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.

Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN-812 (Viloxazine Extended-Release) Pharmacokinetics in Healthy Adults.

SPN-812 (viloxazine extended-release) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Given that SPN-812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN-812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single-sequence, 3-treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN-812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN-812 and paroxetine (period 3). Blood samples were collected for 72 hours post-SPN-812 dosing and analyzed for viloxazine and its primary metabolite, 5-HVLX-gluc. Twenty-two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN-812 and paroxetine was assessed using analysis of variance on the log-transformed pharmacokinetic parameters Cmax , AUC0-t , and AUCinf . The least-squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN-812 alone) Cmax , 116.04%; 90%CI, 109.49%-122.99%; AUC0-t , 134.65%; 90%CI, 127.65-142.03; and AUCinf , 134.80%; 90%CI, 127.94%-142.03%. CYP2D6 inhibition resulted in a modest change (<35%) on viloxazine AUCs with no change in Cmax . All adverse events were mild in severity.

Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status.

Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

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.

Evaluation of the Effect of SPN-812 (Viloxazine Extended-Release) on QTc Interval in Healthy Adults.

OBJECTIVE: To assess the effects of a supratherapeutic dose of SPN-812, a drug currently under investigation as a treatment for attention-deficit/hyperactivity disorder, on cardiac repolarization (QTc) in healthy adults. METHODS: The study was conducted from June 27, 2018, to July 10, 2018. It had a double-blind, randomized, crossover design in which subjects received a 3-treatment sequence-placebo, 400 mg moxifloxacin, and 1,800 mg SPN-812 for 2 consecutive days (separated by at least a 3-day washout). The primary endpoint was the correlation between the change from baseline (CFB) in individual heart rate corrected QT interval (QTcI) (ΔQTcI) and viloxazine and 5-hydroxyviloxazine glucuronide (5-OH-VLX-gluc) plasma concentrations (Cps). The secondary endpoint was the time point placebo-adjusted CFB in QTcI (ΔΔQTcI) for viloxazine. For assay sensitivity, the correlations between moxifloxacin Cp and the ΔQTcI, and moxifloxacin and time point ΔΔQTcI were evaluated. Additional evaluations included Fridericia's formula QT correction, heart rate, and the PR and QRS intervals. Changes in electrocardiogram (ECG) morphology along with other safety parameters were also analyzed and reported. RESULTS: The correlation between ΔQTcI and viloxazine Cp demonstrated a statistically significant negative slope (P = .0012). 5-OH-VLX-gluc Cp and ΔQTcI also demonstrated a statistically significant negative slope (P = .0007). Secondary time point analyses showed no effect of SPN-812 on QTcI. Assay sensitivity with moxifloxacin was confirmed. Safety parameters were acceptable. CONCLUSIONS: This study demonstrated that SPN-812 had no effect on cardiac repolarization or other ECG parameters in healthy adults, suggesting that it is not associated with a risk for cardiac arrhythmias or other electrocardiographic parameters.

Prolonged stationary colonic motility recording in seven patients with severe constipation secondary to antidepressants.

The aim of this study was to determine whether the colonic motor profile of seven patients with constipation secondary to antidepressants differed from the motility of seven patients with idiopathic constipation and seven healthy volunteers. All constipated patients had very severe constipation. Colonic manometric recordings were performed for 24 h. The number of high amplitude propagating contractions (HAPC) was lower in the two groups of constipated patients than in controls. No HAPC were observed in 5/7 patients with constipation secondary to antidepressants and in 1/7 patients with idiopathic constipation. The overall area under the curve (AUC) in the left colon was lower in the two constipated patient groups than in controls. AUC increased after a 1000-kcal standard meal given at noon in controls but not in the two groups of constipated patients. In conclusion, in patients with constipation secondary to antidepressants, the overall AUC was as poor as in patients with idiopathic constipation, and no colonic response to eating was observed. Moreover, the number of HAPC was more markedly decreased in patients with constipation secondary to antidepressants than in patients with idiopathic constipation.

[Antidepressants and sexual stimulation: the correlation]. / Antidépresseurs et stimulation sexuelle: la part des choses.

The purpose of this study is to correlate antidepressant treatment with sexual stimulation. The first part of this paper tries to describe some physiologic aspects of the sexual function. This complex subject includes several neuromediators which belong to adrenergic, cholinergic, dopaminergic and serotoninergic systems. A double-blind study shows that viloxazine, an atypical antidepressant, could act specifically on sex drive by desinhibiting effect. A precise study concludes that moclobemide improve significantly all components of sexual function. The numerous side effects of doxépine is a hindrance to its prescription. More precise studies about viloxazine and moclobemide suggest that both could have a specific effect on different components of sexual activity. In the second part of this paper, we consider the concept of "corrector". These drugs are numerous, however their prescriptions are not very wide spread: yohimbine, cyproheptadine, amantadine, bethanechol.

Citalopram and viloxazine in the treatment of depression by means of slow drop infusion. A double-blind comparative trial.

Antidepressant efficacy and tolerability of citalopram and viloxazine were compared under double-blind conditions during the first two weeks of treatment with slow drop infusion, followed by oral administration for the rest of the six week trial period. The 62 severely depressed and hospitalised patients included in the intention-to-treat analysis had a mean age of 45 years (range 23 to 70 years). About two thirds of the patients were female. Thirty patients were allocated to the citalopram and 32 patients to the viloxazine group. The mean MADRS total score at baseline was 34 in both groups and decreased to 12.3 in the citalopram and to 16.9 in the viloxazine group after 14 days of infusion. On day 42 (end point) the scores dropped to 6.7 in the citalopram and to 13.1 in the viloxazine group respectively. The group differences reached the level of significance at both time points (p < 0.05) in favour of citalopram. The analysis of treatment emergent adverse events based on the UKU scale showed a higher frequency of nausea on day 14 and constipation at study end in the viloxazine group (p < 0.05) whereas reported weight gain (day 21) and concentration difficulty (day 21) were more frequently seen in the citalopram group (p < 0.05). Standard laboratory investigations and ECG analyses did not show clinically relevant abnormalities. It is concluded that antidepressant treatment with citalopram infusion followed by oral citalopram may be more efficacious than a corresponding treatment schedule with viloxazine.

Effects of the antidepressant drug viloxazine on oxcarbazepine and its hydroxylated metabolites in patients with epilepsy.

The effects of Viloxazine (VLX, 100 mg b.i.d. for 10 days) on the steady-state plasma concentrations of Oxcarbazepine (OXC), its active metabolite 10, 11-dihydro-10-hydroxy-carbazepine (MHD) and the corresponding diol (DHD) were studied in a randomized, double-blind cross-over placebo-controlled trial in 6 epileptic patients stabilized on a fixed dosage of OXC. Administration of VLX resulted in an 11% increase in the plasma concentration of MHD (p = 0.003) associated with a 31% fall in DHD levels (p = 0.0001). Plasma concentrations of unchanged OXC were unaffected by VLX. No changes in seizure frequency nor signs of drug toxicity were observed during the study. Although VLX may inhibit the conversion of MHD to the inactive diol, the interaction is unlikely to be of clinical significance.

[Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia]. / Comparación del efecto de la amisulprida y la viloxacina en el tratamiento de la distimia.

An evaluation of the therapeutic efficacy of Amisulpride as compared with Viloxazine in a group of patients diagnosed as dysthymic, according to the DSM-III-R criteria is presented. Study was a double-blind, randomized controlled trial: Subjects were assessed during an initial examination with informed consent, then entering a 4-week treatment trial. The Hamilton Depression Scale, the Widlocher Psychomotor Retardation Scale, and the Andreasen Negative Symptoms Scale were used for evaluating cases. Both the efficacy and safety of drugs were assessed. An analysis of results suggests a better therapeutic response among the Amisulpride group subjects.

Comparación del efecto de la amisulprida y la viloxacina en el tratamiento de la distimia / Comparison of the amisulpride and viloxazine effect in the dysthymia treatment

El presente trabajo se propone evaluar la eficacia terapéutica de la amisulprida, comparándola con la viloxacina en un grupo de pacientes diagnosticados como distímicos de acuerdo con los criterios de clasificación del DSM-III-R. Se trata de un estudio controlado doble ciego con asignación aleatoria, de una serie de 80 pacientes evaluados en un examen incial y a lo largo de 4 semanas de tratamiento. Entre los instumentos empleados para la evaluación figuran la escala de depresión de Hamilton, la del retardo psicomotor de Widlocher y la de síntomas negativos de Andreasen. Se evalúa tanto la eficacia como la seguridad de los medicamentos. Se presentan un análisis de los resultados que sugiere una mejor respuesta terapéutica en el grupo de la amisulprida

Comparación del efecto de la amisulprida y la viloxacina en el tratamiento de la distimia / Comparison of the amisulpride and viloxazine effect in the dysthymia treatment

El presente trabajo se propone evaluar la eficacia terapéutica de la amisulprida, comparándola con la viloxacina en un grupo de pacientes diagnosticados como distímicos de acuerdo con los criterios de clasificación del DSM-III-R. Se trata de un estudio controlado doble ciego con asignación aleatoria, de una serie de 80 pacientes evaluados en un examen incial y a lo largo de 4 semanas de tratamiento. Entre los instumentos empleados para la evaluación figuran la escala de depresión de Hamilton, la del retardo psicomotor de Widlocher y la de síntomas negativos de Andreasen. Se evalúa tanto la eficacia como la seguridad de los medicamentos. Se presentan un análisis de los resultados que sugiere una mejor respuesta terapéutica en el grupo de la amisulprida (AU)

Alcoholism and depression: a placebo controlled study with viloxazine.

Depressive disorders are frequently associated with alcohol abuse. Though many studies have been carried out to clarify the role of antidepressant drugs in the management of alcoholic patients, the data are controversial. The present placebo-controlled study was planned to assess the antidepressant and attenuating drinking-behaviour efficacy of viloxazine (400 mg per os daily) versus a placebo in 30 dysthymic patients affected by alcohol dependence. The results significantly favour viloxazine treatment in alleviating depression and in reducing alcohol abuse. All patients showed baseline haematochemical evidence of liver dysfunction that did not change significantly during the treatment.

[The use of viloxazine in the treatment of primary enuresis]. / L'utilisation de la Viloxazine dans le traitement de l'énurésie primaire.

The use of Viloxazine (a non tricyclic antidepressant) could be a less toxic alternative to Imipramine (cardiotoxic tricyclic antidepressant) in the treatment of childhood primary enuresis. Bladder overactivity, infection or psychological disturbances should be excluded before start of treatment, the drug seems to have a good efficacy in cases of "heavy sleepers".

A study of the interaction of viloxazine with theophylline.

The effect of viloxazine on the pharmacokinetics of theophylline was studied in eight healthy volunteers. Theophylline 200 mg/day (théophylline Bruneau 100 mg tablets) was administered on day 1; after a 3-day washout period, viloxazine 300 mg/day (Vivalan 100 mg tablets) was administered orally from days 5 to 7. On day 8, theophylline 200 mg and viloxazine 100 mg were concomitantly administered. The pharmacokinetic parameters of theophylline alone and after coadministration of viloxazine were determined. Viloxazine significantly increased the plasma concentrations (p less than 0.01) and the area-under-the-curve values (p less than 0.01) of theophylline and decreased its body clearance (p less than 0.05). Our results suggest that the dosage of theophylline should be decreased and its plasma concentrations monitored when viloxazine is prescribed.

[Nonpsychotic involutional inhibited depressions and psycho-organic deteriorations: treatment with Viloxazine and piracetam]. / Depressioni involutive, inibite, non psicotiche e decadimenti psico-organici: trattamento con viloxazina e piracetam.

Involutional depression is often the first symptom of a psycho-organic syndrome or dementia and may not present overt symptoms itself; these depressive states have been variously classified by different schools in various countries. The hypothesis of catecholamine and indolamine in the aetiopathogenic agent is oversimplistic and the theory that abnormal receptor hypersensitivity is the cause of the condition is more convincing. On the basis of this hypothesis numerous studies have been conducted into the efficacy of various antidepressants in the treatment of this hypersensitivity. Involutional depressions are more common among women and are found in about 10% of 60-65 year olds. This report claims that combined viloxazine-piracetam is the most appropriate treatment for involutional depression. This approach (200 mg oral viloxazine and 9 g oral piracetam a day) was adopted for 3 months in 33 out patients about 64 years old who were subsequently put on maintenance doses (100 mg viloxazine, 3 g piracetam a day). The various Hamilton scale parameters were assessed as were reaction times to auditory and visual simple stimuli. Result sat the start and end of treatment were then compared. About three quarters of the patients showed improvement in both depression and psycho-organic syndrome symptoms, while total remission or lasting improvement in both pathologies was obtained in about 50%.