Atomoxetine for ADHD: Dosing, Monitoring, and Safety
Positioning in Treatment Algorithm
Atomoxetine is FDA-approved as first-line therapy for ADHD in children ≥6 years, adolescents, and adults, but the American Academy of Pediatrics recommends stimulants as first-line due to larger effect sizes (70-80% response rate), positioning atomoxetine as second-line therapy in most cases. 1
When to Use Atomoxetine as First-Line:
- Comorbid substance use disorders (no abuse potential) 1
- Tic disorders or Tourette's syndrome 1
- Comorbid anxiety disorders or prominent agitation/racing thoughts (stimulants lose their advantage and may worsen these symptoms) 1
- Autism spectrum disorder with ADHD (fewer sleep disturbances than stimulants) 1
- Sleep disturbances on stimulants (provides 24-hour coverage without peaks/valleys) 1
Dosing Regimens
Initial Dosing:
- Children/adolescents ≤70 kg: Start 0.5 mg/kg/day 1, 2
- Children/adolescents >70 kg and adults: Start 40 mg/day 1, 2
Target Dosing:
- Children/adolescents ≤70 kg: Target 1.2 mg/kg/day 1, 2
- Children/adolescents >70 kg and adults: Target 80 mg/day 1, 2
Maximum Dosing:
Titration Schedule:
- Adjust dose every 7-14 days based on tolerability 1
- Use slow titration with divided doses initially to minimize adverse effects during the first several weeks 3
Administration Options:
- Once-daily dosing (morning or evening) OR split into two evenly divided doses 1, 4
- Evening dosing can be advantageous if initial somnolence occurs 1
- Transition to once-daily after tolerability is established 1
Dose Adjustments for Special Populations
CYP2D6 Poor Metabolizers (7% Caucasians, 2% African Americans):
- Experience 10-fold higher drug exposure with half-life ~24 hours 1
- Reduce dose and monitor closely for adverse effects 1, 2
Hepatic Impairment:
- Moderate impairment (Child-Pugh Class B): Reduce to 50% of normal dose 2
- Severe impairment (Child-Pugh Class C): Reduce to 25% of normal dose 2
Concomitant Strong CYP2D6 Inhibitors (paroxetine, fluoxetine, quinidine):
- Reduce atomoxetine dose due to increased plasma concentrations 1, 2
- Initial dose: 0.5 mg/kg/day, increase to 1.2 mg/kg/day only if symptoms do not improve after 4 weeks and dose is well-tolerated 2
Contraindications
Absolute Contraindications:
- Hypersensitivity to atomoxetine or product constituents 2
- Use within 2 weeks of MAOI discontinuation or other drugs affecting brain monoamine concentrations 2
- Narrow-angle glaucoma 2
- Pheochromocytoma or history of pheochromocytoma 2
- Severe cardiovascular disorders that might deteriorate with clinically important increases in heart rate and blood pressure 2
Relative Contraindications:
- Known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities in children/adolescents (generally should not be used) 2
- Clinically significant cardiac abnormalities in adults (consider not using) 2
Monitoring Requirements
Baseline Assessment:
- Screen for bipolar disorder before initiating therapy 1, 2
- Obtain full medical and family history for sudden death, repeated fainting, or arrhythmias in first-degree relatives 1
- Baseline blood pressure and heart rate 1, 5
- Baseline height and weight in pediatric patients 1
Ongoing Monitoring:
- Suicidal ideation: Close monitoring during first few months or after dose changes, especially in children/adolescents (FDA Black Box Warning) 1, 2
- Blood pressure and heart rate at each visit 1, 5
- Height and weight in pediatric patients (track growth) 1, 2
- Liver function: Discontinue if jaundice or laboratory evidence of liver injury develops 2
- Cardiovascular symptoms: Prompt cardiac evaluation if emergent symptoms occur 2
- Aggressive behavior or hostility: Monitor for appearance or worsening 2
Response Assessment:
- Evaluate after 6-12 weeks due to delayed onset of therapeutic effect 1
- Trial period of at least 6-8 weeks, perhaps longer, before declaring treatment failure 3
Common Adverse Effects
Children and Adolescents (≥5% and ≥2× placebo):
- Nausea 1, 2
- Vomiting 1, 2
- Fatigue 1, 2
- Decreased appetite 1, 2
- Abdominal pain 1, 2
- Somnolence (especially if dose escalated too rapidly) 1, 2
- Headache 1
Adults (≥5% and ≥2× placebo):
- Constipation 2
- Dry mouth 2, 6
- Nausea 2
- Fatigue 2
- Decreased appetite 2
- Dizziness 2, 6
- Erectile dysfunction (~2% of patients) 2, 6
- Urinary hesitation/retention 2, 6
- Decreased libido 6
Management of Adverse Effects:
- Split dosing (morning and evening) reduces side effects 1
- Slow titration minimizes gastrointestinal symptoms and somnolence 1, 3
- Most adverse effects are transient and resolve with continued treatment 7, 6
Critical Safety Warnings
Black Box Warning – Suicidal Ideation:
- Increased risk in children and adolescents (no suicides occurred in clinical trials) 1, 2
- No increased risk demonstrated in adult trials 1
- Monitor closely during initiation and dose changes 2
Severe Liver Injury:
- Discontinue and do not restart if jaundice or laboratory evidence of liver injury occurs 2
Cardiovascular Events:
- Sudden death, stroke, and myocardial infarction reported in association with atomoxetine 2
- Increases in blood pressure and heart rate occur 2
- Orthostasis and syncope may occur 2
Priapism:
- Prompt medical attention required if suspected 2
- Counsel patients/families about this rare but serious adverse effect 2
Allergic Reactions:
- Anaphylactic reactions, angioedema, urticaria, and rash reported 2
Urinary Retention:
- Urinary hesitancy and retention may occur, particularly in adults 2
Discontinuation Protocol
Atomoxetine can be discontinued abruptly without rebound effects or discontinuation syndrome, unlike alpha-2 agonists (clonidine/guanfacine) which require tapering to avoid rebound hypertension. 1, 5, 3
Recommended Approach:
- Gradual taper over 1-2 weeks is recommended by guidelines to minimize potential adverse effects, despite research suggesting abrupt discontinuation is safe 5
- Monitor for return of ADHD symptoms during and after discontinuation 5
- Continue cardiovascular monitoring during tapering 5
- Allow 1-week washout period before initiating another non-stimulant medication 5
- Common side effects resolve after stopping atomoxetine 1
Combination Therapy Strategies
For Residual Hyperactivity/Impulsivity/Aggression:
- Add clonidine 0.05 mg (half tablet) at bedtime, increase slowly, never exceeding 0.3 mg/day 1
- Monitor blood pressure and heart rate closely with combination therapy 1
- Screen for cardiac history in patient and first-degree relatives before adding clonidine 1
For Residual Anxiety:
- Add SSRI (fluoxetine or sertraline) if anxiety persists after ADHD symptoms improve 1
- Caution with CYP2D6-inhibiting SSRIs (paroxetine) due to increased atomoxetine levels 1
For Partial Response:
- Consider adding a stimulant (extended-release methylphenidate) as first-line adjunctive therapy 1
- Co-administration with methylphenidate during switching is safe with appropriate cardiovascular monitoring 3
For Acute Agitation (in children/adolescents with treatment-resistant aggression):
- Lorazepam 0.5-1 mg as needed for breakthrough agitation, limit to 2-3 times per week 1
- Avoid chronic antipsychotic therapy for anger management 1
- Implement behavioral de-escalation techniques during acute episodes 1
Key Clinical Pearls
- Delayed onset of action (6-12 weeks) requires patience and counseling of patients/families 1, 4
- Smaller effect size than stimulants (0.7) but advantage of 24-hour coverage without peaks/valleys 1
- No abuse potential (not a controlled substance) 6, 8
- Can miss occasional doses without rebound effects 3
- Discontinuation rate 3.5% (vs. 1.4% placebo), dose-dependent, higher at >1.5 mg/kg/day 6
- Approximately 50% of methylphenidate non-responders will respond to atomoxetine 3
- Approximately 75% of methylphenidate responders will also respond to atomoxetine 3