Fluoxetine

Mechanism

Fluoxetine (SSRI) raises synaptic serotonin. Linezolid reversibly inhibits MAO. The pair is notable because fluoxetine's active metabolite, norfluoxetine, persists for up to 5 weeks – the serotonergic effect outlasts dosing.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Management

The combination is not prescribed. Stop fluoxetine at least 5 weeks before planned linezolid. For acute antibiotic need, use vancomycin or daptomycin. If linezolid is still required, monitor for serotonin syndrome during therapy plus 5 weeks after fluoxetine discontinuation.

Mechanism

Methylene blue (methylthioninium chloride) inhibits monoamine oxidase: the fluoxetine SmPC lists it among MAO-A inhibitors, and the FDA methylene blue label cites literature describing it as a potent reversible inhibitor of this enzyme. Fluoxetine blocks serotonin reuptake. Together they can cause severe, sometimes fatal serotonin syndrome (labels of both drugs). Fluoxetine and its active metabolite norfluoxetine are eliminated slowly, so the risk persists after fluoxetine is stopped (fluoxetine labels).

Symptoms

Serotonin syndrome. Mental status changes: agitation, hallucinations, confusion, delirium, coma. Autonomic signs: tachycardia, labile blood pressure, dizziness, sweating, flushing, fever. Neuromuscular signs: tremor, rigidity, myoclonus, hyperreflexia, incoordination, seizures. Gastrointestinal: nausea, vomiting, diarrhoea. Some reported cases were fatal (FDA methylene blue label).

Management

Starting fluoxetine in a patient receiving intravenous methylene blue is contraindicated in the FDA fluoxetine label. The methylene blue labels approved by the European Medicines Agency (EMA) and the FDA say to avoid it in patients taking selective serotonin reuptake inhibitors, and the Spanish fluoxetine SmPC lists the combination as not recommended. If a patient on fluoxetine urgently needs methylene blue and there is no acceptable alternative, stop fluoxetine promptly and give methylene blue (FDA fluoxetine label) at the lowest possible dose, then observe the patient for nervous system effects for 4 hours (methylene blue labels). Monitor for serotonin syndrome for 5 weeks or until 24 hours after the last methylene blue dose, whichever comes first (FDA fluoxetine label). The FDA fluoxetine label allows restarting fluoxetine 24 hours after the last methylene blue dose, while the FDA methylene blue label advises no serotonergic drugs for 72 hours after it. Monitor the ECG and blood pressure during and after methylene blue (EMA methylene blue SmPC). If serotonin syndrome develops, stop methylene blue and start supportive treatment (methylene blue labels).

Mechanism

Phenelzine irreversibly inhibits MAO; fluoxetine blocks serotonin reuptake. Combined use causes synaptic serotonin accumulation and serotonin syndrome: hyperthermia, myoclonus, agitation, coma. FDA Nardil Section 4 strict contraindication. A 5-week washout is required between fluoxetine and phenelzine (due to norfluoxetine's long T½).

Symptoms

Within hours: agitation, confusion, tachycardia, hypertension, hyperthermia, tremor, myoclonus, hyperreflexia. Severe cases – seizures, coma, rhabdomyolysis, DIC.

Management

Combination contraindicated. Allow 5-week washout between stopping fluoxetine and starting phenelzine. Allow 2-week washout between stopping phenelzine and starting any SSRI (MAO resynthesis time).

Mechanism

Selegiline selectively inhibits monoamine oxidase type B (MAO-B), the enzyme mainly responsible for dopamine breakdown in the brain (selegiline SmPC). The US Food and Drug Administration (FDA) label for selegiline in Parkinson's disease adds that this inhibition is irreversible, that selectivity for MAO-B may be incomplete even at the recommended dose, and that it is lost above it (selegiline SmPC: above 10 mg a day). Fluoxetine is a selective serotonin reuptake inhibitor (SSRI). Both fluoxetine and its active metabolite norfluoxetine have a very long elimination half-life (selegiline and fluoxetine SmPCs). With serotonin breakdown slowed and reuptake blocked, serotonin builds up in the synapse. The selegiline SmPC contraindicates the combination with SSRIs because of the risk of serotonin syndrome and names fluoxetine. The FDA label for the selegiline patch reports serious, sometimes fatal central nervous system toxicity when nonselective MAO inhibitors are combined with serotonergic drugs. The FDA label for selegiline in Parkinson's disease reports fatal and non-fatal cases of serotonin syndrome in patients treated with antidepressants together with selegiline. Because fluoxetine is cleared so slowly, the risk persists for weeks after it is stopped. That is why the documents require a 5-week gap before selegiline is started.

Symptoms

For the combination with selective serotonin reuptake inhibitors (SSRIs), the selegiline SmPC lists confusion, hypomania, hallucinations and manic episodes, agitation, myoclonus, hyperreflexia, incoordination, shivering, tremor, seizures, ataxia, sweating, diarrhoea, fever and hypertension. All of these can be part of serotonin syndrome. The fluoxetine SmPC describes the reaction with a monoamine oxidase (MAO) inhibitor as hyperthermia, rigidity, myoclonus, autonomic instability with rapid swings in vital signs, and mental changes ranging from confusion and irritability to extreme agitation, delirium and coma. The US Food and Drug Administration (FDA) label for the selegiline patch adds tachycardia, labile blood pressure, nausea and vomiting.

Management

The combination is contraindicated. The selegiline SmPC names fluoxetine among the drugs selegiline must not be used with (section 4.3) and bans selegiline with all selective serotonin reuptake inhibitors (SSRIs) (section 4.5). The US Food and Drug Administration (FDA) label for the selegiline patch contraindicates fluoxetine (section 4). The FDA fluoxetine label contraindicates monoamine oxidase (MAO) inhibitors intended to treat psychiatric disorders (section 4.1). The fluoxetine SmPC itself only asks for caution and closer follow-up with selegiline, but the stricter documents take precedence. When switching from selegiline to fluoxetine, allow at least 14 days after stopping selegiline (selegiline SmPC, section 4.5; FDA label for selegiline in Parkinson's disease; FDA fluoxetine label). When switching from fluoxetine to selegiline, allow at least 5 weeks after the last dose of fluoxetine, because fluoxetine and norfluoxetine are cleared so slowly (selegiline SmPC, sections 4.3 and 4.5; FDA label for the selegiline patch; FDA fluoxetine label). The FDA label for selegiline in Parkinson's disease allows an even longer gap after prolonged or high-dose fluoxetine. If a patient is already taking both, stop both immediately at the first signs of serotonin syndrome and start supportive treatment (FDA label for the selegiline patch; FDA fluoxetine label). The fluoxetine SmPC allows cyproheptadine or dantrolene for such a reaction. No selegiline dose reduction is needed for fluoxetine's inhibition of CYP3A4. The FDA label for the selegiline patch requires no dose adjustment with CYP3A4 inhibitors, and in the FDA label for selegiline in Parkinson's disease itraconazole did not change selegiline pharmacokinetics.

Mechanism

Tranylcypromine is an irreversible MAOI. Combined with fluoxetine causes serotonin syndrome. AEMPS Parnate Section 4.3.

Symptoms

Hyperthermia, myoclonus, tachycardia, hypertension.

Management

Combination contraindicated. 5-week washout from fluoxetine.

Mechanism

Fluoxetine, like other SSRIs, blocks serotonin uptake into platelets, and platelets need serotonin to stop bleeding. Aspirin irreversibly blocks platelet cyclooxygenase and injures the stomach lining. Together they raise the risk of bleeding, above all from the upper gastrointestinal tract (aspirin 100 mg and fluoxetine labels).

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black stools, blood in urine. Severe cases include gastrointestinal or intracranial haemorrhage.

Management

Aspirin SmPCs, including those for 100 mg products, advise avoiding SSRIs with aspirin whenever possible because of bleeding risk, especially gastrointestinal (aspirin 100 mg and 500 mg SmPCs). If the combination is needed, use it with caution (fluoxetine SmPC) and explain the signs of bleeding to the patient in advance: black stools, vomiting blood, abdominal pain, weakness, dizziness, cold sweat. If they appear, the patient stops treatment and seeks medical care at once (aspirin 100 mg SmPC). The FDA also asks prescribers to warn patients about the higher bleeding risk when fluoxetine is combined with aspirin (US fluoxetine label).

Mechanism

Fluoxetine slows the elimination of alprazolam. According to the FDA alprazolam label, co-administration raised alprazolam peak concentration by 46%, reduced its clearance by 21%, prolonged its half-life by 17% and worsened psychomotor performance. The FDA fluoxetine label describes the same: alprazolam levels rise and psychomotor function suffers more. The Spanish alprazolam SmPC lists fluoxetine among drugs that need special attention, because inhibitors of liver enzymes, mainly CYP3A4, raise alprazolam levels. Both drugs also act on the central nervous system, and the alprazolam SmPC warns that CNS depression can be enhanced when alprazolam is combined with antidepressants.

Symptoms

Drowsiness, slowed reactions and impaired psychomotor performance, as the FDA labels of both drugs describe for this combination. In older people, sedation and muscle weakness raise the risk of falls, often with serious consequences (alprazolam SmPC). Driving and operating machinery become riskier.

Management

Use the combination with caution and with limits on dose and duration: the alprazolam SmPC requires limiting the dose and duration of alprazolam use with antidepressants and asks for special attention when it is combined with fluoxetine. The FDA fluoxetine label advises considering a lower starting dose of the co-administered drug, slow titration and monitoring of the patient's clinical state. Alprazolam itself is given for as short a time as possible, no longer than 2–4 weeks without reassessment, and older people start at a lower dose (alprazolam SmPC). The long half-life of fluoxetine and its metabolite norfluoxetine has to be taken into account when assessing interactions (fluoxetine SmPC).

Mechanism

Fluoxetine blocks CYP2D6 (a minor amiodarone clearance route) and modestly prolongs QT. Amiodarone plasma levels rise and QT effects add up. The long half-life of fluoxetine and norfluoxetine (up to 5 weeks) is relevant.

Symptoms

QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

Avoid the combination. Alternative antidepressants with minimal QT effect and no CYP2D6 inhibition: mirtazapine or agomelatine. Interaction potential persists up to 5 weeks after fluoxetine discontinuation.

Mechanism

The combination works along three lines. Kinetics: fluoxetine strongly inhibits CYP2D6, which clears amitriptyline, so amitriptyline levels can rise markedly (labels of both drugs). The FDA fluoxetine label gives data for imipramine and desipramine: their stable plasma levels rose 2- to 10-fold, and the effect lasted 3 weeks or longer after fluoxetine was stopped. Serotonin: both drugs enhance it and together raise the risk of serotonin syndrome. Heart and seizures: both can prolong the QT interval, and the combination can raise seizure risk (labels of both drugs).

Symptoms

Signs of amitriptyline excess: drowsiness, dry mouth, constipation, urinary retention, dilated pupils, fast heartbeat, dizziness on standing and confusion. High levels can cause arrhythmias, QT prolongation, seizures and marked hypotension (amitriptyline SmPC). Serotonin syndrome as described in the FDA fluoxetine label: agitation, hallucinations, delirium, tremor, rigidity, myoclonus, hyperreflexia, fever, sweating, tachycardia, labile blood pressure, nausea, vomiting, diarrhoea.

Management

The combination is acceptable only with careful dosing. While the patient takes fluoxetine and for 5 weeks after it is stopped, amitriptyline is started or adjusted within the lowest therapeutic range (fluoxetine SmPC). The FDA fluoxetine label warns that the tricyclic dose may need to be reduced and its plasma level monitored for a while, including after fluoxetine was recently stopped. When fluoxetine is added to amitriptyline, consider a lower amitriptyline dose and monitoring of its level (amitriptyline SmPC). Watch for serotonin syndrome at the start of treatment and after each dose increase; if it appears, stop both drugs at once and start supportive treatment (FDA labels of both drugs). In stable heart disease consider an ECG before starting fluoxetine; with risk factors for QT prolongation consider periodic ECGs as well; stop fluoxetine if signs of arrhythmia appear (fluoxetine labels). Low potassium or magnesium raises the risk of arrhythmia, so take it into account when prescribing (labels of both drugs).

Mechanism

Bupropion and its metabolite hydroxybupropion inhibit CYP2D6, which metabolises fluoxetine, so fluoxetine exposure can rise. Bupropion itself is not a CYP2D6 substrate: hydroxybupropion is formed by CYP2B6. Both drugs lower the seizure threshold, and together they can cause serotonin syndrome.

Symptoms

Seizures (generalised tonic-clonic or focal), agitation, tremor, insomnia. Patients with prior epilepsy or eating disorders are at particular risk.

Management

The combination is used to augment antidepressant response, but bupropion is contraindicated in patients with a seizure history, bulimia or anorexia nervosa per the label. Start bupropion at a low dose and titrate gradually. Start fluoxetine at the low end of its dose range when bupropion is already on board, and if bupropion is added to fluoxetine, consider reducing the fluoxetine dose. When bupropion is prescribed for smoking cessation in a patient taking an antidepressant, the label advises a maximum of 150 mg a day. Watch for agitation, tremor, myoclonus and fever during the first weeks and after dose increases.

Mechanism

Fluoxetine is a potent CYP2D6 inhibitor, the main carvedilol metabolic route. Carvedilol plasma levels rise 2- to 3-fold. Marked hypotension and bradycardia emerge.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall risk.

Management

Halve the carvedilol dose when combined; monitor blood pressure and pulse. Alternative beta-blockers without CYP2D6 dependence: bisoprolol or nebivolol. Alternative antidepressants without CYP2D6 inhibition: sertraline or escitalopram.

Mechanism

Fluoxetine belongs to the same class, and its SmPC warns about serotonergic reactions when it is combined with other serotonergic agents. Two SSRIs bring no added benefit, while the serotonergic effect stacks.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, sweating, diarrhoea, tachycardia, and in severe cases hyperthermia and rigidity. Symptoms usually appear within a day of adding the second drug or raising the dose. In patients with cardiac risk factors QTc is tracked separately.

Management

Stopping fluoxetine does not end the interaction at once: its SmPC gives a half-life of 4-6 days, and 4-16 days for the active metabolite norfluoxetine. A switch is measured in weeks, and the same label requires this to be taken into account when changing antidepressant.

Mechanism

Fluoxetine inhibits CYP2C19, the enzyme converting clopidogrel into its active metabolite. Active levels fall and antiplatelet effect weakens. Fluoxetine also depletes the platelet serotonin pool, impairing primary haemostasis.

Symptoms

Dual risk: weakened antiplatelet effect (raising thrombosis risk) alongside increased upper GI bleeding risk.

Management

Alternative antidepressants: sertraline or escitalopram (weaker CYP2C19 inhibitors), or mirtazapine/agomelatine (minimal platelet effect). Alternative antiplatelet: ticagrelor (not CYP2C19-dependent). PPI cover with pantoprazole is mandatory.

Mechanism

Fluoxetine blocks CYP2D6 (strongly) and CYP3A4 (moderately). Dronedarone plasma levels may rise. Additive QT risk.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. Alternative antidepressants without CYP3A4/CYP2D6 inhibition: sertraline or escitalopram. Alternative antiarrhythmic: a beta-blocker for rate control.

Mechanism

Fluoxetine is a potent CYP2D6 inhibitor; duloxetine is minorly metabolised by CYP2D6. Additive serotonergic load with dual SSRI/SNRI dosing.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.

Management

The combination is not prescribed. When switching from fluoxetine to duloxetine, allow a 5-week washout (due to norfluoxetine); from duloxetine to fluoxetine, 1 week.

Mechanism

Fluoxetine belongs to the same class, and its SmPC warns about serotonergic reactions when it is combined with other serotonergic agents. Two SSRIs bring no added benefit, while the serotonergic effect stacks.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, sweating, diarrhoea, tachycardia, and in severe cases hyperthermia and rigidity. Symptoms usually appear within a day of adding the second drug or raising the dose. In patients with cardiac risk factors QTc is tracked separately.

Management

Stopping fluoxetine does not end the interaction at once: its SmPC gives a half-life of 4-6 days, and 4-16 days for the active metabolite norfluoxetine. A switch is measured in weeks, and the same label requires this to be taken into account when changing antidepressant.

Mechanism

SSRI + NSAID – increased GI bleeding risk.

Symptoms

GI bleeding in at-risk patients.

Management

PPI gastroprotection or paracetamol alternative.

Mechanism

Fluoxetine is a strong inhibitor of the CYP2D6 enzyme (fluoxetine SmPC), and metoprolol is a CYP2D6 substrate (metoprolol SmPC). Strong CYP2D6 inhibitors, including fluoxetine, roughly double metoprolol concentrations, and metoprolol loses its cardioselectivity (US metoprolol label). The risk of marked bradycardia, hypotension and AV block rises.

Symptoms

Bradycardia, dizziness, fainting, a drop in blood pressure on standing. The metoprolol SmPC treats a heart rate below 50–55 beats per minute as significant. In heart failure: worsening breathlessness and oedema.

Management

In heart failure the combination is contraindicated: the Spanish fluoxetine SmPC contraindicates fluoxetine with metoprolol used for this indication because of the risk of excessive bradycardia (fluoxetine SmPC). For other indications, the FDA advises combining metoprolol with a CYP2D6 inhibitor only when this cannot be avoided, and then monitoring the patient closely (US metoprolol label). Drugs metabolised by CYP2D6 are started or titrated at the lowest dose in patients on fluoxetine, and this also applies for 5 weeks after fluoxetine is stopped (fluoxetine SmPC). If the patient already takes metoprolol, its dose may need to be reduced when fluoxetine is started (metoprolol SmPC). If the heart rate falls below 50–55 beats per minute, reduce the metoprolol dose gradually or withdraw it slowly (metoprolol SmPC).

Mechanism

Additive serotonergic effect. Mirtazapine blocks 5-HT2/3 but activates 5-HT1A. Combined with a potent SSRI, serotonin syndrome has been reported, especially at high doses.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.

Management

The combination is used for augmentation in resistant depression ('California rocket fuel'). Keep doses low: fluoxetine 20 mg, mirtazapine 30 mg/day. Monitor mental status in the early weeks.

Mechanism

These are two SSRIs, so serotonergic load doubles with no proven therapeutic gain. The sertraline label bars combining it with other serotonergic agents such as moclobemide precisely because of serotonin syndrome risk. A pharmacokinetic issue is added: fluoxetine inhibits CYP2D6 and its active metabolite persists for weeks, so the overlap continues long after the last capsule.

Symptoms

Agitation, tremor, sweating, dilated pupils, diarrhoea, tachycardia, muscle rigidity and fever: serotonin syndrome develops within hours. Mild forms are mistaken for anxiety or flu. At high doses QT prolongation adds to the risk.

Management

The two SSRIs are not taken together. Switching from fluoxetine to sertraline needs a washout because of the long half-life of the active metabolite; the reverse switch allows shorter gaps. If tremor, sweating and tachycardia appear after the second drug is added, stop the addition.

Mechanism

Fluoxetine is a strong CYP2D6 inhibitor. Endoxifen falls 60%.

Symptoms

Tumour progression on long-term use.

Management

Alternative – sertraline, escitalopram or venlafaxine.

Mechanism

Dual mechanism. Fluoxetine (SSRI) raises synaptic serotonin; tramadol weakly inhibits serotonin reuptake – combined serotonergic activity adds up. Fluoxetine also blocks CYP2D6 – the route activating tramadol to O-desmethyltramadol – so analgesia weakens.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.

Management

If a patient taking fluoxetine needs tramadol, start at the lowest dose and keep it at the low end of the therapeutic range. The fluoxetine SmPC requires this for all drugs metabolised by CYP2D6, including for 5 weeks after fluoxetine is stopped. Fluoxetine reduces formation of tramadol's active metabolite, so analgesia may be weaker while the risk of seizures and serotonin syndrome is higher (FDA tramadol label). At the start and after each dose increase, watch for signs of serotonin syndrome and stop tramadol if it is suspected. Paracetamol is a suitable analgesic. NSAIDs taken with SSRIs increase bleeding risk (fluoxetine SmPC).

Mechanism

SSRI + SNRI – serotonin syndrome. Fluoxetine is also a potent CYP2D6 inhibitor and raises venlafaxine levels.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.

Management

The combination is not prescribed. When switching from fluoxetine to venlafaxine, allow at least 5 weeks of washout (due to norfluoxetine). From venlafaxine to fluoxetine, 1 week.

Mechanism

Fluoxetine and its active metabolite norfluoxetine moderately block CYP3A4 – the main amlodipine metabolic route. Amlodipine plasma levels may rise modestly. In older patients: additive hypotension.

Symptoms

Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.

Management

The combination is acceptable in most patients without dose change. In older patients, monitor blood pressure and hypotension symptoms 2 weeks after start.

Mechanism

Fluoxetine, like other SSRIs, impairs primary haemostasis by inhibiting platelet serotonin reuptake. Additively with apixaban, GI bleeding risk rises.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

The combination is acceptable. In patients over 65 or with prior peptic ulcer: pantoprazole 20 mg/day. The long half-life of fluoxetine and its active metabolite norfluoxetine (4–6 days) prolongs bleeding risk for another 4–6 weeks after discontinuation.

Mechanism

Additive QT prolongation (fluoxetine weakly prolongs QT at high doses).

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

For short azithromycin courses (3–5 days) with normal potassium and magnesium, the combination is acceptable. In cardiovascular disease or fluoxetine doses above 40 mg: ECG before start or alternative antibiotics (doxycycline, a cephalosporin).