What is the half-life of fluoxetine (selective serotonin reuptake inhibitor)?

Fluoxetine Half-Life

Fluoxetine has an elimination half-life of 1-3 days after acute administration and 4-6 days after chronic administration, while its active metabolite norfluoxetine has a significantly longer half-life of 4-16 days. 1

Pharmacokinetic Profile

Fluoxetine's pharmacokinetic profile is characterized by:

• Parent compound (fluoxetine):

  • Acute administration: 1-3 days half-life
  • Chronic administration: 4-6 days half-life
  • Nonlinear pharmacokinetics (metabolism is not proportional to dose) 1

• Active metabolite (norfluoxetine):

  • Acute administration: Mean terminal half-life of 8.6 days
  • Chronic administration: Mean terminal half-life of 9.3 days
  • Overall range: 4-16 days
  • Linear pharmacokinetics 1, 2

Clinical Implications

The long elimination half-lives of fluoxetine and norfluoxetine have several important clinical implications:

• Steady state: Requires 4-5 weeks of consistent dosing to achieve steady-state plasma concentrations 1

• Drug persistence: Active drug substances persist in the body for weeks after discontinuation, depending on:

  • Individual patient characteristics
  • Previous dosing regimen
  • Length of previous therapy 1

• Drug interactions: Potential for interactions with other medications even weeks after fluoxetine discontinuation 1, 2

• Dosing flexibility: The extended half-life may allow for less frequent dosing in some patients after steady state is achieved 3

• Discontinuation syndrome: Lower risk of discontinuation symptoms compared to shorter-acting SSRIs due to gradual elimination 4

Special Populations

• Hepatic impairment: Elimination half-life is significantly prolonged:

  • Fluoxetine: Mean of 7.6 days in cirrhotic patients (vs 2-3 days in healthy subjects)
  • Norfluoxetine: Mean of 12 days in cirrhotic patients (vs 7-9 days in healthy subjects)
  • Lower or less frequent dosing is recommended 1, 2

• Renal impairment: No significant impact on half-life; standard dosing generally appropriate 1, 2

• Elderly patients: No significant age-related changes in half-life, unlike many other psychotropic medications 4

Monitoring Considerations

When conducting therapeutic drug monitoring (TDM) for fluoxetine:

• Blood should be collected at least 5 drug half-lives after dose changes to ensure steady-state conditions
• For most antidepressants, sampling is recommended immediately before the morning dose (12-16 hours after last dose)
• However, fluoxetine is specifically noted as an exception to standard TDM timing protocols due to its long half-life 5

Metabolic Pathway

Fluoxetine is extensively metabolized in the liver to norfluoxetine through demethylation. Both the parent compound and metabolite are potent serotonin reuptake inhibitors, with the S-fluoxetine enantiomer being eliminated more slowly and predominating in plasma at steady state 1, 2.

The complexity of fluoxetine metabolism has important clinical implications, particularly regarding genetic variability in metabolism. Approximately 7% of the population are "poor metabolizers" due to reduced CYP2D6 enzyme activity, which can affect S-fluoxetine metabolism 1, 2.