Haloperidol

Mechanism

Dual QT prolongation. Torsades de pointes cases reported.

Symptoms

QTc above 500 ms, syncope, torsades de pointes risk.

Management

Combination contraindicated.

Mechanism

Both drugs prolong the QT interval on the electrocardiogram. The azithromycin SmPC reports QT prolongation and torsades de pointes with macrolides, azithromycin included. The haloperidol SmPC reports QT prolongation, ventricular arrhythmias and sudden death; the risk is higher with high doses, high plasma levels and parenteral use, especially intravenous. Together the effects add up.

Symptoms

QT prolongation on the electrocardiogram (ECG) causes no symptoms by itself. Palpitations, dizziness or fainting may occur. The dangerous complication is torsades de pointes, a ventricular tachycardia that can end in cardiac arrest (azithromycin SmPC). The risk is higher in women and older people, with low potassium or magnesium, marked bradycardia, heart disease or severe heart failure (azithromycin and haloperidol SmPCs).

Management

The combination is contraindicated: the Spanish haloperidol SmPC contraindicates haloperidol with drugs that prolong the QT interval and names azithromycin among them (haloperidol SmPC). The azithromycin SmPC asks for caution with such drugs, antipsychotics included (azithromycin SmPC), and the azithromycin label approved by the US Food and Drug Administration (FDA) advises weighing the risk of fatal QT prolongation in patients who take them (azithromycin FDA label). Before haloperidol is started, an electrocardiogram (ECG) is recorded and low potassium and magnesium are corrected; if the corrected QT interval (QTc) lengthens, the haloperidol dose is reduced, and haloperidol is stopped if QTc exceeds 500 ms (haloperidol SmPC).

Mechanism

Haloperidol is a typical antipsychotic, and its own SmPC outright forbids giving it with QTc-prolonging drugs. The SSRI labels name it as their antipsychotic example. The citalopram SmPC lists ongoing treatment with any drug capable of prolonging the QT interval among its contraindications, with no exceptions.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope. The end point is polymorphic ventricular tachycardia of the torsade type progressing to ventricular fibrillation. The risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, decompensated heart failure and in women.

Management

The pair sits in the citalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. The ban stands on both sides, and parenteral haloperidol carries more risk than oral. If an antipsychotic is needed, the question is settled on that side, not by trimming the antidepressant dose.

Mechanism

Both drugs prolong the QT interval on the electrocardiogram. The clarithromycin SmPC reports QT prolongation and a risk of torsades de pointes with macrolides, clarithromycin included. The haloperidol SmPC reports QT prolongation, ventricular arrhythmias and sudden death; the risk is higher with high doses and high plasma levels. There is a second mechanism: clarithromycin is a strong CYP3A4 inhibitor (clarithromycin SmPC), and haloperidol is partly cleared by this enzyme, although its main pathways are different. With CYP3A4 inhibitors haloperidol levels may rise by 20–40%, in some cases by up to 100%, and the risk of QT prolongation rises with them (haloperidol SmPC).

Symptoms

QT prolongation on the electrocardiogram (ECG) causes no symptoms by itself. Palpitations, dizziness or fainting may occur. The dangerous complication is torsades de pointes, which can progress to ventricular fibrillation (clarithromycin SmPC). The risk is higher with low potassium or magnesium, coronary artery disease, severe heart failure, conduction disorders or marked bradycardia (clarithromycin and haloperidol SmPCs).

Management

The combination is contraindicated: the Spanish haloperidol SmPC contraindicates haloperidol with drugs that prolong the QT interval and names clarithromycin (haloperidol SmPC). The clarithromycin label approved by the US Food and Drug Administration (FDA) says to avoid clarithromycin in patients who take QT-prolonging drugs (clarithromycin FDA label). Clarithromycin itself is contraindicated with low potassium or magnesium and with a history of QT prolongation (clarithromycin SmPC). The haloperidol SmPC also contraindicates azithromycin, erythromycin, levofloxacin and moxifloxacin. Before haloperidol is started, an electrocardiogram (ECG) is recorded and low potassium and magnesium are corrected; if the corrected QT interval (QTc) lengthens, the haloperidol dose is reduced, and haloperidol is stopped if QTc exceeds 500 ms (haloperidol SmPC).

Mechanism

Both drugs prolong the QT interval on the electrocardiogram. Dronedarone prolongs the corrected QT interval (QTc) by about 10 ms and can itself cause arrhythmias when used with other drugs that favour arrhythmias (dronedarone SmPC). The haloperidol SmPC reports QT prolongation, ventricular arrhythmias and sudden death; the risk is higher with high doses, high plasma levels and parenteral use, especially intravenous. There is a second mechanism: dronedarone is a moderate CYP3A4 inhibitor and a weak CYP2D6 inhibitor (dronedarone SmPC), and haloperidol is partly cleared by both enzymes; with such inhibitors its levels may rise by 20–40%, in some cases by up to 100% (haloperidol SmPC).

Symptoms

QT prolongation on the electrocardiogram (ECG) causes no symptoms by itself. Palpitations, dizziness or fainting may occur. The dangerous complication is torsades de pointes, a ventricular tachycardia. The risk is higher with low potassium or magnesium (dronedarone and haloperidol SmPCs), bradycardia or heart disease (haloperidol SmPC). Haloperidol can also cause a fast heart rate and a drop in blood pressure on standing (haloperidol SmPC).

Management

The combination is contraindicated: the Spanish haloperidol SmPC contraindicates haloperidol with drugs that prolong the QT interval and names dronedarone (haloperidol SmPC). The dronedarone SmPC approved by the European Medicines Agency (EMA) contraindicates it with drugs that can induce torsades de pointes and gives phenothiazines, tricyclic antidepressants, some macrolides and class I and III antiarrhythmics as examples; haloperidol is not on that list (dronedarone SmPC). Potassium and magnesium deficits are corrected before the start and checked during treatment (dronedarone and haloperidol SmPCs). Before haloperidol is started, an electrocardiogram (ECG) is recorded; if the corrected QT interval (QTc) lengthens, the haloperidol dose is reduced, and haloperidol is stopped if QTc exceeds 500 ms (haloperidol SmPC). On dronedarone the ECG is monitored, and dronedarone is stopped if QTc reaches 500 ms or more (dronedarone SmPC). Haloperidol solution for injection is given intramuscularly only; if it is given intravenously, the ECG is monitored continuously (haloperidol injection SmPC).

Mechanism

Haloperidol is a typical antipsychotic, and its own SmPC outright forbids giving it with QTc-prolonging drugs. The SSRI labels name it as their antipsychotic example. The escitalopram SmPC contraindicates any QT-prolonging drug alongside it: the ban is written broadly, and the classes in brackets are examples.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope. The end point is polymorphic ventricular tachycardia of the torsade type progressing to ventricular fibrillation. The risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, decompensated heart failure and in women.

Management

The pair sits in the escitalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. The ban stands on both sides, and parenteral haloperidol carries more risk than oral. If an antipsychotic is needed, the question is settled on that side, not by trimming the antidepressant dose.

Mechanism

Both drugs prolong the QT interval on the electrocardiogram. The haloperidol SmPC reports QT prolongation, ventricular arrhythmias and sudden death; the risk is higher with high doses, high plasma levels and parenteral use, especially intravenous. Moxifloxacin prolongs QT more as its concentration rises, and its SmPC does not exclude an additive effect with other QT-prolonging drugs (moxifloxacin SmPC). Together they raise the risk of torsades de pointes.

Symptoms

QT prolongation on the electrocardiogram (ECG) causes no symptoms by itself. Palpitations, dizziness or fainting may occur. The dangerous complication is torsades de pointes, a ventricular tachycardia that can lead to cardiac arrest (moxifloxacin SmPC). The risk is higher in women and older people, with low potassium or magnesium, marked bradycardia or heart disease (moxifloxacin and haloperidol SmPCs).

Management

Both Spanish SmPCs contraindicate this combination. The haloperidol SmPC contraindicates haloperidol with drugs that prolong the QT interval and names moxifloxacin, and the moxifloxacin SmPC contraindicates moxifloxacin with antipsychotics and names haloperidol. The moxifloxacin label approved by the US Food and Drug Administration (FDA) advises avoiding it with antipsychotics (moxifloxacin FDA label). The haloperidol SmPC also contraindicates other antibiotics from the same groups: levofloxacin, azithromycin, clarithromycin, erythromycin. Before haloperidol is started, an electrocardiogram (ECG) is recorded and low potassium and magnesium are corrected; if the corrected QT interval (QTc) lengthens, the haloperidol dose is reduced, and haloperidol is stopped if QTc exceeds 500 ms (haloperidol SmPC). If signs of arrhythmia appear on moxifloxacin, it is stopped and an ECG is recorded; the recommended dose is not exceeded (moxifloxacin SmPC).

Mechanism

Both drugs prolong the QT interval. For haloperidol, there are reports of QTc prolongation, ventricular arrhythmias and sudden death, with higher risk at high doses, high plasma concentrations and parenteral, especially intravenous, use (haloperidol label). For pimozide, there are reports of QT prolongation, torsade de pointes, ventricular tachycardia and ventricular fibrillation at therapeutic doses (pimozide label). Both labels assume the effects add up, and each lists the other drug among contraindicated QT-prolonging drugs. There is also a kinetic side: haloperidol inhibits CYP2D6 (haloperidol label), this enzyme partly metabolises pimozide, and the Spanish pimozide label contraindicates CYP2D6 inhibitors (pimozide label). The labels cite no study of pimozide concentrations on haloperidol. Both drugs block dopamine D2 receptors, so motor side effects, hyperprolactinaemia and the risk of neuroleptic malignant syndrome add up.

Symptoms

QT prolongation causes no symptoms and shows only on the ECG; arrhythmia presents as palpitations, dizziness or syncope, and both labels report sudden death (haloperidol and pimozide labels). Double dopamine blockade brings tremor, rigidity, hypersalivation, bradykinesia, akathisia and acute dystonia (haloperidol label). Neuroleptic malignant syndrome usually starts with high fever, followed by muscle rigidity, unstable blood pressure and pulse, and altered consciousness (both labels).

Management

The combination is contraindicated. The Spanish haloperidol label bans concomitant use with drugs that prolong the QT interval and names pimozide among the examples (haloperidol label, AEMPS). The Spanish pimozide label contraindicates any drug known to prolong QT as well as CYP2D6 inhibitors (pimozide label). The US pimozide label contraindicates other drugs that prolong the QT interval (pimozide label, FDA). The US haloperidol label is softer and only calls for particular caution with such drugs (haloperidol label, FDA), but the strictest document applies. Under the US label, pimozide in Tourette's disorder is meant for patients who cannot tolerate or do not respond to haloperidol (pimozide label, FDA): the two are replacements for each other, not partners. If a patient takes both, stop one of them. For each drug on its own: before starting haloperidol, take an ECG, correct potassium and magnesium and then monitor electrolytes; reduce the dose if QTc lengthens and stop haloperidol if QTc exceeds 500 ms (haloperidol label). On pimozide, take an ECG before the start and repeat it during treatment, and stop the drug if QT or QTc exceeds 500 ms (pimozide label).

Mechanism

Both drugs prolong the QT interval and the effects add up. The haloperidol label describes QTc prolongation, ventricular arrhythmias and sudden death, with higher risk at high doses, high plasma concentrations and parenteral, especially intravenous, use (4.4). Ziprasidone prolongs QT in a dose-related way. In the study cited in the FDA label, oral ziprasidone lengthened QTc by 9–14 ms more than haloperidol; after a second intramuscular injection ziprasidone added 12.8 ms and haloperidol 14.7 ms (Geodon, 5.3). There is no kinetic component. According to its label, ziprasidone does not change the concentrations of CYP2D6 or CYP3A4 substrates to a clinically relevant degree (Zeldox, 4.5).

Symptoms

QTc prolongation on the ECG, torsade de pointes, ventricular fibrillation, sudden death. Clinically this means palpitations, dizziness, syncope or seizures: the ziprasidone label names them as reasons to suspect a malignant arrhythmia and record an ECG (Zeldox, 4.4). The risk is higher with bradycardia, hypokalaemia and hypomagnesaemia, heart disease, a family history of QT prolongation, in CYP2D6 poor metabolisers with high haloperidol concentrations, and with intravenous haloperidol (both labels).

Management

The combination is contraindicated: the AEMPS haloperidol label (sections 4.3 and 4.5) bars haloperidol with QT-prolonging drugs and names ziprasidone in the list. The ziprasidone label says it should not be given with QT-prolonging drugs (Zeldox, 4.4), and the FDA label says to avoid the combination (Geodon, 5.3). The second antipsychotic is not added on top of the first; one replaces the other. Before starting either drug, record a baseline ECG (haloperidol label, 4.4; ziprasidone label, 4.4 – in patients with heart disease) and correct potassium and magnesium (both labels). Decide on ECG monitoring during treatment (haloperidol label, 4.4). If QTc lengthens, reduce the haloperidol dose and stop it at QTc above 500 ms (haloperidol label, 4.4). Ziprasidone is also stopped at QTc above 500 ms (Zeldox, 4.4). Palpitations, dizziness, syncope or seizures in a patient taking both call for an ECG and an arrhythmia work-up (Zeldox, 4.4). Intravenous haloperidol adds risk on its own (haloperidol label, 4.4; FDA label).

Mechanism

Both drugs depress the central nervous system (CNS). The alprazolam SmPC warns that with antipsychotics the depressant effect can increase, up to respiratory depression, coma and death, and the haloperidol SmPC says haloperidol can enhance the effect of hypnotics and sedatives. The haloperidol SmPC also lists alprazolam among CYP3A4 inhibitors that may raise haloperidol levels, usually by 20–40% and in some cases by up to 100%. Higher haloperidol levels raise the risk of its adverse effects, including QT prolongation on the electrocardiogram.

Symptoms

Drowsiness, slowed reactions, poor coordination and confusion. Marked central nervous system depression can lead to slowed breathing and coma (alprazolam SmPC). In older people, sedation and muscle weakness raise the risk of falls, often with serious consequences (alprazolam SmPC). Haloperidol can cause a fast heart rate and a drop in blood pressure on standing, and QT prolongation carries a risk of ventricular arrhythmias (haloperidol SmPC).

Management

The combination is not prohibited, but the alprazolam SmPC requires limiting the dose and duration of its use with antipsychotics, and haloperidol is one of them. The US Food and Drug Administration (FDA) alprazolam label likewise requires limiting the alprazolam dose and duration with any central nervous system depressant. Alprazolam is given for as short a time as possible, no longer than 2–4 weeks without reassessment, and older or debilitated patients start at a lower dose. In chronic respiratory insufficiency the alprazolam dose is reduced, and in severe respiratory insufficiency or sleep apnoea syndrome alprazolam is contraindicated (alprazolam SmPC). Before haloperidol is started, a baseline electrocardiogram (ECG) is recorded and potassium and magnesium are corrected. With alprazolam the patient is watched for stronger or longer haloperidol effects and the haloperidol dose is reduced if needed; haloperidol is stopped if the QTc interval exceeds 500 ms (haloperidol SmPC).

Mechanism

Additive QT prolongation and anticholinergic effect. Both drugs are sedating. In elderly patients with dementia, severe delirium and arrhythmias have been reported.

Symptoms

Drowsiness, sedation, confusion, delirium (especially in older patients). Dry mouth, constipation, urinary retention. QT prolongation on ECG with torsades de pointes risk.

Management

Avoid the combination, especially in older patients. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole. Alternative antidepressants without QT effect: mirtazapine or agomelatine.

Mechanism

Haloperidol is a CYP2D6 substrate; bupropion is a potent CYP2D6 inhibitor. Haloperidol plasma levels rise 2- to 3-fold. Risk of extrapyramidal symptoms and QT prolongation emerges. Both drugs also lower the seizure threshold.

Symptoms

Extrapyramidal symptoms (tremor, rigidity, akathisia), QT prolongation on ECG, seizures. Older patients: fall risk.

Management

Avoid the combination. Alternative antipsychotics without CYP2D6 dependence: olanzapine or aripiprazole. Alternative antidepressants without CYP2D6 inhibition: sertraline or escitalopram.

Mechanism

Carbamazepine induces CYP3A4 – a partial haloperidol clearance route. Haloperidol plasma levels fall by 50% and antipsychotic effect weakens.

Symptoms

Return of positive symptoms: hallucinations, delusions, agitation. In schizophrenia, risk of acute relapse.

Management

During carbamazepine therapy, increase haloperidol 1.5- to 2-fold under clinical monitoring. Alternative anticonvulsants without induction: sodium valproate, levetiracetam, lamotrigine (no CYP3A4 induction).

Mechanism

Dual mechanism: both prolong QT (additively), and ciprofloxacin blocks CYP1A2 – a partial haloperidol clearance route. Haloperidol levels rise.

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 antibiotics: a cephalosporin or nitrofurantoin. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole.

Mechanism

Dual mechanism. Fluconazole prolongs QT and blocks CYP3A4 and CYP2D6 – haloperidol metabolic routes. Haloperidol plasma levels rise; QT effects add up.

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 antifungals: terbinafine or echinocandins. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole.

Mechanism

Ketoconazole is a potent CYP3A4 inhibitor – the main haloperidol metabolic route. Haloperidol plasma levels rise 2- to 3-fold. Ketoconazole itself prolongs QT; effects add up.

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 antifungals: terbinafine or echinocandins. Alternative antipsychotics: olanzapine or aripiprazole.

Mechanism

Mirtazapine prolongs QT dose-dependently, additively with haloperidol (especially parenteral). Plus combined sedation.

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 mirtazapine above 30 mg and parenteral haloperidol. At low doses and normal potassium, the combination is acceptable with ECG monitoring at 2 weeks. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole.

Mechanism

Additive CNS depression and sedation. Severe hypotension and respiratory depression have been reported, especially in older patients.

Symptoms

Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.

Management

Avoid the combination in older patients. For opioid-induced nausea, use ondansetron (no QT issue in short courses in older patients) or metoclopramide. For acute delirium, dexmedetomidine (no respiratory depression).

Mechanism

Dual antipsychotic therapy – additive risk of extrapyramidal symptoms, sedation, QT prolongation, and metabolic side effects. Polypharmacy without therapeutic rationale in most cases.

Symptoms

Sedation, extrapyramidal symptoms (tremor, rigidity, akathisia), QT prolongation on ECG. Metabolic effects: weight gain, dyslipidaemia (from quetiapine).

Management

Avoid the combination. Choose one antipsychotic: quetiapine for schizophrenia with anxious-depressive component or bipolar disorder; haloperidol for acute psychotic agitation. If dual therapy is needed, restrict to short-term use during acute psychotic episodes.

Mechanism

Rifampicin strongly induces CYP3A4 – the main haloperidol metabolic route. Haloperidol plasma levels fall by 70%; antipsychotic effect weakens.

Symptoms

Return of positive symptoms: hallucinations, delusions, agitation. In schizophrenia: risk of acute relapse.

Management

During anti-TB therapy, increase haloperidol 2- to 3-fold with clinical monitoring. Alternative antipsychotics without CYP3A4 dependence: olanzapine or aripiprazole.

Mechanism

Sertraline at high doses prolongs QT, additively with haloperidol. Sertraline also weakly blocks CYP2D6, so haloperidol levels may rise.

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 sertraline above 100 mg and parenteral haloperidol. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole. Alternative antidepressants: mirtazapine or agomelatine.

Mechanism

Additive QT prolongation. Haloperidol strongly prolongs QT, especially parenterally (IV). Tacrolimus prolongs QT with hypomagnesaemia. Combined action raises torsades de pointes 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, especially IV haloperidol. Alternative antipsychotics with minimal QT effect post-transplant: olanzapine or aripiprazole. For acute delirium: dexmedetomidine (no QT effect).

Mechanism

Tramadol lowers seizure threshold and prolongs QT. Haloperidol is a strong QT prolonger, especially parenterally. Additive seizure and torsades de pointes 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. For analgesia on haloperidol, use paracetamol, an NSAID, or morphine/oxycodone. Alternative antipsychotics: olanzapine or aripiprazole.

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

Additive hypotension (haloperidol blocks α1-adrenoceptors) and sedation. Haloperidol prolongs QT; amlodipine does not contribute to QT.

Symptoms

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

Management

Avoid the combination, especially with parenteral haloperidol. Alternative antipsychotics with minimal α1-blockade: olanzapine or aripiprazole.

Mechanism

Additive hypotension (haloperidol blocks α1-adrenoceptors) and QT prolongation risk (haloperidol is a known QT prolonger).

Symptoms

Lower blood pressure, postural dizziness, syncope. ECG: QT prolongation. Older patients: fall risk.

Management

Avoid the combination, especially parenteral haloperidol. Alternative antipsychotics with minimal α1 and QT effect: olanzapine or aripiprazole. For acute delirium: dexmedetomidine.