Fluoxetine is an antidepressant (SSRI) used for depression, obsessive-compulsive disorder, bulimia and premenstrual syndrome. It is effective, but takes a few weeks to work and may cause nausea, insomnia and changes in sexual desire at the start.
Also known as: Prozac
Risk of serotonin syndrome. Fluoxetine inhibits CYP2D6, raising Tramadol levels.
The fluoxetine label lists tramadol among the serotonergic drugs whose concomitant use increases the risk of serotonin syndrome, potentially life-threatening, especially at treatment initiation and dose increases; the tramadol label states that concomitant use with CYP2D6 inhibitors (fluoxetine is a potent CYP2D6 inhibitor) has complex effects on tramadol and active metabolite M1 levels, with an increased risk of serious adverse events, including seizures and serotonin syndrome. Whenever possible, avoid the combination or use the lowest effective dose, monitor for serotonin symptoms (agitation, tachycardia, hyperthermia, hyperreflexia) and signs of seizures.
Fluoxetine + tramadol: risk of serotonin syndrome and seizures (SSRI + tramadol, CYP2D6 inhibition). Monitor closely.
Serotonin accumulation: the SSRI effect added to Tramadol's, plus inhibition of its metabolism.
Serotonin signs in the first days.
Agitation, hyperthermia, diarrhoea, tremor, clonus, confusion.
Use an alternative analgesic or monitor signs; avoid combining two serotonergic drugs unless needed.
DailyMed/FDA (NIH/NLM) — approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490 ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=552955e6-2bb3-8755-e063-6394a90ab21c
Similar risk to other SSRIs: Isoniazid with Fluoxetine may precipitate serotonin syndrome.
Isoniazid has some monoamine oxidase inhibiting activity (the label states that "isoniazid has some monoamine oxidase inhibiting activity", with an interaction with tyramine-rich foods, and warns about the risk of interaction with MAO inhibitors), and fluoxetine is a selective serotonin reuptake inhibitor (SSRI) whose label contraindicates the combination with MAO inhibitors "because of an increased risk of serotonin syndrome". Combining an SSRI with a drug with MAO activity can cause serotonin syndrome (agitation, confusion, hyperthermia, hyperreflexia, myoclonus, diaphoresis, tachycardia) or a hypertensive crisis. Avoid whenever possible; if the combination is unavoidable (e.g. tuberculosis in a patient with depression), use the lowest effective dose, actively watch for serotonin signs and neurological toxicity, and instruct the patient to seek immediate help with agitation, fever or rigidity.
Isoniazid + fluoxetine: isoniazid has MAO-inhibiting activity — risk of serotonin syndrome with the SSRI. Watch for symptoms.
Weak MAO effect of isoniazid and serotonin reuptake inhibition, with long fluoxetine half-life.
Signs of serotonin syndrome.
Agitation, confusion, tremor, hyperthermia.
Watch for serotonergic signs; counsel the patient.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490
CYP1A2 inhibitor + CYP1A2 substrate: fluoxetine may increase theophylline levels 10-20%.
Fluoxetine weakly inhibits CYP1A2. The effect on theophylline levels is generally modest (10-20%), clinically significant only at high fluoxetine doses (>40 mg/day) or in CYP2D6 poor metabolisers. Monitor levels if high dose.
Fluoxetine weakly inhibits CYP1A2, increasing theophylline 10-20%. Effect generally modest.
Fluoxetine weakly inhibits CYP1A2, potentially slightly increasing theophylline levels. The effect is generally modest.
Theophylline levels.
Monitor theophylline levels if high-dose fluoxetine.
DailyMed/FDA; EMC-UK
Antipsychotic + CYP2D6 inhibitor: fluoxetine may increase aripiprazole levels.
Fluoxetine inhibits CYP2D6, the main metabolic pathway for aripiprazole. Levels may increase 30-40%.
Signs of akathisia, agitation.
Severe akathisia.
Reduce aripiprazole dose by 50% if combined with potent CYP2D6 inhibitor.
DailyMed/FDA; EMC-EMC PT
Beta-blocker + CYP2D6 inhibitor: fluoxetine may increase carvedilol levels.
Carvedilol is metabolised by CYP2D6. Fluoxetine inhibits CYP2D6, increasing levels.
Heart rate, blood pressure, signs of bradycardia.
Symptomatic bradycardia.
Monitor heart rate and blood pressure. Reduce dose if necessary.
DailyMed/FDA; EMC-EMC PT
Combining Clozapine with Fluoxetine increases Clozapine concentrations, with a risk of toxicity.
Clozapine is metabolised by CYP1A2 and CYP2D6, and fluoxetine inhibits these enzymes: the clozapine label explicitly states that "fluoxetine, quinidine, duloxetine, terbinafine or sertraline can increase clozapine levels and lead to adverse reactions". Raised clozapine levels potentiate the dose-dependent effects: sedation, sialorrhoea, constipation, tachycardia, hypotension, seizures and, above all, agranulocytosis/neutropenia and myocarditis (serious reactions requiring blood count monitoring). The combination requires: monitoring clozapine plasma levels (or reducing the dose by 30–50% in clinical practice), watching sedation, anticholinergic symptoms and the blood count, and reassessing when fluoxetine is discontinued (levels fall).
Clozapine + fluoxetine: fluoxetine inhibits CYP1A2/2D6 and raises clozapine levels. Monitor levels and adverse effects.
Fluoxetine, a CYP2D6/3A4 inhibitor, reduces Clozapine metabolism, raising its serum levels.
Excessive sedation, drooling, seizures or fever require reassessment.
Sedation, seizures or signs of haematological dyscrasia require reassessment.
Monitor signs of Clozapine toxicity and consider reducing the dose; watch the blood count.
DailyMed/FDA (NIH/NLM) — approved Clozapine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61fe53d5-ed5c-4e45-9189-709d08d386cb ; approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Decongestant + SSRI: possible increased pressor effect.
Pseudoephedrine is a sympathomimetic with vasoconstrictor and pressor effects; fluoxetine can potentiate the adrenergic effects (tachycardia, hypertension, tremor) and there is also a theoretical risk of serotonin syndrome from the serotonergic component of pseudoephedrine. The interaction is mild in most patients, but caution is recommended in hypertensive, cardiac and hyperthyroid patients: monitor blood pressure, use the lowest dose and shortest duration of the decongestant, and prefer non-sympathomimetic alternatives (nasal corticosteroids, saline) when possible.
Decongestant + SSRI: possible increased pressor effect. Monitor blood pressure and adrenergic symptoms.
Additive sympathomimetic effect in patients on SSRIs (risk of hypertension/tachycardia).
Blood pressure.
Hypertension, palpitations.
Monitor blood pressure and heart rate.
DailyMed (FDA) — approved Pseudoephedrine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=78faa497-6743-b85b-e053-2a91aa0ae822 ; approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Fluoxetine may raise dextromethorphan levels and the risk of serotonin syndrome.
Fluoxetine is a "potent inhibitor of the CYP2D6 enzyme pathway" (fluoxetine label, section 7.7) and dextromethorphan is primarily metabolised by CYP2D6 (its main metabolite, dextrorphan, is active). CYP2D6 inhibition by fluoxetine can significantly raise dextromethorphan concentrations, and both drugs have serotonergic activity — dextromethorphan is a weak serotonin reuptake inhibitor and fluoxetine is a potent SSRI. The risk of serotonin syndrome (agitation, confusion, fever, tremor, clonus, hyperreflexia) adds to the risk of raised dextromethorphan levels (sedation, dizziness, nausea, ataxia). The combination is frequent in over-the-counter cough medicines in patients taking fluoxetine. Avoid dextromethorphan in patients taking fluoxetine; if unavoidable, use the lowest dose and shortest duration possible, and advise the patient to watch for serotonergic symptoms (agitation, twitching, fever) and neurological symptoms (dizziness, ataxia). Consider alternative non-serotonergic antitussives.
Fluoxetine + dextromethorphan: fluoxetine inhibits CYP2D6 (raises dextromethorphan levels) and both are serotonergic — risk of serotonin syndrome.
Fluoxetine inhibits CYP2D6, the main metabolic pathway of dextromethorphan, and both are serotonergic.
Monitor agitation, tremor, hyperthermia, myoclonus and mental status changes.
Serotonin syndrome (hyperthermia, rigidity, confusion).
Avoid the combination; if unavoidable, use the lowest dextromethorphan dose and monitor.
DailyMed (FDA) — approved Dextromethorphan label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0d99237c-0b52-0af6-e063-6394a90aba14 ; approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Fluoxetine markedly increases imipramine levels, with risk of toxicity (delirium, urinary retention, arrhythmias, seizures).
Fluoxetine is a potent CYP2D6 inhibitor, imipramine\u2019s main metabolic pathway.
ECG (QT, QRS), anticholinergic and neurological signs.
Marked dry mouth, urinary retention, palpitations, confusion, seizures.
Avoid the combination; if a therapeutic switch is needed, reduce the TCA dose by 25–50% and monitor ECG.
DailyMed — Tofranil (imipramine) label, Drug Interactions (CYP2D6 inhibitors): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=649837df-147f-436c-9553-32ffecf4c6f1
Beta-blocker + SSRI: CYP2D6 inhibition increases metoprolol levels.
Fluoxetine potently inhibits CYP2D6, increasing metoprolol plasma levels 2-5 fold. Risk of bradycardia and hypotension.
DailyMed/FDA (NIH/NLM) — approved Metoprolol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5466243e-1e3d-175e-e063-6394a90a5dee
Fluoxetine may reduce tamoxifen's effectiveness in breast cancer by blocking the enzyme that converts it into the active form of the drug. Talk to your doctor before taking them together.
Tamoxifen is a prodrug: its conversion to endoxifen (a metabolite with ~100-fold higher affinity for the oestrogen receptor) depends on CYP2D6. Fluoxetine is a potent inhibitor of this isoenzyme; pharmacokinetic studies show a 65–75% reduction in endoxifen levels, and observational studies link the concomitant use of CYP2D6-inhibiting SSRIs to worse breast cancer outcomes. The tamoxifen SmPC (EMC-UK) recommends avoiding, whenever possible, co-administration with potent CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine, cinacalcet, bupropion). Sertraline inhibits CYP2D6 moderately and in a dose-dependent manner. If an antidepressant is needed, agents with less CYP2D6 impact should be preferred.
Potent CYP2D6 inhibitors (fluoxetine, paroxetine) reduce endoxifen (tamoxifen's active metabolite) levels by 65–75%, with possible loss of efficacy. Avoid the combination; prefer SSRIs with weaker CYP2D6 inhibition (e.g. citalopram, escitalopram, venlafaxine).
Fluoxetine inhibits CYP2D6, reducing the formation of endoxifen (the active tamoxifen metabolite).
Tamoxifen adherence and response; depressive symptoms and SSRI adverse effects.
Clinical worsening of breast cancer; serotonin syndrome (rare in this combination, but watch for tremor, agitation, hyperthermia).
Avoid the combination; if an SSRI is needed, choose one with weak CYP2D6 inhibition (citalopram, escitalopram, venlafaxine) and reassess therapy with the oncologist.
EMC-UK (MHRA) — approved Tamoxifen SmPC: https://www.medicines.org.uk/emc/product/101398/smpc ; DailyMed/FDA (NIH/NLM) — approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490 ; PubMed — https://pubmed.ncbi.nlm.nih.gov/20141708/ and https://pubmed.ncbi.nlm.nih.gov/23760858/ ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Fluoxetine can increase the effect of glimepiride and lower blood sugar too much. Watch for the signs of hypoglycaemia.
The glimepiride SmPC (EMC-UK) lists fluoxetine and MAOIs among the drugs that may potentiate the hypoglycaemic effect of sulfonylureas, through mechanisms involving enzyme inhibition and altered insulin sensitivity. Blood glucose monitoring is recommended at the start and during SSRI treatment, particularly in the first days.
The glimepiride SmPC (EMC-UK) lists fluoxetine among the drugs that potentiate the hypoglycaemic effect. Monitor blood glucose when starting or adjusting the SSRI.
Enzyme inhibition and altered insulin sensitivity by fluoxetine.
Capillary glucose at the start of SSRI treatment.
Hypoglycaemia — tremor, sweating, confusion.
Reinforce self-monitoring of blood glucose when starting fluoxetine; adjust the sulfonylurea dose if needed.
EMC-UK (MHRA) — approved Glimepiride SmPC: https://www.medicines.org.uk/emc/product/10742/smpc ; DailyMed/FDA (NIH/NLM) — approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
High risk of serotonin syndrome: combining two SSRIs (Sertraline + Fluoxetine) accumulates serotonin and can be dangerous.
Fluoxetine and sertraline increase synaptic serotonin through the same mechanism (blockade of the SERT transporter); in combination, the risk of serotonin syndrome increases, especially at high doses or with other serotonergic drugs. Fluoxetine has a long half-life (1 to 3 days; 4 to 16 days for norfluoxetine), so the washout when switching drugs must be longer. In practice, two SSRIs should not be used simultaneously; the combination is only justified in very short, supervised transitions, and warning symptoms (agitation, tremor, hyperreflexia, hyperthermia, diarrhoea) should lead to immediate discontinuation.
Two SSRIs simultaneously: risk of serotonin syndrome (agitation, tremor, hyperthermia, rigidity, diarrhoea) and additive effects. Avoid; when switching SSRIs, respect the washout period (fluoxetine has a long half-life).
Both inhibit serotonin reuptake; Fluoxetine has long-acting metabolites that potentiate the second SSRI.
Monitor serotonin signs in the first weeks; advise against dose doubling.
Agitation, hyperthermia, tachycardia, tremor, clonus, diarrhoea, confusion.
Avoid the combination. When switching is necessary, respect a washout period and use single low doses.
DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 ; approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490
High risk of serotonin syndrome: Linezolid is an MAO inhibitor and with Fluoxetine serotonin accumulates — it can be dangerous.
Linezolid is a reversible, non-selective monoamine oxidase inhibitor and fluoxetine blocks serotonin reuptake: the combined effect can cause severe serotonin syndrome — agitation, tremor, hyperthermia, rigidity, hyperreflexia and diarrhoea, and in severe cases seizures, rhabdomyolysis and death. The approved labels of linezolid and fluoxetine warn of this risk. The combination should be avoided whenever possible; if clinically indispensable, use the lowest effective dose, closely monitor for serotonergic symptoms and discontinue immediately if signs appear.
Linezolid (MAO inhibitor) + SSRI: risk of potentially fatal serotonin syndrome. Avoid; if unavoidable, close monitoring of serotonergic symptoms.
MAO inhibition (linezolid) and serotonin reuptake inhibition (fluoxetine), with long fluoxetine half-life.
Watch for serotonergic signs.
Confusion, agitation, hyperthermia, tremor, rigidity, autonomic instability.
Avoid the combination; wait at least 2 weeks after stopping one of them.
DailyMed/FDA (NIH/NLM) — approved Linezolid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=374af2a7-d994-40bd-a86a-cd9038d0b72c ; approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490
Combining Lithium with Fluoxetine increases the risk of serotonin syndrome and may raise Lithium levels.
Lithium can precipitate serotonin syndrome, potentially life-threatening, and the risk increases with concomitant use of other serotonergic drugs, including SSRIs such as fluoxetine; the lithium and fluoxetine labels recommend informing the patient of the increased risk and monitoring symptoms (agitation, hallucinations, delirium, tachycardia, hyperthermia, tremor, rigidity, myoclonus, hyperreflexia, seizures, gastrointestinal symptoms), especially at initiation and dose increases. If symptoms arise, stop lithium and the serotonergic agents and start supportive treatment.
Fluoxetine + lithium: risk of serotonin syndrome. Inform the patient and monitor symptoms, especially at initiation and dose increases.
Lithium and Fluoxetine increase serotonergic activity; SSRIs may also reduce Lithium excretion, raising its levels.
Watch for agitation, tremor, hyperthermia, hyperreflexia, myoclonus or diarrhoea (serotonin syndrome).
Fever, agitation, hyperreflexia or myoclonus (serotonin syndrome) require discontinuation and urgent evaluation.
Use the combination cautiously, at low doses, and monitor Lithium levels.
DailyMed/FDA (NIH/NLM) — approved Lithium label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0e6b0a2d-b79c-44d8-b785-5267df9e8f72 ; approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
CYP2D6 inhibitor SSRI + antipsychotic: risperidone levels increased 2-4-fold. Risk of extrapyramidal effects.
Fluoxetine is a potent CYP2D6 inhibitor (Ki ~0.2 μM), the main metabolic pathway for risperidone (70% of clearance). Co-administration increases risperidone levels 2-4-fold, depending on the patient's CYP2D6 phenotype. The risk of extrapyramidal effects (tremor, rigidity, parkinsonism) increases significantly. In severe cases, neuroleptic malignant syndrome may occur (hyperthermia >40°C, muscular rigidity, unconsciousness, autonomic instability). Fluoxetine has a long half-life (2-6 days) and its active metabolite (norfluoxetine) inhibits CYP2D6 for 2-3 weeks after discontinuation. The Portuguese Prontuário Terapêutico recommends reducing risperidone dose by 50% or switching to an antipsychotic not metabolised by CYP2D6 (e.g. aripiprazole, quetiapine).
CYP2D6 inhibitor SSRI + antipsychotic: risperidone levels increased 2-4-fold. Risk of EPS and neuroleptic malignant syndrome.
Fluoxetine is a potent CYP2D6 inhibitor (Ki ~0.2 μM), the main metabolic pathway for risperidone. Co-administration may increase risperidone levels 2-4-fold, increasing the risk of extrapyramidal effects, parkinsonism, and neuroleptic malignant syndrome.
Extrapyramidal effects, torticollis, rigidity.
Neuroleptic malignant syndrome (hyperthermia, rigidity, unconsciousness).
If possible, avoid. If necessary, reduce risperidone dose by 50% and monitor for extrapyramidal effects.
DailyMed/FDA
CYP2D6 inhibitor SSRI + TCA: amitriptyline levels increased 2-4-fold. Risk of cardiac toxicity.
Fluoxetine inhibits CYP2D6, the main metabolic pathway for amitriptyline (N-demethylation). TCA levels may increase 2-4-fold, with risk of cardiac toxicity: QTc prolongation >500 ms, ventricular arrhythmias (torsades de pointes), seizures, and CNS depression. Amitriptyline has a narrow therapeutic index (toxic level: >250 ng/mL). Monitor ECG and TCA levels if co-administration is unavoidable. Reduce TCA dose by 50% and maintain low dose. Consider switching fluoxetine to an SSRI with less CYP2D6 inhibition (sertraline, citalopram).
CYP2D6 inhibitor SSRI + TCA: amitriptyline levels increased 2-4-fold. Risk of cardiac toxicity (QTc prolongation, arrhythmias).
Fluoxetine inhibits CYP2D6, the main metabolic pathway for amitriptyline. TCA levels may increase significantly, with risk of QTc prolongation, arrhythmias, and seizures.
ECG (QTc), TCA levels, signs of toxicity (dry mouth, urinary retention, confusion).
QTc >500 ms, arrhythmias, seizures.
Avoid combination if possible. If necessary, reduce TCA dose by 50% and monitor ECG and TCA levels.
DailyMed/FDA
SSRI + CYP3A4 inhibitor: fluoxetine levels increased. Risk of serotonin syndrome.
Ritonavir inhibits CYP3A4 and CYP2C19, and fluoxetine is metabolised by CYP2D6 and CYP3A4. Co-administration may increase fluoxetine levels 2-3-fold. The main risk is serotonin syndrome (agitation, hyperreflexia, diaphoresis, hyperthermia, rigidity), especially when combined with other serotonergic drugs. Ritonavir may also inhibit norfluoxetine (active metabolite) metabolism, prolonging the effect. Monitor for serotonergic signs. Reduce SSRI dose by 50% or switch to citalopram (metabolised by CYP3A4/2C19, less susceptible).
CYP3A4/CYP2D6 inhibitor + SSRI metabolised by CYP2D6: fluoxetine levels increased 2-3-fold. Risk of serotonin syndrome.
Ritonavir inhibits CYP3A4 and CYP2D6, the metabolic pathways for fluoxetine. Levels may increase significantly, with risk of serotonin syndrome.
Serotonergic signs (myoclonus, hyperreflexia, hyperthermia, agitation).
Severe serotonin syndrome (hyperthermia >41°C, seizures, rhabdomyolysis).
Avoid combination. If necessary, reduce fluoxetine dose by 50% and monitor for serotonergic signs.
DailyMed/FDA
SSRI + biguanide: SSRI may potentiate hypoglycaemic effect.
Fluoxetine may slightly reduce renal blood flow via prostaglandin inhibition, but the effect is significantly less than with NSAIDs. The risk of metformin accumulation is low in patients with normal renal function. In patients with borderline GFR (45-60), consider monitoring GFR. There is no evidence of clinically significant interaction in most patients.
SSRI + biguanide: SSRI may reduce GFR via renal prostaglandin effect. Theoretical risk of metformin accumulation.
Fluoxetine may improve insulin sensitivity and potentiate the hypoglycaemic effect of metformin. Risk of hypoglycaemia, especially in the elderly.
Blood glucose, signs of hypoglycaemia (tremor, sweating, confusion).
Severe hypoglycaemia.
Monitor blood glucose during the first weeks. Adjust metformin dose if necessary.
DailyMed/FDA
SSRI + CYP inhibitor: cimetidine may increase fluoxetine levels.
Cimetidine moderately inhibits CYP1A2, CYP2D6, and CYP3A4. Fluoxetine is metabolised by CYP2D6 and CYP3A4. Co-administration may increase fluoxetine levels by 10-20%, but the effect is generally clinically insignificant. In elderly patients or with polypharmacy, consider switching cimetidine to ranitidine/famotidine (do not significantly inhibit CYP). No routine dose adjustment required.
SSRI + H2 blocker: cimetidine may slightly increase fluoxetine levels (CYP inhibition). Effect generally minimal.
Cimetidine moderately inhibits CYP2D6 and CYP3A4. The effect on fluoxetine levels is modest but clinically relevant in the elderly.
Serotonergic signs.
Serotonin syndrome.
Monitor for serotonergic syndrome signs. Consider alternative (ranitidine does not inhibit CYP).
DailyMed/FDA
SSRI + benzodiazepine: additive sedative effect and fall risk.
Fluoxetine moderately inhibits CYP2C19 and CYP3A4, metabolic pathways for diazepam. Diazepam levels may increase slightly, prolonging sedation. The effect is generally modest. Monitor sedation and respiratory function, especially in the elderly. Consider switching diazepam to lorazepam (not metabolised by CYP) or alprazolam (metabolised by CYP3A4 but with short half-life).
SSRI + benzodiazepine: fluoxetine may inhibit diazepam metabolism (CYP2C19/3A4). Prolonged sedation.
Additive CNS effect — sedation, cognitive impairment, fall risk (especially elderly). Fluoxetine may inhibit diazepam metabolism via CYP3A4.
Sedation, coordination, falls.
Falls with fractures in the elderly.
Start with low benzodiazepine dose. Re-evaluate need for combination.
DailyMed/FDA
SSRI + CYP3A4 inducer: carbamazepine may reduce fluoxetine levels.
Carbamazepine induces CYP3A4 and CYP2C9, partial metabolic pathways for fluoxetine. Co-administration may reduce fluoxetine levels by 30-40%, decreasing antidepressant efficacy. It may be necessary to increase fluoxetine dose by 20-50%. Monitor antidepressant response. Alternative: switch carbamazepine to valproate or lamotrigine (weak inducers).
SSRI + CYP inducer: carbamazepine may reduce fluoxetine levels by 30-40%. Risk of loss of antidepressant efficacy.
Carbamazepine is a potent CYP3A4 inducer and may reduce fluoxetine levels by 20-30%. Antidepressant efficacy may be compromised.
Antidepressant efficacy, signs of depression.
Depressive relapse.
Monitor antidepressant efficacy. Consider higher fluoxetine dose.
DailyMed/FDA
SSRI + NaSSA: additive serotonergic effect. Combined therapeutically for treatment-resistant depression.
Mirtazapine is a NaSSA (noradrenergic and specific serotonergic antidepressant) that increases serotonin release via α2 blockade. Combined with fluoxetine (SSRI), it increases synaptic serotonin availability additively. The risk of serotonin syndrome is moderate (higher than with two SSRIs). Monitor signs: agitation, tremor, diaphoresis, hyperthermia. This combination is used clinically in treatment-resistant depression, but requires vigilance.
SSRI + NaSSA: additive serotonergic effect. Moderate risk of serotonin syndrome.
The combination is used therapeutically ("dual reuptake inhibition") for treatment-resistant depression. The risk of serotonin syndrome exists but is low at therapeutic doses.
Serotonergic signs.
Serotonin syndrome (rare).
Start with low doses. Monitor for serotonergic signs.
DailyMed/FDA
SSRI + anticoagulant: SSRI may potentiate anticoagulant effect (platelet inhibition).
SSRIs inhibit platelet serotonin reuptake, reducing platelet aggregation. Combined with warfarin (anticoagulant), bleeding risk increases moderately (OR 1.5-2x). The mechanism is additive (platelet + coagulation). Monitor INR and signs of bleeding. Fluoxetine may also inhibit CYP2C9, slightly increasing S-warfarin levels. Maintain low warfarin dose if possible.
SSRI + anticoagulant: SSRI inhibits platelet serotonin reuptake, increasing bleeding risk. Additive effect with warfarin.
SSRIs inhibit platelet serotonin reuptake, reducing aggregation. Combined with warfarin, bleeding risk increases moderately.
INR, signs of bleeding.
Significant bleeding.
Monitor INR and signs of bleeding.
DailyMed/FDA
SSRI + antimetabolite: SSRI may reduce renal clearance of methotrexate.
Some SSRIs may reduce tubular secretion of methotrexate, increasing levels. The effect is less than with NSAIDs, but clinically relevant at high methotrexate doses (>15 mg/week). Monitor blood count if concomitant treatment. At low methotrexate doses (7.5-15 mg/week for rheumatoid arthritis), the risk is lower.
SSRI + antimetabolite: SSRI may reduce renal clearance of methotrexate. Risk of pancytopenia.
Some SSRIs may reduce tubular secretion of methotrexate. The effect is less than with NSAIDs.
Blood count.
Pancytopenia.
Monitor blood count if concomitant treatment.
DailyMed/FDA
Alcohol potentiates the central nervous system depression of fluoxetine and can worsen hepatotoxicity.
Avoid alcohol intake during treatment.
DailyMed/FDA (NIH/NLM) — approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=583c5021-2948-7db4-e063-6294a90ae7dc
Fluoxetine can be administered with or without food; taking it with food may slightly reduce initial nausea.
Take at the same time every day, with or without food.
DailyMed/FDA (NIH/NLM) — approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=583c5021-2948-7db4-e063-6294a90ae7dc
Fluoxetine is metabolised in the liver; hepatic impairment reduces elimination and increases the risk of accumulation.
Reduce the dose and monitor adverse effects in hepatic impairment.
DailyMed/FDA (NIH/NLM) — approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=583c5021-2948-7db4-e063-6294a90ae7dc
Fluoxetine can prolong the QT interval; the risk is higher at high doses and in patients with risk factors.
Monitor the ECG in patients with risk factors and avoid QT-prolonging combinations.
DailyMed/FDA (NIH/NLM) — approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=583c5021-2948-7db4-e063-6294a90ae7dc
Hepatic toxicity — monitor liver function.
Monitor liver function during treatment.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 3, Drugs and hepatic impairment: Hepatic toxicity — monitor liver function.
SSRIs in the third trimester are associated with persistent pulmonary hypertension of the newborn and neonatal adaptation syndrome.
Avoid if possible in the third trimester; assess risk/benefit in severe maternal depression.
Present in breast milk; generally considered compatible, monitoring the infant.
No specific contraception required.
DailyMed/FDA (NIH/NLM) — approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=583c5021-2948-7db4-e063-6294a90ae7dc ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 1, Drugs and Pregnancy: In a prospective cohort study no increased risk was found; in animal studies it may produce perhaps permanent brain changes. ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 2, Drugs and Breastfeeding: See Antidepressants (serotonin reuptake inhibitors).
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
SSRI antidepressant. Blocks neuronal reuptake of serotonin; much more potent for serotonin than norepinephrine. It binds with lower potency than tricyclics to muscarinic, histaminergic and α1-adrenergic receptors. 50/50 racemic mixture of R- and S-fluoxetine; about 94.5% bound to serum proteins.
Inhibition of CNS neuronal uptake of serotonin (presumed mechanism); it blocks serotonin uptake into human platelets. The active metabolite norfluoxetine, formed by demethylation, is also a potent and selective inhibitor of serotonin uptake.
Peak plasma concentrations 6 to 8 hours after a single 40 mg oral dose; food may delay absorption by 1 to 2 hours, without clinical significance, so it may be given with or without food.
Extensively metabolised in the liver to norfluoxetine and other metabolites; involves CYP2D6 (about 7% of the population are poor metabolisers) and alternative non-saturable pathways that prevent unlimited accumulation. In cirrhosis, the fluoxetine half-life is prolonged to a mean of 7.6 days.
Elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration; norfluoxetine 4 to 16 days. The significant accumulation in chronic use means the active substance persists in the body for weeks after discontinuation.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
