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Drug Reference

fluoxetine

Selective serotonin reuptake inhibitor (SSRI)· Brands: Prozac, Sarafem, Rapiflux, Fontex, FluctinePO

Mechanism of action
Fluoxetine selectively inhibits serotonin reuptake at the presynaptic terminal by blocking the serotonin transporter (SERT), increasing serotonin availability in the synaptic cleft. This is thought to mediate its antidepressant and anxiolytic effects, with downstream adaptive changes in receptor sensitivity and neuroplasticity. It is a racemic mixture and belongs to the selective serotonin reuptake inhibitor (SSRI) class.
Pharmacokinetics
Fluoxetine is well absorbed orally with a bioavailability of around 60-80%. It undergoes extensive hepatic metabolism via CYP2D6 and CYP2C9 to produce its active metabolite, norfluoxetine. Fluoxetine has a half-life of 4-6 days, and norfluoxetine has a half-life of 7-15 days, allowing once-daily dosing and gradual steady-state attainment over 2-4 weeks. It is a potent inhibitor of CYP2D6, leading to significant drug interactions. It is excreted primarily in urine, mostly as metabolites.
Indications & dosing

Major Depressive Disorder

Starting dose 20 mg once daily; may be increased after 2-4 weeks. Higher doses are divided.

  • adult · PO: 20–80 mg once daily · Starting dose 20 mg once daily; may be increased after 2-4 weeks. Higher doses are divided.

Obsessive-Compulsive Disorder

Starting dose 20 mg once daily; may be increased gradually.

  • adult · PO: 20–60 mg once daily · Starting dose 20 mg once daily; may be increased gradually.

Bulimia Nervosa

Licensed for bulimia nervosa; dose is 60 mg daily.

  • adult · PO: 60 mg once daily · Licensed for bulimia nervosa; dose is 60 mg daily.

Panic Disorderoff-label

Off-label in some regions; start at 20 mg, increase as tolerated.

  • adult · PO: 20–60 mg once daily · Off-label in some regions; start at 20 mg, increase as tolerated.

Premenstrual Dysphoric Disorderoff-label

Off-label; can be used continuously or intermittently (luteal phase).

  • adult · PO: 20 mg once daily · Off-label; can be used continuously or intermittently (luteal phase).
Contraindications & precautions
  • Concomitant use with monoamine oxidase inhibitors (MAOIs) · Risk of serotonin syndrome. Allow at least 14 days after stopping an MAOI before starting fluoxetine, and at least 5 weeks after stopping fluoxetine before starting an MAOI.
  • Hypersensitivity to fluoxetine or any component of the formulation · Risk of anaphylaxis, angioedema, or other allergic reactions.
  • Concomitant use with pimozide · Risk of QT prolongation and ventricular arrhythmias.
  • Monitor for worsening depression or suicidality, particularly during initiation and dose changes.
  • Use with caution in patients with bipolar disorder due to risk of inducing mania.
  • Use with caution in patients with hepatic impairment; consider lower dose or extended dosing interval.
  • Use with caution with other serotonergic drugs, NSAIDs, or antiplatelet agents due to increased bleeding risk.
  • Do not discontinue abruptly; taper dose to avoid withdrawal symptoms.
Adverse effects
  • Nausea
  • Insomnia
  • Sexual dysfunction
  • Serotonin syndromeserious
  • Hyponatraemiaserious
  • Increased suicidal thoughts or behaviourserious
Interactions
  • warfarinmajorAvoid concurrent use if possible. If combined, monitor the international normalised ratio closely for at least two weeks after starting fluoxetine and after any dose change, and adjust warfarin dose accordingly. Review the patient for signs of bleeding and consider alternative antidepressants with less interaction potential.
  • ibuprofenmajorAvoid co-prescription when possible, especially in high-risk patients. If concurrent use is necessary, use the lowest effective dose of ibuprofen for the shortest duration, and consider gastroprotection with a proton pump inhibitor. Monitor patients for signs of GI bleeding, such as black stools, blood in vomit, or dizziness. Advise patients to report any unusual bleeding or abdominal pain.
  • clopidogrelmoderateIf concomitant use is necessary, consider an alternative SSRI that is less likely to inhibit CYP2C19 (e.g., sertraline, citalopram), or use an alternative P2Y12 inhibitor (e.g., prasugrel or ticagrelor) if clinically appropriate. Monitor for signs of bleeding and thrombotic events. Where possible, prescribe the lowest effective dose of fluoxetine and regularly review the combination.
  • risperidonemajorIf co-prescription is necessary, consider reducing the risperidone dose and monitor for signs of extrapyramidal symptoms, sedation, and hypotension. Monitor blood pressure and ECG if risk factors for QT prolongation. When discontinuing fluoxetine, risperidone levels may fall, requiring dose adjustment. Consider alternative antidepressants with less CYP2D6 inhibition.
  • tramadolmajorAvoid the concurrent use of fluoxetine and tramadol. Choose alternative analgesic or antidepressant drugs. If co-prescription is considered essential, use the lowest possible doses, closely monitor for signs of serotonin syndrome, and inform the patient to seek urgent help. Since fluoxetine inhibits CYP2D6 for at least 2 weeks after stopping, consider this when starting tramadol. Monitor for analgesic response, and do not increase the tramadol dose without specialist advice.
  • olanzapinemoderateIf the combination is initiated, consider a lower starting dose of olanzapine and monitor for signs of excessive sedation, weight gain, metabolic changes, and extrapyramidal symptoms. If fluoxetine is discontinued, monitor for reduced olanzapine efficacy and consider adjusting the olanzapine dose. Individualise treatment based on clinical response and tolerability.
  • sumatriptanmajorPrescribers should be cautious, especially if the patient requires both drugs. Consider alternative treatments where possible. If co-prescription is necessary, closely monitor the patient for emerging symptoms of serotonin syndrome, particularly in the first days of therapy or after dose changes. Advise the patient to seek medical attention if they experience symptoms such as confusion, sweating, tremors, or muscle twitching. Consider dose reduction of sumatriptan or fluoxetine, or using a different triptan or antiemetic.
  • linezolidcontraindicatedAvoid concomitant use. If linezolid is essential for a severe infection, stop fluoxetine and allow a washout period of at least 5 to 6 weeks due to its long half-life and active metabolite. If urgent co-administration is unavoidable, monitor closely in a hospital setting for signs of serotonin syndrome and be prepared for supportive care including benzodiazepines, active cooling and discontinuation of both agents. Consult current formularies and specialist guidance.
  • clozapinemajorAvoid co-prescription if feasible. If necessary, use a lower clozapine dose, monitor plasma clozapine concentrations, and watch for signs of toxicity. Consider alternative antidepressants that do not inhibit CYP2D6 or CYP3A4.
  • phenytoinmajorIf concurrent use is required, monitor plasma phenytoin concentrations before and after initiating or discontinuing fluoxetine. Repeat levels within 1 to 2 weeks of any change, and adjust the phenytoin dose accordingly. Monitor the patient for clinical signs of phenytoin toxicity. Advise the patient to report any new neurological symptoms.
  • amitriptylinemajorAvoid the combination if possible. If co-prescription is deemed necessary, use extreme caution. Consider an alternative antidepressant that does not inhibit CYP2D6. If used, reduce the amitriptyline dose and monitor for signs of toxicity and serotonin syndrome. Monitor ECG, blood pressure and heart rate. Advise the patient to report any symptoms such as palpitations, syncope or serotonin syndrome features. Monitoring should continue for several weeks after stopping fluoxetine due to its long half-life.
  • tamoxifenmajorAvoid the combination where possible. Consider an alternative antidepressant that does not inhibit CYP2D6, such as venlafaxine or citalopram. If fluoxetine is necessary, monitor clinical response and consider dose adjustment, but this is not generally advised.
  • carbamazepinemajorMonitor carbamazepine plasma concentrations and clinical signs of toxicity when starting, stopping, or changing the dose of fluoxetine. Adjust the carbamazepine dose accordingly. Monitor for signs of reduced fluoxetine efficacy and consider alternative antidepressants with less enzyme inhibition if appropriate.
Renal & hepatic adjustment
  • eGFR 0+: No dose adjustment usually required; use caution in severe renal impairment.
  • Hepatic impairment (severe): Use a lower dose (e.g., 10 mg daily) and titrate cautiously; monitor hepatic function.
Monitoring, pregnancy & toxicity
  • Mood and suicidal ideation · Baseline, then regularly (e.g., every 1-2 weeks initially, then less frequently)
  • Symptoms of serotonin syndrome · During dose titration and when adding serotonergic drugs
  • Serum sodium · Baseline and periodically, especially in elderly or patients on diuretics
  • Hepatic function · In patients with pre-existing hepatic impairment or if symptoms develop
  • Pregnancy: Fluoxetine should be used in pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. It is generally considered an option for women already on fluoxetine who are well controlled; however, its long half-life and that of its active metabolite may result in neonatal withdrawal symptoms if used close to delivery. In the third trimester, consider tapering before delivery if clinically safe, but avoid abrupt discontinuation. Monitor for neonatal adaptation reactions. Seek specialist advice.
  • Toxicity: Serotonin syndrome (agitation, confusion, hyperreflexia, autonomic instability) · Supportive care, discontinue fluoxetine and other serotonergic drugs, administer benzodiazepines, monitor vital signs, and consider cyproheptadine in severe cases.
  • Toxicity: Cardiac effects (QT prolongation, tachyarrhythmias) · Continuous cardiac monitoring, obtain ECG, correct electrolytes, discontinue drug, and treat arrhythmias as per ACLS.
  • Toxicity: Seizures · Administer benzodiazepines, monitor airway, and supportive care.
  • Toxicity: GI upset (nausea, vomiting, diarrhoea) · Supportive care, IV fluids, antiemetics if necessary.
Clinical notes
Fluoxetine is indicated for major depressive disorder, obsessive-compulsive disorder, bulimia nervosa, and panic disorder. Because of its long half-life, it is less likely to cause acute discontinuation symptoms but may take longer to reach steady state and to be eliminated. It is a CYP2D6 inhibitor and can raise levels of co-administered drugs such as tricyclic antidepressants, antipsychotics, and some beta-blockers. Monitor for serotonin syndrome, especially with other serotonergic drugs. The lowest effective dose should be used in elderly patients and those with hepatic impairment. Gastrointestinal side effects, insomnia, and sexual dysfunction are common. Do not use within 14 days of MAOIs.

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BNF; local formulary