Fluvoxamine

Mechanism

Dual risk. Fluvoxamine is a potent CYP1A2 inhibitor, the main duloxetine metabolic route. Duloxetine plasma levels rise 6-fold. Plus additive serotonergic load.

Symptoms

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

Management

The AEMPS label for duloxetine lists the combination with fluvoxamine as contraindicated. The combination is not prescribed. Choose one antidepressant: duloxetine for pain syndromes, fluvoxamine for obsessive-compulsive disorder. For augmentation, add mirtazapine.

Mechanism

Linezolid is a reversible monoamine oxidase (MAO) inhibitor. Fluvoxamine (SSRI) raises synaptic serotonin. Co-administration: serotonin syndrome, fatal cases reported (FDA safety alert).

Symptoms

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

Management

The AEMPS label for fluvoxamine lists the combination with linezolid as contraindicated. The combination is not prescribed. Stop fluvoxamine at least 2 weeks before linezolid. For urgent antibiotic therapy: vancomycin, daptomycin, or ceftaroline by susceptibility.

Mechanism

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI). Moclobemide reversibly inhibits monoamine oxidase (MAO), mainly type A, and slows the breakdown of serotonin, noradrenaline and dopamine (moclobemide summary of product characteristics, SmPC, section 5.1). Drugs that impair serotonin metabolism, that is, MAO inhibitors, increase the risk of life-threatening serotonin syndrome with SSRIs (fluvoxamine label, US Food and Drug Administration, FDA, section 5.2). Moclobemide inhibits the enzyme CYP2C19 and can raise plasma levels of fluvoxamine (moclobemide SmPC, section 4.5). Fluvoxamine in turn strongly inhibits CYP2C19, which partly breaks down moclobemide. According to the moclobemide SmPC, such changes are generally not therapeutically important and should not need a dose change (fluvoxamine and moclobemide SmPCs, section 5.2). The half-life of fluvoxamine is 13–15 hours after a single dose and 17–22 hours with repeated dosing (fluvoxamine SmPC, section 5.2).

Symptoms

Serotonin syndrome during fluvoxamine treatment can be life-threatening, especially with other serotonergic drugs. It brings hyperthermia, rigidity, myoclonus and autonomic instability with rapid swings in vital signs. Mental changes include confusion, irritability and extreme agitation progressing to delirium and coma (fluvoxamine summary of product characteristics, SmPC, section 4.4). When moclobemide has been combined with antidepressants, fluvoxamine among them, isolated cases of hyperthermia, confusion, hyperreflexia and myoclonus have occurred (moclobemide SmPC, section 4.5). Hallucinations, tachycardia, dizziness, sweating, flushing, tremor, incoordination, seizures, nausea, vomiting and diarrhoea are also possible (fluvoxamine label, US Food and Drug Administration, FDA, section 5.2).

Management

The combination is contraindicated (fluvoxamine summary of product characteristics, SmPC, sections 4.3 and 4.5; fluvoxamine label, US Food and Drug Administration, FDA, section 4). The moclobemide SmPC is softer: it lists fluvoxamine among antidepressants to give with caution alongside moclobemide (moclobemide SmPC, section 4.5). The strictest document applies. The documents differ on switching intervals. The Spanish fluvoxamine SmPC names moclobemide as a reversible monoamine oxidase inhibitor (MAOI) and allows fluvoxamine to start the day after moclobemide is stopped (fluvoxamine SmPC, section 4.3). The moclobemide SmPC says the same for any antidepressant (section 4.5). The FDA label requires at least 14 days after stopping an MAOI used for psychiatric disorders (FDA fluvoxamine label, sections 2.4 and 4). When switching the other way, allow at least one week between the last dose of fluvoxamine and the first dose of an MAOI (fluvoxamine SmPC, section 4.3) or at least 14 days (FDA fluvoxamine label, sections 2.4 and 4). The moclobemide SmPC asks prescribers to consider the half-life of the previous selective serotonin reuptake inhibitor (moclobemide SmPC, section 4.5). Do not stop fluvoxamine abruptly. Taper the dose over at least one to two weeks (fluvoxamine SmPC, section 4.2). If signs of serotonin syndrome appear, stop fluvoxamine and other serotonergic drugs at once and start symptomatic treatment (fluvoxamine SmPC, section 4.4; FDA fluvoxamine label, section 5.2). Keep the patient under medical supervision and admit to hospital if needed (moclobemide SmPC, section 4.5).

Mechanism

The liver breaks down pimozide mainly through the enzymes CYP3A4 and CYP2D6, and to a lesser extent CYP1A2 (pimozide label). Fluvoxamine inhibits all three: CYP1A2 strongly, CYP3A4 and CYP2D6 to a lesser degree (fluvoxamine label). The US fluvoxamine label considers it a likely potent CYP3A4 inhibitor because fluvoxamine 100 mg daily roughly doubled the plasma concentrations of alprazolam, a CYP3A4 substrate (fluvoxamine label, US Food and Drug Administration, FDA). The Spanish fluvoxamine label explains the contraindication by the narrow therapeutic index of pimozide and its known ability to prolong the QT interval. According to the US label, raised pimozide levels prolong QT and have been linked to torsade de pointes, sometimes fatal. The labels give no study of pimozide levels with fluvoxamine.

Symptoms

QT interval prolongation itself causes no symptoms and shows only on the electrocardiogram (ECG). The danger is ventricular arrhythmia: torsade de pointes, ventricular tachycardia and ventricular fibrillation, up to cardiac arrest and sudden death (pimozide and fluvoxamine labels). An episode presents as palpitations, dizziness or fainting. Excess pimozide also strengthens its usual effects, above all extrapyramidal ones: tremor, muscle rigidity and akathisia, an inability to sit still (pimozide label). The risk of arrhythmia is higher with low potassium or magnesium and with a slow heart rate (pimozide label).

Management

The combination is contraindicated. The Spanish fluvoxamine summary of product characteristics (SmPC) bans it in both the contraindications and the interactions sections (fluvoxamine SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). The US label lists it under contraindications (fluvoxamine label, US Food and Drug Administration, FDA). The US pimozide label places fluvoxamine among the less potent inhibitors of the enzyme CYP3A4 that should also be avoided (pimozide label, FDA). The Spanish pimozide SmPC contraindicates pimozide with any inhibitor of CYP3A4 or CYP2D6 (pimozide SmPC, AEMPS). If a patient taking pimozide needs an antidepressant, do not prescribe fluvoxamine. If a patient already takes both drugs, stop one of them. Many other antidepressants are also ruled out with pimozide: sertraline, paroxetine, citalopram and escitalopram by name, fluoxetine as a CYP2D6 inhibitor and tricyclic antidepressants as drugs that prolong the QT interval (pimozide SmPC, AEMPS). Choose the replacement outside those lists. For any pimozide treatment, record an electrocardiogram (ECG) before the start and repeat it during treatment. Keep potassium and magnesium in the normal range, and stop pimozide if the QT or corrected QT (QTc) interval exceeds 500 ms (pimozide labels, AEMPS and FDA).

Mechanism

Fluvoxamine, like other selective serotonin reuptake inhibitors (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 and fluvoxamine labels).

Symptoms

Gum bleeding, epistaxis, bruising without trauma. Severe cases: GI bleeding.

Management

Aspirin SmPCs, including those for 100 mg products, advise avoiding selective serotonin reuptake inhibitors (SSRIs) with aspirin whenever possible because of the bleeding risk, especially from the upper gastrointestinal tract (aspirin 100 mg SmPCs). If the combination is needed, use it with caution, particularly in older people (fluvoxamine SmPC), and explain the signs of bleeding to the patient in advance: black stools, vomiting blood, low blood pressure, cold sweat, abdominal pain, dizziness. If they appear, the patient stops treatment and sees a doctor at once (aspirin 100 mg SmPC). The US Food and Drug Administration (FDA) also requires prescribers to warn patients about the higher bleeding risk when fluvoxamine is combined with aspirin (fluvoxamine FDA label).

Mechanism

Alprazolam is cleared in the liver mainly by CYP3A4, and fluvoxamine inhibits this enzyme (labels of both drugs). The FDA fluvoxamine label describes a study with fluvoxamine 100 mg a day: alprazolam AUC, peak concentration and half-life roughly doubled and its clearance fell by about half. At fluvoxamine 300 mg the effect may be stronger. 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 and memory, as the FDA fluvoxamine label describes 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. Marked depression of the central nervous system can lead to slowed breathing and coma (alprazolam SmPC).

Management

Avoid the combination where possible: the FDA alprazolam label says so and names fluvoxamine. If it cannot be avoided, start alprazolam at no more than half the usual initial dose and titrate to the lowest effective dose; the fluvoxamine dose does not need changing (FDA fluvoxamine label). The Spanish fluvoxamine SmPC also requires a lower dose of such benzodiazepines during co-treatment, and the alprazolam SmPC requires limiting the dose and duration of alprazolam use with antidepressants. In older people alprazolam is started at a lower dose anyway (alprazolam SmPC). Fluvoxamine is unlikely to change the clearance of benzodiazepines eliminated by glucuronidation, such as lorazepam and oxazepam (FDA fluvoxamine label).

Mechanism

Amitriptyline is cleared in the liver by several enzymes, mainly CYP2D6 and CYP2C19, and to a lesser extent CYP1A2 and CYP3A4 (amitriptyline SmPC). Fluvoxamine strongly inhibits CYP1A2 and CYP2C19 (fluvoxamine SmPC). The amitriptyline SmPC states that fluvoxamine raises amitriptyline plasma levels, and the FDA fluvoxamine label reports significantly increased levels of tricyclic antidepressants, amitriptyline included. Both drugs also enhance serotonin activity, so the combination raises the risk of serotonin syndrome (amitriptyline SmPC, FDA fluvoxamine label).

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: agitation, hallucinations, tremor, muscle rigidity, myoclonus, fever, sweating, tachycardia, labile blood pressure, nausea, vomiting, diarrhoea (FDA fluvoxamine label, amitriptyline SmPC).

Management

Avoid the combination: the Spanish amitriptyline SmPC says so directly. If both drugs are still used, the fluvoxamine SmPC asks to consider lowering the amitriptyline dose when fluvoxamine is started, and the FDA fluvoxamine label advises monitoring tricyclic plasma levels and reducing the tricyclic dose if needed. Watch for serotonin syndrome at the start of treatment and after each dose increase. If it appears, stop amitriptyline and other serotonergic drugs at once and start supportive treatment (FDA amitriptyline label). Use amitriptyline with caution in marked bradycardia, decompensated heart failure and with QT-prolonging drugs; potassium or magnesium disturbances raise the risk of arrhythmia (amitriptyline SmPC).

Mechanism

Budesonide is broken down mainly by the CYP3A4 enzyme. Fluvoxamine moderately inhibits this enzyme (fluvoxamine SmPC), so budesonide levels may rise, and with them the risk of systemic corticosteroid effects. These effects are less likely with inhaled than with oral budesonide (inhaled budesonide SmPC), but they are possible: with high-dose inhaled budesonide, itraconazole raised its plasma levels about fourfold on average (inhaled budesonide SmPC).

Symptoms

On long-term therapy: moon face, weight gain with fat redistribution, skin thinning, acne, muscle weakness, mood disturbance, hyperglycaemia.

Management

The fluvoxamine SmPC requires drugs metabolised by the CYP3A4 enzyme to be started or adjusted to the low end of their dose range when given with fluvoxamine, with monitoring of their effects and side effects and dose reduction if needed (fluvoxamine SmPC). Oral budesonide should not be combined with CYP3A4 inhibitors unless the benefit outweighs the higher risk of systemic corticosteroid effects; if the combination is used, monitor the patient for these effects (oral budesonide SmPC). The inhaled budesonide SmPC says to avoid strong CYP3A inhibitors and gives itraconazole, ketoconazole, human immunodeficiency virus (HIV) protease inhibitors and cobicistat-containing products as examples. With a 1–2 week course the interaction with inhaled budesonide is of limited relevance; in long-term treatment take it into account, watch for systemic effects and keep the inhaled corticosteroid at the lowest dose that controls asthma (inhaled budesonide SmPC).

Mechanism

Fluvoxamine is a weak CYP2D6 inhibitor but a strong CYP2C19 and CYP1A2 inhibitor. Bupropion levels may rise. Both drugs lower the seizure threshold.

Symptoms

Seizures (especially with prior epilepsy or eating disorders), anxiety, insomnia. Agitation possible.

Management

The combination is possible for augmentation. Keep doses low: bupropion ≤300 mg, fluvoxamine ≤100 mg/day. Avoid with prior epilepsy or eating disorders.

Mechanism

Fluvoxamine strongly inhibits CYP2C19 and, to a lesser degree, CYP3A4 and CYP2D6 (fluvoxamine SmPC), and citalopram is cleared by all three: about 38% via CYP2C19, 31% via CYP3A4 and 31% via CYP2D6 (citalopram SmPC). Citalopram levels rise, and its QT prolongation is dose-dependent, so the US Food and Drug Administration (FDA) caps citalopram at 20 mg/day with any CYP2C19 inhibitor. Both drugs are serotonergic, and the fluvoxamine SmPC warns that the combination can lead to a life-threatening serotonin syndrome.

Symptoms

Serotonin syndrome: agitation, hallucinations, delirium up to coma; tachycardia, labile blood pressure, dizziness, sweating, hyperthermia; tremor, rigidity, myoclonus, hyperreflexia, incoordination; seizures; nausea, vomiting, diarrhoea. Higher citalopram levels prolong the QT interval: dizziness, palpitations, syncope and, in severe cases, torsade de pointes.

Management

The labels do not ban the pair, but it is used with limits. While the patient takes fluvoxamine, the citalopram dose stays at or below 20 mg/day (US Food and Drug Administration (FDA) citalopram label). The fluvoxamine SmPC requires such drugs to be started at the lower end of the dose range with monitoring for adverse effects, and the Spanish citalopram SmPC asks for caution with fluvoxamine. Potassium and magnesium are corrected before citalopram is started (citalopram SmPC). If serotonin syndrome develops, both drugs are stopped at once and supportive treatment is started (citalopram FDA label). If signs of arrhythmia appear, citalopram is stopped and an electrocardiogram (ECG) is done (citalopram SmPC).

Mechanism

Clopidogrel is a prodrug, activated by CYP2C19. Fluvoxamine is a potent CYP2C19 inhibitor. The active clopidogrel metabolite is not formed and antiplatelet effect is lost.

Symptoms

The patient feels no symptoms – the weakened antiplatelet effect is silent. The combination raises recurrent myocardial infarction, stent thrombosis, and stroke risks.

Management

The combination is not prescribed. Alternative antidepressants without CYP2C19 effect: sertraline or escitalopram (moderate but weaker effect), or mirtazapine/agomelatine (no effect). Alternative antiplatelet: ticagrelor (not CYP2C19-dependent).

Mechanism

Fluvoxamine blocks CYP2C19 and CYP3A4 – both diazepam metabolic routes. Diazepam plasma levels rise 2-fold, with stronger and longer effect.

Symptoms

Marked sedation, drowsiness, ataxia. In older patients: fall and fracture risk. Symptoms appear within 3–5 days.

Management

Halve the diazepam dose when combined. Alternative benzodiazepines without CYP dependence: lorazepam or oxazepam (glucuronidated). Alternative antidepressants without CYP2C19/CYP3A4 effect: sertraline or agomelatine.

Mechanism

Serotonergic load from combining two drugs with different mechanisms. Fluvoxamine also blocks CYP1A2 (a minor mirtazapine metabolic route); mirtazapine levels may rise.

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: mirtazapine 15–30 mg, fluvoxamine 100 mg/day. Monitor mental status in the early weeks.

Mechanism

Fluvoxamine is a potent inhibitor of CYP1A2, the liver enzyme that mainly clears olanzapine (fluvoxamine and olanzapine labels). With fluvoxamine, mean peak olanzapine concentration (Cmax) rose by 54% in female non-smokers and by 77% in male smokers, and the area under the concentration-time curve (AUC) by 52% and 108% (olanzapine label).

Symptoms

Olanzapine adverse effects become stronger: somnolence, dizziness, orthostatic hypotension (a drop in blood pressure on standing), increased appetite and weight gain with longer use.

Management

The pair is not banned. Drugs cleared through CYP1A2 are started at, or brought down to, the lower end of their dose range when given with fluvoxamine; their effects and adverse reactions are then monitored and the dose is lowered further if needed (fluvoxamine SmPC). If the patient already takes fluvoxamine, olanzapine is started at a lower dose; if fluvoxamine is added to olanzapine, a lower olanzapine dose is considered (olanzapine SmPC). The US Food and Drug Administration (FDA) olanzapine label also advises lower olanzapine doses with fluvoxamine.

Mechanism

Fluvoxamine inhibits CYP1A2, the main clearance route of theophylline. In the study cited in the FDA label, fluvoxamine 50 mg twice daily cut theophylline clearance about 3-fold. Theophylline has a narrow therapeutic range, so a rise of this size can lead to toxicity.

Symptoms

Signs of theophylline toxicity: vomiting, agitation, pressured speech, confusion, fever, tachycardia and low blood pressure. In adults severe toxicity can cause seizures and cardiac arrest, as the theophylline SmPC describes overdose.

Management

If the combination is needed, reduce the theophylline dose to one third of the usual maintenance dose and monitor theophylline blood levels, as the FDA label states. The Spanish fluvoxamine SmPC also asks for careful monitoring and theophylline dose adjustment if needed. An antidepressant without a relevant CYP1A2 effect is sertraline: its SmPC states that it does not inhibit this enzyme to a clinically significant degree.

Mechanism

SSRI (fluvoxamine) + tramadol – serotonin syndrome. Tramadol also lowers seizure threshold.

Symptoms

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

Management

Avoid the combination. For analgesia on fluvoxamine, use paracetamol, an NSAID, or morphine/oxycodone. For neuropathic pain, gabapentin or pregabalin.

Mechanism

Fluvoxamine blocks CYP1A2 (a minor venlafaxine metabolic route). Venlafaxine plasma levels rise modestly. Plus additive serotonergic load.

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 antidepressants, allow a 1-week washout. Alternative for augmentation: mirtazapine or agomelatine.

Mechanism

Fluvoxamine inhibits CYP2C19 and CYP1A2 – minor warfarin clearance routes. INR rises within 1–2 weeks of co-administration. Fluvoxamine (an SSRI) also depletes the platelet serotonin pool, impairing primary haemostasis.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

After starting fluvoxamine, check INR at 1 and 2 weeks, then monthly. If INR rises above target, reduce warfarin by 10–20%. Alternative antidepressants without CYP1A2/CYP2C19 effect: sertraline or escitalopram with pantoprazole cover.

Mechanism

Fluvoxamine is a strong CYP1A2 inhibitor and moderate CYP3A4 inhibitor. Levels of amiodarone and its active metabolite (desethylamiodarone) can rise, amplifying the QT effect.

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

Avoid the combination. In depression and anxiety on amiodarone, alternatives: sertraline or escitalopram (the latter cautiously in older patients, cap at 10 mg). If unavoidable, start fluvoxamine at 25 mg/day and check ECG at 1 and 2 weeks.

Mechanism

Fluvoxamine impairs primary haemostasis by inhibiting platelet serotonin reuptake. Additively with the direct factor Xa inhibitor apixaban, GI bleeding risk rises by 30–50%.

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 for short courses. If long-term SSRI is needed, in patients over 65 or with prior peptic ulcer add gastroprotection (pantoprazole 20 mg/day). Antidepressant alternatives without platelet effect: mirtazapine, agomelatine, trazodone.

Mechanism

Fluvoxamine blocks CYP3A4 – a partial atorvastatin metabolic route. Atorvastatin plasma levels may rise modestly, raising myalgia risk.

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Symptoms usually appear 2–6 weeks after starting the combination.

Management

When combined, cap atorvastatin at 40 mg/day if needed. Check creatine kinase on muscle symptoms. Alternative antidepressants without CYP3A4 effect: sertraline or escitalopram.