Atomoxetine (Strattera): Indications and Side Effects
Primary Indication
Atomoxetine is FDA-approved for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children (6 years and older), adolescents, and adults. 1 It is a selective norepinephrine reuptake inhibitor—the first non-stimulant medication approved for ADHD treatment—and should be used as part of a comprehensive treatment program that may include counseling or other behavioral therapies. 2, 1
Mechanism of Action
- Atomoxetine selectively inhibits presynaptic norepinephrine transporters, increasing synaptic noradrenaline levels throughout the brain. 2, 3
- In the prefrontal cortex specifically, where dopamine transporters are scarce, norepinephrine transporters also regulate dopamine reuptake, resulting in increased concentrations of both noradrenaline and dopamine in this critical region. 2, 3
- This dual neurotransmitter effect in the prefrontal cortex is thought to underlie atomoxetine's therapeutic benefits for attention, impulsivity, and hyperactivity. 2
Clinical Advantages
- Provides "around-the-clock" symptom control with once-daily dosing, with effects extending into the evening and next morning. 3
- Carries negligible risk of abuse or diversion and is not a controlled substance in the United States, making it particularly useful for patients at risk of substance abuse. 1, 4, 5
- May be especially beneficial for patients with comorbid anxiety disorders or tic disorders. 4
- Does not require the same regulatory controls as stimulants, allowing for more convenient repeat prescriptions during long-term treatment. 5
Side Effects Profile
Common Side Effects (Occur Frequently)
Gastrointestinal effects are the most common adverse events:
- Nausea (10% of patients) 3
- Vomiting (11% of patients) 3
- Abdominal pain (18% of patients) 3
- Decreased appetite (16% of patients) 3
- Constipation 5
Other frequent side effects include:
- Headache 4
- Somnolence/drowsiness 4
- Dry mouth (particularly in adults: 35% in poor CYP2D6 metabolizers vs 17% in extensive metabolizers) 3
- Insomnia 5
- Dizziness 5
Most of these adverse events are mild to moderate in severity and often transient, particularly the gastrointestinal symptoms. 4, 6
Serious Side Effects Requiring Monitoring
1. Suicidal Ideation (Black Box Warning)
Atomoxetine carries an FDA black box warning for increased risk of suicidal thoughts in children and adolescents. 1
- Analysis of 12 placebo-controlled trials with over 2,200 pediatric ADHD patients showed 4 out of every 1,000 patients developed suicidal thoughts (no completed suicides occurred). 2, 1
- This increased risk was NOT observed in adult populations. 2
- Risk is highest early during treatment and during dose adjustments. 1
Required monitoring includes watching for: 1
- Anxiety, agitation, panic attacks
- Irritability, hostility, aggressiveness
- Impulsivity, restlessness
- Mania or depression
- Suicidal thoughts or unusual behavior changes
Clinical action: Close monitoring is mandatory, especially during the first few months of treatment or with any dose changes. Immediate physician contact is required if any concerning symptoms emerge. 2, 1
2. Severe Liver Injury
Atomoxetine can cause severe hepatic injury, including hepatic failure, though this is rare. 1
- Postmarketing data identified three patients with liver-related adverse events deemed probably related to atomoxetine. 4
- Atomoxetine must be discontinued immediately and not restarted if jaundice or clinically significant liver dysfunction develops. 3, 1
Warning signs requiring immediate medical attention: 1
- Itching
- Right upper abdominal pain
- Dark urine
- Yellow skin or eyes (jaundice)
- Unexplained flu-like symptoms
3. Cardiovascular Effects
Atomoxetine causes mild but consistent increases in heart rate and blood pressure that require regular monitoring. 3, 1
- Average increases: 1-2 beats per minute for heart rate and 1-4 mm Hg for blood pressure. 3
- These changes are statistically but not typically clinically significant in healthy individuals. 4
Serious cardiovascular risks include: 1
- Sudden death in patients with pre-existing structural cardiac abnormalities or serious heart defects
- Stroke and myocardial infarction in adults
- Orthostatic hypotension and syncope (3% in poor CYP2D6 metabolizers vs 1% in extensive metabolizers) 3
Contraindications and precautions: 1
- Should generally NOT be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems
- Consider not using in adults with clinically significant cardiac abnormalities
- Baseline cardiac evaluation is required before starting treatment 1
- Regular blood pressure and heart rate monitoring throughout treatment is mandatory 1
Seek immediate medical attention for: 1
- Chest pain
- Shortness of breath
- Fainting episodes
4. Psychiatric Symptoms
New or worsening psychiatric symptoms can emerge, particularly in children and adolescents. 1
- New psychotic symptoms: hearing voices, paranoia, believing things that are not true 1
- New manic symptoms 1
- Emergence or worsening of aggressive behavior or hostility 1
Clinical action: Consider discontinuing atomoxetine if new psychiatric symptoms occur; immediate physician contact is required. 1 Screen all patients for bipolar disorder before initiating treatment. 1
5. Growth Effects in Children
Initial decreases in expected height and weight trajectories occur in the first 1-2 years of atomoxetine treatment. 3
- Growth parameters typically return to expected measurements after 2-3 years on average. 3
- Height and weight should be monitored regularly in pediatric patients throughout treatment. 1
6. Urogenital Effects
Urinary hesitancy and retention may occur, particularly in patients with pre-existing urinary outflow conditions. 1
Priapism (rare but serious): 1
- Prompt medical attention is required if priapism is suspected
- Can lead to permanent damage if not treated immediately
- Erectile dysfunction (21% in poor CYP2D6 metabolizers vs 9% in extensive metabolizers) 3
- Other sexual problems reported in adult patients 5
Critical Drug Interactions and Metabolism Considerations
CYP2D6 Metabolism
Atomoxetine is primarily metabolized through the CYP2D6 pathway, creating two distinct patient populations with different side effect profiles. 2, 3
Poor CYP2D6 metabolizers (~7% of population): 3
Dose adjustment may be necessary in poor metabolizers or when used with potent CYP2D6 inhibitors. 1
Contraindicated Drug Combinations
Atomoxetine is absolutely contraindicated with MAOIs (monoamine oxidase inhibitors). 1
- Must not be taken within 14 days of MAOI use due to risk of serotonin syndrome. 3, 1
- Examples of MAOIs: phenelzine (Nardil), tranylcypromine (Parnate), selegiline transdermal (Emsam) 1
Important Drug Interactions
Potent CYP2D6 inhibitors (particularly SSRIs like paroxetine) can significantly elevate atomoxetine levels. 2, 3
- These interactions produce pharmacokinetic changes similar to those in poor CYP2D6 metabolizers. 4, 7
- Dose adjustment of atomoxetine may be necessary when co-administered with CYP2D6 inhibitors. 1
Other medications requiring caution: 1
- Blood pressure medications
- Asthma medications
- Cold or allergy medicines containing decongestants
Absolute Contraindications
Do not use atomoxetine in patients with: 1
- Current or recent (within 14 days) MAOI use
- Narrow-angle glaucoma
- Pheochromocytoma (rare adrenal tumor)
- Known allergy to atomoxetine or its components
Dosing and Administration
- Available in capsules: 10,18,25,40,60,80, or 100 mg, and oral solution (4 mg/ml). 2
- Titration follows a sequential, weight-based approach. 2
- Maximum recommended dose: 1.4 mg/kg/day or 100 mg/day, whichever is lower. 2
- Can be administered once daily or split into two evenly divided doses. 4, 5
- Capsules should not be chewed, crushed, or opened. 1
- Slower onset of action (6-12 weeks) compared to stimulants. 3
Special Populations
Pregnancy and Breastfeeding
- Atomoxetine does not appear to be associated with major congenital malformations or significant adverse obstetrical outcomes, though data are limited. 2
- Possible increased risk for spontaneous abortion, but confounding by indication cannot be ruled out. 2
- A pregnancy registry exists for females exposed to ADHD medications during pregnancy (1-866-961-2388). 1
- Limited data on breastfeeding; atomoxetine likely passes into breast milk, and caution is advised. 2
Hepatic Insufficiency
- Patients with hepatic insufficiency show increased atomoxetine exposure and may require dose adjustment. 4