Venlafaxine

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.

Mechanism

Venlafaxine is an SNRI with strong serotonin effect. Combined with phenelzine causes severe serotonin syndrome.

Symptoms

Hyperthermia, myoclonus, tachycardia, rhabdomyolysis.

Management

Combination contraindicated. 2-week washout (1 week for venlafaxine due to short T½).

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.

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.

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.

Mechanism

Venlafaxine blocks serotonin and noradrenaline reuptake, so the serotonergic effect stacks with an SSRI. Its SmPC bans only irreversible MAOIs, describing other serotonergic combinations as ones to be watched. QTc prolongation and torsade were recorded post-marketing, mostly in overdose.

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

The pair usually appears while switching from one antidepressant to another, and the overlap is kept short. Agitation, tremor, sweating and hyperthermia in the first days after a dose change are the warning signs.

Mechanism

Additive QT prolongation. Venlafaxine prolongs QT at high doses; dronedarone carries an FDA 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.

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.

Mechanism

Venlafaxine blocks serotonin and noradrenaline reuptake, so the serotonergic effect stacks with an SSRI. Its SmPC bans only irreversible MAOIs, describing other serotonergic combinations as ones to be watched. QTc prolongation and torsade were recorded post-marketing, mostly in overdose.

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

The pair usually appears while switching from one antidepressant to another, and the overlap is kept short. Agitation, tremor, sweating and hyperthermia in the first days after a dose change are the warning signs.

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

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

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.

Mechanism

Venlafaxine blocks the reuptake of serotonin and noradrenaline, and ondansetron blocks serotonin type 3 (5-HT3) receptors. Serotonin syndrome has occurred when ondansetron was given with serotonin and noradrenaline reuptake inhibitors, the antidepressant group that includes venlafaxine (ondansetron SmPC). Ondansetron also prolongs the QT interval in a dose-dependent way. Post-marketing reports with venlafaxine describe QT prolongation and ventricular arrhythmias, mostly in overdose or with other risk factors, so the cardiac effects of the two drugs add up (both SmPCs). Levels of both drugs barely change, because ondansetron does not induce or inhibit the metabolism of other drugs and several liver enzymes clear it (ondansetron SmPC).

Symptoms

Most reports of serotonin syndrome with ondansetron come from post-anaesthesia care units and infusion centres (US Food and Drug Administration, FDA, ondansetron label). Signs include agitation, confusion, hallucinations, sweating, fever, fast heart rate, swings in blood pressure, tremor, muscle twitching and stiffness, overactive reflexes, nausea, vomiting and diarrhoea. QT prolongation itself causes no symptoms and shows only on an electrocardiogram. If torsade de pointes develops, it causes palpitations, dizziness or fainting.

Management

Avoid combining venlafaxine with drugs that prolong the QT interval (venlafaxine SmPC). Ondansetron prolongs QT in a dose-dependent way (ondansetron SmPC). If the patient still needs ondansetron, correct low potassium and magnesium before dosing and do not give a single intravenous dose above 16 mg (ondansetron SmPC). Monitor the electrocardiogram in patients taking other QT-prolonging drugs or with electrolyte abnormalities, heart failure or bradyarrhythmias (ondansetron label, US Food and Drug Administration, FDA). Warn the patient about serotonin syndrome and watch closely for it, especially at the start of the combination and after a venlafaxine dose increase (venlafaxine and ondansetron labels). If symptoms appear, stop ondansetron and start supportive treatment (ondansetron FDA label).

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).

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.

Mechanism

Venlafaxine inhibits the reuptake of serotonin and noradrenaline. Platelets low in serotonin are worse at stopping bleeding, and the venlafaxine label describes bleeding from bruising and nosebleeds to life-threatening gastrointestinal haemorrhage. Aspirin irreversibly blocks platelet cyclooxygenase and injures the stomach lining, so together the drugs raise the risk of bleeding (Spanish and US venlafaxine labels).

Symptoms

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

Management

The combination can be used with caution: the venlafaxine SmPC asks for caution in patients taking platelet inhibitors, and aspirin is one of them. The US Food and Drug Administration (FDA) requires prescribers to warn patients about the higher bleeding risk when venlafaxine is combined with aspirin (venlafaxine FDA label). Explain the signs of bleeding to the patient in advance: bruising without injury, nosebleeds, black stools, vomiting blood. With black stools, vomiting blood or any other sign of gastric bleeding, the patient stops aspirin and sees a doctor at once (aspirin 100 mg SmPC).

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.

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.

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.

Mechanism

No label names this pair. The risks come from the properties of each drug. Metamizole can cause agranulocytosis, and this reaction does not depend on the dose (metamizole label). The venlafaxine label also lists agranulocytosis, neutropenia and aplastic anaemia among rare adverse reactions, and thrombocytopenia among very rare ones. Venlafaxine may reduce platelet function and raises the risk of bleeding, including gastrointestinal bleeding (venlafaxine label). Gastrointestinal bleeding has also occurred with metamizole. Many of those patients were taking other drugs linked to such bleeding, such as nonsteroidal anti-inflammatory drugs (metamizole label). Metamizole may act partly through the central nervous system (metamizole label), and the venlafaxine labels ask for caution with other drugs active in the central nervous system. Metamizole induces the enzymes CYP2B6 and CYP3A4 and may lower the levels of the drugs its label names, but venlafaxine is not on that list. The enzyme CYP2D6 mainly converts venlafaxine to its active metabolite (both labels).

Symptoms

Bleeding with venlafaxine ranges from bruises, haematomas, nosebleeds and petechiae to life-threatening gastrointestinal bleeding (venlafaxine label). Gastrointestinal bleeding shows as black stools, vomiting blood or coffee-ground material, and weakness. Agranulocytosis starts with fever, chills, sore throat and painful changes in the lining of the mouth, nose, throat, genital or anal area. Metamizole lowers fever, so some of these signs may go unnoticed (metamizole label). Other signs of a blood disorder are bruising, bleeding, pallor, persistent fever and general malaise (metamizole label).

Management

The combination is acceptable under supervision. No label forbids it or names the pair. The venlafaxine labels advise caution when it is taken with other substances active in the central nervous system (Spanish Agency of Medicines and Medical Devices, AEMPS, section 4.5; US Food and Drug Administration, FDA, section 7.2). Use venlafaxine with caution in patients predisposed to bleeding (AEMPS, 4.4). Tell the patient to stop metamizole and contact a doctor straight away if fever, sore throat, mouth ulcers, bruising, bleeding or pallor appear (metamizole label, 4.4). If agranulocytosis is suspected, order a full blood count with differential and stop metamizole without waiting for the result. If agranulocytosis is confirmed, do not restart metamizole (metamizole label, 4.4). In older patients and in renal or hepatic impairment, give metamizole only after weighing benefit against risk (metamizole label, 4.4). Venlafaxine is not on the list of drugs whose levels metamizole lowers through enzyme induction, and the labels give no other guidance on the kinetics of this pair (metamizole label, 4.5).

Mechanism

Both drugs enhance serotonergic transmission. Venlafaxine inhibits serotonin and noradrenaline reuptake; mirtazapine blocks presynaptic α2 receptors and increases noradrenergic and serotonergic transmission. Together they raise the risk of serotonin syndrome (both SmPCs). Post-marketing reports of QT prolongation and torsades de pointes exist for both drugs, mostly in overdose or with other risk factors. In a dedicated QT study, mirtazapine 45 and 75 mg prolonged QT by an amount not considered clinically meaningful (FDA mirtazapine label).

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever. Signs of arrhythmia: palpitations, skipped beats, fainting.

Management

Mirtazapine is added to venlafaxine on purpose when depression has not responded, or has responded only partly, to an antidepressant. NICE allows such a combination of drugs from different classes, but advises warning the patient about a possible higher side-effect burden and considering a specialist consultation. Observe the patient closely at the start of co-treatment and after each dose increase (both SmPCs). If signs of serotonin syndrome appear, stop both drugs at once and start symptomatic treatment (FDA labels of both drugs). Before starting venlafaxine, measure blood pressure and bring existing hypertension under control; then check blood pressure regularly and after each dose increase (venlafaxine labels). In patients at high risk of serious arrhythmia or QT prolongation, weigh benefit and risk before prescribing venlafaxine (venlafaxine SmPC). In known cardiovascular disease or a family history of QT prolongation, prescribe mirtazapine with caution (mirtazapine labels).