AHFS Class:

• Respiratory and CNS Stimulants 28:20.32

Generic Name(s):

• Viloxazine Hydrochloride

Viloxazine hydrochloride is a selective norepinephrine reuptake inhibitor.1,5,6

Attention-Deficit Hyperactivity Disorder

Viloxazine hydrochloride is used for the treatment of attention-deficit hyperactivity disorder (ADHD) in adults and pediatric patients ≥6 years of age.1

Efficacy and safety of viloxazine for the treatment of ADHD were evaluated in 4 short-term (6 or 8 week), double-blind, randomized controlled studies; 3 studies were conducted in pediatric patients (Studies 1, 2, and 3) and one study was conducted in adults (Study 4).1,2,3,4,5 All patients had a primary diagnosis of ADHD, defined according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).2,3,4,5 The efficacy outcome measures, ADHD Rating Scale (ADHD-RS-5) and Clinical Global Impression-Improvement (CGI-I) score in the pediatric studies and ADHD Investigator Symptom Rating Scale (AISRS) and Clinical Global Impression-Severity of Illness (CGI-S) in the adult study, were significantly improved (reduced score from baseline) compared to placebo in all studies.1,2,3,4,5

Clinical Experience in Pediatric Patients

Study 1 (NCT03247530) randomized patients 6 to 11 years of age to placebo, viloxazine 100 mg, or viloxazine 200 mg given once daily as a single dose in the morning.1,2 All patients underwent a 1-week titration period followed by a 5-week maintenance phase.1,2 The mean age of patients was 8.5 years; 63% were male, 51.3% were white, and 43.7% were Black or African American.2

Total ADHD-RS-5 score was significantly reduced in the first week of treatment and at 6 weeks in both viloxazine treatment groups compared to placebo.1,2 The inattention component and the hyperactivity/impulsivity component of the ADHD-RS-5 were reduced at 6 weeks in both treatment groups compared to placebo.2 The 50% responder rate per the ADHD-RS-5, defined as the proportion of patients who exhibited ≥50% reduction (improvement) in change from baseline ADHD-RS-5 total score, was 19.8, 34.2, and 41.2% in the placebo, viloxazine 100 mg, and viloxazine 200 mg groups, respectively.2 These results were statistically significant for both viloxazine dosage groups compared to placebo.2 A statistically significant greater reduction (improvement) in CGI-I score at 6 weeks was also observed with both dosages of viloxazine compared with placebo.1,2

Study 2 (NCT03247543) randomized patients 6 to 11 years of age to placebo, viloxazine 200 mg, or viloxazine 400 mg given once daily as a single dose in the morning.1,3 All patients underwent a 3-week titration period (starting at 100 mg once daily) followed by a 5-week maintenance period.1,3 The mean age of patients was 8.4 years; 64.5% were male, 52.8% were white, and 41.5% were Black.1,3

Total ADHD-RS-5 score was significantly reduced in the first week of treatment in the viloxazine 200 mg group, at week 5 in the viloxazine 400 mg group, and was sustained throughout the remaining weeks of the study (8 weeks total) in both treatment groups compared to placebo.1,3 The inattention component and the hyperactivity/impulsivity component of the ADHD-RS-5 were reduced at 8 weeks in both treatment groups compared to placebo.3 The 50% responder rate per the ADHD-RS-5, defined as the proportion of patients who exhibited ≥50% reduction (improvement) in change from baseline ADHD-RS-5 total score, was 25.8, 36, and 41.2% in the placebo, viloxazine 200 mg, and viloxazine 400 mg groups, respectively.3 Compared to placebo, this was statistically significant in the 400 mg group, but not the 200 mg group.3 A statistically significant greater reduction (improvement) in CGI-I score at 8 weeks was observed both in patients treated with viloxazine 200 mg and in patients treated with viloxazine 400 mg, compared to placebo.1,3

Study 3 (NCT03247517) randomized patients 12 to 17 years of age to placebo, viloxazine 200 mg, or viloxazine 400 mg given once daily as a single dose in the morning.1,4 All patients underwent a 1-week titration period followed by a 5-week maintenance phase.1,4 The mean age of patients was 13.9 years; 63.5% were male, 56.8% were white, and 39.2% were Black or African American.1,4

Total ADHD-RS-5 score was significantly reduced in the first week of treatment in the viloxazine 400 mg group, at week 3 in the viloxazine 200 mg group, and sustained throughout the remaining weeks of the study (6 weeks total) in both treatment groups compared to placebo.1,4 The inattention component and the hyperactivity/impulsivity component of the ADHD-RS-5 were reduced at 8 weeks in both treatment groups compared to placebo.4 The 50% responder rate per the ADHD-RS-5, defined as the proportion of patients who exhibited ≥50% reduction (improvement) in change from baseline ADHD-RS-5 total score, was 27, 45.8, and 44.6% in the placebo, viloxazine 200 mg, and viloxazine 400 mg groups, respectively.4 Compared to placebo, this was statistically significant in both treatment groups.4 A statistically significant greater reduction (improvement) in CGI-I score at 6 weeks was observed with both viloxazine treatment groups compared to placebo.1,4

Clinical Experience in Adults

Study 4 (NCT04016779) randomized patients 18 to 65 years of age to placebo or a flexible dose of viloxazine 200 to 600 mg given once daily as a single dose in the morning.1,5 Patients assigned to viloxazine received an initial dosage of 200 mg once daily; dosage was titrated up to a maximum of 600 mg once daily based on the investigator's discretion.1,5 The mean age of patients was 34.8 years; 54.8% were male, 78.5% were white, and 13.8% were Black or African American.1,5 The mean dose of viloxazine at the end of study was 504 mg per day.1,5

Total AISRS score was significantly reduced at week 2 in those assigned to viloxazine and sustained throughout the remaining weeks of the study (6 weeks total) compared to placebo.1,5 The Inattention component and the Hyperactivity/Impulsivity component of the AISRS were reduced at 6 weeks in the viloxazine group compared to placebo.5 The 50% responder rate per the AISRS, defined as the proportion of patients who exhibited ≥50% reduction (improvement) in change from baseline AISRS total score, was 32.9 and 39.2% in the placebo and viloxazine groups, respectively.5 Compared to placebo, this was not statistically significant.5 The 30% responder rate was significantly higher in the viloxazine versus the placebo group (60 versus 47.6%).5 In addition, a statistically significant greater reduction (improvement) in CGI-S score at 6 weeks was observed in patients treated with viloxazine compared with placebo.1,5

Clinical Perspective

ADHD is a neurodevelopmental disorder that typically begins in childhood and often persists into adulthood.5,6,500 ADHD is characterized by hyperactivity, impulsivity, or inattention severe enough to cause functional impairment; the goal of treatment is to reduce functional impairment.5,6 To help ensure an accurate diagnosis, clinicians should employ Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria in the context of their clinical assessment to diagnose ADHD.500

Current clinical practice guidelines from the American Academy of Pediatrics (AAP) recommend age-based and location-based (i.e., home, classroom) educational and behavioral interventions in addition to the use of FDA-approved ADHD medications (e.g., stimulants [i.e., methylphenidate, amphetamines], selective norepinephrine reuptake inhibitors [e.g. atomoxetine], or selective α-2 adrenergic agonists [i.e., guanfacine extended-release, clonidine extended-release]) for the treatment of ADHD.500

AAP considers stimulants and nonstimulants to be first- and second-line therapy, respectively, among school age children (6-12 years of age) and adolescents (12-17 years of age) with ADHD.500 Nonstimulant effectiveness at reducing core symptoms of ADHD has been established in school-aged children and adolescents; however, experts state the effect size is less robust than that of stimulant medications.500

Although stimulants are considered first-line, experts state nonstimulant medications may be considered when families are concerned about the use of stimulants or the potential for abuse and/or diversion of such agents or when there is no access to first-line medications.500 Nonstimulants may be considered when patients have a suboptimal response to an adequate trial of first-line agents or when significant adverse effects occur.500 Among the currently available nonstimulants (i.e., viloxazine, atomoxetine, extended-release [ER] guanfacine, or clonidine ER), experts do not recommend one agent over another.500 There are no viloxazine-specific recommendations as the AAP guideline predates FDA approval of the drug.500

Other experts have issued recommendations for the treatment of adults with ADHD; however, these recommendations predate the availability of viloxazine.9,10 Similar to the AAP recommendations,500 these experts recommend a multimodal approach to the treatment of adults with ADHD that includes nonpharmacologic (e.g., psychoeducation, cognitive behavioral therapy) and drug therapies (e.g., stimulants [i.e., methylphenidate, amphetamines], selective norepinephrine reuptake inhibitors [e.g., atomoxetine]), with stimulants recommended as the first-line choice of drug therapy due to their effectiveness and tolerability.9,10

General

Pretreatment Screening

• Assess heart rate and blood pressure prior to initiating treatment with viloxazine.1
• Screen patients prior to initiating treatment with viloxazine to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a personal or family history of suicide, bipolar disorder, and depression.1

Patient Monitoring

• Assess heart rate and blood pressure following increases in viloxazine dosage, and periodically thereafter.1
• Closely monitor all viloxazine-treated patients for clinical worsening and for emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes.1 Observe patients for the emergence of precursor symptoms (e.g., depressed mood, anxiety, agitation, akathisia, mania, hypomania, panic attacks, impulsive behavior, aggression).1
• Periodically reevaluate the long-term use of vilozaxine and adjust dosage as needed.1
• Viloxazine may affect weight; monitor body weight periodically.1

Administration

Oral Administration

Viloxazine is administered orally without regard to meals.1 Swallow viloxazine capsules whole; capsules should not be cut, crushed, or chewed.1

If the patient is unable to swallow the capsule whole, open the capsule and sprinkle the entire contents over a teaspoonful or tablespoonful of pudding or applesauce.1 This mixture of food and drug should be consumed in its entirety, without chewing, within 15 minutes for pudding or within 2 hours for applesauce; do not store for future use.1

Store viloxazine capsules at 20 to 25°C (excursions permitted to 15-30°C).1

Dosage

Dosage of viloxazine hydrochloride is expressed in terms of viloxazine.1

Adults

The recommended initial dosage of viloxazine for the treatment of attention-deficit hyperactivity disorder (ADHD) in adults is 200 mg orally once daily.1

Dosage may be titrated in increments of 200 mg at weekly intervals to the maximum recommended dosage of 600 mg once daily, depending on response and tolerability.1

Pediatric Patients

The recommended initial dosage of viloxazine in pediatric patients 6 to 11 years of age for the treatment of ADHD is 100 mg orally once daily.1 Dosage may be titrated in increments of 100 mg at weekly intervals to the maximum recommended dosage of 400 mg once daily, depending on response and tolerability.1

The recommended initial dosage of viloxazine in adolescents 12 to 17 years of age for the treatment of ADHD is 200 mg orally once daily.1 After 1 week, dosage may be titrated by an increment of 200 mg to the maximum recommended dosage of 400 mg once daily, depending on response and tolerability.1

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

In patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/minute per 1.73 m²), the recommended initial dosage of viloxazine is 100 mg orally once daily.1 Dosage may be titrated in weekly increments of 50 to 100 mg once daily, to a maximum recommended dosage of 200 mg once daily.1

No dosage adjustment is recommended in patients with mild to moderate (eGFR of 30 to 89 mL/minute per 1.73 m²) renal impairment.1

Geriatric Use

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• Concomitant administration of monoamine oxidase inhibitors (MAOI), or within 14 days after discontinuing an MAOI, because of an increased risk of hypertensive crisis.1
• Concomitant administration of sensitive cytochrome P-450 (CYP) isoenzyme 1A2 substrates or CYP1A2 substrates with a narrow therapeutic range.1

Warnings/Precautions

Suicidal Thoughts and Behaviors

A boxed warning about the risk of suicidal thoughts and behavior is included in the prescribing information for viloxazine.1 Higher rates of suicidal thoughts and behaviors were reported in pediatric and adult patients with ADHD treated with viloxazine compared to patients treated with placebo.1

The Columbia Suicide Severity Rating Scale (C-SSRS), a validated scale that assesses suicide risk, was utilized in the pediatric and adult placebo-controlled viloxazine trials.1 Among 1019 pediatric patients exposed to viloxazine 100 to 400 mg, 0.9% of patients reported suicidal ideation, behavior, or both.1 Among 463 patients treated with placebo in these studies, two patients (0.4%) reported suicidal ideation on the C-SSRS.1 No patients treated with placebo reported suicidal behavior; no completed suicides occurred in these trials.1 Among 189 adults treated with viloxazine in a clinical trial, three patients (1.6%) reported suicidal ideation on the C-SSRS, versus 0 of 183 adults treated with placebo.1 No adults treated with either viloxazine or placebo reported suicidal behavior on the C-SSRS.1 No attempted or completed suicides occurred in the trial.1

Viloxazine-treated patients had higher rates of insomnia and irritability compared to placebo.1 Although a causal link between the emergence of insomnia and irritability and the emergence of suicidal impulses has not been established, there is concern that these and other symptoms such as depressed mood, anxiety, agitation, akathisia, mania, hypomania, panic attacks, impulsive behavior, and aggression may represent precursors to emerging suicidal ideation or behavior. 2 Observe patients being treated with viloxazine for the emergence of precursor symptoms.1

Closely monitor all viloxazine-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes.1 Consider changing the therapeutic regimen, including possible discontinuance, in patients who are experiencing emergent suicidal thoughts and behaviors or symptoms that might be precursors to emerging suicidal ideation or behavior, especially if these symptoms are severe or abrupt in onset, or were not part of the patient's presenting symptoms.1

Advise family members or caregivers of patients to monitor for the emergence of suicidal ideation or behavior, and to report such symptoms immediately to the healthcare provider.1

Cardiovascular Effects

Viloxazine may cause an increase in heart rate and diastolic blood pressure.1

In pediatric patients 6 to 11 years of age, 22% of patients treated with viloxazine 100 mg daily experienced an increase in heart rate ≥20 beats per minute (bpm) at any time point in one study, compared to 9% of patients who received placebo.1 In a second dose-comparison study, this finding was observed in 31% of patients who received the 200 mg daily dosage of viloxazine, compared to 15% of patients in the placebo group, and in 28% of patients who received the 400 mg daily dosage of viloxazine, compared to 23% of patients who received placebo.1

In pediatric patients 12 to 17 years of age, 22% of patients treated with viloxazine 200 mg daily experienced an increase in heart rate ≥20 bpm at any time point in the clinical trial, compared to 14% who received placebo.1 This finding was observed in 34% of patients who received the 400 mg daily dosage compared to 17% of patients in the placebo group.1 Of patients who received viloxazine 400 mg daily, 25% had a ≥15 mmHg increase in diastolic blood pressure at any time in the clinical trial, compared to 13% of patients in the placebo group.1

In adult patients 18 to 60 years of age, 29% of patients treated daily with viloxazine 200 to 600 mg had a ≥20 bpm increase in heart rate at any time point in one study, compared to 13% of patients who received placebo.1 Of patients treated daily with viloxazine 200 to 600 mg, 13% had a ≥15 mmHg increase in diastolic blood pressure at any time in the study compared to 9% of patients in the placebo group.1

Assess heart rate and blood pressure prior to initiating viloxazine treatment, following increases in dosage, and periodically thereafter.1

Precipitation of Manic Symptoms

Noradrenergic drugs (e.g., viloxazine) may induce a manic or mixed episode in patients with bipolar disorder.1

Screen patients prior to initiating treatment with viloxazine to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a personal or family history of suicide, bipolar disorder, and depression.1

Somnolence and Fatigue

Viloxazine may cause somnolence and fatigue.1

In pediatric patients 6 to 17 years of age with ADHD, somnolence (including lethargy and sedation) was reported in 16% of viloxazine-treated patients compared to 4% of placebo-treated patients; fatigue was reported in 6 and 2% of patients, respectively.1

In adults, somnolence was reported in 6% of viloxazine-treated patients versus 2% in placebo-treated patients; fatigue was reported in 12 and 3% of patients, respectively.1

Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by viloxazine.1

Specific Populations

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to viloxazine during pregnancy.1 Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at [Web].1

Based on findings from animal reproduction studies, viloxazine may cause maternal harm when used during pregnancy.1 Discontinue viloxazine when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the mother.1 Available data from case series with viloxazine use in pregnant women are insufficient to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes.1

Oral administration of viloxazine during the period of organogenesis caused fetal toxicities and delayed fetal development in rats and maternal toxicities in rabbits at doses approximately equal to the maximum recommended human dose (MRHD) of 600 mg in adults, based on mg/m².1

Maternal toxicities and deaths and fetal toxicities have been observed following viloxazine oral administration to pregnant rats and mice during pregnancy and lactation at doses ≤ the MRHD of 600 mg in adults, based on mg/m².1

Lactation

There are no data on the presence of viloxazine in human milk or the effects of the drug on the breastfed infant or on milk production.1

Viloxazine is likely present in rat milk and it is also likely the drug will be present in human milk.1

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for viloxazine and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Females and Males of Reproductive Potential

No adverse effects on fertility parameters were observed in male and female rats administered oral viloxazine.1

Pediatric Use

The safety and effectiveness of viloxazine in pediatric patients 6 to 17 years of age with ADHD have been established based on randomized, placebo-controlled studies.1 The safety and effectiveness of viloxazine have not been established in pediatric patients <6 years of age.1

In juvenile rat studies, decreased body weight, weight gain, and food consumption were observed following administration of viloxazine at 217 mg/kg per day; sexual maturation, reproductive capacity, and learning and memory were not affected.1

Patients treated with viloxazine should be monitored for suicidal thoughts and behavior, and for changes in weight.1

Geriatric Use

In clinical trials of viloxazine for the treatment of ADHD, an insufficient number of patients ≥65 years of age were included; it is unknown whether these patients respond differently compared to younger adults.1

Hepatic Impairment

Viloxazine peak plasma concentration and AUC were not significantly changed in patients with mild, moderate, and severe hepatic impairment.1

Renal Impairment

Viloxazine exposure increases in patients with renal impairment.1

Dosage reduction is recommended in patients with severe (eGFR < 30 mL/minute per 1.73 m² based on Modification of Diet in Renal Disease [MDRD] equation) renal impairment.1

No dosage adjustment is recommended in patients with mild to moderate (eGFR 30 to 89 mL/minute per 1.73 m² [MDRD]) renal impairment.1

Common Adverse Effects

Common adverse effects of viloxazine (≥5%) in patients 6 to 17 years of age were somnolence, decreased appetite, fatigue, nausea, vomiting, insomnia, and irritability.1

Common adverse effects of viloxazine (≥5%) in adults were insomnia, headache, somnolence, fatigue, nausea, decreased appetite, dry mouth, and constipation.1

Viloxazine is primarily metabolized by cytochrome (CYP) P-450 isoenzyme 2D6 and uridine diphosphoglucuronosyltransferase (UGT) 1A9 and 2B15.1

Viloxazine is a reversible inhibitor of CYP1A2, 2B6, 2D6, 3A4/5, and a potential inducer of CYP1A2 and 2B6.1 Viloxazine does not inhibit CYP2C8, 2C9, or 2C19.1

Based on in vitro data, drugs that inhibit CYP1A2, 2B6, 2D6, 2C8, 2C9, 2C19, 2E1, and 3A4 are not expected to have a significant impact on the pharmacokinetic profile of viloxazine.1

Viloxazine appears to be a weak inhibitor of the multidrug and toxin extrusion (MATE) 1 transporter; a clinically important interaction is unlikely.1,6 Viloxazine is not an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), MATE2-K, organic anion-transporting polypeptides (OATP) 1B1*1a, and 1B3 transporters.1 Viloxazine is not a substrate of either OATP1B1*1a or OATP1B3 transporters.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2D6 Inhibitors

When viloxazine and paroxetine, a strong CYP2D6 inhibitor, were coadministered, a modest change in viloxazine AUC (<35%) occurred.1,11

CYP1A2 Substrates

Viloxazine is a strong CYP1A2 inhibitor.1

Sensitive CYP1A2 Substrates or CYP1A2 Substrates with a Narrow Therapeutic Range

Viloxazine increases the AUC of caffeine, a sensitive CYP1A2 substrate, by up to 5-fold.1,6 Concomitant use of viloxazine significantly increases the total exposure, but not peak exposure, of sensitive CYP1A2 substrates (e.g., alosetron, duloxetine, ramelteon, tasimelteon, tizanidine, theophylline), which may increase the risk of adverse reactions associated with these CYP1A2 substrates.1,6

Concomitant administration of sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic range is contraindicated.1

Moderately Sensitive CYP1A2 Substrate

Concomitant use of viloxazine significantly increases the total exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may increase the risk of adverse reactions associated with these CYP1A2 substrates.1,6

Although the effect of viloxazine on moderately sensitive CYP1A2 substrates has not yet been evaluated, coadministration of viloxazine with moderately sensitive CYP1A2 substrates (e.g., clozapine, pirfenidone) is not recommended and a dose reduction may be warranted.1,6

CYP2D6 Substrates

Viloxazine is a weak inhibitor of CYP2D6 and increases the exposure of CYP2D6 substrates when coadministered.1 Viloxazine increases the AUC of dextromethorphan, a CYP2D6 substrate, approximately 2-fold.1 Monitor patients for adverse reactions and adjust dosages of CYP2D6 substrates as clinically indicated.1

CYP3A4 Substrates

Viloxazine is a weak CYP3A4 inhibitor, which increases the exposure of CYP3A4 substrates (e.g., midazolam) when coadministered.1 Monitor patients for adverse reactions and adjust dosages of CYP3A4 substrates as clinically indicated.1

Alcohol

When viloxazine 200 mg extended-release capsules were administered with orange juice containing 4 and 20% alcohol, there was no significant effect on viloxazine peak plasma concentration or AUC.1 When the drug was administered with orange juice containing 40% alcohol, viloxazine time to peak plasma concentration was 2 hours, which is 3 hours less than without alcohol; peak plasma concentration and AUC decreased by about 32 and 19%, respectively.1,6

Methylphenidate

In a single-dose, crossover study, co-administration of viloxazine extended-release and methylphenidate (Concerta^®) did not impact the pharmacokinetics of viloxazine or methylphenidate, relative to administration of either drug alone in healthy adults.1,6

Lisdexamfetamine

In a single-dose, crossover study, co-administration of viloxazine extended-release and lisdexamfetamine did not impact the pharmacokinetics of viloxazine or lisdexamfetamine, relative to administration of either drug alone in healthy adults.1,6

Monoamine Oxidase Inhibitors

Viloxazine is a very weak, competitive, and reversible inhibitor of monoamine oxidase (MAO) A and B.11 Concomitant administration of an MAOI, or administering viloxazine within 14 days after discontinuing an MAOI, is contraindicated because this may lead to a potentially life-threatening hypertensive crisis.1

Description

Viloxazine binds to norepinephrine transporter (NET) and selectively inhibits norepinephrine reuptake; it is not considered a stimulant.1,5,6

The exact mechanism(s) of action of viloxazine in the management of attention deficit hyperactivity disorder (ADHD) has not been fully elucidated but, based on in vitro studies, the drug appears to increase brain norepinephrine concentrations via norepinephrine reuptake blockade, with no direct effect on in vitro norepinephrine release.1,6,11 In vitro evidence is inadequate to support a clear drug effect, agonist or antagonist activity, on serotonin (5-HT) receptors 1A, 1B, 2B, 2C, and 7.6 Nonclinical studies suggest the potential for viloxazine to inhibit cardiac sodium channels; however, no effect was observed on the PR interval or QRS duration when healthy volunteers received viloxazine.1 Viloxazine did not prolong the QT interval to any clinically relevant extent at a dose 3 times the maximum recommended dose.1

The relative bioavailability of viloxazine hydrochloride extended-release (ER) capsules relative to an immediate-release formulation (IR) is about 88%.1 Following a single 200 mg dose, the median time to peak plasma concentration of viloxazine was approximately 5 hours (range 3 to 9 hours); the mean half-life was 7.02 hours.1 Over a dosage range from 100 to 600 mg once daily, viloxazine peak plasma concentration and AUC increased proportionally; steady-state was reached after two days and no accumulation was observed.1

Administration of viloxazine with a high-fat meal reduced the peak plasma concentration and AUC by about 9 and 8%, respectively; time to peak plasma concentration increased by about 2 hours.1 Sprinkling the contents of a viloxazine ER capsule on applesauce reduced the peak plasma concentration and AUC by about 10 and 5%, respectively.1

Viloxazine is 76-82% protein bound.1 The drug is primarily metabolized by cytochrome (CYP) P-450 isoenzyme 2D6 and uridine diphosphoglucuronosyltransferase (UGT) 1A9 and 2B15; the major metabolite detected in plasma is 5-hydroxy-viloxazine glucuronide.1 Renal excretion is the primary route of elimination; 90% of a radiolabeled viloxazine dose was recovered in urine within the first 24 hours post-dose.1 Less than 1% of the dose is excreted in the feces.1

The estimated steady-state peak plasma concentration and exposure (AUC) of viloxazine and its major metabolite, at doses ranging from 200 to 400 mg, was approximately 130 to 250% and 60 to 140% higher in pediatric patients 6 to 11 and 12 to 17 years of age, respectively, compared to adults.1

Viloxazine peak plasma concentration and AUC were not significantly changed in patients with mild, moderate, and severe hepatic impairment.1 Viloxazine peak plasma concentration and AUC increased in patients with severe renal impairment compared to those with mild or moderate impairment.1 No clinically significant differences in the pharmacokinetics of viloxazine was observed based on race and sex.1 No pharmacokinetic studies were conducted in the geriatric population.1

Pharmacogenomics

The impact of CYP2D6 metabolizer status on viloxazine pharmacokinetics was assessed in a multiple-dose study conducted in healthy volunteers classified as poor metabolizers (PM) and extensive metabolizers (EM).1,6 At steady state, viloxazine geometric means for peak plasma concentration and AUC were 21 and 26% higher in PMs compared to EMs, respectively; this is not expected to be clinically meaningful.1,6

Advice to Patients

• Advise patients and caregivers to monitor for the emergence of suicidal thoughts or behaviors that mght be precursors to emerging suicidal ideation or behavior.1 Patients, caregivers, and family members should immediately inform a clinician if clinical worsening, new or worse anxiety, agitation, akathisia, panic attacks, insomnia, new or worse irritability, aggression, hostility, impulsivity, restlessness, mania, hypomania, new or worse depression, suicidal ideation or behaviors, or unusual changes in behavior occur, particularly during the first few months after initiation of therapy or following dosage adjustments.1
• Caution patients about the importance of avoiding concomitant use of viloxazine and monoamine oxidase inhibitors (MAOI), or within 14 days after discontinuing an MAOI, because of an increased risk of hypertensive crisis.1
• Advise patients and caregivers on the risk of elevated blood pressure and heart rate and to monitor for such effects.1
• Advise patients and caregivers on the risk of activation of mania/hypomania and to monitor for such effects.1
• Advise patients about the potential for somnolence and fatigue.1 Advise patients and/or caregivers to use caution when performing activities requiring mental alertness (e.g., driving a motor vehicle, operating hazardous machinery), until they know how they will be affected by viloxazine.1
• Advise patients and/or caregivers that viloxazine may affect weight; monitor body weight.1
• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to viloxazine during pregnancy.1 Advise females of reproductive potential to discuss with their healthcare provider if viloxazine should be discontinued; contact the National Pregnancy Registry for Psychiatric Medications by calling 1-866-961-2388 or go to [Web].1
• Advise patients and/or caregivers to administer viloxazine one time each day, with or without food.1
• Advise patients to swallow the capsule whole or sprinkle the capsule contents over a teaspoonful or tablespoonful of applesauce or pudding and consume without chewing within 15 minutes when mixed with pudding or within 2 hours when mixed with applesauce.1 Do not store the food mixture.1 Do not cut, chew, or crush the capsule.1
• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

1. Supernus Pharmaceuticals. QELBREE^® (viloxazine hydrochloride) oral prescribing information. 2022 Apr. [Web]

2. Nasser A, Liranso T, Adewole T et al. A Phase III, Randomized, Placebo-controlled Trial to Assess the Efficacy and Safety of Once-daily SPN-812 (Viloxazine Extended-release) in the Treatment of Attention-deficit/Hyperactivity Disorder in School-age Children. Clin Ther. 2020 Aug;42(8):1452-1466. Doi: 10.1016/j.clinthera.2020.05.021. Epub 2020 Jul 25. PMID: 32723670.

3. Nasser A, Liranso T, Adewole T et al. Once-Daily SPN-812 200 and 400 mg in the treatment of ADHD in School-aged Children: A Phase III Randomized, Controlled Trial. Clin Ther. 2021 Apr;43(4):684-700. doi: 10.1016/j.clinthera.2021.01.027. Epub 2021 Mar 6. PMID: 33750646.

4. Nasser A, Liranso T, Adewole T et al. A Phase 3, Placebo-Controlled Trial of Once-Daily Viloxazine Extended-Release Capsules in Adolescents With Attention-Deficit/Hyperactivity Disorder. J Clin Psychopharmacol. 2021 Jul-Aug;41(4):370-380. doi: 10.1097/JCP.0000000000001404. PMID: 34181360; PMCID: PMC8244935.

5. Nasser A, Hull JT, Chaturvedi SA et al. A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Efficacy and Safety of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder. CNS Drugs. 2022 Aug;36(8):897-915. doi: 10.1007/s40263-022-00938-w. Epub 2022 Jul 27. PMID: 35896943; PMCID: PMC9328182.

6. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 211964: Integrated review. From FDA website. Accessed 2023 Apr 4. [Web] [Web]

8. Canadian ADHD Resource Alliance (CADDRA): Canadian ADHD Practice Guidelines, Fourth Edition, Toronto ON; CADDRA, 2018.

9. Kooij JJS, Bijlenga D, Salerno L et al. Updated European Consensus Statement on diagnosis and treatment of adult ADHD. Eur Psychiatry. 2019 Feb;56:14-34. doi: 10.1016/j.eurpsy.2018.11.001. Epub 2018 Nov 16. PMID: 30453134.

10. Findling RL, Candler SA, Nasser AF et al. Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status. CNS Drugs. 2021 Jun;35(6):643-653. Doi: 10.1007/s40263-021-00825-w. Epub 2021 May 18. PMID: 34003459; PMCID: PMC8219567.

11. Wang Z, Kosheleff AR, Adeojo LW et al. Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN-812 (Viloxazine Extended-Release) Pharmacokinetics in Healthy Adults. Clin Pharmacol Drug Dev. 2021 Nov;10(11):1365-1374. doi: 10.1002/cpdd.948. Epub 2021 May 4. PMID: 33943033; PMCID: PMC8597116.

500. Wolraich ML, Hagan JF Jr, Allan C et al. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. 2019 Oct;144(4):e20192528. doi: 10.1542/peds.2019-2528. Erratum in: Pediatrics. 2020 Mar;145(3): PMID: 31570648; PMCID: PMC7067282.