Fluoxetine (Prozac)

Pharmacokinetics of Fluoxetine

Absorption Reasonably bioavailable, peaks in 6 to 8 hours
Distribution 95% bound to protein
Metabolism Extensively metabolized by the liver to norfluoxetine, the only active metabolite
Elimination Primarily eliminated via hepatic metabolism to inactive metabolites, which are then excreted by the kidney.
Half-life 1 to 3 days after acute administration, and increases to 4 to 6 days after chronic use.

Fluoxetine: Cytochrome P450 Metabolism

Substrate of (Metabolized by) 2D6
Inhibits 1A2, 2D6 (potent!), 3A4
  • Primarily inhibition of SERT, but also mild NET inhibition
  • 5-HT2C antagonism may cause mild activating effects

Dosing for Fluoxetine

Starting 20 mg PO daily
Titration Increase between 10 to 20 mg every 1 to 2 weeks depending on tolerability
Maximum 80 mg PO daily
Taper Low risk of withdrawal symptoms due to long half-life
  • Fluoxetine comes in
  • Concomitant administration of fluoxetine and risperidone may increase the plasma concentration of risperidone by 2-3 fold through CYP2D6 inhibition.[1]
  • Fluoxetine has an active metabolite with long half-life, making it helpful in patients who are forgetful and miss doses!
  • Both fluoxetine and norfluoxetine (metabolite) inhibit their own hepatic metabolism, thus, repeated administration of fluoxetine causes the half-life to continue to increase.[2]
  • If a patient is experiencing antidepressant withdrawal with a potent antidepressant such as venlafaxine or paroxetine, one can start fluoxetine for 2 weeks to help with tapering (e.g. fluoxetine 10 mg x 2 days after stopping the first antidepressant)