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.

Current nonstimulant medications for adults with attention-deficit/hyperactivity disorder.

INTRODUCTION: Stimulants, including methylphenidate and amphetamines, are the first-line pharmacological treatment of ADHD in adults. However, in patients who do not respond or poorly tolerate stimulants, non-stimulant medications are usually recommended. AREAS COVERED: The authors provide a narrative review of the literature on non-stimulant treatments for adult ADHD, including controlled and observational clinical studies conducted on adult samples. Atomoxetine has been extensively studied and showed significant efficacy in treating adult ADHD. Issues related to dosing, treatment duration, safety, and use in the case of psychiatric comorbidity are summarized. Among other compounds indicated for ADHD in adults, antidepressants sharing at least a noradrenergic or dopaminergic component, including tricyclic compounds, bupropion, and viloxazine, have shown demonstratable efficacy. Evidence is also available for antihypertensives, particularly guanfacine, as well as memantine, metadoxine, and mood stabilizers, while negative findings have emerged for galantamine, antipsychotics, and cannabinoids. EXPERT OPINION: While according to clinical guidelines, atomoxetine may serve as the only second-line option in adults with ADHD, several other nonstimulant compounds may be effectively used in order to personalize treatment based on comorbid conditions and ADHD features. Nevertheless, further research is needed to identify and test more personalized treatment strategies for adults with ADHD.

Recent advances in pharmacological management of attention-deficit/hyperactivity disorder: moving beyond stimulants.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder characterized by impairing inattention and/or hyperactivity and impulsivity in children and adults. Although medications have been available to treat ADHD symptoms for decades, many are stimulant formulations. Stimulants, such as amphetamine and methylphenidate, are available in more than two dozen formulations, but all have similar adverse effects and carry a risk of misuse and dependence. AREAS COVERED: In the United States (US), several nonstimulants are available to treat ADHD. Two, including atomoxetine and viloxazine extended-release (ER), are approved by the Food and Drug Administration for the treatment of ADHD in children and adults. Two others, clonidine ER and guanfacine ER, are only approved for children and adolescents in the US. Several other compounds are under investigation. Drugs in Phase 3 trials include centanafadine, solriamfetol, and L-threonic acid magnesium salt. Efficacy and safety data for nonstimulants is presented. EXPERT OPINION: Although many effective formulations for the treatment of ADHD are available, more than 33% of children and 50% of adults discontinue treatment during the first year. The lack of individual drug response and tolerability are reasons many stop treatment. The development of new nonstimulants may offer hope for patients who need medication alternatives.

Attention-deficit/hyperactivity disorder in pregnancy and the postpartum period.

Attention-deficit/hyperactivity disorder is a childhood-onset neurodevelopmental disorder that frequently persists into adulthood with 3% of adult women having a diagnosis of attention-deficit/hyperactivity disorder. Many women are diagnosed and treated during their reproductive years, which leads to management implications during pregnancy and the postpartum period. We know from clinical practice that attention-deficit/hyperactivity disorder symptoms frequently become challenging to manage during the perinatal period and require additional support and attention. There is often uncertainty among healthcare providers about the management of attention-deficit/hyperactivity disorder in the perinatal period, particularly the safety of pharmacotherapy for the developing fetus. This guideline is focused on best practices in managing attention-deficit/hyperactivity disorder in the perinatal period. We recommend (1) mitigating the risks associated with attention-deficit/hyperactivity disorder that worsen during the perinatal period via individualized treatment planning; (2) providing psychoeducation, self-management strategies or coaching, and psychotherapies; and, for those with moderate or severe attention-deficit/hyperactivity disorder, (3) considering pharmacotherapy for attention-deficit/hyperactivity disorder, which largely has reassuring safety data. Specifically, providers should work collaboratively with patients and their support networks to balance the risks of perinatal attention-deficit/hyperactivity disorder medication with the risks of inadequately treated attention-deficit/hyperactivity disorder during pregnancy. The risks and impacts of attention-deficit/hyperactivity disorder in pregnancy can be successfully managed through preconception counselling and appropriate perinatal planning, management, and support.

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.

Viloxazine Increases Extracellular Concentrations of Norepinephrine, Dopamine, and Serotonin in the Rat Prefrontal Cortex at Doses Relevant for the Treatment of Attention-Deficit/Hyperactivity Disorder.

Background: Viloxazine ER (viloxazine extended-release capsules; Qelbree®), a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment, has known activity as a norepinephrine (NE) transporter (NET) inhibitor. In vitro studies have also shown direct pharmacological effects on specific serotonin (5-HT) receptors, but not on the serotonin transporter (SERT). An in vivo microdialysis study in rats showed viloxazine (50 mg/kg i.p.) increased extracellular 5-HT, NE, and dopamine (DA) in the prefrontal cortex (PFC), a key brain region in ADHD pathology. This study evaluated whether these effects occur at clinically relevant concentrations. Methods: Microdialysis experiments were conducted in freely-moving, Sprague-Dawley rats (males, 8 weeks). Viloxazine (1, 3, 10, 30 mg/kg) was administered intraperitoneally to establish the dose range in rats at which viloxazine plasma concentrations aligned with those of individuals with ADHD administered therapeutic doses of viloxazine ER. Concentrations of unbound viloxazine, NE, 5-HT, DA, and NE and 5-HT metabolites (3,5-dihydroxyphenylglycol [DHPG] and 5-hydroxyindoleacetic acid [5-HIAA]) were measured in PFC interstitial fluid. After identifying a therapeutically relevant dose (30 mg/kg), the experiment was repeated using 30 and 50 mg/kg viloxazine (as 50 mg/kg increased NE, 5-HT, and DA in prior studies). Results: Viloxazine unbound (free drug) plasma concentrations in rats at 30 mg/kg were comparable to free drug concentrations in individuals with ADHD taking clinically effective doses (based on validated population PK models). Viloxazine 30 mg/kg significantly increased extracellular NE, 5-HT, and DA PFC levels compared to vehicle. Concomitant decreases in DHPG, but not 5-HIAA, support the inhibitory effect of viloxazine on NET but not SERT. Conclusion: At clinically relevant concentrations, viloxazine increases PFC NE, DA, and 5-HT. Prefrontal augmentation of 5-HT does not appear to result from 5-HT reuptake inhibition but may be related to activation of 5-HT neurons. The potential therapeutic role of serotonergic effects in ADHD treatment merits further exploration.

Efficacy and Safety of SPN-812 (Extended-Release Viloxazine) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: SPN-812 has been approved for attention-deficit/hyperactivity disorder (ADHD) treatment in children and adolescents. OBJECTIVE: We aimed to analyze the efficacy and safety of different doses of SPN-812 for ADHD pediatric patients of different ages, verify its clinical efficacy, and evaluate its safety. METHODS: Up until 30 August 2023, randomized controlled trials (RCTs) were searched in EMBASE, MEDLINE, the Cochrane Library, and clinicaltrials.gov to evaluate different doses of SPN-812 and a placebo. RESULTS: We pooled 1619 patients from five RCTs with a duration of 6-8 weeks. Patients (6-17 years old) in SPN-812 (100, 200, and 400 mg/d) groups were superior to the control group in all efficacy outcomes with lower attention-deficit/hyperactivity disorder rating scale-5 (ADHD-RS-5), Conners 3-parent short form composite T score (Conners 3-PS), Weiss functional impairment rating scale-parent (WFIRS-P), and increased clinical global impression-improvement (CGI-I) score (both p < 0.05). At the same time, only SPN-812 300 mg/d did not show a significantly high risk of the adverse events (AEs) such as somnolence and decreased appetite (p = 0.09). There was no significant difference between placebo and SPN-812 groups (100, 200, and 400 mg/d) in serious adverse events (SAEs) such as syncope. The subgroup analyses showed that, both in children and adolescents subgroups, SPN-812 showed better efficacy than the placebo. The two age subgroups showed a significantly higher risk of AEs and an insignificant risk of SAEs than the placebo. CONCLUSION: At present, SPN-812 (100, 200, and 400 mg/d) is superior to the corresponding control in efficacy measures. However, the safety problem cannot be ignored.

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.

An updated safety review of the current drugs for managing ADHD in children.

INTRODUCTION: Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent condition that causes persistent problems with attention and/or hyperactivity-impulsivity and often results in significant impairment when left untreated. Medications for this disorder continue to evolve and provide new treatment options. Ongoing review of related medication safety and tolerability remains an important task for prescribers. AREAS COVERED: This manuscript provides an updated safety review of medications used to treat ADHD in children and adolescents. PubMed and OneSearch online databases were utilized to search for literature relevant to the topic of ADHD medications and safety. Clinical trials of medications used to treat ADHD, systematic reviews and meta-analyses, and articles covering specific safety issues (adverse or unfavorable events) such as cardiovascular effects, seizures, impact on growth, depression, suicidal ideation, substance use disorders, psychosis, and tics are described. EXPERT OPINION: Available pharmacologic treatments for ADHD have favorable efficacy, safety and tolerability and allow many patients to achieve significant improvement of their symptoms. Despite the availability of multiple stimulant and non-stimulant formulations, some individuals with ADHD may not tolerate available medications or attain satisfactory improvement. To satisfy unmet clinical needs, ADHD pharmaceutical research with stimulant and nonstimulant formulations targeting dopamine, norepinephrine, and novel receptors is ongoing.

Pediatric attention deficit hyperactivity disorder (ADHD): 2022 updates on pharmacological management.

INTRODUCTION: Pediatric attention-deficit disorder (ADHD) impacts a significant percentage of the population world-wide. Pharmacologic treatments have been shown to be safe and effective for managing symptoms. Various medication formulations exist, and new medication agents are continually approved each year. AREAS COVERED: This article offers an overview of ADHD, an overview of both stimulant and non-stimulant medication options as well as an overview of stimulant misuse. It explores the medication mechanisms of action and side effect profiles, as well as offering an in-depth summary of the novel agents recently approved and soon-to-be approved for use in youth. PubMed and Medline were utilized. Search terms included children, adolescents, ADHD, and medication. FDA package inserts were reviewed for all medications. EXPERT OPINION: New formulations of medications include an evening administered, extended, and delayed-release form of methylphenidate (DR/ER MPH), a methylphenidate pro-drug (serdexmethylphenidate) and an amphetamine patch. The availability of a new SNRI (selective norepinephrine reuptake inhibitor), viloxazine extended-release (VER), and the pending approval of a triple reuptake inhibitor (centanafadine) provides welcome additions to the prescriber's toolbox.

This article is a review of pharmacological treatment options for pediatric attention-deficit disorder (ADHD). It provides an overview of ADHD, an overview of the current stimulant and non-stimulant medication options as well as detailed information on the newer psychopharmacological options to assist in the education of the wide array of medication options for treatment. As ADHD is a heterogeneous illness, a wide array of medication options is helpful in the clinician's toolbox. Learning the mechanisms of action along with the side effect profile for newer medication options is the focus of this review. There are new options for patches and new combinations for long-acting and delayed-release formulations as well as new non-stimulant options which target different receptors.

Adult attention deficit hyperactivity disorder: a comprehensive review.

Attention deficit hyperactivity disorder (ADHD) is a common childhood disorder, with only 2-3% prevalence into adulthood. The epidemiology and proposed causes of ADHD are multifactorial, including genetic, prenatal and environmental influences. The diagnosis of ADHD is often complicated by masking coping mechanisms, an overlap of symptoms with other, more commonly diagnosed disorders. Traditionally, it has been treated with stimulant medications. Non-stimulant options often target norepinephrine and dopamine regulation and are preferred in cases of comorbid substance use disorder, anxiety and other complicating factors, due to an improved side-effect profile and patient preference. They include atomoxetine and viloxazine. The latter, Viloxazine, in the form of extended-release capsules, is the first novel, non-stimulant option approved for adults with ADHD, in the past two decades. Its therapeutic effects are predominantly produced by its action as a norepinephrine reuptake inhibitor and may also modulate the serotonergic system. Viloxazine is relatively safe and effective in treating other disorders such as depression, anxiety, epilepsy and substance use disorder. Its pharmacokinetics includes metabolization by CYP enzymes. As antiepileptics inhibit CYP1A2, therefore, a special consideration would be needed, when co-administering with anti-epileptic drugs. Similarly, individuals with liver or cardiovascular disease and a personal or family history of bipolar disorder require close monitoring, while on this medication. A thorough review of the history, mechanism of action, pharmacokinetics and drug-drug interactions has been presented here, with special attention on treatment in adults with comorbid conditions. This study conducted an all-language literature search on Medline, Cochrane, Embase, and Google Scholar until December 2022. The following search strings and Medical Subject Headings (MeSH) terms were used: "Viloxazine," "ADHD," "Stimulants," and "adult ADHD." We explored the literature on the growing knowledge of Viloxazine. A thorough review of the history, mechanism of action, pharmacokinetics, and drug-drug interactions are reviewed here with special attention on treatment in adults with comorbid conditions.

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.

Viloxazine for the Treatment of Attention Deficit Hyperactivity Disorder.

Purpose of Review: Attention deficit hyperactivity disorder (ADHD) is a widely diagnosed neurodevelopmental disorder giving rise to symptoms of hyperactivity, impulsivity, and inattentiveness that can impair daily functioning. Stimulants, such as methylphenidate and amphetamines, are the mainstay of treatment for ADHD. However, nonstimulant drugs such as viloxazine, atomoxetine, guanfacine, and clonidine are becoming more popular due to minimal adverse effects when compared to stimulants. Recent Findings: Viloxazine is a selective norepinephrine reuptake inhibitor (NRI) originally used to treat depression in adults with activity in both the noradrenergic as well as serotonergic pathways. Studies have demonstrated its efficacy for its use in the treatment of ADHD. Unlike stimulants, viloxazine has a decreased chance of substance abuse, drug dependance, and withdrawal symptoms upon the cessation of therapy. Additionally, dopamine levels in the nucleus accumbens after treatment with viloxazine are elevated considerably less in comparison with traditional stimulant ADHD treatments. Viloxazine provides an alternative, nonstimulant approach to treating ADHD. Summary: Viloxazine is a recently approved, non-stimulant medication functions by inhibiting the uptake of norepinephrine which has been seen to be decreased in patients with ADHD. When patients do not respond to first-line stimulants, cannot tolerate the side effects, or have contraindications to stimulants, viloxazine may be a nonstimulant option offering patients an increasing arsenal of medications to treat ADHD.

Viloxazine, a Non-stimulant Norepinephrine Reuptake Inhibitor, for the Treatment of Attention Deficit Hyperactivity Disorder: A 3 Year Update.

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in childhood. Current treatment options for ADHD include pharmacological treatment (stimulants, non-stimulants, anti-depressants, anti-psychotics), psychological treatment (behavioral therapy with or without parent training, cognitive training, neurofeedback), and complementary and alternative therapies (vitamin supplementation, exercise). Central nervous system (CNS) stimulants are the primary pharmacological therapy used in treatment; however, these stimulant drugs carry a high potential for abuse and severe psychological/physical dependence. Viloxazine, a non-stimulant medication without evidence of drug dependence, is a selective norepinephrine reuptake inhibitor that has historically been prescribed as an anti-depressant medication. The extended-release (ER) form was approved by the US Food and Drug Administration (FDA) in April 2021 for the treatment of ADHD in pediatric patients aged 6-17 years. Phase 2 and 3 randomized control trials have demonstrated significant efficacy of viloxazine in improving ADHD symptoms versus placebo. Related to its long-standing use as an antidepressant, the safety profile and pharmacokinetics of viloxazine are well understood. Viloxazine appears to be a suitable alternative to current standard-of-care pharmacotherapy for ADHD, but the further investigation remains to be done in comparing its efficacy to that of current treatments.

Extended-Release Viloxazine for Children and Adolescents With Attention Deficit Hyperactivity Disorder.

Non-stimulant medication therapy for children, adolescents, and young adults with attention-deficit/hyperactivity disorder (ADHD) has included alpha 2-agonists (guanfacine and clonidine) as well as a norepinephrine reuptake inhibitor (atomoxetine) for multiple years. Although these may be effective options for some children, they are generally considered to be less effective than stimulant medications. In addition, there has been a suicidal ideation concern in early-late adolescence with atomoxetine, emphasizing the need for continued development of other treatment options. Extended-release viloxazine (SPN-812) has been shown in phase 2 and phase 3 trials to be an effective, well-tolerated alternative for some children with ADHD. The mechanism of action of viloxazine is unique, modulating activity of both serotonin and norepinephrine. Treatment-related adverse events most commonly seen included somnolence, decreased appetite, and headache. Although continued evaluation to confirm the reduced symptoms of ADHD in children along with the safety profile is needed, extended-release viloxazine may offer a once-a-day pharmaceutical treatment option for patients in which stimulant medication is not effective or not a favorable option. It may also be beneficial for those children and adolescents with a comorbidity of depression.

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.

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 for Attention-Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

Background: Recently, the United States Food and Drug Administration (USFDA) approved viloxazine extended-release (ER) to manage attention-deficit hyperactivity disorder (ADHD) in pediatric patients of 6-17 years of age. Objective: To perform a meta-analysis to determine the safety and efficacy of viloxazine ER in the management of ADHD. Data Source and Methods: A literature search was performed through the databases Cochrane Library, PubMed, and clinicaltrials.gov, for a period from inception to August 2021, with the keywords: viloxazine, SPN-812, ADHD, and randomized clinical trials. The randomized controlled trials published in English language that analyzed the efficacy and safety were included. The risk of bias (RoB) was assessed by RoB tool. The outcomes included in this study were the proportion of patients with a 50% reduction in ADHD-Rating Scale-5 (ADHD-RS-5 responders) and improvement in CGI-I scale and the proportion of patients with at least one adverse event, the incidence of somnolence and Serious Adverse Events (SAEs). Results: This meta-analysis includes 1605 patients from five randomized clinical trials; all of the trials were at low risk of bias. Viloxazine group had more ADHD-RS-5 responders as compared to placebo; RR = 1.62; 95% CI = 1.36-1.93; P = <.00001. Significantly higher number of patients showed improved CGI-I score; RR = 1.53; 95% CI = 1.32-1.78; P = <.00001. A higher proportion of patients was observed with at least one adverse event (RR = 1.52; 95% CI = 1.24-1.85; P = <.0001), and somnolence (RR = 3.93; 95% CI = 2.11-7.31; P = <.0001) in viloxazine group. The incidence of SAEs was more in viloxazine group (RR = 2.98; 95% CI = .67-13.3; P = .15). Conclusions: Viloxazine was found to be significantly superior to placebo in both efficacy outcomes. Adverse events and somnolence were significantly more than the placebo. The incidence was SAEs was more in the viloxazine group but was not statistically significant.