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fluvoxamine: what international guidelines say – evidence review – Evigrade

Drug–drug interactions

18 pairs found. Sorted from critical to minor.

Major

Amitriptyline

Tricyclic antidepressants (TCA)

Mechanism

Fluvoxamine blocks CYP1A2 and CYP2C19 – the main amitriptyline demethylation routes. TCA plasma levels rise 2- to 4-fold. Plus serotonin syndrome risk.

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. Alternative antidepressants if fluvoxamine fails: sertraline or escitalopram (no CYP1A2 effect). For neuropathic pain, replace amitriptyline with gabapentin or pregabalin.

Sources

FDA: Luvox section 7 (2014)

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Major

Bupropion

Other antidepressants (NDRI)

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.

Sources

FDA: Luvox section 7 (2014)

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Major

citalopram

SSRI (selective serotonin reuptake inhibitor)

Mechanism

Two SSRIs simultaneously – serotonin syndrome without therapeutic purpose. Fluvoxamine also blocks CYP1A2 (a minor citalopram route).

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 SSRIs, allow a 2-week washout. Alternative monotherapy: mirtazapine or agomelatine.

Sources

FDA: Celexa (citalopram) DDC QT warning (2012)

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Major

Clopidogrel

Antiplatelet agents – P2Y12 receptor inhibitors

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).

Sources

FDA: Plavix (clopidogrel) — boxed warning CYP2C19 poor metabolizers (2010)

Major

Diazepam

Anxiolytics. Benzodiazepine derivatives

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.

Sources

FDA: Luvox section 7 (2014)

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Major

duloxetine

SNRI

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 combination is not prescribed. Choose one antidepressant: duloxetine for pain syndromes, fluvoxamine for obsessive-compulsive disorder. For augmentation, add mirtazapine.

Sources

FDA: Cymbalta section 7 (2017)

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Major

Linezolid

Oxazolidinone antibiotic

Mechanism

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

Symptoms

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

Management

The combination is not prescribed. Stop fluvoxamine at least 2 weeks before linezolid. For urgent antibiotic therapy: vancomycin, daptomycin, or ceftaroline by susceptibility.

Sources

FDA: Zyvox (linezolid) — serotonin syndrome warning (2011)

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Major

Mirtazapine

Other antidepressants (NaSSA)

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.

Sources

FDA: Luvox section 7 (2014)

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Major

Theophylline

Methylxanthine

Mechanism

Fluvoxamine is the most potent CYP1A2 inhibitor among SSRIs, and CYP1A2 is the main theophylline metabolic route. Theophylline plasma levels rise 3-fold. Theophylline has a narrow therapeutic window.

Symptoms

Nausea, tachycardia, tremor, insomnia, agitation. At levels above 30 mg/L: seizures and ventricular arrhythmias. Older patients and chronic kidney disease: earlier symptoms.

Management

Avoid the combination. Alternative antidepressants without CYP1A2 effect: sertraline, escitalopram, or agomelatine. If fluvoxamine is needed, reduce theophylline 3-fold and check level at 3–5 days.

Sources

FDA: Luvox section 7 (2014)

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Major

Tramadol

Other opioids

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.

Sources

FDA: Luvox section 7 (2014)

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Major

venlafaxine

SNRI (serotonin-norepinephrine reuptake inhibitor)

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.

Sources

FDA: Effexor + Zoloft drug interactions (2017)

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Major

Warfarin

Vitamin K antagonist anticoagulants

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.

Sources

FDA: Luvox section 7 (2014)

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Moderate

Acetylsalicylic acid

Antiplatelet agents (low dose) / NSAIDs (analgesic dose)

Mechanism

SSRIs block serotonin reuptake into platelets, impairing primary haemostasis. Additively with aspirin's antiplatelet effect: upper GI bleeding risk roughly doubles.

Symptoms

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

Management

The combination is acceptable at low aspirin doses (75–100 mg as cardioprotection). PPI cover with pantoprazole is mandatory. Alternative antidepressants with minimal platelet effect: mirtazapine or agomelatine.

Sources

FDA: Bayer Aspirin (acetylsalicylic acid) prescribing information (2015)

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Moderate

Alprazolam

Benzodiazepines. Short-to-medium-acting anxiolytics

Mechanism

Fluvoxamine inhibits CYP3A4 and CYP1A2. Alprazolam is a CYP3A4 substrate. Alprazolam AUC rises by 50–100%; half-life doubles.

Symptoms

Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk. Morning sedation is especially pronounced.

Management

Avoid the combination. If unavoidable, halve the alprazolam dose and give only at bedtime. Do not prescribe in older patients. Anxiolytic alternatives: buspirone, lorazepam, or oxazepam (CYP3A4-independent). Antidepressant alternatives: sertraline or escitalopram (minimal CYP3A4 effect).

Sources

FDA: Luvox section 7 (2014)

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Moderate

Amiodarone

Class III antiarrhythmics (Vaughan Williams)

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.

Sources

FDA: Cordarone (amiodarone) prescribing information (2018)

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Moderate

Apixaban

Direct oral anticoagulants (factor Xa inhibitors)

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.

Sources

FDA: Eliquis (apixaban) prescribing information (2014)

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Moderate

Atorvastatin

HMG-CoA reductase inhibitors (statins)

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.

Sources

FDA: Luvox section 7 (2014)

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Moderate

Budesonide

Inhaled corticosteroids (ICS)

Mechanism

Fluvoxamine is a CYP3A4 inhibitor; budesonide is a CYP3A4 substrate. Oral budesonide AUC may rise, increasing hypercortisolism risk in long-term therapy. Inhaled budesonide is minimally absorbed — the effect is weaker.

Symptoms

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

Management

For inhaled budesonide and fluvoxamine, no adjustment needed. On oral budesonide over 8 weeks, assess for hypercortisolism and consider antidepressant alternatives — sertraline or escitalopram (minimal CYP3A4 effect).

Sources

FDA: Luvox section 7 (2014)

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