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

Abstract

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.

Introduction

According to statistics compiled by the Centers for Disease Control and Prevention as reported by the American Academy of Pediatrics (AAP), an estimated 6.1 million children (9.4% of US children) had been diagnosed with attention-deficit/hyperactivity disorder (ADHD) in a national 2016 parent survey.¹ In the same year, 6 in 10 children with ADHD were reported to have at least 1 other comorbidity of other mental, emotional, or behavioral disorders. The highest of these included behavior or conduct problem (52%), anxiety (33%), depression (17%), and autism spectrum disorder (14%).¹

The treatment for ADHD as recommended by the AAP is to include behavior therapy and medication, preferably both together, for children 6 years of age and older.^2,3 For those under 6 years, the AAP recommends behavior therapy as first-line treatment.² One study has shown that about 23% of children with ADHD were receiving neither medication treatment nor behavioral treatment.⁴ Of the 77% receiving therapy, about 30% were treated with medication alone, about 15% received behavior treatment alone, and about 32% of children with ADHD received both medication and behavior therapy.⁴

Several medications have been FDA-approved to assist in the treatment of ADHD and generally fall into 2 classes: stimulants and non-stimulants. Table 1 summarizes the medications used for ADHD. In children and adolescents in which stimulant medication is an option, 20% to 30% have an inadequate response.⁵ Non-stimulants, while generally less effective and with slower onset of effect, tend to have fewer limitations with no significant risk of abuse or misuse, and lower risk of cardiovascular events even in patients with preexisting risk factors.^6–8 In years past, stimulant medications were used on school days, and children were given “drug holidays” on weekends and during summer and extended breaks. This practice was introduced to allow parents and children to feel that they were not using medication for “control,” avoid potential side effects, and to reduce the parental concern that these stimulants were causing addictive behaviors. ADHD is considered a chronic condition and should be managed in the same manner as children and youth with special health care needs.² Once medication management is stopped, ADHD symptoms will likely return and may cause difficulties. Treatment discontinuation, even if short-lived or temporary, may place individuals with ADHD at higher risk for catastrophic outcomes including: automobile accidents, criminality, drug-related crimes, depression, and other injuries.²

Table 1.

Summary of Drug Classes and Individual Drugs used in the Treatment of ADHD

Drug Class	Mechanism of Action	Example Medications and Trade Names
CNS stimulant—amphetamines	Increase the concentrations of dopamine and norepinephrine by promoting the release of catecholamines from the presynaptic nerve terminals, and inhibiting pre-synaptic norepinephrine and dopamine reuptake	Amphetamine: Adzenys, Dyanavel, Evekeo; Amphetamine/dextroamphetamine: Adderall, Mydayis; Dextroamphetamine: Dexedrine, ProCentra, Zenzedi; Lisdexamfetamine: Vyvanse; Serdexmethylphenidate/dexmethylphenidate: Azstarys
CNS stimulant—methylphenidate	Increase the concentrations of dopamine and norepinephrine by inhibiting pre-synaptic reuptake	Methylphenidate: Adhansia, Aptensio, Concerta, Cotempla, Daytrana (patch), Jornay, Metadate, Methylin, Quillivant, Relexxii, Ritalin; Dexmethylphenidate: Focalin
Alpha-2-adrenergic agonists	Reduced sympathetic outflow from the CNS, possibly regulating subcortical activity in the prefrontal cortex	Clonidine: Kapvay, Catapres; Guanfacine: Intuniv
Norepinephrine reuptake inhibitor	Increase norepinephrine concentrations by selectively inhibiting norepinephrine reuptake	Atomoxetine: Strattera
Serotonin norepinephrine reuptake inhibitor	Increases norepinephrine concentrations by blocking reuptake; modulates serotonin by activating 5-HT2C receptor and inhibiting the 5-HT2B receptor	Viloxazine: Qelbree

ADHD, attention-deficit/hyperactivity disorder

Viloxazine was approved in the United Kingdom in the 1970s for use in adults with clinical depression. It had been historically described as a norepinephrine reuptake inhibitor (NRI). However, in newer assay studies, it has been found that the mechanism of action for viloxazine can best be explained as a serotonin norepinephrine modulating agent.⁹ The ability to increase serotonin concentrations in the pre-frontal cortex (an area of the brain implicated in ADHD) while also having antagonistic effects on certain serotonin receptor sites is indicative of its modulating activity.⁹ In addition, viloxazine exhibits moderate inhibitory effects on the norepinephrine transporter (NET) and moderate noradrenergic activity.⁹ Based on its minimal effect on dopamine, viloxazine is considered to have low potential for abuse. With its moderate inhibitory activity on NET, cardiac-related effects were not observed in the clinical settings in contrast to those seen with CNS stimulants and NRI treatments. The above findings lead to the proposed conclusion that viloxazine as an extended-release medication is distinct from NRIs due to its multimodal activity on serotonin receptors complemented by moderate NET inhibition and therefore, is properly classified as a serotonin norepinephrine modulating agent.

Dosing and Administration

Viloxazine is indicated for use in children 6 to 17 years of age. It is available as 100-mg, 150-mg, and 200-mg capsules that can be opened and the contents sprinkled on a teaspoonful of applesauce.¹⁰ For children 6 to 11 years, the starting dose is 100 mg daily, with the ability to titrate up each week by 100 mg to a maximum of 400 mg daily.¹⁰ For 12 years and older, the starting dose is 200 mg daily, followed by an increase to 400 mg daily after 1 week if needed based on tolerability and clinical response.¹⁰ A maximum dose of 200 mg daily is recommended for anyone with an estimated glomerular filtration rate < 30 mL/min/1.73 m².¹⁰ The effect of hepatic impairment on viloxazine pharmacokinetics is unknown.¹⁰

Pharmacokinetics

Viloxazine's onset of action is about 1 hour and peak concentrations are observed at about 5 hours, followed by a steady decline in concentration starting at 9 hours.¹⁰ The half-life is 7 ± 4 hours.¹⁰ The drug can be given with or without food. Viloxazine is a substrate of UGT1A9 and UGT2B15 and a minor substrate of CYP2D6.¹⁰ It is a strong inhibitor of CYP1A2 and a weak inhibitor of CYP2D6 and CYP3A4.¹⁰ Dose modification of the substrate medication is only recommended for those that are CYP1A2 substrates and those that are major substrates of CYP2D6 and CYP3A4.¹⁰ It is not recommended to give viloxazine with melatonin, a common medication used to combat insomnia in children with ADHD.¹⁰ Because viloxazine is a strong CYP1A2 inhibitor, use with melatonin could lead to elevated melatonin concentrations leading to excess drowsiness.¹⁰ Clinicians should plan to consult medication references due to the significance and diversity of potential drug interactions.¹⁰

Adverse Effects and Monitoring

Viloxazine does carry a US Food and Drug Administration boxed warning in its' official labeling for suicidal thoughts and behaviors due to higher rates of suicidal thoughts compared with placebo in clinical trials, although this occurred at a low rate in studies and was deemed not statistically significant.¹⁰ Children should be monitored for increases in blood pressure and heart rate at baseline, following dose changes, and thereafter, at least annually.¹⁰ Headache and sedation also occurred at higher rates than placebo.¹⁰

Cost

Viloxazine therapy is expected to cost about $300 per month. This would be similar to other trade name products but more expensive than generic stimulants and non-stimulants.

Clinical Trials

Several clinical trials have been completed in children and adolescents with ADHD. Table 2 summarizes the clinical trial findings for efficacy and safety. Overall, these studies showed consistent improvement in the ADHD Rating Scale-5 for viloxazine 200 mg and 400 mg doses with mixed results for the 100 mg dose. Results of improvement in other ADHD scales demonstrated mixed results as well. One study that evaluated 600-mg dosing did not show any added benefit over 400 mg with the possibility of increased adverse effects.¹¹

Table 2.

Summary of Viloxazine Clinical Trials in Children and Adolescents

Study	Population	Methods	Efficacy	Adverse Effects
Johnson13	222 children with ADHD, ages 6–12 yr	Double blind, randomized placebo-controlled trial Viloxazine dosing: 100 mg, 200 mg, 300 mg, or 400 mg daily. Dosing started at 100 mg daily and increased by 100 mg each week until target dose reached. 8-wk duration	Primary outcome: ADHD Rating Scale-IV total score significantly improved (decreased) compared with placebo for the 200-mg, 300-mg, and 400-mg groups. Secondary outcomes: CGI-S scores only significantly improved compared with placebo for the 300-mg group. CGI-I scores improved compared with placebo for the 200-mg, 300-mg, and 400-mg groups.	Most common adverse effects and more than the placebo group: Somnolence (15%–25%, increasing with increased doses), headache (8%–18%), decreased appetite (8%–16%), nausea (4.9%), fatigue (4.9%). Discontinuations attributed to viloxazine treatment in 13 patients secondary to: irritability, suicidal ideation (1), headache, weight loss.
Nasser14	477 children with ADHD, ages 6–11 yr 460 participants in the ITT population and 474 subjects in the safety population	Double-blind, randomized, placebo-controlled trial Viloxazine dosing: 100 mg or 200 mg daily 6-wk duration	Primary outcome: ADHD Rating Scale-5 significantly improved compared with placebo for both treatment groups. Secondary outcomes: CGI-I score, Conners 3- PS composite T-score, and the WFIRS-P assessment were all significantly improved compared with placebo for both treatment groups.	Adverse effects in > 5% of patients and more than the placebo group: Somnolence (8.9%), decreased appetite (6%), and headache (5.4%). 7 discontinuations attributed to viloxazine treatment: tachycardia, fatigue, dizziness, aggression, sleep terror, decreased appetite
Nasser15	313 children with ADHD, ages 6–11 yr	Double-blind, randomized, placebo-controlled trial Viloxazine dosing: 200 mg or 400 mg daily. Dosing started at 100 mg daily and increased by 100 mg each week until target dose reached. 8-wk duration	Primary outcome: ADHD Rating Scale-5 significantly improved compared with placebo for both treatment groups. Secondary outcomes: CGI-I significantly improved compared with placebo for both treatment group. Conners 3-PS improved compared with placebo only for the 200-mg group. WFIRS-P not significantly different between groups.	Adverse effects in > 5% of patients and more than the placebo group: Somnolence (14%), decreased appetite (7.7%), fatigue (7.2%), headache (6.8%). Discontinuations attributed to viloxazine treatment: severe mood swings (1 in the 200-mg group), severe fatigue (2, 1 in each treatment group), elevated blood pressure (1 in the 400-mg group), tachycardia (1 in the 200-mg group). 1 episode of severe suicidal behavior assessed as not related to viloxazine therapy.
Nasser16	310 adolescents with ADHD, ages 12–17 yr	Double-blind, randomized, placebo controlled trial Viloxazine dosing: 200 mg or 400 mg daily. The 400 mg/day group titrated up from 200 mg during week 1 to the 400 mg daily dosage starting on week 2 6-wk duration	Primary outcome: ADHD Rating Scale-5 significantly improved compared with placebo in both treatment groups. Secondary outcomes: CGI-I significantly improved compared with placebo in both treatment groups. No statistically significant differences between groups for the Conners 3-PS or WFIRS-P.	Most common adverse effects and more than the placebo group: Somnolence (13.7%), decreased appetite (6.9%), nausea (4.9%), fatigue (4.9%). Discontinuations attributed to viloxazine treatment in 6 patients: abdominal pain, anxiety, somnolence, diarrhea, syncope, and insomnia. Four patients with cardiovascular symptoms: Increased blood pressure (200 mg), increased orthostatic heart rate (200 mg), increased heart rate (400 mg), and hypertension (400 mg).
Nasser11	297 adolescents with ADHD, ages 12–17 yr	Double-blind, randomized, placebo-controlled trial Viloxazine dosing: 400 mg or 600 mg daily, started at 200 mg/day with weekly titration to target dose 7-wk duration	Primary outcome: ADHD Rating Scale-5 significantly improved compared with placebo in the 400-mg group only. Secondary outcomes: No significant differences compared with placebo.	Adverse effects in > 5% of patients and more than the placebo group: Somnolence (14%–20%, higher in the 600-mg group), decreased appetite (6%), fatigue (13%), headache (14%), nausea (11%), irritability (6%). There was 1 suicide attempt in the 400-mg group.

ADHD, attention-deficit/hyperactivity disorder; CGI-S, Clinical Global Impression-Severity; CGI-I, Clinical Global Impression-Improvement; Conners 3-PS, Conners 3-Point Parent Short Form; ITT, intent to treat; WFIRS-P, Weiss Functional Impairment Rating Scale-Parent

The most common treatment-emergent adverse effects from the clinical trials included somnolence, headache, decreased appetite, fatigue, and nausea. Suicidal ideation was not statistically more common than in the placebo group but was reported in a few cases, and more than in the placebo group. Some irritability was reported as well as elevations in heart rate and blood pressure. Further details of adverse events are summarized in Table 2.

A post hoc analysis of the published phase 3 trials evaluated the likelihood to be helped or harmed (LHH) with calculation of the probability of patients benefiting from treatment versus discontinuation.¹² The LHH values are determined by the ratio of number needed to harm (NNH) to number needed to treat (NNT) with a higher LHH indicating a more favorable likelihood of benefit from the medication relative to likelihood of having to stop the medication. Therefore, in order to make this ratio more favorable for an LHH, the NNH should be significantly higher than the NNT. By convention, NNH values above 10 for adverse effects suggest potential safety/tolerability concerns, and NNT values less than 10 suggest potential usefulness of the drug. The calculations for the LHH for viloxazine extended-release in the pediatric phase 3 trials ranged from 5 to 13. In relating to what this means for NNH and NNT, they ranged from 31 to 74, and 6 to 7, respectively. Therefore, subjects are 5 to 13 times more likely to benefit from viloxazine rather than discontinue the medication due to adverse effects.¹²

Clinical Considerations

With its unique mechanism of action, along with its clinical efficacy and safety profile, clinicians may be looking at which children with ADHD could potentially benefit from the use of daily viloxazine extended-release. It is not the intent of the authors to direct its clinical use, but rather to add considerations to weigh benefits versus risks in the following settings:

1. Non-responders to stimulant medication. As previously cited, it is estimated that 20% to 30% of children taking medication for ADHD do not respond to stimulant medications.⁵ Prescribers will typically choose 1 class of stimulant medication and have a step-wise dosing increase until symptoms seem best controlled without undesirable side effects. If this stimulant medication is not effective, then they will likely change to the other stimulant medication class. After providing step-wise increases in dosing again, it then may be determined that the child is a non-responder to stimulant medication, or there is another diagnosis/comorbidity that is primary to the child's health concern.

2. Children who have responded to stimulant medications but are experiencing medication side effects that are not tolerable or desired. Common concerns with stimulant medications include the following: insomnia, tachycardia, blood pressure increase, behavior changes, and decreased appetite/weight loss (or poor weight gain). These adverse effects may require discontinuation or the addition of other medications to combat the negative effects.

3. Children with ADHD with accompanying comorbidity of depression. Due to its experience in adults for the treatment of depression, and knowing that there is a high percentage of children with ADHD having other psychological disturbances including depression, anxiety, and oppositional defiant disorder, extended-release viloxazine may offer the benefit of assisting in the treatment of both ADHD and depressive clinical symptoms. The use of viloxazine for the treatment of depression in children has not been evaluated in clinical trials.

Remaining Questions regarding, Viloxazine Use for ADHD

1. Will the use of larger doses for longer duration lead to the emergence of more adverse effects?

2. Will this be an effective option for children who also have depression?

3. Will there be an improved rate of suicidal ideation compared with atomoxetine?

4. Will this be a safe and effective option for children under 6 years old and adults? Studies recruiting and ongoing for adults and preschool-aged children can be found on ClinicalTrials.gov.

Summary

Extended-release viloxazine has been shown in clinical trials to be effective in the treatment of ADHD in children.^13–15 The relative efficacy is unknown as studies available were short-term clinical trials only compared with placebo. The short duration of the studies warrants close follow-up for emergence of long-term adverse effects. Viloxazine as a non-extended release preparation has been used for years in adults living outside the US for depression and anxiety, which may increase comfort with its safety profile. Because the drug offers a different mechanism of action and has demonstrated a favorable safety profile in clinical trials, it could be considered for use in certain clinical situations, providing an additional non-stimulant treatment option for children with ADHD.

ABBREVIATIONS

AAP

American Academy of Pediatrics

ADHD

attention-deficit/hyperactivity disorder

CNS

central nervous system

FDA

US Food and Drug Administration

LHH

likelihood to be helped or harmed

NET

norepinephrine transporter

NNH

number needed to harm

NNT

number needed to treat

NRI

norepinephrine reuptake inhibitor

SPN-812

extended-release viloxazine