder with symptoms that may persist in up to 90% of adults diagnosed during childhood and continue to cause significant impairment throughout the lifespan. In the United States (US), amphetamine and methylphenidate formulations have been available to treat ADHD for several decades. Only one nonstimulant, atomoxetine, was available for the treatment of ADHD in adults until recently. In April 2022, a second nonstimulant, viloxazine extended-release (VLX-ER), became available in the US for the treatment of adult ADHD. Efficacy was previously established in placebo-controlled trials in children and adolescents. AREAS COVERED: VLX-ER is a norepinephrine reuptake inhibitor with serotonin activity. The efficacy in adults, adverse event profile, pharmacokinetics, drug-drug interactions, and metabolism of VLX-ER are reviewed. EXPERT OPINION: Despite the availability of effective pharmacological treatments for ADHD, many patients discontinue treatment in less than 1 year. Stimulants are effective in more than 80% of patients; however, some may have difficulty tolerating them. Although there were no head-to-head studies, the effect size of VLX-ER in an adult efficacy trial was lower than has been shown for stimulants. Nevertheless, the approval of VLX-ER adds another effective ADHD treatment option for adults.

Extended-Release Viloxazine Compared with Atomoxetine for Attention Deficit Hyperactivity Disorder.

BACKGROUND AND OBJECTIVE: In our outpatient pediatric and adult psychiatry centers, we reserve psychostimulants for predominantly inattentive attention deficit hyperactivity disorder (ADHD) due to the potential for appetite and growth suppression, insomnia, wear off, exacerbation of mood, anxiety, and tics, or misuse. We utilize extended-release (ER) alpha-2 agonists primarily for hyperactivity/impulsivity but find them less effective for inattention, and they can cause sedation and hypotension. Oftentimes, we need to combine an alpha-2 agonist for behavior with psychostimulants for inattention. We employ atomoxetine or viloxazine ER (VER) for combined ADHD. However, our patients' insurers mandate a trial of generic atomoxetine prior to covering branded VER. The objective of this study was to determine whether pediatric and adult patients taking atomoxetine for DSM-5-TR ADHD combined type would experience improvement in ADHD symptoms following voluntary, open-label switch to VER. METHODS: 50 patients (35 children) received mean doses of atomoxetine 60 mg (25-100 mg once daily) followed by VER 300 mg (100-600 mg once daily) after a 5-day atomoxetine washout. Both atomoxetine and VER were flexibly titrated according to US Food and Drug Administration (FDA) guidelines. The pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and the Adult Investigator Symptom Rating Scale (AISRS) were completed prior to starting atomoxetine, and 4 weeks after treatment with atomoxetine or upon earlier response or discontinuation due to side effects, whichever occurred first; the same protocol was used after treatment with VER. We conducted a blinded, de-identified, retrospective review of charts from these 50 patients in the regular course of outpatient practice. Statistical analysis was performed using a within-subject, 2-tailed t-test with significance level of p < 0.05. RESULTS: From the baseline total ADHD-RS-5 mean score (40.3 ± 10.3), improvements were greater on VER (13.9 ± 10.2) than atomoxetine (33.1 ± 12.1; t = - 10.12, p < 0.00001) in inattention (t = - 8.57, p < 0.00001) and in hyperactivity/impulsivity (t = - 9.87, p < 0.00001). From the baseline total AISRS mean score (37.3 ± 11.8), improvements were greater on VER (11.9 ± 9.4) than atomoxetine (28.8 ± 14.9; t = - 4.18, p = 0.0009) in inattention (t = - 3.50, p < 0.004) and in hyperactivity/impulsivity (t = - 3.90, p < 0.002). Of patients on VER, 86% reported positive response by 2 weeks versus 14% on atomoxetine. A total of 36% discontinued atomoxetine for side effects, including gastrointestinal (GI) upset (6 patients), irritability (6), fatigue (5), and insomnia (1), versus 4% who discontinued VER due to fatigue. A total of 96% preferred VER over atomoxetine, with 85% (22 out of 26) choosing to taper psychostimulants following stabilization on VER. 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.

Nonstimulant Medications for Attention-Deficit/Hyperactivity Disorder (ADHD) in Adults: Systematic Review and Meta-analysis.

BACKGROUND: For some adults with Attention-Deficit/Hyperactivity Disorder (ADHD), nonstimulants need to be considered either as a monotherapy or as an adjunct to stimulants. OBJECTIVES: The objectives of this systematic review and meta-analysis were to assess the efficacy, acceptability, and tolerability of nonstimulants in adults with ADHD. METHODS: Data sources, searches, and study selection were based on a previously published network meta-analysis of randomized clinical trials (RCTs) by Cortese at al. (Lancet Psychiatry 5(9):727-738, 2018), which we updated in March 2022. Specifically, we searched PubMed, BIOSIS Previews, CINAHL, the Cochrane Central Register of Controlled Trials, EMBASE, ERIC, MEDLINE, PsycINFO, OpenGrey, Web of Science Core Collection, ProQuest Dissertations and Theses (UK and Ireland), ProQuest Dissertations and Theses (abstracts and international), and the WHO International Trials Registry Platform, including ClinicalTrials.gov for double-blind RCTs with a placebo arm, lasting at least one week, including adults with a diagnosis of ADHD based on DSM-III, DSM-III-R, DSM-IV(TR), DSM-5 or ICD-9- or 10, and reporting data on efficacy, tolerability (drop-out due to side effects) and acceptability (drop-out due to any cause) of guanfacine, clonidine, or atomoxetine. Additionally, we searched for RCTs of viloxazine extended release (ER), approved for ADHD in 2021. Random-effects meta-analyses were conducted, and the risk of bias for individual RCTs was assessed using the Cochrane Risk of Bias tool. RESULTS: We included 18 studies in the meta-analyses (4308 participants) plus one additional study in the narrative synthesis (374 participants). The meta-analysis showed that atomoxetine (15 RCTs) (Hedge's g = - 0.48, 95% CI [- 0.64; - 0.33]), guanfacine (two RCTs) (Hedge's g = - 0.66, 95% CI [- 0.94; - 0.38]) and viloxazine ER (one RCT) were significantly more efficacious than placebo. Atomoxetine was less well tolerated than placebo, while tolerability of guanfacine and viloxazine ER could not be meta-analysed, since only one study, for each medication, reported on it. CONCLUSIONS: All investigated nonstimulants were more efficacious in the treatment of ADHD in adults, than placebo, while the placebo had better acceptability and tolerability. PROTOCOL: https://osf.io/5vnmt/?view_only=2bf87ed12ba94645babedceeee4c0120 .

Extended-Release Viloxazine for the Treatment of Attention-Deficit Hyperactivity Disorder in School-Age Children and Adolescents.

OBJECTIVE: To describe the efficacy and safety of extended-release viloxazine (viloxazine ER; Qelbree) for the treatment of attention-deficit hyperactivity disorder (ADHD) in school-age children and adolescents (6-17 years). DATA SOURCES: A literature search was conducted with PubMed using the following terms: viloxazine and ADHD (August 1, 2017 to February 1, 2023). STUDY SELECTION AND DATA EXTRACTION: All relevant English-language articles examining the efficacy and safety of viloxazine ER were considered for inclusion. DATA SYNTHESIS: Phase III studies reported significant improvement in ADHD symptoms after viloxazine ER treatment in both school-age children (100 mg/d, P = 0.0004 and 200 mg/d, P < 0.0001; NCT03247530) and adolescents (200 mg/d, P = 0.0232; 400 mg/d, P = 0.0091; NCT03247517) compared with placebo. Common adverse effects associated with viloxazine ER included somnolence, fatigue, irritability, decreased appetite, and headache. Together, the studies demonstrated the efficacy and safety of viloxazine ER in patients with ADHD. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Viloxazine ER is a serotonin-norepinephrine modulator, which is administered once daily orally. It is classified as a nonstimulant medication, which can be used in patients with ADHD who do not respond to or cannot tolerate stimulant medications. Even though atomoxetine and viloxazine ER have not been directly compared, clinical studies have suggested that viloxazine ER has a faster onset of action (~1-2 weeks) compared with atomoxetine (~4 weeks). Like atomoxetine, viloxazine ER carries a boxed warning for suicidal ideation and/or behavior. CONCLUSION: Viloxazine ER is a useful addition to other nonstimulant medications available to treat patients with ADHD.

Response of peer relations and social activities to treatment with viloxazine extended-release capsules (Qelbree® ): A post hoc analysis of four randomized clinical trials of children and adolescents with attention-deficit/hyperactivity disorder.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is associated with impairments related to peer relations (PR) and social activities (SA). The objective of this post hoc analysis was to assess the degree to which viloxazine extended-release (viloxazine ER; viloxazine extended-release capsules; Qelbree® ) improves clinical assessments of PR and SA in children and adolescents with ADHD. METHODS: Data were used from four Phase III placebo-controlled trials of 100 to 600 mg/day of viloxazine ER (N = 1354; 6-17 years of age). PR and SA were measured with the Peer Relations content scale of the Conners 3rd Edition Parent Short Form's Peer Relation content scale (C3PS-PR) and the Social Activities domain of the Weiss Functional Impairment Rating Scale-Parent Report's (WFIRS-P-SA) at baseline and end of study. ADHD symptoms were assessed weekly with the ADHD Rating Scale, 5th Edition. The analyses relied on the general linear mixed model with the subject as a random effect. RESULTS: Improvement in C3PS-PR (p = .0035) and WFIRS-P-SA (p = .0029) scores were significantly greater in subjects treated with viloxazine ER compared with placebo. When using measures of clinically meaningful response, the C3PS-PR responder rate was significantly higher for viloxazine ER (19.2%) compared with placebo (14.1%) and the difference was statistically significant (p = .0311); the Number Needed to Treat (NNT) was 19.6. The WFIRS-P-SA responder rate was significantly higher for viloxazine ER (43.2%) compared with placebo (28.5%) and the difference was statistically significant (p < .0001); the NNT was 6.8. The standardized mean difference effect size for both PR and SA was 0.09. CONCLUSIONS: Viloxazine ER significantly reduces the impairment of PR and SA in children and adolescents with ADHD. Although its effects on PR and SA are modest, many ADHD patients can be expected to achieve clinically meaningful improvements in PR and SA with viloxazine ER treatment for longer than 6 weeks.

A post hoc analysis of the effect of viloxazine extended-release capsules on learning and school problems in children and adolescents with attention-deficit/hyperactivity disorder.

Improvement in attention-deficit/hyperactivity disorder (ADHD) symptoms vs. placebo was reported in a series of pediatric clinical trials of viloxazine extended-release capsules (viloxazine ER; Qelbree™). This post hoc analysis of those studies evaluated the effect of viloxazine ER on learning and school problems (LSPs). We used data from four Phase 3 placebo-controlled trials of 100-600 mg/day viloxazine ER (N = 1354; 6-17 years of age). LSPs were evaluated using the School domain of the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P-S) and the Learning Problems content scale of the Conners 3rd Edition-Parent Short Form (C3PS-LP) at baseline and end of study (≥ Week 6). ADHD symptoms were assessed weekly using the ADHD Rating Scale 5th Edition. The analyses were performed using the general linear mixed model with participant as a random effect. The responder analyses were performed using the Chi-square test. Viloxazine ER demonstrated significantly greater improvements in WFIRS-P-S (p < 0.0001) and C3PS-LP (p = 0.0113) scores vs. placebo. The response rate for the WFIRS-P-S was significantly greater for viloxazine ER vs. placebo (p = 0.001), and the number needed to treat (NNT) was 10.3 (effect size 0.7). Conversely, response rates for C3PS-LP did not differ between groups (p = 0.9069). In addition to ADHD symptoms improvement demonstrated in previous studies, viloxazine ER significantly reduced LSPs in pediatric subjects with ADHD. The responder analyses and NNT estimates indicate that a substantial number of children and adolescents with ADHD treated with viloxazine ER improved in clinically assessed LSPs.

Predicting efficacy of viloxazine extended-release treatment in adults with ADHD using an early change in ADHD symptoms: Machine learning Post Hoc analysis of a phase 3 clinical trial.

Early response to viloxazine extended-release (viloxazine ER, Qelbree®) treatment predicted efficacy outcome in pediatric subjects with attention-deficit/hyperactivity disorder (ADHD). This study sought to determine whether the machine learning lasso model used in the pediatric study would predict response to viloxazine ER in an adult population based on early improvements in ADHD symptoms. We used data from a double-blind, placebo-controlled, flexible-dose (200-600 mg) study of viloxazine ER (N = 354; 18 to 60 years old). Area under the Receiver Operating Characteristic Curve (ROC AUC) statistics were computed using the lasso model from pediatric data to predict responder status in adults. Response was defined as ≥50% reduction from baseline in the Adult ADHD Investigator Symptoms Rating Scale (AISRS) Total score at Week 6. The adult study sample included 127 viloxazine ER-treated subjects with Week 6 data. Fifty-one subjects (40.2%) were categorized as responders. The ROC curves indicated that data collected up to Week 2 were sufficient to accurately predict treatment response at Week 6 with 68% positive predictive power, 80% sensitivity, and 74% specificity. This analysis demonstrated that the predictive model estimated from the child data generalizes to adults with ADHD, further supporting the consistency of viloxazine ER treatment across age groups.

A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Efficacy and Safety of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND AND OBJECTIVE: Attention-deficit/hyperactivity disorder is a neurodevelopmental disorder that typically begins in childhood and often persists into adulthood. Recent phase III trials have demonstrated the efficacy and safety of viloxazine extended-release capsules (viloxazine ER; Qelbree®) in pediatrics (6-17 years of age). The aim of this study was to evaluate the efficacy and safety of viloxazine ER in adults with attention-deficit/hyperactivity disorder. METHODS: This was a phase III, randomized, double-blind, placebo-controlled, two-arm trial in adults (18-65 years of age) with attention-deficit/hyperactivity disorder. Eligible subjects were randomized 1:1 to viloxazine ER (flexible dose of 200-600 mg/day) or matched placebo. The primary efficacy endpoint was the change from baseline at end of study (week 6) in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score. The key secondary endpoint was the change from baseline at end of study in the Clinical Global Impressions-Severity of Illness (CGI-S) score. Additional secondary outcome measures included the AISRS Inattention and Hyperactivity/Impulsivity subscales, the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), the Generalized Anxiety Disorder-7 Item (GAD-7), and the Clinical Global Impressions-Improvement (CGI-I); each was analyzed at end of study. Responder rates on CGI scales and the AISRS were also assessed. RESULTS: A total of 374 subjects were randomized. At end of study, the mean viloxazine ER dose was 504 mg. The reduction in the change from baseline at end of study AISRS total score (least-square means ± standard error) was significantly greater in subjects treated with viloxazine ER (-15.5 ± 0.91) compared with placebo (-11.7 ± 0.90), p = 0.0040. The reduction in the CGI-S score was also significantly greater in subjects treated with viloxazine ER (-1.4 ± 0.10) compared with placebo (-1.0 ± 0.10), p = 0.0023. The viloxazine ER group demonstrated significantly greater improvements in the AISRS Inattention (p = 0.0015) and Hyperactivity/Impulsivity (p = 0.0380) subscales, the CGI-I (p = 0.0076), and the BRIEF-A Global Executive Composite (p = 0.0468) and Metacognition Index (p = 0.0100). Analysis of categorical secondary endpoints revealed that the viloxazine ER group had a significantly higher AISRS 30% response rate compared with placebo (p = 0.0395); all other comparisons were not significant. Many treatment effects (including the primary and key secondary endpoints) were significant by week 2. The most common treatment-related adverse events that occurred in ≥5% of subjects receiving viloxazine ER were insomnia (14.8%), fatigue (11.6%), nausea (10.1%), decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). Viloxazine ER was well tolerated, with a 9.0% discontinuation rate due to adverse events compared with 4.9% in the placebo group. CONCLUSIONS: Treatment with viloxazine ER resulted in a statistically significant improvement in primary and key secondary endpoints, indicating improvements in attention-deficit/hyperactivity disorder symptomology, executive function, and overall clinical illness severity in adults. Viloxazine ER was well tolerated at the tested doses in adults with attention-deficit/hyperactivity disorder. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04016779.

Attention-deficit/hyperactivity disorder (ADHD) is a condition characterized by inattention (difficulty maintaining focus), and/or impulsiveness/hyperactivity. In 2021, a nonstimulant medication called viloxazine ER (brand name: Qelbree^®) received US FDA-approval for ADHD in children and adolescents (aged 6 to 17 years), based on efficacy and safety demonstrated in clinical trials. Here we present results of a phase 3, randomized, double-blind, placebo-controlled, clinical trial that enrolled 374 adults with ADHD. In this trial, half the patients received viloxazine ER, and half received placebo (identical capsule without active ingredient). Medication doses ranged from 200­600 mg/day, based on symptom response and presence of side effects. To reduce bias, patients and investigators did not know which medication the patient was receiving. The primary measure of efficacy was the Adult ADHD Investigator Symptom Rating Scale (AISRS), a standardized questionnaire rating presence and severity of patient-reported ADHD symptoms. At the end of the 6-week trial, participants receiving viloxazine ER showed greater improvement in ADHD symptoms according to AISRS than those receiving placebo. Improvement was seen in both the Inattentive and Impulsive/Hyperactive components of ADHD and in other study measures, including a measure of behaviors called Executive Function. Viloxazine ER was generally safe and well-tolerated in the trial. The most common side effects were insomnia (14.8%), fatigue (11.6%), and nausea (10.1%). Overall, 9.0% of patients receiving viloxazine and 5% receiving placebo left the trial because of side effects. Due to these positive results, the US FDA recently approved viloxazine ER to treat adults with ADHD.

Viloxazine ER (Qelbree®): A New Non-Stimulant Option in the Treatment of Pediatric Attention-Deficit/Hyperactivity Disorder.

The current article provides a brief overview for psychiatric-mental health nurse practitioners of viloxazine extended-release (Qelbree®) for the treatment of pediatric attention-deficit/hyperactivity disorder. [Journal of Psychosocial Nursing and Mental Health Services, 60(7), 7-9.].

Evaluating the pharmacokinetics of extended release viloxazine in the treatment of children with attention-deficit/hyperactivity disorder.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and impacts function negatively in multiple settings. Current treatments include stimulants, which inhibit the reuptake of dopamine and norepinephrine, a nonstimulant norepinephrine reuptake inhibitor (NRI) atomoxetine, and alpha-2 agonists clonidine extended release (ER) and guanfacine ER. Despite the effectiveness of these medications some patients do not respond to available drugs or may experience tolerability issues that hinder their use. AREAS COVERED: Viloxazine, a serotonin norepinephrine modulating agent, was used outside of the United States (U.S.) as an effective antidepressant for several decades, but its use fell out of favor due to the need for multiple daily dosing. An ER viloxazine formulation was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD. The efficacy, pharmacokinetics and metabolism of viloxazine and viloxazine ER are reviewed. EXPERT OPINION: Viloxazine ER is the first nonstimulant approved to treat ADHD in more than a decade. Although they have not been directly compared, the effect size of viloxazine ER is less than has been observed for stimulants. However, its pharmacokinetic properties and tolerability make viloxazine ER a useful addition to the collection of FDA approved ADHD treatments.