Selective serotonin reuptake inhibitor (SSRI)
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
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 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)
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
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
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.
