Does fluoxetine double the plasma concentration of atomoxetine?

Fluoxetine and Atomoxetine Drug Interaction

Yes, fluoxetine substantially increases atomoxetine plasma concentrations, with extensive metabolizers experiencing approximately 6- to 8-fold increases in AUC and 3- to 4-fold increases in peak plasma concentrations when these drugs are combined. 1

Mechanism of Interaction

Fluoxetine is a potent CYP2D6 inhibitor that converts approximately 43% of extensive metabolizers to functional poor metabolizer phenotype during chronic use. 2 Since atomoxetine is primarily metabolized through the CYP2D6 pathway, this inhibition creates a "phenocopy" effect that dramatically elevates atomoxetine levels. 2

• In extensive metabolizers treated with fluoxetine, atomoxetine steady-state plasma concentrations increase to exposures similar to those observed in genetic poor metabolizers. 1
• This interaction occurs because fluoxetine blocks the aromatic ring-hydroxylation pathway that normally converts atomoxetine to 4-hydroxyatomoxetine, the primary metabolic route for atomoxetine clearance. 3

Clinical Implications for Safety

The combination creates significant risk for increased adverse effects and potential toxicity. Poor metabolizers (whether genetic or drug-induced) experience:

• Markedly greater increases in heart rate and diastolic blood pressure compared to extensive metabolizers (p < .001). 4
• Higher frequency of adverse events including decreased appetite and tremor (p < .05). 4
• Smaller increases in weight (p < .05). 4
• Atomoxetine plasma half-life extends from 5.2 hours in extensive metabolizers to 21.6 hours in poor metabolizers. 3

The FDA label explicitly warns that CYP2D6 inhibitors like fluoxetine increase atomoxetine exposure 6- to 8-fold in extensive metabolizers. 1

Dosing Adjustments Required

When combining these medications, atomoxetine dosing must be substantially reduced:

• Start atomoxetine at lower doses (e.g., 0.5 mg/kg/day) rather than the standard initial target. 1
• The maximum recommended dose should not exceed 1.2 mg/kg/day or 80 mg/day (whichever is lower) when combined with strong CYP2D6 inhibitors like fluoxetine, compared to the standard maximum of 1.4 mg/kg/day or 100 mg/day. 1
• Titrate more slowly and monitor closely for cardiovascular effects and other adverse events. 2

Monitoring Requirements

Assess for adverse effects within 24-48 hours after starting the combination or adjusting doses: 5

• Monitor blood pressure and heart rate at each visit, as cardiovascular effects are significantly amplified in poor metabolizers. 4
• Watch for decreased appetite, tremor, somnolence, nausea, and other common atomoxetine adverse effects that occur more frequently with elevated drug levels. 2, 4
• Be vigilant for signs of excessive noradrenergic stimulation including agitation, insomnia, or anxiety. 6

Alternative Considerations

If both medications are clinically necessary, consider whether an alternative antidepressant with minimal CYP2D6 inhibition would be safer: 5

• Citalopram, escitalopram, sertraline, or venlafaxine have substantially less CYP2D6 inhibitory activity than fluoxetine. 5
• This approach avoids the additive pharmacokinetic risk while still addressing both ADHD and mood/anxiety symptoms. 5

Evidence from Combined Use

A randomized controlled trial specifically examined atomoxetine combined with fluoxetine in pediatric patients with ADHD and comorbid depressive or anxiety symptoms: 6

• The combination was well tolerated overall, though the combination group had greater increases in blood pressure and pulse than atomoxetine monotherapy. 6
• Both ADHD and mood/anxiety symptoms improved significantly (p < .001). 6
• Completion rates and discontinuation rates for adverse events were similar between combination and monotherapy groups. 6

However, this study used careful dose titration and close monitoring, which is essential when combining these agents. 6

Critical Pitfall to Avoid

Do not assume standard atomoxetine dosing is safe when adding fluoxetine to an established atomoxetine regimen, or vice versa. The interaction is bidirectional—whether fluoxetine is added to atomoxetine or atomoxetine is added to fluoxetine, the atomoxetine dose requires adjustment. 1 The 6- to 8-fold increase in exposure means that a patient on 60 mg/day of atomoxetine could experience drug levels equivalent to 360-480 mg/day when fluoxetine is added, far exceeding safe therapeutic ranges. 1, 3