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venlafaxine: what international guidelines say – evidence review – Evigrade

Drug–drug interactions

18 pairs found. Sorted from critical to minor.

Critical

Linezolid

Oxazolidinone antibiotic

Mechanism

Venlafaxine is a serotonin–norepinephrine reuptake inhibitor (SNRI). Linezolid reversibly inhibits MAO. Combined action raises both serotonin and norepinephrine, risking serotonin syndrome.

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 venlafaxine at least 1 week before linezolid. For acute antibiotic need, use vancomycin or daptomycin. After completing linezolid, venlafaxine may resume 24 hours later.

Sources

FDA: Zyvox (linezolid) boxed warning - MAO/serotonergic (2010)

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Major

Amiodarone

Class III antiarrhythmics (Vaughan Williams)

Mechanism

Dual mechanism. Venlafaxine (SNRI) prolongs QT at high doses. Amiodarone is a potent QT prolonger and also blocks CYP2D6 – the venlafaxine metabolic route. Venlafaxine plasma levels rise; QT effects add up.

Symptoms

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

Management

Avoid the combination. Alternative antidepressants with minimal QT effect: mirtazapine or agomelatine. If venlafaxine is needed, cap at 75 mg/day; ECG before start and at 2 weeks.

Sources

FDA: Cordarone (amiodarone) section 7 (2018)

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Major

Amitriptyline

Tricyclic antidepressants (TCA)

Mechanism

Venlafaxine (SNRI) has serotonin and noradrenergic activity; amitriptyline (TCA) acts the same way. Co-administration: additive serotonin syndrome, hypertension, and cardiotoxicity 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. For neuropathic pain, choose one: venlafaxine (SNRI) or gabapentin/pregabalin. Alternative for depression: mirtazapine or agomelatine.

Sources

FDA: Effexor XR (venlafaxine) prescribing information (2017)

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Major

Bupropion

Other antidepressants (NDRI)

Mechanism

Additive seizure threshold reduction plus elevated synaptic norepinephrine. Venlafaxine prolongs QT at high doses.

Symptoms

Tachycardia, hypertension, tremor, agitation. Seizures (especially with prior epilepsy) and QT prolongation at high venlafaxine doses are possible.

Management

The combination is possible for augmentation. Cap bupropion at 300 mg and venlafaxine at 150 mg/day. ECG at 2 weeks; monitor blood pressure and pulse. Avoid with prior epilepsy.

Sources

FDA: Effexor XR (venlafaxine) prescribing information (2017)

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Major

citalopram

SSRI (selective serotonin reuptake inhibitor)

Mechanism

SSRI + SNRI – serotonin syndrome, additive QT prolongation at high venlafaxine doses.

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. For augmentation, use mirtazapine or agomelatine.

Sources

FDA: Effexor XR (venlafaxine) prescribing information (2017)

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Major

Dronedarone

Class III antiarrhythmic

Mechanism

Additive QT prolongation. Venlafaxine prolongs QT at high doses; dronedarone carries an boxed warning for this effect.

Symptoms

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

Management

Avoid the combination. Alternative antidepressants with minimal QT effect: mirtazapine or agomelatine. Alternative antiarrhythmic: a beta-blocker for rate control.

Sources

FDA: Multaq (dronedarone) prescribing information (2017)

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Major

duloxetine

SNRI

Mechanism

Dual SNRI – doubling the same pharmacological effect without therapeutic benefit. Risk of serotonin syndrome, hypertension, and tachycardia.

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: venlafaxine for depression or generalised anxiety disorder, duloxetine for pain syndromes (diabetic neuropathy, fibromyalgia). When switching, allow a 1-week washout.

Sources

FDA: Effexor XR (venlafaxine) prescribing information (2017)

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Major

Escitalopram

Selective serotonin reuptake inhibitors (SSRIs)

Mechanism

SSRI + SNRI – serotonin syndrome without therapeutic rationale.

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. For augmentation, use mirtazapine or agomelatine.

Sources

FDA: Effexor XR (venlafaxine) prescribing information (2017)

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Major

Fluoxetine

Selective serotonin reuptake inhibitors

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.

Sources

FDA: Effexor XR (venlafaxine) prescribing information (2017)

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Major

fluvoxamine

SSRI

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

Haloperidol

First-generation antipsychotics. Butyrophenone derivatives

Mechanism

Additive QT prolongation. Venlafaxine at high doses (above 150 mg/day) prolongs QT; haloperidol does so on its own (especially parenterally).

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 with high venlafaxine doses and parenteral haloperidol. At low venlafaxine doses (75 mg) and oral haloperidol, the combination is acceptable with ECG monitoring at 2 weeks. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole.

Sources

FDA: Haldol (haloperidol) prescribing information (2008)

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Major

Mirtazapine

Other antidepressants (NaSSA)

Mechanism

'California rocket fuel' augmentation – mirtazapine (5-HT2/3 blocker) + venlafaxine (SNRI). Used in resistant depression. Serotonin syndrome is rare but possible 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. Keep doses low: mirtazapine 30 mg, venlafaxine 75–150 mg/day. Monitor blood pressure, pulse, and mental status in the early weeks.

Sources

FDA: Effexor XR (venlafaxine) prescribing information (2017)

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Major

Sertraline

Selective serotonin reuptake inhibitors (SSRIs)

Mechanism

SSRI (sertraline) + SNRI (venlafaxine) – additive serotonergic load. The combination is not used in clinical practice.

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. For augmentation, add mirtazapine or agomelatine (different class).

Sources

FDA: Effexor + Zoloft drug interactions (2017)

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Major

Tramadol

Other opioids

Mechanism

Venlafaxine (SNRI) + tramadol – serotonin syndrome plus additive seizure risk. Tramadol itself is a weak serotonin-norepinephrine reuptake inhibitor with proconvulsant effect.

Symptoms

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

Management

Avoid the combination. For analgesia on venlafaxine, use paracetamol, an NSAID, or morphine/oxycodone (without serotonergic activity). For neuropathic pain: gabapentin or pregabalin.

Sources

FDA: Ultram (tramadol) prescribing information (2017)

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Moderate

Acetylsalicylic acid

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

Mechanism

Venlafaxine (SNRI) depletes the platelet serotonin pool, impairing primary haemostasis. With aspirin: additive GI bleeding risk.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools. Severe cases: GI bleeding.

Management

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

Sources

FDA: Effexor XR (venlafaxine) prescribing information (2017)

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Moderate

Alprazolam

Benzodiazepines. Short-to-medium-acting anxiolytics

Mechanism

Additive CNS depression (minimal for venlafaxine, mainly from alprazolam). High-dose venlafaxine (above 150 mg/day) also raises BP.

Symptoms

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

Management

On starting the combination, begin alprazolam at the minimum dose. For long-term anxiety treatment, prioritise antidepressant monotherapy with CBT and gradual benzodiazepine taper. In arterial hypertension, check BP 2 weeks after starting venlafaxine.

Sources

FDA: Xanax (alprazolam) prescribing information (2016)

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Moderate

Apixaban

Direct oral anticoagulants (factor Xa inhibitors)

Mechanism

Venlafaxine (SNRI) moderately 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. Venlafaxine also raises blood pressure at doses above 150 mg/day — consider alternatives in arterial hypertension.

Sources

FDA: Eliquis (apixaban) prescribing information (2014)

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Moderate

Azithromycin

Macrolides

Mechanism

Additive QT prolongation (venlafaxine prolongs QT at doses above 150 mg).

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 venlafaxine ≤150 mg, the combination is acceptable. At higher venlafaxine doses or cardiovascular disease: ECG before start or alternative antibiotics.

Sources

FDA: Effexor XR (venlafaxine) prescribing information (2017)

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