Drug Monograph
Fluoxetine (Prozac)
fluoxetine hydrochloride
Pharmacokinetic Profile
Half-Life
1–4 days (fluoxetine); 7–9 days (norfluoxetine)
Metabolism
CYP2D6 → norfluoxetine (active); potent CYP2D6 inhibitor
Protein Binding
94.5%
Tmax
6–8 h
Steady State
4–5 weeks (due to long t½)
Clinical Information
Drug Class
SSRI
Available Doses
Capsules: 10, 20, 40 mg; Solution: 20 mg/5 mL
Route
Oral
Renal Adjustment
Not routinely necessary
Hepatic Adjustment
Lower/less frequent dose in cirrhosis
Pregnancy
Use only if benefit justifies risk; third trimester PPHN/withdrawal risk
Lactation
Not recommended (present in breast milk)
Schedule
Rx only; Not controlled
Generic Available
Yes
Black Box Warning
Suicidal thoughts & behaviors in youth/young adults
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major depressive disorder (MDD) | Adults and paediatric ≥8 years | Monotherapy (acute and maintenance) | FDA Approved |
| Obsessive-compulsive disorder (OCD) | Adults and paediatric ≥7 years | Monotherapy (acute and maintenance) | FDA Approved |
| Bulimia nervosa | Adults | Monotherapy (acute and maintenance; moderate to severe) | FDA Approved |
| Panic disorder | Adults | Monotherapy (with or without agoraphobia; acute treatment) | FDA Approved |
| Bipolar I depressive episodes | Adults and paediatric ≥10 years | Combination with olanzapine only | FDA Approved |
| Treatment-resistant depression | Adults | Combination with olanzapine only | FDA Approved |
Fluoxetine was the first SSRI approved in the United States (1987) and remains one of the most widely prescribed antidepressants globally. It is the only SSRI with FDA-approved indications for bulimia nervosa. In paediatric populations, fluoxetine has the strongest evidence base among SSRIs for the treatment of depression, supported by AACAP guidelines recommending it as the preferred first-line SSRI for children and adolescents with MDD. Notably, fluoxetine monotherapy is not indicated for bipolar depression or treatment-resistant depression — these require combination with olanzapine.
Off-Label Uses
PMDD: Previously FDA-approved as Sarafem; approval withdrawn April 2024 at manufacturer request (not for safety reasons). Generic fluoxetine remains widely used off-label. Evidence quality: High. Premature ejaculation, PTSD, body dysmorphic disorder, Raynaud phenomenon, fibromyalgia: Evidence quality: Low–Moderate.
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MDD — adults | 20 mg/day | 20 mg/day | 80 mg/day | Take in the morning. 20 mg/day sufficient for most patients. Increase after several weeks if needed. Doses >20 mg: once daily AM or divided AM/noon. Full effect may be delayed 4+ weeks. |
| MDD — paediatric (≥8 yr) | 10–20 mg/day | 20 mg/day | 20 mg/day | Lower weight children: start and target 10 mg/day. After 1 week at 10 mg, increase to 20 mg. Trials used 10–20 mg/day range. |
| OCD — adults | 20 mg/day | 20–60 mg/day | 80 mg/day | Full therapeutic effect may take 5+ weeks. Doses >20 mg: AM or divided AM/noon. No dose-response demonstrated in one trial. |
| OCD — paediatric (adolescents & higher weight) | 10 mg/day | 20–60 mg/day | 60 mg/day | After 2 weeks → 20 mg. Increase further after several more weeks if needed. |
| OCD — paediatric (lower weight) | 10 mg/day | 20–30 mg/day | 60 mg/day | Very limited experience >20 mg; no experience >60 mg in this group. |
| Bulimia nervosa — adults | 60 mg/day | 60 mg/day | 60 mg/day | Take in the morning. May titrate up over several days. Only 60 mg was significantly superior to placebo. Doses above 60 mg not studied. Maintenance benefit demonstrated up to 52 weeks. |
| Panic disorder — adults | 10 mg/day | 20 mg/day | 60 mg/day | After 1 week → 20 mg. Most commonly administered dose was 20 mg in trials. Start low to avoid initial symptom exacerbation. |
| Hepatic impairment (cirrhosis) | Lower dose or less frequent dosing | Clearance decreased; t½ prolonged. No specific dose recommendation — titrate cautiously. | ||
| Elderly | Lower or less frequent dosing | Consider starting at 10 mg/day. | ||
Critical: 5-Week MAOI Washout After Stopping Fluoxetine
Due to the extremely long elimination half-lives of fluoxetine (1–4 days) and norfluoxetine (7–9 days), at least 5 weeks must elapse after stopping fluoxetine before starting an MAOI, thioridazine, or pimozide. This is unique among SSRIs and a critical safety consideration. Conversely, at least 14 days should elapse after stopping an MAOI before starting fluoxetine.
Pharmacology
Mechanism of Action
Fluoxetine selectively inhibits the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane by blocking the serotonin transporter (SERT), thereby increasing serotonin availability in the synaptic cleft. It has only weak effects on norepinephrine and dopamine reuptake. Its active metabolite norfluoxetine is an equally potent SSRI. Fluoxetine is considered the most activating SSRI, likely related to 5-HT2C receptor antagonism, which may contribute to its pro-energising effects but also to anxiety, insomnia, and agitation, particularly in the early weeks of treatment. This activating profile distinguishes it from more sedating SSRIs like paroxetine.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax 6–8 h; well absorbed orally; bioavailability ~72%; food does not substantially affect absorption | Take with or without food; once-daily morning dosing preferred due to activating profile |
| Distribution | Protein binding 94.5%; extensive tissue distribution; large Vd | High protein binding means potential displacement interactions with other highly bound drugs (warfarin, digoxin) |
| Metabolism | Hepatic via CYP2D6 to norfluoxetine (active metabolite, equally potent SSRI); norfluoxetine t½ 7–9 days. Fluoxetine is a potent CYP2D6 inhibitor and also inhibits CYP2C9 and CYP3A4 (norfluoxetine). ~7% of Caucasians are CYP2D6 poor metabolisers | Potent CYP2D6 inhibition is a major interaction liability — elevates levels of TCAs, antipsychotics, beta-blockers, antiarrhythmics, codeine/tramadol (reduced analgesic efficacy). Drug effects persist for weeks after discontinuation |
| Elimination | t½ 1–4 days (fluoxetine), 7–9 days (norfluoxetine); steady state ~4–5 weeks; renal excretion of unchanged drug minimal; hepatic impairment: clearance decreased, t½ prolonged | Longest t½ of all SSRIs: dose changes take weeks to reach new steady state. Gradual self-tapering on discontinuation (lower discontinuation syndrome risk). 5-week washout required before MAOI/thioridazine |
Side Effects
The following rates are from US placebo-controlled MDD trials (FDA PI). AE rates may be higher in OCD and bulimia trials due to higher doses used (up to 60–80 mg). For example, insomnia reaches 28% in OCD trials and 33% in bulimia trials (at 60 mg) compared to 16% in MDD trials.
≥10%Very Common — MDD Trials (FDA PI)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 21% (vs 9% placebo) | Most common AE; dose-related; usually improves within 1–2 weeks |
| Insomnia | 16% (vs 9% placebo) | Fluoxetine is the most activating SSRI; dose in the morning. Reaches 28% in OCD and 33% in bulimia |
| Nervousness | 14% (vs 9% placebo) | Related to 5-HT2C antagonism; often self-limiting |
| Diarrhoea | 12% (vs 7% placebo) | Usually transient |
| Anxiety | 12% (vs 6% placebo) | Paradoxical anxiety early in treatment; start at lower dose in panic disorder |
| Somnolence | 12% (vs 6% placebo) | Despite activating profile, sedation occurs in some patients |
| Anorexia (decreased appetite) | 11% (vs 2% placebo) | Significant weight loss possible; monitor especially in underweight/bulimic patients (FDA PI Section 5.6) |
| Asthenia | 11% (vs 6% placebo) | General weakness/fatigue |
| Tremor | 10% (vs 3% placebo) | Fine postural tremor; dose-related; assess for serotonin syndrome if severe |
2–10%Common (MDD Trials)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dry mouth | 9% (vs 6% placebo) | Mild anticholinergic-like effect |
| Sweating | 8% (vs 3% placebo) | May persist throughout treatment |
| Dyspepsia | 8% (vs 4% placebo) | Take with food to mitigate |
| Rash | 4% (vs 3% placebo); 7% of 10,782 patients overall | Higher rash incidence than other SSRIs; discontinue if allergic phenomena develop (see PI Section 5.3) |
| Libido decreased | 3% (vs <1% placebo) | Underreported; inquire proactively |
| Abnormal ejaculation (males) | 2% (vs 0% placebo) | Underreported in trials; true rate likely higher |
| Yawning | 3% (vs 0% placebo) | Serotonergic effect; usually benign |
SeriousSerious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Suicidal thoughts/behaviours | 14 per 1,000 (<18 yr); 5 per 1,000 (18–24 yr) vs placebo | First weeks or dose changes | Close monitoring; FDA Boxed Warning |
| Serotonin syndrome | Rare | Hours to days | Discontinue all serotonergic agents; supportive care |
| Allergic reactions / severe rash | Rare (vasculitis, serum sickness-like, SJS reported) | Variable | Discontinue immediately; systemic reactions including lung, kidney, liver involvement possible; deaths reported |
| QTc prolongation / TdP | Rare (post-marketing) | Variable; dose-related | ECG in at-risk patients; avoid QTc-prolonging co-medications |
| Mania/hypomania | 0.1% (MDD); 0.8% (OCD); 0.7% overall (10,782 patients) | First weeks | Screen for bipolar disorder before prescribing; discontinue if mania develops |
| Seizures | 0.2% (10,782 patients) | Variable | Use with caution in seizure disorders |
| Hyponatraemia (SIADH) | Uncommon | First weeks | Check sodium if confusion/weakness/falls; discontinue if symptomatic |
DiscontinuationDiscontinuation
Overall (Combined Indications)
Low risk
Top reasons: Anxiety (2% in OCD), insomnia (1% combined, 2% in bulimia), nervousness (1% in MDD). The long t½ of fluoxetine/norfluoxetine provides natural self-tapering, making discontinuation syndrome less common than with other SSRIs
Paediatric
1.8%
Primary reason: Mania/hypomania (1.8% vs 0% placebo) in 3 paediatric trials (N=228 fluoxetine, N=190 placebo)
Managing Appetite and Weight Changes
Fluoxetine carries a distinct warning about altered appetite and weight. In MDD trials, 11% of patients reported anorexia (vs 2% placebo) and weight loss was reported in 1.4% (vs 0.5% placebo). This can be particularly concerning in underweight depressed or bulimic patients. Monitor weight regularly and reassess treatment if clinically significant weight loss occurs.
Drug Interactions
Fluoxetine is a potent inhibitor of CYP2D6 and, through its metabolite norfluoxetine, also inhibits CYP3A4. This gives fluoxetine the highest drug interaction potential among SSRIs. Its long elimination half-life means that interaction effects persist for weeks after discontinuation. It is highly protein-bound (94.5%), creating potential for displacement interactions.
MajorMAOIs
MechanismDual serotonin reuptake inhibition and metabolism blockade
EffectPotentially fatal serotonin syndrome; hyperthermia, rigidity, myoclonus, autonomic instability
ManagementContraindicated. 14-day washout before starting fluoxetine; 5-WEEK washout after stopping fluoxetine
FDA PI — ContraindicationMajorPimozide & Thioridazine
MechanismCYP2D6 inhibition by fluoxetine increases levels; both drugs prolong QTc
EffectRisk of QTc prolongation, ventricular arrhythmias, TdP
ManagementContraindicated. Do not use thioridazine within 5 weeks of stopping fluoxetine
FDA PI — ContraindicationMajorTCAs (desipramine, imipramine, nortriptyline)
MechanismPotent CYP2D6 inhibition markedly increases TCA levels
EffectTCA toxicity (cardiac arrhythmia, seizures); interaction persists weeks after fluoxetine discontinuation
ManagementMonitor TCA levels; reduce TCA dose substantially; monitor ECG
FDA PIModerateCYP2D6 substrates (antipsychotics, beta-blockers, antiarrhythmics, opioids)
MechanismPotent CYP2D6 inhibition; makes normal metabolisers resemble poor metabolisers
EffectElevated haloperidol, clozapine, metoprolol, propafenone, flecainide levels. Reduced codeine/tramadol efficacy (blocked CYP2D6 activation)
ManagementStart CYP2D6 substrates at low end of dose range; monitor for toxicity
FDA PIModerateAnticonvulsants (phenytoin, carbamazepine)
MechanismCYP inhibition by fluoxetine increases anticonvulsant levels
EffectPotential anticonvulsant toxicity
ManagementMonitor anticonvulsant levels; adjust doses as needed
FDA PIModerateNSAIDs / Anticoagulants
MechanismSSRI-mediated platelet serotonin depletion + pharmacodynamic interaction
EffectIncreased bleeding risk
ManagementMonitor for bleeding; monitor INR with warfarin (also protein binding displacement)
FDA PIMonitoring
- Suicidality / Clinical WorseningWeekly × 4 wk, biweekly × 4 wk, then monthly
RoutineFDA Boxed Warning. Monitor closely in patients <25. Note dose changes take weeks to reach steady state due to long t½. - Weight / AppetiteBaseline, then monthly initially
RoutineSignificant weight loss possible (anorexia 11% vs 2%). Especially important in underweight, bulimic, paediatric, and elderly patients. - Rash / Allergic PhenomenaOngoing during treatment
Trigger-based7% of patients in clinical trials developed rash/urticaria; ~1/3 of these required discontinuation. Systemic reactions (vasculitis, serum sickness) reported; deaths have occurred. - Sexual FunctionBaseline, then at follow-up
RoutineInquire proactively; PI specifically advises pre-treatment assessment. - Bipolar ScreeningBefore initiation
RoutineScreen for personal/family history. Mania occurred in 0.7% of 10,782 patients overall. - Serum SodiumIf at risk or symptomatic
Trigger-basedSIADH-related hyponatraemia, especially in elderly and those on diuretics. - Glycaemic ControlIf diabetic, at initiation and discontinuation
Trigger-basedFluoxetine may alter glycaemic control: hypoglycaemia during therapy, hyperglycaemia on discontinuation. Adjust insulin/oral hypoglycaemics as needed (FDA PI).
Contraindications & Cautions
Absolute Contraindications
- Concomitant MAOI use or within 14 days of stopping MAOIs (including linezolid and IV methylene blue). At least 5 weeks must elapse after stopping fluoxetine before starting an MAOI.
- Concomitant pimozide — risk of QTc prolongation and elevated pimozide levels via CYP2D6 inhibition.
- Concomitant thioridazine — risk of QTc prolongation. Do not use within 5 weeks of stopping fluoxetine.
Relative Contraindications (Specialist Input Recommended)
- Unscreened or known bipolar disorder: Screen before prescribing; fluoxetine monotherapy is not indicated for bipolar depression.
- Untreated anatomically narrow angles: Mydriasis may trigger angle-closure glaucoma.
Use with Caution
- Pregnancy: Use only if benefit justifies risk. Third trimester SSRI exposure: neonatal complications (respiratory distress, withdrawal, PPHN).
- Lactation: Breastfeeding is not recommended (PI). Fluoxetine is less preferred during breastfeeding vs sertraline due to longer t½ and higher infant exposure.
- Seizure disorders: 0.2% seizure rate in clinical trials; use with caution.
- Hepatic impairment: Reduced clearance and prolonged t½ — use lower/less frequent dosing.
- Diabetes: May alter glycaemic control.
- Patients on multiple CYP2D6 substrates: High interaction potential persisting weeks after discontinuation.
FDA Boxed Warning
Suicidal Thoughts and Behaviours in Children, Adolescents, and Young Adults
Antidepressants increased the risk of suicidal thoughts and behaviours in patients <18 years (14 additional per 1,000) and 18–24 years (5 additional per 1,000) in short-term studies. No suicides occurred in paediatric trials. In adults 25–64, there was a reduction (1 fewer per 1,000); in adults ≥65, a further reduction (6 fewer per 1,000). Monitor all patients closely. Fluoxetine is not approved for use in children <7 years of age.
Patient Counselling
Purpose of Therapy
Fluoxetine increases serotonin levels in the brain to help improve mood, reduce anxiety, manage obsessive thoughts, or reduce binge-eating behaviours depending on the condition being treated. Full benefits typically take 4–5 weeks or longer. Patients should continue taking fluoxetine even after feeling better.
How to Take
Take in the morning (or morning and noon if split dosing) with or without food. For bulimia, the full 60 mg dose is taken in the morning. Capsules should be swallowed whole.
Mood Changes & Suicidal Thoughts
Tell patientAntidepressants may initially cause new or worsening mood symptoms in some people, especially under 25. Have a trusted person monitor you closely during the first weeks.
Call prescriberImmediately if you experience worsening depression, anxiety, panic, agitation, irritability, or thoughts of self-harm.
Anxiety, Insomnia & Activation
Tell patientFluoxetine is the most activating SSRI. Some people experience nervousness, restlessness, or difficulty sleeping early in treatment. These effects typically improve over time. Take in the morning to minimise insomnia.
Call prescriberIf anxiety or insomnia is severe or not improving after 2–3 weeks.
Rash
Tell patientSkin rash occurs more frequently with fluoxetine than other SSRIs. Most rashes are mild, but serious allergic reactions are possible.
Call prescriberImmediately if you develop a rash, hives, joint pain, swelling, fever, or difficulty breathing.
Stopping Treatment & Drug Interactions After Stopping
Tell patientFluoxetine stays in your body for several weeks after you stop taking it. This means drug interactions can persist long after your last dose. Always tell your healthcare providers that you recently took fluoxetine, even if you stopped weeks ago.
Call prescriberBefore starting any new medication, especially migraine drugs, pain medications, or herbal supplements, within 5 weeks of stopping fluoxetine.
Sources
Regulatory (PI / SmPC)
- Eli Lilly and Company. PROZAC (fluoxetine capsules): US Prescribing Information. NDA 018936. Revised 08/2023. FDA LabelPrimary source for all dosing, pharmacokinetic, safety, and indication data in this monograph.
Key Clinical Trials
- Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357–1366. doi:10.1016/S0140-6736(17)32802-7Landmark NMA; fluoxetine showed modest efficacy compared to some SSRIs but high acceptability profile.
- March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS). JAMA. 2004;292(7):807–820. doi:10.1001/jama.292.7.807Pivotal paediatric depression trial demonstrating fluoxetine efficacy in adolescents, with best outcomes from fluoxetine + CBT combination.
- Geller DA, Hoog SL, Heiligenstein JH, et al. Fluoxetine treatment for obsessive-compulsive disorder in children and adolescents: a placebo-controlled clinical trial. J Am Acad Child Adolesc Psychiatry. 2001;40(7):773–779. doi:10.1097/00004583-200107000-00011Key paediatric OCD trial supporting FDA approval of fluoxetine in children aged 7–17.
- Goldstein DJ, Wilson MG, Thompson VL, Potvin JH, Rampey AH Jr. Long-term fluoxetine treatment of bulimia nervosa. Br J Psychiatry. 1995;166(5):660–666. doi:10.1192/bjp.166.5.66052-week maintenance trial supporting continued efficacy of fluoxetine 60 mg/day for bulimia nervosa.
Guidelines
- National Institute for Health and Care Excellence (NICE). Depression in children and young people: identification and management. NICE guideline [NG134]. June 2019. NICE NG134UK guideline recommending fluoxetine as the first-line antidepressant for children and adolescents with depression.
- American Psychiatric Association. Practice guideline for the treatment of patients with eating disorders, third edition. Am J Psychiatry. 2006;163(7 Suppl):4–54. APA GuidelinesAPA guideline recommending fluoxetine 60 mg/day as pharmacotherapy of choice for bulimia nervosa when CBT alone is insufficient.
Mechanistic / Basic Science
- Wong DT, Perry KW, Bymaster FP. The discovery of fluoxetine hydrochloride (Prozac). Nat Rev Drug Discov. 2005;4(9):764–774. doi:10.1038/nrd1821Historical perspective on the discovery and development of the first SSRI; covers mechanism of action and pharmacological rationale.
- Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors: serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. 1998;51(3):215–235. doi:10.1016/S0165-0327(98)00221-3Foundational SSRI pharmacology review; explains receptor-mediated effects relevant to fluoxetine’s activating profile.
Pharmacokinetics / Special Populations
- Altamura AC, Moro AR, Percudani M. Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet. 1994;26(3):201–214. doi:10.2165/00003088-199426030-00004Comprehensive PK review establishing fluoxetine’s unique long half-life profile and clinical implications.
- Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors: an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32(Suppl 1):1–21. doi:10.2165/00003088-199700321-00003Comparative SSRI PK review; positions fluoxetine as the most potent CYP2D6 inhibitor among SSRIs.
- Heikkinen T, Ekblad U, Palo P, Laine K. Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation. Clin Pharmacol Ther. 2003;73(4):330–337. doi:10.1016/S0009-9236(02)17634-XStudy characterising fluoxetine PK in pregnancy and breast milk exposure, informing risk-benefit decisions.