Major
Established
Description
Fluoxetine is a potent CYP2D6 inhibitor that substantially increases duloxetine plasma levels, while both agents also increase serotonin syndrome risk.
Mechanism
Fluoxetine inhibits CYP2D6, reducing duloxetine clearance and raising systemic exposure; additive SERT inhibition further increases serotonergic tone.
Clinical Significance
Pharmacokinetic interaction can increase duloxetine AUC several-fold, increasing side effects; combined serotonergic effect also raises toxicity risk.
Management
Avoid concurrent use; if switching, allow a 5-week washout after fluoxetine before starting duloxetine.