Pharmacokinetics of Viloxazine ER: What to Expect From Onset to Duration

A solid grasp of viloxazine extended-release’s pharmacokinetics can significantly enhance ADHD treatment outcomes. This article provides a practical breakdown of viloxazine ER’s absorption, metabolism, and elimination profiles, explaining how these features support its once-daily dosing and 24-hour symptom coverage. Key clinical takeaways include dosing strategies across age groups, the impact of hepatic and renal impairment, drug interaction risks (particularly CYP1A2 and CYP2D6 considerations), and the timing of therapeutic effects. 

Understanding ADHD Treatment and the Critical Role of Pharmacokinetics

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by inattention, hyperactivity, and impulsivity.¹ While stimulants (eg, methylphenidate, amphetamines) remain first-line therapies, 30% of patients experience suboptimal responses or intolerable side effects, driving demand for non-stimulant alternatives such as viloxazine extended-release (ER).^1,2

Drugs metabolized too rapidly may fail to sustain therapeutic effects, while slow metabolism risks toxicity.² Similarly, erratic absorption (eg, sharp plasma peaks) can worsen side effects such as insomnia or rebound symptoms.³ Ideal ADHD medications balance predictable absorption for all-day coverage, minimal drug-interaction risk, and tolerable clearance pathways for diverse populations.⁴ Viloxazine’s ER formulation and absorption, distribution, metabolism, and elimination (ADME) profile address these priorities, offering clinicians a tool to tailor treatment for patients with unique metabolic needs.⁵

Understanding the pharmacokinetic (PK) profile of viloxazine ER is critical for optimizing ADHD treatment. This article details viloxazine’s ADME profile, alongside key considerations for dosing and patient management, to ensure clinicians can leverage its full therapeutic potential.

Absorption, Distribution, Metabolism, and Elimination

Absorption:
Viloxazine’s ER formulation ensures gradual absorption, with peak plasma concentrations (Tmax) achieved approximately 5 hours post-dose. The once-daily regimen maintains steady-state plasma levels, avoiding the sharp peaks associated with immediate-release formulations.⁵

Distribution:
Viloxazine is 76% to 82% protein-bound, primarily to albumin, with a volume of distribution indicating moderate tissue penetration. This binding profile minimizes drug-drug interactions related to protein displacement.⁵ 

Metabolism:
Hepatic metabolism via CYP2D6 and CYP3A4 converts viloxazine into inactive metabolites, notably 5-hydroxyviloxazine glucuronide. Concurrent use of CYP2D6 inhibitors (eg, paroxetine) or inducers (eg, rifampin) may necessitate dose adjustments.⁵  Notably, viloxazine itself inhibits CYP1A2, requiring caution with drugs metabolized by this enzyme (eg, duloxetine, theophylline).⁵

Elimination:
Approximately 90% of viloxazine is excreted renally as metabolites, with a terminal half-life of ~7 hours.⁵

Onset of Therapeutic Effect

• Onset: Clinical effects emerge as early as Week 1, with reductions in ADHD Rating Scale-5 (ADHD-RS-5) scores observed in phase 3 trials.⁶

Optimal efficacy is typically achieved by Week 4, supporting a structured titration schedule:

• Children (6 to 11 years): Start at 100 mg/day, titrate weekly by 100 mg to a maximum of 400 mg.⁵ 
• Adolescents (12 to 17 years): Start at 200 mg/day, titrate to 400 mg.⁵ 

Key Pharmacokinetic Considerations for Clinical Practice

• Renal Impairment:
  • No dose adjustment is recommended for mild-to-moderate renal impairment, but dose adjustment is recommended for patients with severe impairment (eGFR <30 mL/min/1.732m²).⁵
• Drug Interactions:
  • Avoid concurrent use with strong CYP1A2 substrates.⁵
  • Monitor for interactions with CYP2D6 inhibitors/inducers.⁵
• Pediatric vs Adolescent Dosing: Higher initial doses in adolescents account for faster metabolic clearance.⁵ 
• Adherence Counseling: Emphasize once-daily morning dosing to maintain therapeutic levels and minimize somnolence.⁵ 

Conclusion

Viloxazine ER’s PK profile—marked by gradual absorption, hepatic metabolism, and renal elimination—supports its once-daily use with predictable efficacy. Clinicians should tailor dosing to hepatic function, screen for interactions, and counsel patients on adherence to maximize outcomes in ADHD management.

References:

1. Edinoff AN, Akuly HA, Wagner JH, et al. Viloxazine in the treatment of attention deficit hyperactivity disorder. Front Psychiatry. 2021;12:789982. doi:10.3389/fpsyt.2021.789982
2. Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: A systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727-738. doi:10.1016/S2215-0366(18)30269-4
3. Wilens TE, Spencer TJ. Understanding attention-deficit/hyperactivity disorder from childhood to adulthood. Postgrad Med. 2010;122(5):97-109. doi:10.3810/pgm.2010.09.2206
4. Childress AC. Novel formulations of ADHD medications: Stimulant selection and management. Focus (Am Psychiatr Publ). 2021 Jan;19(1):31-38. doi:10.1176/appi.focus.20200032
5. Qelbree. Prescribing information. Supernus Pharmaceuticals. Revised January 2025. Accessed May 12, 2025. https://www.supernus.com/sites/default/files/Qelbree-Prescribing-Info.pdf
6. 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;42(8):1452-1466. doi:10.1016/j.clinthera.2020.05.021