What is the classification, mechanism of action (MOA), common side effects, and clinical considerations for Viloxazine (Selective Norepinephrine Reuptake Inhibitor - SNRI)?

Viloxazine: Classification, Mechanism of Action, Side Effects, and Clinical Pearls

Viloxazine is classified as a selective norepinephrine reuptake inhibitor (SNRI) that inhibits the presynaptic reuptake of norepinephrine and also exhibits partial agonist activity at the serotonin 5-HT2C receptor, making it effective for conditions like ADHD. 1

Classification and Mechanism of Action

• Viloxazine is classified as a selective norepinephrine reuptake inhibitor (SNRI) that primarily works by inhibiting the reuptake of norepinephrine 1
• It has been more specifically described as a "serotonin norepinephrine modulating agent" with serotonin modulation contributing to its therapeutic effect 2
• Viloxazine binds to and inhibits the norepinephrine transporter with a Ki value of 0.13 μM 1
• It also exhibits partial agonist activity at the serotonin 5-HT2C receptor (Ki=0.66 μM), which may contribute to its therapeutic effects 1
• Originally developed in the 1970s, viloxazine was used as an antidepressant in Europe for approximately 30 years before being withdrawn from European markets in 2002 2
• It has been recently repurposed in an extended-release formulation for ADHD treatment in the United States 3

Common Side Effects

• Gastrointestinal symptoms are the most commonly reported side effects, including nausea, vomiting, abdominal discomfort, and diarrhea 3, 4
• Other common adverse effects include diaphoresis (excessive sweating), dry mouth, dizziness, headache, tremor, insomnia, somnolence, decreased appetite, and weight loss 4
• Cardiovascular effects may include increased blood pressure and increased pulse 4
• Fatigue and somnolence have been reported with moderate strength of evidence 4
• Sleep disturbances include diminished sleep duration, more frequent transitions to wakefulness, decreased slow-wave sleep, and reduced REM sleep 5

Serious Adverse Effects

• Suicidal thinking and behavior (through age 24 years) is a potential risk, as with other antidepressants 4
• Other uncommon but potentially serious adverse effects include behavioral activation/agitation, hypomania, mania, sexual dysfunction, seizures, abnormal bleeding, and serotonin syndrome 4
• Viloxazine has been associated with impaired concentration and mood in some patients 5
• Weight loss has been reported, which may correlate with gastrointestinal symptoms 5
• Unlike tricyclic antidepressants, viloxazine has a relatively low risk for cardiotoxicity 3

Drug Interactions

• Concomitant use with MAOIs is contraindicated due to risk of potentially life-threatening hypertensive crisis 1
• Viloxazine is a strong CYP1A2 inhibitor and can significantly increase exposure of sensitive CYP1A2 substrates 1
• It is also a weak inhibitor of CYP2D6 and CYP3A4, requiring monitoring of patients taking substrates of these enzymes 1
• Coadministration with sensitive CYP1A2 substrates or those with a narrow therapeutic range is contraindicated 1
• Patients taking CYP2D6 or CYP3A4 substrates should be monitored for adverse reactions, and dosage adjustments may be necessary 1

Clinical Pearls

• Viloxazine has a rapid onset of action, with significant improvements observed as early as one week after treatment initiation 6
• The extended-release formulation is typically started at 200 mg once daily for ADHD treatment 2
• It can be titrated by 200 mg increments at weekly intervals based on response and tolerability, with a maximum daily dose of 600 mg/day 2
• Dosage reduction is recommended in patients with severe renal impairment (eGFR < 30 mL/min/1.73m²) 1
• No dosage adjustment is needed for patients with mild to moderate renal impairment 1
• Unlike stimulant medications used for ADHD, viloxazine does not show evidence of drug dependence, making it a suitable alternative for patients with concerns about stimulant abuse potential 7
• Withdrawal symptoms including vomiting and prostration have been reported, particularly in older patients, suggesting the need for gradual discontinuation 5
• Limited data is available regarding its use during pregnancy and breastfeeding, warranting caution in these populations 2

Pharmacokinetics

• Steady-state is reached after two days of once-daily administration with no accumulation observed 1
• The median time to peak plasma concentration is approximately 5 hours (range 3-9 hours) following a single 200 mg dose 1
• The mean half-life of viloxazine is approximately 7 hours 1
• Viloxazine is 76-82% bound to human plasma proteins 1
• It is primarily metabolized by CYP2D6, UGT1A9, and UGT2B15 1
• Renal excretion is the primary route of elimination, with 90% of the dose recovered in urine within 24 hours post-dose 1