What is the recommended dosage and treatment regimen for atomoxetine (non-stimulant medication) in pediatric and young adult patients with Attention Deficit Hyperactivity Disorder (ADHD)?

Atomoxetine Dosing and Treatment Regimen for Pediatric and Young Adult ADHD

Atomoxetine should be initiated at 0.5 mg/kg/day in children and adolescents up to 70 kg (or 40 mg/day in those over 70 kg and adults), increased after a minimum of 3 days to a target dose of 1.2 mg/kg/day (or 80 mg/day), with a maximum of 1.4 mg/kg/day or 100 mg/day, whichever is lower. 1

Initial Dosing Strategy

For Children and Adolescents ≤70 kg:

• Start at 0.5 mg/kg/day for the first 3 days minimum 1
• Titrate to target dose of 1.2 mg/kg/day after this initial period 2, 1
• Maximum dose: 1.4 mg/kg/day or 100 mg/day, whichever is lower 2, 1
• Doses higher than 1.2 mg/kg/day have not demonstrated additional benefit 1

For Children and Adolescents >70 kg and Adults:

• Start at 40 mg/day for the first 3 days minimum 1
• Titrate to target dose of 80 mg/day 2, 1
• After 2-4 additional weeks, may increase to maximum of 100 mg/day if optimal response not achieved 1
• No data support increased effectiveness at higher doses 1

Administration Options

Atomoxetine can be administered as either a single daily dose (morning or evening) or split into two evenly divided doses (morning and late afternoon/early evening). 1

• Split dosing may reduce initial side effects, particularly gastrointestinal symptoms and somnolence 2, 3
• Single morning dosing provides "around-the-clock" symptom control extending through waking hours into late evening 2, 4
• The medication may be taken with or without food 1
• Capsules must be swallowed whole and should not be opened 1

Special Dosing Adjustments

CYP2D6 Poor Metabolizers or Concurrent Strong CYP2D6 Inhibitors:

When using strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) or in known CYP2D6 poor metabolizers:

• Children/adolescents ≤70 kg: Initiate at 0.5 mg/kg/day and only increase to 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and initial dose is well tolerated 1
• Children/adolescents >70 kg and adults: Initiate at 40 mg/day and only increase to 80 mg/day if symptoms fail to improve after 4 weeks and initial dose is well tolerated 1
• Approximately 7% of Caucasians and 2% of African Americans are poor CYP2D6 metabolizers, resulting in 10-fold higher drug exposure 2

Hepatic Impairment:

• Moderate hepatic impairment (Child-Pugh Class B): Reduce initial and target doses to 50% of normal 1
• Severe hepatic impairment (Child-Pugh Class C): Reduce initial and target doses to 25% of normal 1

Timeline for Therapeutic Effect

Atomoxetine has a delayed onset of action requiring 6-12 weeks for full therapeutic effect, unlike stimulants which work within hours. 2

• Initial improvements may be seen earlier, but full benefit requires patience 2, 4
• A trial period of at least 6-8 weeks is recommended before evaluating overall efficacy 3
• Slow titration with divided doses minimizes impact of adverse events in the first several weeks 3

Positioning in Treatment Algorithm

Stimulants remain first-line therapy for ADHD due to larger effect sizes, with atomoxetine positioned as second-line therapy. 2

However, atomoxetine may be considered as first-line in specific clinical scenarios:

• Comorbid substance use disorders (no abuse potential) 2, 4
• Comorbid tic disorders or Tourette's syndrome 2
• Sleep disturbances on stimulants (atomoxetine causes less sleep disruption) 2
• Comorbid anxiety disorders 3, 4
• Patients or families preferring non-controlled substances 4
• Risk of stimulant diversion or misuse 3

Maintenance Treatment

Long-term treatment with atomoxetine has demonstrated sustained efficacy, with patients maintained on the same dose used to achieve initial response. 1

• Benefit of maintenance therapy demonstrated in controlled trials up to 18 months 5, 6
• Physicians should periodically reevaluate long-term usefulness for individual patients 1
• The medication provides continuous 24-hour symptom coverage without peaks and valleys of stimulants 2

Monitoring Requirements

Baseline Assessment:

• Screen for personal or family history of bipolar disorder, mania, or hypomania before initiating 1
• Document baseline vital signs, particularly blood pressure and heart rate 7

Ongoing Monitoring:

• Monitor blood pressure and heart rate regularly as atomoxetine can cause statistically (but not clinically) significant increases 2, 4
• Close monitoring for suicidal ideation, especially during first few months or with dose changes, per FDA Black Box Warning 2
• Assess for common adverse effects: decreased appetite, nausea, vomiting, fatigue, abdominal pain, headache, somnolence 2
• Monitor growth parameters, though initial delays typically normalize after 2-3 years 5

Discontinuation Protocol

Atomoxetine can be discontinued without tapering, though gradual tapering over 1-2 weeks is recommended by clinical guidelines to minimize potential adverse effects. 7, 1

• No evidence of rebound symptoms or acute discontinuation syndrome 6, 4
• Patients may miss occasional doses without rebound effects 3
• Allow at least 1-week washout period before initiating another non-stimulant medication 7

Critical Safety Considerations

FDA Black Box Warning:

Increased risk of suicidal ideation in children and adolescents - requires close monitoring particularly during treatment initiation and dose changes 5, 2

Rare but Serious Adverse Effects:

• Severe hepatotoxicity (extremely rare, but documented in postmarketing surveillance) 5
• Patients should be instructed to report jaundice, dark urine, upper right quadrant tenderness, or unexplained flu-like symptoms 5

Common Adverse Effects:

• Decreased appetite, headache, stomach pain, initial somnolence 2
• Gastrointestinal symptoms (nausea, vomiting, abdominal pain) 2, 4
• These are generally mild to moderate and transient 6, 4

Clinical Pearls for Optimization

• Start low and titrate slowly to minimize adverse effects, particularly gastrointestinal symptoms 2, 3
• Consider split dosing initially if side effects are problematic, then consolidate to once-daily if tolerated 2
• Set appropriate expectations about delayed onset - patients and families must understand this is not like stimulants 2
• Approximately 50% of methylphenidate non-responders will respond to atomoxetine, and 75% of methylphenidate responders will also respond to atomoxetine 3
• Atomoxetine can be co-administered with methylphenidate during switching without undue concern, though cardiovascular monitoring is necessary 3

Special Population: Preschool Children (Ages 4-5)

No nonstimulant medication, including atomoxetine, has received sufficient rigorous study in preschool-aged children to be recommended for ADHD treatment in this age group. 5

• Methylphenidate is the recommended medication for preschool children with moderate-to-severe ADHD who fail behavioral interventions 5
• Atomoxetine lacks adequate evidence for safety and efficacy in children under 6 years 5