Viloxazine (Monograph)

Drug class: Respiratory and CNS Stimulants

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Selective norepinephrine reuptake inhibitor.

Uses for Viloxazine

Attention-Deficit Hyperactivity Disorder (ADHD)

Treatment of ADHD in adults and pediatric patients ≥6 years of age.

Has been shown to reduce functional impairment caused by hyperactivity, impulsivity, and inattention.

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 use of FDA-approved ADHD medications for treatment of ADHD.

Although stimulants are generally considered first-line drug therapy, experts state nonstimulant medications may be considered when there is concern 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.

Other experts have issued recommendations for the treatment of adults with ADHD. Similar to AAP recommendations, these experts recommend a multimodal approach to the treatment of adults with ADHD that includes nonpharmacologic and pharmacologic therapies.

Viloxazine Dosage and Administration

General

Pretreatment Screening

• Assess heart rate and BP prior to initiating treatment with viloxazine.

• 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.

Patient Monitoring

• Assess heart rate and BP following increases in viloxazine dosage, and periodically thereafter.

• Closely monitor 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. Observe patients for emergence of precursor symptoms (e.g., depressed mood, anxiety, agitation, akathisia, mania, hypomania, panic attacks, impulsive behavior, aggression).

• Periodically reevaluate the long-term use of vilozaxine and adjust dosage as needed.

• Viloxazine may affect weight; monitor body weight periodically.

Administration

Oral Administration

Administer orally without regard to meals. Do not cut, crush, or chew capsules.

Capsules may be swallowed whole, or the capsule can be opened and the contents sprinkled onto a teaspoonful or tablespoonful of applesauce or pudding. If sprinkled on pudding or applesauce, consume within 15 minutes or 2 hours, respectively, without chewing.

Dosage

Dosage of viloxazine hydrochloride is expressed in terms of viloxazine.

Pediatric Patients

ADHD

Oral

Children 6 to 11 years of age: Initially 100 mg once daily. Titrate in increments of 100 mg at weekly intervals, depending on response and tolerability. Maximum dosage: 400 mg once daily.

Adolescents 12 to 17 years of age: Initially 200 mg once daily. After 1 week, may titrate by an increment of 200 mg, depending on response and tolerability. Maximum dosage: 400 mg once daily.

Adults

ADHD

Oral

Initially 200 mg once daily. Titrate in increments of 200 mg at weekly intervals, depending on response and tolerability. Maximum dosage: 600 mg once daily.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

Mild to moderate (eGFR of 30 to 89 mL/minute per 1.73 m²) renal impairment: No dosage adjustment necessary.

Severe renal impairment (eGFR <30 mL/minute per 1.73 m²): Initial dosage 100 mg once daily. May titrate in weekly increments of 50–100 mg once daily to a maximum recommended dosage of 200 mg once daily.

Geriatric Use

No specific dosage recommendations.

Cautions for Viloxazine

Contraindications

• Concomitant administration with MAO inhibitors, or within 14 days after discontinuing the MAO inhibitors, because of an increased risk of hypertensive crisis.

• Concomitant administration with sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic range.

Warnings/Precautions

Suicidal Thoughts and Behaviors

Suicidal thoughts and behavior reported in pediatric and adult patients with ADHD treated with viloxazine.

Higher rates of insomnia and irritability also reported in patients receiving viloxazine. Although causal link not established, there is concern that these and other symptoms (e.g., depressed mood, anxiety, agitation, akathisia, mania, hypomania, panic attacks, impulsive behavior, and aggression) may be precursors to emerging suicidal ideation or behavior.

Observe patients for the emergence of precursor symptoms.

Closely monitor 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.

Consider changing the therapeutic regimen, including possibly discontinuing viloxazine, in patients who experience 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.

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.

Cardiovascular Effects

Viloxazine may cause an increase in heart rate and diastolic BP.

Assess heart rate and BP prior to initiating viloxazine treatment, following increases in dosage, and periodically while on therapy.

Precipitation of Manic Symptoms

Noradrenergic drugs (e.g., viloxazine) may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating treatment, screen patients 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.

Somnolence and Fatigue

Viloxazine may cause somnolence and fatigue.

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.

Specific Populations

Pregnancy

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

May cause maternal harm when used during pregnancy based on findings from animal reproduction studies. Available data in pregnant women insufficient to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes.

Discontinue viloxazine when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the mother.

Lactation

No data on presence of viloxazine in human milk, effects on the breast-fed infant, or effects on milk production. Viloxazine is likely present in rat milk, and it is likely present in human milk.

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for viloxazine and any potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

Females and Males of Reproductive Potential

No adverse effects on fertility observed in animal studies.

Pediatric Use

Safety and effectiveness not established in pediatric patients <6 years of age.

Viloxazine decreased body weight, weight gain, and food consumption in male and female juvenile rats.

Monitor patients for suicidal thoughts and behavior, and for changes in weight.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Peak plasma concentration and AUC not significantly changed in those with mild, moderate, and severe hepatic impairment.

Renal Impairment

Dosage reduction is recommended in patients with severe (eGFR of <30 mL/minute per 1.73 m² [MDRD]) renal impairment.

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

Viloxazine exposure increases in patients with renal impairment.

Common Adverse Effects

Common adverse effects (≥5%) in pediatric patients 6 to 17 years of age: Somnolence, decreased appetite, fatigue, nausea, vomiting, insomnia, irritability.

Common adverse effects (≥5%) in adults: Insomnia, headache, somnolence, fatigue, nausea, decreased appetite, dry mouth, constipation.

Drug Interactions

Metabolized by CYP2D6.

Strong inhibitor of CYP1A2; weak inhibitor of 2D6 and 3A4.

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Viloxazine AUC increased modestly (<35%) when coadministered with paroxetine.

Drugs Metabolized by Hepatic Microsomal Enzymes

Sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic range: Potential for increased AUC of substrate drug. May increase the risk of adverse reactions associated with sensitive or narrow therapeutic range CYP1A2 substrates (e.g., alosetron, duloxetine, ramelteon, tasimelteon, tizanidine, theophylline).

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

Moderately sensitive CYP1A2 substrates (e.g., clozapine, pirfenidone): Not yet evaluated. Not recommended for coadministration with viloxazine; dose reduction may be warranted.

CYP2D6 substrates: Dextromethorphan AUC increased approximately 2-fold. Monitor for adverse reactions; adjust dosage of substrate drug as clinically indicated.

CYP3A4 substrates: Possible increased AUC of substrate drug. Monitor for adverse reactions; adjust dosage of substrate drug as clinically indicated.

Monoamine Oxidase Inhibitors

Viloxazine is a weak, competitive, and reversible inhibitor of monoamine oxidase (MAOI) A and B.

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.

Specific Drugs

Viloxazine Pharmacokinetics

Absorption

Bioavailability

Relative bioavailability of extended-release capsules relative to an immediate-release formulation is about 88%.

Food

Peak plasma concentration and AUC reduced by about 9 and 8%, respectively, when administered with food; time to peak plasma concentration increased by about 2 hours.

Peak plasma concentration and AUC reduced by about 10 and 5%, respectively, when capsule contents were sprinkled on applesauce.

Plasma Protein Binding

76-82%

Elimination

Metabolism

Primarily metabolized by CYP2D6 and UGT1A9 and 2B15; major metabolite is 5-hydroxy-viloxazine glucuronide.

Elimination Route

Urine: 90% recovered within the first 24 hours.

Feces: <1%.

Half-life

Mean 7.02 hours.

Special Populations

Estimated steady-state peak plasma concentration and AUC of viloxazine (200-400 mg) and its major metabolite were 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.

Peak plasma concentration and AUC increased in patients with severe renal impairment compared to those with mild or moderate impairment.

At steady state, viloxazine peak plasma concentration and AUC were 21 and 26% higher, respectively, in CYP2D6 poor metabolizers compared to extensive metabolizers.

No clinically significant differences in viloxazine pharmacokinetics observed based on race, sex or hepatic impairment (mild, moderate, or severe).

No pharmacokinetic studies conducted in the geriatric population.

Stability

Storage

Oral

Extended-release Capsules

20–25°C (excursions permitted to 15–30°C).

Capsule opened and mixed with pudding: 15 minutes, do not store.

Capsule opened and mixed with applesauce: 2 hours, do not store.

Actions

• Mechanism of action in treatment of ADHD unclear, however, thought to be related to inhibition of norepinephrine reuptake and subsequent increased brain norepinephrine concentrations.

• Reduces functional impairment caused by hyperactivity, impulsivity, and inattention in patients with ADHD.

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. 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.

• 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.

• Advise patients and caregivers on the risk of elevated blood pressure and heart rate and to monitor for such effects.

• Advise patients and caregivers on the risk of activation of mania/hypomania and to monitor for such effects.

• Advise patients about the potential for somnolence and fatigue. 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.

• Advise patients and/or caregivers that viloxazine may affect weight; monitor body weight.

• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to viloxazine during pregnancy. 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].

• Advise patients and/or caregivers to administer viloxazine one time each day, with or without food.

• 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. Do not store the food mixture. Do not cut, chew, or crush the capsule.

• 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.

• Inform patients of other important precautionary information.

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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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