Viloxazine

Indications

• FDA-approved for attention-deficit/hyperactivity disorder in pediatric patients age 6 to 17 years as a once-daily extended-release capsule.
• FDA-approved for ADHD in adults since 2022, making it the first new non-stimulant with an adult indication in nearly two decades.
• Useful when abuse, diversion, or a contraindication to controlled substances makes stimulants unsuitable for the patient or family.
• Reasonable alternative when atomoxetine failed for tolerability, since the receptor profile and time course differ despite both being noradrenergic.
• Used off-label as an adjunct to stimulant therapy for residual inattention, although controlled combination data are limited.
• Not indicated for depression, anxiety, or narcolepsy, even though viloxazine was marketed as an antidepressant in Europe decades ago.

Mechanism of action

• Inhibits the norepinephrine transporter, increasing synaptic norepinephrine and, in prefrontal cortex, extracellular dopamine.
• Acts as a 5-HT2B receptor antagonist and a 5-HT2C receptor agonist, a serotonergic profile that distinguishes it from atomoxetine.
• Serotonergic modulation is thought to contribute to effects on emotional dysregulation and irritability alongside core ADHD symptoms.
• No meaningful dopamine release in nucleus accumbens occurs, so there is no euphoria and the drug is not a controlled substance.
• Benefit accumulates over weeks through downstream receptor adaptation, though separation from placebo can appear as early as week 1.

Pharmacokinetics

• Extended-release capsules give a Tmax of about 5 hours, and food lowers peak concentration modestly without changing overall exposure.
• Elimination half-life is approximately 7 hours, and once-daily dosing is supported by the extended-release delivery system.
• Metabolized by CYP2D6 hydroxylation and by UGT1A9 and UGT2B15 conjugation, with excretion mainly renal as the glucuronide.
• Viloxazine is a strong CYP1A2 inhibitor, a weak CYP2D6 and CYP3A4 inhibitor, and this is the dominant interaction concern.
• Severe renal impairment raises exposure and requires a lower starting dose and a hard maximum of 200 mg daily.

Dosing

• Children 6-11 years: start 100 mg PO once daily and titrate by 100 mg weekly to a maximum of 400 mg/day.
• Adolescents 12-17 years: start 200 mg PO once daily and, after 1 week, may increase by 200 mg to a maximum of 400 mg/day.
• Adults: start 200 mg PO once daily and titrate in 200 mg weekly increments to a maximum of 600 mg/day.
• Severe renal impairment with eGFR 15-29 mL/min/1.73 m2: start 100 mg daily, titrate weekly by 50-100 mg, and do not exceed 200 mg/day.
• Capsules may be swallowed whole or opened and sprinkled onto applesauce or pudding, but the beads must not be chewed or crushed.
• No taper is required, and stopping does not produce a discontinuation syndrome, though ADHD symptoms return within days.

Adverse effects

• In children and adolescents the common effects are somnolence, decreased appetite, fatigue, nausea, vomiting, insomnia, and irritability.
• In adults the common effects are insomnia, headache, somnolence, fatigue, nausea, decreased appetite, dry mouth, and constipation.
• Somnolence and fatigue are the usual reasons for discontinuation and can be reduced by evening rather than morning dosing.
• Blood pressure and heart rate increase modestly, so vitals should be measured before treatment, after each increase, and periodically.
• Activation of mania or hypomania can occur, so screen for bipolar disorder and family history of mania before starting.
• Suicidal thoughts and behaviors were more frequent than with placebo, the basis for the boxed warning that applies at all ages.

Monitoring

• Measure heart rate and blood pressure before starting, after each dose increase, and periodically during maintenance treatment.
• Screen for personal and family history of suicide, bipolar disorder, and depression before the first dose, as the label directs.
• Ask about new or worsening suicidal thinking, agitation, and unusual behavior change at every visit, especially in the first weeks.
• Track response with a validated ADHD rating scale at baseline and at weeks 2 and 6, since full benefit takes about 6 weeks.
• Check renal function when eGFR is uncertain in older or medically complex patients, because severe impairment caps the dose at 200 mg.

Interactions

• Coadministration with sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic index is contraindicated.
• Practically this means avoiding tizanidine and theophylline, and using caution with clozapine, olanzapine, duloxetine, and caffeine.
• Contraindicated with monoamine oxidase inhibitors and within 2 weeks of stopping one because of potential hypertensive crisis.
• As a weak CYP2D6 and CYP3A4 inhibitor it can raise levels of substrates such as atomoxetine, risperidone, and some benzodiazepines.
• Additive blood pressure and heart rate effects occur with stimulants, decongestants, and other noradrenergic drugs.

Special populations

• Pregnancy: animal data show maternal and fetal toxicity, and the label directs discontinuation when pregnancy is recognized unless benefit outweighs risk.
• Lactation: there are no human milk data, so an alternative agent or infant monitoring for sedation and poor feeding is advisable.
• Pediatric: approved from age 6 years; safety and effectiveness in children under 6 have not been established.
• Geriatric: clinical trials did not include enough patients over 65 to determine differences in response or tolerability.
• Severe renal impairment requires the reduced dosing schedule; use in end-stage renal disease has not been studied.

Clinical pearls

• A strong CYP1A2 inhibitor: screen for tizanidine, theophylline, clozapine, and olanzapine first.
• Move the dose to evening when somnolence appears rather than abandoning the drug.
• The boxed suicidality warning applies to adults too, unlike the atomoxetine warning.