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Add SSRI suicidality boxed warning (monitoring + counseling) and MAOI contraindication / serotonin-syndrome interactions; reconcile half-life to FDA label. Parser pharm-audit fix, mark-greenlit, servops-applied.
 
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| onset            =  
| onset            =  
| duration          = Very long
| duration          = Very long
| halflife          = 1–4 days (7–15 days for norfluoxetine)
| halflife          = 1-3 days acute, 4-6 days chronic; 4-16 days for norfluoxetine<ref name="prozac-label"/>
| bioavailability  = 70–90% (oral)
| bioavailability  = 70–90% (oral)
| pregnancy        = Category C<ref name="lactmed">S0</ref>
| pregnancy        = Category C<ref name="lactmed">S0</ref>
Line 59: Line 59:
| pk_absorption    = 70–90%<ref name="statpearls">S3</ref> oral bioavailability.
| pk_absorption    = 70–90%<ref name="statpearls">S3</ref> oral bioavailability.
| pk_distribution  = Fluoxetine has plasma protein binding of approximately 94.5%, bound to albumin and alpha-1 glycoprotein. Fluoxetine readily crosses the blood–brain barrier, with a brain-to-plasma ratio of 2.6:1 in humans. The volume of distribution (Vd) of fluoxetine and its metabolite ranges between 20 to 42 L/kg. Some studies report that fluoxetine has the maximum volume of distribution (Vd) of any SSRI (between 14 and 100 L/kg).<ref name="statpearls"/>
| pk_distribution  = Fluoxetine has plasma protein binding of approximately 94.5%, bound to albumin and alpha-1 glycoprotein. Fluoxetine readily crosses the blood–brain barrier, with a brain-to-plasma ratio of 2.6:1 in humans. The volume of distribution (Vd) of fluoxetine and its metabolite ranges between 20 to 42 L/kg. Some studies report that fluoxetine has the maximum volume of distribution (Vd) of any SSRI (between 14 and 100 L/kg).<ref name="statpearls"/>
| pk_metabolism    = Fluoxetine's active metabolite is norfluoxetine, produced when the cytochrome P450 enzyme ([[Enzyme:CYP2D6|CYP2D6]]) acts on it. Prescribers must remember that fluoxetine has several med-med interactions due to its metabolism through the CYP2D6 isoenzyme. Additionally, norfluoxetine can have an inhibitory effect on [[Enzyme:CYP3A4|CYP3A4]]. Fluoxetine has a half-life of 2 to 4 days, and its active metabolite norfluoxetine has a half-life of 7 to 9 days. Approximately 7% of individuals definitively exhibit poor metabolism of fluoxetine due to reduced activity of CYP2D6.<ref name="statpearls"/>
| pk_metabolism    = Fluoxetine's active metabolite is norfluoxetine, produced when the cytochrome P450 enzyme ([[Enzyme:CYP2D6|CYP2D6]]) acts on it. Prescribers must remember that fluoxetine has several med-med interactions due to its metabolism through the CYP2D6 isoenzyme. Additionally, norfluoxetine can have an inhibitory effect on [[Enzyme:CYP3A4|CYP3A4]]. Fluoxetine has an elimination half-life of 1 to 3 days after a single dose and 4 to 6 days with chronic dosing, and its active metabolite norfluoxetine has a half-life of 4 to 16 days.<ref name="prozac-label"/> Approximately 7% of individuals definitively exhibit poor metabolism of fluoxetine due to reduced activity of CYP2D6.<ref name="statpearls"/>
| pk_elimination    =  
| pk_elimination    =  
| pharmacodynamics  =  
| pharmacodynamics  =  
| interactions      = <pharmaInteractions/>
| interactions      = <pharmaInteractions/>
The clinically important interactions for prescribers:
* '''MAO inhibitors: contraindicated.''' Combination with non-selective MAOIs (isocarboxazid, phenelzine, tranylcypromine), or with linezolid or intravenous methylene blue, can produce serotonin syndrome, which may be life-threatening. At least 14 days must elapse between stopping an MAOI and starting fluoxetine. Because of the long half-life of fluoxetine and its active metabolite norfluoxetine, at least 5 weeks must elapse between stopping fluoxetine and starting an MAOI.<ref name="prozac-label">U.S. Food and Drug Administration. Prozac (fluoxetine hydrochloride) prescribing information. NDA 018936.</ref>
* '''Other serotonergic medicines: serotonin-syndrome risk.''' Triptans, tramadol, other SSRIs and SNRIs, lithium, and St John's wort raise serotonergic load; combine with caution and counsel on serotonin-syndrome symptoms.
* '''Strong CYP2D6 inhibition.''' Fluoxetine is a strong CYP2D6 inhibitor and norfluoxetine inhibits CYP3A4, so levels of many CYP2D6 substrates rise (several tricyclics, some neuroleptics, metoprolol, atomoxetine; tamoxifen activation is blunted). Because of the long half-life, this effect persists for weeks after fluoxetine is stopped.
| pregnancy_details =  
| pregnancy_details =  
| monitoring        = None required
| monitoring        = '''Boxed warning: monitor closely for worsening mood, suicidal ideation, and behavioral activation,''' especially during the first weeks of treatment, with any dose change, and particularly in patients under age 25. No routine laboratory monitoring required. Because of fluoxetine's very long effective half-life, both therapeutic change and adverse effects (including activation or emergent suicidality) appear and resolve more slowly than with shorter-acting SSRIs. Watch for emergent manic or hypomanic symptoms throughout treatment and treat new rapid mood elevation, agitation, or pressured speech as a possible bipolar switch.
| counseling        =  
| counseling        = '''Before starting:''' screen for a personal or family history of bipolar disorder; fluoxetine, like all antidepressants, can precipitate a manic or mixed switch in susceptible patients. '''Boxed warning:''' counsel patients (and family members, where appropriate) about the increased risk of suicidal ideation and behavioral activation in patients under 25, and ask them to report promptly any worsening mood, intrusive thoughts of self-harm, agitation, irritability, or unusual behavioral changes, particularly in the first weeks of treatment and after any dose change.
| anecdotes        = <anecdote slug="2026-05-12" perspective="provider" author="MDElliottMD">
| anecdotes        = <anecdote slug="2026-05-12" perspective="provider" author="MDElliottMD">
Fluoxetine is great for getting off other SxRIs! Especially [[Venlafaxine|venlafaxine]] and [[Duloxetine|duloxetine]].
Fluoxetine is great for getting off other SxRIs! Especially [[Venlafaxine|venlafaxine]] and [[Duloxetine|duloxetine]].

Latest revision as of 13:10, 10 June 2026

SSRI, Anxiolytic, Antidepressant
Fluoxetine
Prozac
Fluoxetine, marketed as Prozac, was the first selective serotonin reuptake inhibitor (SSRIs) brought to market and the medicine that opened the SSRI era. It was discovered at Eli Lilly's laboratories in Indianapolis on 24 July 1972 by a team that included the chemists Bryan Molloy and Klaus Schmiegel and the pharmacologist David Wong,[4] approved by the FDA in December 1987, and launched in the United States as Prozac in January 1988. It is notable for the extremely long half-life of its active metabolite norfluoxetine, which gives the medicine an unusually mild discontinuation profile and makes it useful as a bridge in tapering patients off shorter-acting serotonergic medicines.

History

The compound that became fluoxetine emerged from an Eli Lilly program that began in the late 1960s under Molloy and Schmiegel, who synthesized a series of aryloxyphenylpropylamines starting from the antihistamine diphenhydramine as a structural lead. Wong, who had followed the European literature implicating serotonin in mood regulation, proposed screening the new compounds specifically for serotonin uptake inhibition. On 24 July 1972 the team identified the compound then designated Lilly 110140 as a potent and selective inhibitor of serotonin uptake in rat brain synaptosomes. The finding was published in 1974 as the first description of what is now known as a selective serotonin reuptake inhibitor.[4]

Lilly renamed the compound fluoxetine in 1975, filed an investigational application with the FDA, and pursued clinical development through the late 1970s and early 1980s. The FDA approved fluoxetine for major depressive disorder in December 1987, and Lilly launched it as Prozac in January 1988. The marketing name itself was a departure: medicines had historically been named to reflect chemical structure, and Prozac was among the first to be commissioned from an outside naming firm. Within five years of launch Prozac was one of the most prescribed medicines in the United States, and Peter Kramer's 1993 book Listening to Prozac made the SSRI era a subject of popular discussion. Lilly's US patent expired in August 2001, after which generic fluoxetine became broadly available.

Fluoxetine is a prescription-only medicine in the United States. It remains on the WHO Model List of Essential Medicines and is one of the most widely prescribed serotonergic medicines worldwide. The serotonergic framing under which the medicine was discovered and marketed has not aged uniformly well; the TrkB/BDNF account of its mechanism, developed primarily in the 2000s, is the principal contemporary alternative and is reflected in the mechanism field above.

Experience

👥 No personal reports yet
⚕ 1 provider report · avg efficacy 40.0/100 · avg side-effect burden 40.0/100 · 150 patients managed total

Log in to add your own experience.

Problems

Depressive disorders1.0n=1
Anxiety disorders broadly4.0n=2
Including generalized anxiety, panic, and social anxiety.
Panic disorder1.3n=2
Social anxiety disorder1.0n=1
Obsessive-compulsive disorder3.0n=1
PTSD0.1n=1
Potentially.
Premature ejaculation0.1n=2
+ Add a problem

Titration strategies

Standard adult or child+1
Start no higher than 10 mg for the first dose. May increase by 10 mg every 2–12 weeks, or remain at 10 mg if the response is adequate, up to a typical starting maximum of 40 mg. Absolute max: 80 mg.
OCD+1
Start at 10 mg daily; increase by 10–20 mg every 2–6 weeks, up to 80 mg. OCD typically requires elevated doses (60–80 mg).

+ Add a titration strategy

Effects

  • Anxiolysis👤 no reports yet⚕️ ~33% +67.0 (n=1)
    Classically starting at 3–4 weeks and improving for another 8–12.
  • Delayed orgasm/ejaculation👤 0% — (n=3)⚕️ ~80% +38.0 (n=1)
  • Mood enhancement👤 no reports yet⚕️ ~5% +67.0 (n=1)
  • Nausea👤 no reports yet⚕️ ~5% -33.0 (n=1)
    Common, often improves over 1–2 weeks.
  • Decreased libido👤 no reports yet⚕️ ~33% -100.0 (n=1)
  • Temporary erectile dysfunction👤 no reports yet⚕️ ~20% -67.0 (n=1)
  • Persistent Sexual Dysfunction👤 no reports yet⚕️ ~0% -100.0 (n=1)
    Historically associated with SSRIs.
Anorgasmia👤 no reports yet⚕️ ~5% -100.0 (n=1)

+ Add an effect

Pharmacokinetics

Absorption

70–90%[5] oral bioavailability.

Distribution

Fluoxetine has plasma protein binding of approximately 94.5%, bound to albumin and alpha-1 glycoprotein. Fluoxetine readily crosses the blood–brain barrier, with a brain-to-plasma ratio of 2.6:1 in humans. The volume of distribution (Vd) of fluoxetine and its metabolite ranges between 20 to 42 L/kg. Some studies report that fluoxetine has the maximum volume of distribution (Vd) of any SSRI (between 14 and 100 L/kg).[5]

Metabolism

Fluoxetine's active metabolite is norfluoxetine, produced when the cytochrome P450 enzyme (CYP2D6) acts on it. Prescribers must remember that fluoxetine has several med-med interactions due to its metabolism through the CYP2D6 isoenzyme. Additionally, norfluoxetine can have an inhibitory effect on CYP3A4. Fluoxetine has an elimination half-life of 1 to 3 days after a single dose and 4 to 6 days with chronic dosing, and its active metabolite norfluoxetine has a half-life of 4 to 16 days.[2] Approximately 7% of individuals definitively exhibit poor metabolism of fluoxetine due to reduced activity of CYP2D6.[5]

Interactions

Pharmacogenomic + mechanism interactions5 edges
Pharmacokinetic mechanismSubstrate / metabolism relationships from primary literature
Enzyme:CYP2D6 inhibitor strong Primary 90 / 100
FDA Drug Interactions Table: strong index inhibitor of CYP2D6.
⏱ mechanism-based, interaction persists ~4-6 weeks after stopping the inhibitor
Inferred from pharmacokinetic dataMaterialised by the inference engine; provenance shown per row
Codeine pk lowers via CYP2D6 Inferred 90 / 100
Fluoxetine inhibits CYP2D6 (inhibitor_strong, intensity 90); Codeine is a prodrug_activated_by of CYP2D6 (intensity 100). Derived: Codeine exposure lowered.
⏱ mechanism-based, interaction persists ~4-6 weeks after stopping the inhibitor
Inferred via Enzyme:CYP2D6 (exposure lowered)
Nebivolol pk raises via CYP2D6 Inferred 72 / 100
Fluoxetine inhibits CYP2D6 (inhibitor_strong, intensity 90); Nebivolol is a substrate_major of CYP2D6 (intensity 80). Derived: Nebivolol exposure raised.
⏱ mechanism-based, interaction persists ~4-6 weeks after stopping the inhibitor
Inferred via Enzyme:CYP2D6 (exposure raised)
Desipramine pk raises via CYP2D6 Inferred 72 / 100
Fluoxetine inhibits CYP2D6 (inhibitor_strong, intensity 90); Desipramine is a substrate_major of CYP2D6 (intensity 80). Derived: Desipramine exposure raised.
⏱ mechanism-based, interaction persists ~4-6 weeks after stopping the inhibitor
Inferred via Enzyme:CYP2D6 (exposure raised)
Dextromethorphan pk raises via CYP2D6 Inferred 72 / 100
Fluoxetine inhibits CYP2D6 (inhibitor_strong, intensity 90); Dextromethorphan is a substrate_major of CYP2D6 (intensity 80). Derived: Dextromethorphan exposure raised.
⏱ mechanism-based, interaction persists ~4-6 weeks after stopping the inhibitor
Inferred via Enzyme:CYP2D6 (exposure raised)

Patient experience

MDMA👤 exp n/a/5 outcome n/a (n=1)⚕️ exp 3.0/5 outcome -33.0 (n=1)
Antidepressants👤 exp n/a/5 outcome n/a (n=1)⚕️ exp 1.0/5 outcome +33.0 (n=1)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)👤 no reports yet⚕️ exp 4.0/5 outcome +33.0 (n=1)

The clinically important interactions for prescribers:

  • MAO inhibitors: contraindicated. Combination with non-selective MAOIs (isocarboxazid, phenelzine, tranylcypromine), or with linezolid or intravenous methylene blue, can produce serotonin syndrome, which may be life-threatening. At least 14 days must elapse between stopping an MAOI and starting fluoxetine. Because of the long half-life of fluoxetine and its active metabolite norfluoxetine, at least 5 weeks must elapse between stopping fluoxetine and starting an MAOI.[2]
  • Other serotonergic medicines: serotonin-syndrome risk. Triptans, tramadol, other SSRIs and SNRIs, lithium, and St John's wort raise serotonergic load; combine with caution and counsel on serotonin-syndrome symptoms.
  • Strong CYP2D6 inhibition. Fluoxetine is a strong CYP2D6 inhibitor and norfluoxetine inhibits CYP3A4, so levels of many CYP2D6 substrates rise (several tricyclics, some neuroleptics, metoprolol, atomoxetine; tamoxifen activation is blunted). Because of the long half-life, this effect persists for weeks after fluoxetine is stopped.

    Monitoring

Boxed warning: monitor closely for worsening mood, suicidal ideation, and behavioral activation, especially during the first weeks of treatment, with any dose change, and particularly in patients under age 25. No routine laboratory monitoring required. Because of fluoxetine's very long effective half-life, both therapeutic change and adverse effects (including activation or emergent suicidality) appear and resolve more slowly than with shorter-acting SSRIs. Watch for emergent manic or hypomanic symptoms throughout treatment and treat new rapid mood elevation, agitation, or pressured speech as a possible bipolar switch.

Patient counseling

Before starting: screen for a personal or family history of bipolar disorder; fluoxetine, like all antidepressants, can precipitate a manic or mixed switch in susceptible patients. Boxed warning: counsel patients (and family members, where appropriate) about the increased risk of suicidal ideation and behavioral activation in patients under 25, and ask them to report promptly any worsening mood, intrusive thoughts of self-harm, agitation, irritability, or unusual behavioral changes, particularly in the first weeks of treatment and after any dose change.

Relevant anecdote

⚕️ Provider by MDElliottMD0
Fluoxetine is great for getting off other SxRIs! Especially venlafaxine and duloxetine.

+ Add an anecdote

Relevant Literature

No literature entries yet.

Log in to submit relevant literature.

See also

Sertraline, Duloxetine

References

  1. ↑ S1
  2. ↑ 2.0 2.1 2.2 U.S. Food and Drug Administration. Prozac (fluoxetine hydrochloride) prescribing information. NDA 018936.
  3. ↑ S0
  4. ↑ 4.0 4.1 Wong DT, Horng JS, Bymaster FP, Hauser KL, Molloy BB. A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. Life Sciences. 1974;15(3):471-479. PMID: 4549929.
  5. ↑ 5.0 5.1 5.2 S3
Pharmacy
Starting dose
10 mg
Preparations
10 mg, 20 mg, 40 mg caps
US FDA Max
40 mg/d
Pill ID
  • 10 mg: green/cream capsule, "PLIVA 647"
  • 20 mg: green/cream capsule, "PROZAC 20"
  • 40 mg: olive/cream capsule, "DISTA 3107"
  • Oral solution: 20 mg / 5 mL, clear
Common uses
Common uses
+ 3 more uses →
Structure
Structure of Fluoxetine
Classification(s)
Classes
SSRI, Anxiolytic, Antidepressant
Pharmacology
Routes
Oral
Duration
Very long
Half-life
1-3 days acute, 4-6 days chronic; 4-16 days for norfluoxetine[2]
Bioavailability
70–90% (oral)
Pregnancy
Category C[3]
Legal status
Rx-only in US
Purported mechanism
TrkB/BDNF[1] Fluoxetine is a selective serotonin reuptake inhibitor.0
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