How should atomoxetine be dosed and monitored in children (6‑11 years), adolescents (≥12 years) and adults, including adjustments for moderate hepatic impairment, contraindications such as uncontrolled hypertension, cardiac arrhythmias, structural heart disease, recent myocardial infarction, baseline blood pressure, heart rate, electrocardiogram assessments, and management of common adverse effects?

Atomoxetine Dosing and Clinical Management

Initial Dosing

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, with titration to a target dose of 1.2 mg/kg/day (maximum 1.4 mg/kg/day or 100 mg/day, whichever is lower) after a minimum of 3 days. 1

Weight-Based Dosing Algorithm

Children and adolescents ≤70 kg:

• Initial dose: 0.5 mg/kg/day 1
• Target dose: 1.2 mg/kg/day after minimum 3 days 1
• Maximum dose: 1.4 mg/kg/day or 100 mg/day, whichever is lower 1

Children and adolescents >70 kg and adults:

• Initial dose: 40 mg/day 1
• Target dose: 80 mg/day after minimum 3 days 1
• May increase to 100 mg/day after 2-4 additional weeks if suboptimal response 1
• Maximum dose: 100 mg/day 1

Dosing Schedule Options

Atomoxetine can be administered either as a single daily dose (morning or evening) or split into two evenly divided doses (morning and late afternoon/early evening). 1, 2 Split dosing may reduce early adverse effects, particularly decreased appetite and somnolence, during the first 2 weeks of treatment. 3 The slow titration with twice-daily dosing showed lower rates of somnolence (4.2% vs 14.3%) and decreased appetite (8.0% vs 14.3%) compared to fast once-daily titration. 3

Dosing Adjustments for Special Populations

Moderate Hepatic Impairment (Child-Pugh Class B)

Reduce initial and target doses to 50% of normal dose. 1

Severe Hepatic Impairment (Child-Pugh Class C)

Reduce initial and target doses to 25% of normal dose. 1

CYP2D6 Poor Metabolizers or Concomitant Strong CYP2D6 Inhibitors

Approximately 7% of Caucasians and 2% of African Americans are CYP2D6 poor metabolizers, resulting in 10-fold higher drug exposure and a half-life of approximately 24 hours (versus 5.2 hours in extensive metabolizers). 4, 5

For patients ≤70 kg:

• Initial dose: 0.5 mg/kg/day 1
• Increase to target 1.2 mg/kg/day only if symptoms fail to improve after 4 weeks AND initial dose is well tolerated 1

For patients >70 kg and adults:

• Initial dose: 40 mg/day 1
• Increase to target 80 mg/day only if symptoms fail to improve after 4 weeks AND initial dose is well tolerated 1

Strong CYP2D6 inhibitors include paroxetine, fluoxetine, and quinidine. 1, 5 Some SSRIs can elevate serum atomoxetine levels through CYP2D6 inhibition. 6

Contraindications

Absolute contraindications to atomoxetine include: 1

• Hypersensitivity to atomoxetine or product constituents 1
• Use within 2 weeks of MAOI discontinuation (risk of hypertensive crisis and serotonin syndrome) 1, 6
• Narrow-angle glaucoma 1
• Pheochromocytoma or history of pheochromocytoma 1
• Severe cardiovascular disorders that might deteriorate with clinically important increases in heart rate and blood pressure 1

Cardiovascular Screening Requirements

Before initiating atomoxetine, obtain:

• Complete cardiovascular history including family history of sudden death, repeated fainting, or arrhythmias 4
• Physical examination to assess for structural cardiac abnormalities, cardiomyopathy, or serious heart rhythm abnormalities 1
• Baseline blood pressure and heart rate 4
• Baseline electrocardiogram assessment 4

Atomoxetine generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems. 1 Consideration should be given to not using atomoxetine in adults with clinically significant cardiac abnormalities. 1

Monitoring Requirements

Cardiovascular Monitoring

At each visit, monitor:

• Blood pressure and heart rate 4, 7
• Assess for bradycardia, hypotension, or hypertension 4

Atomoxetine causes small but statistically significant increases in vital signs: average increases of 1-2 beats per minute for heart rate and 1-4 mm Hg for blood pressure. 6, 7 These increases tend to occur early in therapy, stabilize, and return toward baseline upon discontinuation. 7 Use with caution in patients with hypertension, tachycardia, or cardiovascular/cerebrovascular disease. 1

Psychiatric Monitoring

Monitor closely for suicidal ideation, clinical worsening, and unusual behavior changes, especially during the first few months of treatment or at times of dose change. 1, 6 The FDA has a black box warning for increased risk of suicidal ideation in children and adolescents (but not adults). 6, 2 No suicides occurred in clinical trials. 1

Screen for bipolar disorder before initiating treatment by obtaining personal and family history of bipolar disorder, mania, or hypomania. 1 Consider discontinuing atomoxetine if new psychotic or manic symptoms emerge. 1

Monitor for appearance or worsening of aggressive behavior or hostility. 1

Growth Monitoring

Monitor height and weight in pediatric patients. 1 Initial decreases in expected height and weight trajectories occur in the first 1-2 years of treatment, with return to expected measurements after 2-3 years on average. 6, 2

Hepatic Monitoring

Discontinue atomoxetine immediately if jaundice or clinically significant liver dysfunction develops. 6 Severe liver injury, including hepatic failure, has been reported rarely. 2 Do not restart atomoxetine in patients with jaundice or laboratory evidence of liver injury. 1

Management of Common Adverse Effects

Gastrointestinal Effects

Most common adverse effects in children/adolescents: 1, 6

• Nausea (10%) 6
• Vomiting (11%) 6
• Abdominal pain (18%) 6
• Decreased appetite (16%) 6

Management strategy: Use slow titration with twice-daily dosing to reduce early GI adverse effects. 3 These effects are typically mild to moderate and often diminish over time. 2

Somnolence and Fatigue

Somnolence is more common with atomoxetine than stimulants. 2 Initial somnolence occurs particularly if dosage is increased too rapidly. 4 Consider split dosing or evening administration if daytime somnolence is problematic. 4

Adult-Specific Adverse Effects

Most common in adults: 1

• Dry mouth 1
• Constipation 1
• Nausea 1
• Fatigue 1
• Decreased appetite 1
• Dizziness 1
• Erectile dysfunction 1
• Urinary hesitation 1

Poor CYP2D6 metabolizers experience higher rates of dry mouth (35% vs 17%), erectile dysfunction (21% vs 9%), and syncope (3% vs 1%). 6

Urinary Effects

Monitor for urinary hesitancy and retention. 1 This is more common in adults and may require dose adjustment or discontinuation. 1

Priapism

Prompt medical attention is required in the event of suspected priapism. 1 Counsel patients and caregivers about this rare but serious adverse effect. 1

Timeline for Therapeutic Response

Atomoxetine has a delayed onset of therapeutic effect requiring 6-12 weeks for full benefit. 4, 6 This contrasts with stimulants, which have immediate effects. 4 Assess response after 6-12 weeks before declaring treatment failure. 4

Discontinuation

Atomoxetine can be discontinued without tapering. 1 This contrasts with alpha-2 agonists (clonidine, guanfacine), which require tapering to avoid rebound hypertension. 4 Discontinuation is generally well tolerated with low incidence of discontinuation-emergent adverse events. 2

Clinical Positioning

Atomoxetine is recommended as second-line therapy after stimulants due to smaller effect sizes. 4 However, it may be considered first-line in specific situations: 4

• Comorbid substance use disorders 4
• Tic disorders or Tourette's syndrome 4
• Comorbid anxiety disorders 4
• Autism spectrum disorder with ADHD 4
• Patients who prefer non-controlled substances 2

Atomoxetine provides "around-the-clock" symptom control without peaks and valleys, which may benefit patients requiring continuous coverage throughout the day and evening. 4, 6