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.

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.

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.

The role of placebo response in the efficacy outcome assessment in viloxazine extended-release pivotal trials in paediatric subjects with attention-deficit/hyperactivity disorder.

AIMS: Four Phase 3 studies evaluated efficacy and safety of viloxazine extended-release in the treatment of attention-deficit/hyperactivity disorder (ADHD). The primary efficacy objective-change from baseline in ADHD Rating Scale-5 (ADHD-RS-5) Total score at end of study (EOS)-was not met in one of the studies (812P304). A band-pass analysis was performed to evaluate the impact of placebo response on the results. METHODS: The distribution of placebo response at EOS of each trial was evaluated. The 2.5th and 97.5th percentiles of the distribution of ADHD-RS-5 Total score were used as boundaries for the band-pass analysis. An independent mixed model for repeated measures analysis was conducted for each trial using all eligible data (active and placebo) from the total and band-pass filtered populations. RESULTS: The 2.5th and 97.5th percentiles at EOS were 3.5 and 53.5, respectively. Application of the band-pass filter (filtering out all subjects [active, n = 305 (32.1%) and placebo, n = 134 (33.5%)] of clinical sites with placebo scores <3.5 or >53.5) revealed statistically significant improvement at the primary endpoint (600-mg/d viloxazine ER vs. placebo) in Study 812P304 (mean [confidence interval] = 4.9537 [0.5405-9.3669]), previously masked by a high placebo response (mean [confidence interval] = 3.5756 [-0.3332-7.4844]). The outcome of the analysis indicated that the impact of the band-pass adjustment is greater when placebo response is higher. CONCLUSION: This analysis indicated that a higher placebo response in Study 812P304 confounded the assessment of treatment effect. Application of the band-pass methodology confirmed the positive results of the 3 prior studies and the signal detection confounder in the fourth study.

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.].

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Lisdexamfetamine in Healthy Adults.

BACKGROUND: Viloxazine extended-release is a novel nonstimulant under investigation as a potential treatment for attention-deficit/hyperactivity disorder (ADHD). Given the potential for viloxazine extended-release to be co-administered with stimulant ADHD pharmacotherapies, this trial investigated the pharmacokinetics and safety of combination viloxazine extended-release + lisdexamfetamine dimesylate (lisdexamfetamine) versus viloxazine extended-release and lisdexamfetamine alone. METHODS: In this single-center, cross-over, open-label trial, healthy, non-ADHD adults received single oral doses of 700 mg viloxazine extended-release alone, 50 mg lisdexamfetamine alone, and a combination of viloxazine extended-release (700 mg) + lisdexamfetamine (50 mg), with blood samples collected over 4 days postadministration. The active drug in viloxazine extended-release (viloxazine) and primary metabolite of lisdexamfetamine (d-amphetamine) were measured using chromatographic tandem mass spectrometry. Safety assessments included adverse events, vital signs, echocardiograms, and clinical laboratory evaluations. RESULTS: Thirty-six adults were enrolled, and 34 completed the trial. The least squares geometric mean ratios are reported as [combination / single drug (90% confidence intervals)]. Viloxazine extended-release: Cmax = 95.96% (91.33-100.82), area under the concentration-time curve from 0 to the last measurable time (AUC0-t) = 99.19% (96.53-101.91), and area under the concentration-time curve from 0 to infinity (AUCinf) = 99.23% (96.61-101.93). Lisdexamfetamine: Cmax = 112.78% (109.93-115.71), AUC0-t = 109.64% (105.25-114.22), and AUCinf = 109.52% (105.19-114.03). All reported adverse events, except 1 (moderate vomiting), were mild in severity. CONCLUSIONS: Co-administration of viloxazine extended-release and lisdexamfetamine did not impact the pharmacokinetics of viloxazine or d-amphetamine relative to administration of either drug alone. After single dose administration, the combination appeared to be safe and well tolerated.

A Phase 3, Placebo-Controlled Trial of Once-Daily Viloxazine Extended-Release Capsules in Adolescents With Attention-Deficit/Hyperactivity Disorder.

PURPOSE: This phase 3 clinical trial evaluated the efficacy and safety of viloxazine extended-release capsules (VLX-ER) as a monotherapy for attention-deficit/hyperactivity disorder (ADHD) in adolescents (12-17 years). METHODS: Eligible subjects (n = 310) were randomized to receive once-daily 200 and 400 mg VLX-ER, or placebo for 6 weeks. The primary efficacy end point was change from baseline (CFB) at the end of study (EOS) in ADHD Rating Scale-5 Total score. Key secondary end points were Clinical Global Impression-Improvement score at EOS, CFB at EOS in Conners 3-Parent Short Form Composite T-score, and CFB at EOS in Weiss Functional Impairment Rating Scale-Parent Total average score. RESULTS: In the 200-mg/d and 400-mg/d VLX-ER treatment groups, a significant improvement was found in the CFB at EOS in ADHD Rating Scale-5 Total (P = 0.0232, P = 0.0091) and Inattention (P = 0.0424, P = 0.0390) and Hyperactivity/Impulsivity (P = 0.0069, P = 0.0005) subscale scores versus placebo. The Clinical Global Impression-Improvement score was significantly improved at EOS in the 200-mg/d and 400-mg/d VLX-ER groups versus placebo (P = 0.0042, P = 0.0003). The Conners 3-Parent Short Form composite T-score and Weiss Functional Impairment Rating Scale-Parent Total average score exhibited improvement in both VLX-ER groups; however, the difference versus placebo was not statistically significant. The most common treatment-related adverse events were somnolence, headache, decreased appetite, nausea, and fatigue. The adverse event-related discontinuation rates were <5% in all groups. CONCLUSIONS: Viloxazine extended-release demonstrated statistically significant and clinically meaningful improvement in ADHD symptoms in adolescents and was generally well tolerated.

Evaluating the likelihood to be helped or harmed after treatment with viloxazine extended-release in children and adolescents with attention-deficit/hyperactivity disorder.

AIMS: When clinicians evaluate potential medications for their patients, they must weigh the probability of a treatment's benefits against the possible risks. To this end, the present analyses evaluate the novel nonstimulant viloxazine extended-release (viloxazine ER) using measures of effect size to describe the potential benefits of its treatment in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) as well as the risk of discontinuation because of intolerable adverse events. METHODS: These post hoc analyses use pooled data from four pivotal Phase 3 trials in paediatric patients treated with viloxazine ER. The Likelihood to be Helped or Harmed (LHH) effect size measure was calculated to describe the probability of patients benefiting from treatment vs discontinuing. The Number Needed to Treat (NNT) was calculated from frequently used thresholds of response. The Number Needed to Harm (NNH) was calculated using discontinuations because of adverse events. RESULTS: LHH values for viloxazine ER ranged from 5 to 13, suggesting that subjects were 5-13 times more likely to benefit from, rather than discontinue, viloxazine ER treatment. Specifically, NNT values for viloxazine ER treatment ranged from 6 to 7. NNH values for viloxazine ER treatment ranged from 31 to 74. By convention, single-digit NNTs (<10) suggest the intervention is potentially useful, while NNH values ≥10 for adverse events suggest it is potentially safe or tolerable. CONCLUSIONS: These results indicate that patients with ADHD are likely to benefit from treatment with viloxazine ER, and are unlikely to discontinue, as viloxazine ER treatment was associated with favourable LHH, NNT, and NNH values. Clinicaltrials.gov: NCT03247530, NCT03247543, NCT03247517, NCT03247556.

Metabolism and in vitro drug-drug interaction assessment of viloxazine.

Viloxazine is currently being developed as a treatment for attention deficit/hyperactivity disorder (ADHD). The aim of these studies is to update the understanding of the rat and human metabolism and the in vitro drug-drug interaction profile of viloxazine to a degree where it meets current regulatory standards for such investigations. In vivo absorption-distribution-metabolism-excretion (ADME) studies demonstrated that in humans 5-hydroxylation followed by glucuronidation is the major metabolic route. This route was also seen as a minor route in rats where the major route is O-deethylation with subsequent sulfation. In humans, the 5-hydoxylation pathway is mediated by CYP2D6. An estimate for the fraction of the metabolism via this pathway suggests a PM/EM difference of <2-fold, making it highly unlikely that this will be an issue of clinical significance. Viloxazine forms a unique N-carbamoyl glucuronide in humans. The chemical reactivity characteristics of this metabolite are similar to stable glucuronide conjugates and dissimilar from acyl glucuronides; therefore, it is regarded as a stable Phase II conjugate. In vitro drug-drug interaction (DDI) testing indicates that viloxazine is not a significant inhibitor or inducer of CYPs and transporters with the exception of CYP1A2.

Selective noradrenaline reuptake inhibitors for schizophrenia.

BACKGROUND: Schizophrenia is frequently a chronic and disabling illness with a heterogeneous range of symptoms. The positive symptoms usually respond to antipsychotics but the cognitive and negative symptoms of schizophrenia are difficult to treat with conventional antipsychotics and significantly impact on quality of life and social outcomes. Selective noradrenaline reuptake inhibitors (NRIs) increase prefrontal dopamine and noradrenaline levels without significantly affecting subcortical dopamine levels, making them an attractive candidate for treating cognitive and negative symptoms. OBJECTIVES: To investigate the effects of selective noradrenaline reuptake inhibitors (NRIs), compared with a placebo or control treatment, for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (up to 7 February 2017) which is based on regular searches of MEDLINE, Embase, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and registries of clinical trials. There are no language, date, document type, or publication status limitation for inclusion of records into the register. We inspected references of all included studies for further relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing NRIs with either a control treatment or placebo for people with schizophrenia or related disorders (such as schizoaffective disorder) by any means of diagnosis. We included trials that met our selection criteria and provided useable information. DATA COLLECTION AND ANALYSIS: We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR), for continuous data we calculated mean difference (MD), and for cognitive outcomes we derived standardised mean difference (SMD) effect sizes, all with 95% confidence intervals (CI) and using a random-effects model. We assessed risk of bias for the included studies and used the GRADE approach to produce a 'Summary of findings' table which included our prespecified main outcomes of interest. MAIN RESULTS: Searching identified 113 records. We obtained the full text of 48 of these records for closer inspection. Sixteen trials, randomising a total of 919 participants are included. The majority of trials included adults with schizophrenia or similar illness who were inpatients, and while they were poorly characterised, most appeared to include patients with a chronic presentation. The intervention NRI in nine of the 16 trials was reboxetine, with atomoxetine and viloxazine used in the remaining trials. 14 trials compared NRIs with placebo. Only two trials provided data to compare NRIs against an active control and both compared reboxetine to citalopram but at 4 weeks and 24 weeks respectively so they could not be combined in a meta-analysis.One trial was described as 'open' and we considered it to be at high risk of bias for randomisation and blinding, three trials were at high risk of bias for attrition, six for reporting, and two for other sources of bias. Our main outcomes of interest were significant response or improvement in positive/negative mental state, global state and cognitive functioning, average cognitive functioning scores, significant response or improvement in quality of life and incidence of nausea. All data for main outcomes were short term.NRIs versus placeboMental state results showed significantly greater rates of improvement in negative symptoms scores (1 RCT, n = 50; RR 3.17, 95% CI 1.52 to 6.58; very low quality evidence) with NRIs on the PANSS negative. No data were reported for significant response or improvement in positive symptoms, but average endpoint PANSS positive scores were available and showed no difference between NRIs and placebo (5 RCTs, n = 294; MD -0.16, 95% CI -0.96 to 0.63; low-quality evidence). Improvement in clinical global status was similar between groups (1 RCT, n = 28; RR 0.99, 95% CI 0.45 to 2.20; very low quality evidence). Significant response or improvement in cognitive functioning data were not reported. Average composite cognitive scores showed no difference between NRIs and placebo (4 RCTs, n = 180; SMD 0.04, 95% CI -0.28 to 0.36; low-quality evidence). Significant response or improvement in quality of life data were not reported, however average endpoint scores from the GQOLI-74 were reported. Those receiving NRIs had better quality of life scores compared to placebo (1 RCT, n = 114; MD 9.36, 95% CI 7.89 to 10.83; very low quality evidence). All-cause withdrawals did not differ between the treatment groups (8 RCTs, n = 401, RR 0.94 95% CI 0.63 to 1.39; moderate-quality evidence). Rates of nausea were not greater with NRIs (3 RCTs, n = 176; RR 0.49, 95% CI 0.10 to 2.41; low-quality evidence). AUTHORS' CONCLUSIONS: Our results provide tentative very low quality evidence that compared to placebo, NRIs (specifically reboxetine) may have a benefit on the negative symptoms of schizophrenia. Limited evidence also suggests that NRIs have no effect on the positive symptoms of schizophrenia or cognitive functioning. NRIs appear generally well tolerated with no real differences in adverse effects such as nausea noted between NRIs and placebo. However, these results are based on short-term follow-up and are poor quality - there is need for more good-quality evidence. A large RCT of reboxetine over a longer period of time, focusing specifically on negative and cognitive symptoms as well as more detailed and comprehensive reporting of outcomes, including adverse events, is required.

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.

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.

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.

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.

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 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.

Successful Add-on Viloxazine to Clozapine-Responsive Schizophrenia Mitigated Cognitive, Negative and Metabolic Domains.

Early-onset schizophrenia is notorious for poor prognostication and treatment-refractoriness. Clozapine remains a viable option, albeit off-label, but is clearly underutilized in this population. Use is typically fraught with panoply of drastic side effects. Here, authors report on an adolescent case with schizophrenia that responded ultimately to clozapine. Add-on viloxazine was advantageous spanning different symptom domains, mitigating metabolic parameters and addressing clozapine-sialorrhea. This might open new venues for such complicated, yet commonplace, clinical scenarios.