- Last edited on March 9, 2021
Atomoxetine (Strattera)
Primer
Atomoxetine (Trade name: Strattera) is a selective norepinephrine reuptake inhibitor (selective NRI) used in the treatment of attention-deficit/hyperactivity disorder.
Pharmacokinetics
See also article: Introduction to Pharmacology
Pharmacokinetics of Atomoxetine
Absorption | Rapid and is not affected by food (Tmax=1-2 hrs) |
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Distribution | Volume of distribution is low, distributed in total body water and highly bound to plasma albumin (99%)[1] |
Metabolism | Hepatic |
Elimination | Urine |
Half-life | • ~5 hours in extensive 2D6 metabolizers • ~22 hours in poor 2D6 metabolizers |
See also article: Cytochrome (CYP) P450 Metabolism
Atomoxetine: Cytochrome P450 Metabolism
Substrate of (Metabolized by) | CYP2D6 (but does not inhibit or induce 2D6), a minor metabolic pathway (<10%) involves CYP2C19[2] |
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Induces | - |
Inhibits | - |
Cytochrome P450 Metabolism
See also article: Cytochrome (CYP) P450 Metabolism
Atomoxetine: Cytochrome P450 Metabolism
Substrate of (Metabolized by) | CYP2D6 (but does not inhibit or induce 2D6), a minor metabolic pathway (<10%) involves CYP2C19[3] |
---|---|
Induces | - |
Inhibits | - |
Pharmacodynamics
Mechanism of Action
- Atomoxetine causes inhibition of the norepinephrine (NE) transporter and prevents synaptic clearance of NE, resulting in increased synaptic NE.
Toxicity
Indications
Second line for:
- Attention-Deficit/Hyperactivity Disorder (ADHD) (one added benefit of using atomoxetine is that it may also treat any underlying anxiety or depressive symptoms given its “antidepressant” mechanism of action)
- Response rate: 45% (≥40% improvement) to 60% (≥25% improvement).[4]
- Atomoxetine is not typically used for other psychiatric disorders or indications.
Dosing
Adults
Dosing for Atomoxetine (Adults)
Starting | 40mg PO daily for 1 to 2 weeks |
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Titration | Then increase to 80mg PO daily |
Maximum | One month after starting, a maximum dose of 100mg PO daily can be reached |
Taper | It does not need to be tapered and can be stopped immediately, and there does not appear to be withdrawal or rebound effects. |
Children and Adolescents (Weight-Based)
Dosing for Atomoxetine for Children and Adolescents (Weight-Based)
Starting | Start at 0.5 mg/kg/day (max 40 mg) for 7 to 14 days |
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Titration | • Then increase to 0.8 mg/kg/day (max 60 mg) for 7 to 14 days • Then increase to “target dose” of 1.2 mg/kg/day (max 80 mg) |
Maximum | If inadequate response after at least 1 month: • Consider increase to between 1.4 to 1.8 mg/kg/day.[5] |
Notes | >1.8 mg/kg/day has been shown not to provide additional benefit.[6] |
Taper | It does not need to be tapered and can be stopped immediately, and there does not appear to be withdrawal or rebound effects. |
General
- Once daily dosing (usually in the morning) is most common
- If the patient is a poor CYP 2D6 metabolizer or is taking a drug that's a 2D6 inhibitor, then continue 0.5 mg/kg/day (max 40 mg) for 2-4 weeks before considering any further increase in dose
- BID dosing and slower titration may improve tolerability (especially appetite, GI side effects, and somnolence)
- Capsules should be swallowed whole
Formulations
- Atomoxetine comes in oral formulation
Monitoring
- Like most antidepressants (and unlike stimulants):
- Atomoxetine mMlly over weeks to months
- Suicidal ideation and behaviours should be monitored for during treatment. Atomoxetine is associated with increased risk of suicide-related behaviours
- Heart rate and and blood pressure at baseline and regularly thereafter, especially with dose increases
- Height and weight plotted on a growth chart
- Baseline liver function tests are not necessary, but should be done at the first signs or symptoms of liver dysfunction
Contraindications
Absolute
- Treatment with MAOI and for up to 14 days after discontinuation
- Narrow angle glaucoma
- Uncontrolled hyperthyroidism
- Advanced arteriosclerosis
- Known hypersensitivity or allergy
- Pheochromocytoma
- Moderate to severe hypertension
- Symptomatic cardiovascular disease
- Severe cardiovascular disorders
Relative
Drug-Drug Interactions
- Monoamine oxidase inhibitors are contraindicated
- Inhibitors of CYP2D6 (e.g. - paroxetine, fluoxetine, bupropion, quinidine) may increase atomoxetine serum concentrations
- To a much lesser extent, this also occurs with 2C19 inhibitors
- Decongestants (e.g. - pseudoephedrine) may possibly increase blood pressure and heart rate
- QT prolonging agents (e.g. - quetiapine, quinidine) may prolong QTc interval
- Although there is no interaction with stimulants, there is no evidence to support combining a stimulant with atomoxetine in the treatment of ADHD.[7]
- Beta-2 agonist-induced tachycardia and hypertension can be potentiated by atomoxetine, so this combination should be avoided
Side Effects
- Common side effects of atomoxetine include nausea, dry mouth, insomnia, sedation, fatigue, decreased appetite, tachycardia (mean increase <10 bpm), hypertension (mean increase <4 mmHg), urinary hesitation/retention, constipation, and dizziness.
- Important side effects to inform patients of include sexual dysfunction such as decreased libido
Adverse Events
- QTc prolongation and adverse cardiac events.[8]
- Rare cases of liver failure
- Risk of priapism
Clinical Pearls
- Advantages of using atomoxetine for the treatment of ADHD over stimulants include:
- More continuous coverage throughout the day
- No potential for drug abuse
- Less likely to be used for weight loss in an individual with an eating disorder
- Less concern about growth suppression.[9]
- Likely lower risk of exacerbating tics, and may even improve tics.[10]
- Less concern about sudden cardiac death (relative to stimulants), though rare cases have been reported.[11]
Special Populations
Geriatric
See main article: Geriatric Pharmacology
Pediatric
See main article: Pediatric Pharmacology
Obstetric and Fetal
See main article: Obstetric and Fetal Pharmacology
Medically Ill
See main article: Psychotropic Dosing in the Medically Ill
Resources
References
1)
Sauer, J. M., Ring, B. J., & Witcher, J. W. (2005). Clinical pharmacokinetics of atomoxetine. Clinical pharmacokinetics, 44(6), 571-590.
2)
Yu, G., Li, G. F., & Markowitz, J. S. (2016). Atomoxetine: a review of its pharmacokinetics and pharmacogenomics relative to drug disposition. Journal of child and adolescent psychopharmacology, 26(4), 314-326.
3)
Yu, G., Li, G. F., & Markowitz, J. S. (2016). Atomoxetine: a review of its pharmacokinetics and pharmacogenomics relative to drug disposition. Journal of child and adolescent psychopharmacology, 26(4), 314-326.
4)
Schwartz, S., & Correll, C. U. (2014). Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression. Journal of the American Academy of Child & Adolescent Psychiatry, 53(2), 174-187.
5)
Pliszka, S., & AACAP Work Group on Quality Issues. (2007). Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 46(7), 894-921.
6)
Kratochvil, C. J., Vaughan, B. S., Mayfield-Jorgensen, M. L., March, J. S., Kollins, S. H., Murray, D. W., ... & Stoner, J. (2007). A pilot study of atomoxetine in young children with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 17(2), 175-186.
7)
Treuer, T., Gau, S. S. F., Méndez, L., Montgomery, W., Monk, J. A., Altin, M., ... & Dueñas, H. J. (2013). A systematic review of combination therapy with stimulants and atomoxetine for attention-deficit/hyperactivity disorder, including patient characteristics, treatment strategies, effectiveness, and tolerability. Journal of child and adolescent psychopharmacology, 23(3), 179-193.
8)
Yamaguchi, H., Nagumo, K., Nakashima, T., Kinugawa, Y., & Kumaki, S. (2014). Life-threatening QT prolongation in a boy with attention-deficit/hyperactivity disorder on atomoxetine. European journal of pediatrics, 173(12), 1631-1634.
9)
Reed, V. A., Buitelaar, J. K., Anand, E., Day, K. A., Treuer, T., Upadhyaya, H. P., ... & Savill, N. C. (2016). The safety of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of research. CNS drugs, 30(7), 603-628.