What are the important drug interactions with haloperidol?

Drug Interactions with Haloperidol

Critical QT-Prolonging Drug Combinations

Avoid combining haloperidol with other QT-prolonging agents, particularly in patients with baseline QT prolongation, electrolyte disturbances, or arrhythmia history, to prevent torsades de pointes. 1

• Haloperidol prolongs the QT interval by approximately 7 ms at usual doses, placing it in the moderate-risk category for cardiac arrhythmia 1
• Intravenous haloperidol carries higher QT prolongation risk than intramuscular administration; prefer the IM route for parenteral dosing when feasible 1
• High-risk combinations to avoid include thioridazine (adds 25–30 ms QT), ziprasidone (adds 5–22 ms QT), and other antipsychotics with significant QT effects 1
• Obtain baseline ECG before initiating therapy, especially when combining with other QT-prolonging medications 1
• Monitor patients with electrolyte abnormalities (hypokalemia, hypomagnesemia), bradycardia, or concomitant QT-prolonging medications 1

Common pitfall: Assuming oral haloperidol is safer than IV; the FDA warning applies to all routes, and QT monitoring is required whenever risk factors are present 1

Beneficial Combination: Haloperidol + Benzodiazepines

Combining haloperidol 5 mg with lorazepam 2–4 mg provides superior rapid agitation control compared with either drug alone, but mandates close monitoring for respiratory depression and hypotension. 1, 2

• This combination can be administered in the same syringe for intramuscular use and is physically compatible 2
• The haloperidol-lorazepam regimen yields significantly greater reduction in agitation scores than monotherapy and requires fewer repeat doses 1, 2
• Monitor closely for respiratory depression, hypotension, and excessive sedation when using this combination 1, 2
• Cardiorespiratory monitoring and pulse oximetry should be employed when feasible 2
• Extrapyramidal symptoms occur in approximately 20% of patients receiving haloperidol, higher than with benzodiazepine monotherapy; consider prophylactic or concurrent antiparkinson medication 1

Major CYP-Mediated Drug Interactions

Strong Inducers (Avoid or Significantly Increase Haloperidol Dose)

Carbamazepine, phenobarbital, phenytoin, and rifampin should be avoided as they require dose-correction factors of 2–5 times the usual haloperidol dose. 3

• Rifampin decreases plasma haloperidol levels by a mean of 70%, with corresponding increases in psychiatric symptom scores 4
• Discontinuation of rifampin in haloperidol-treated patients produces a mean 3.3-fold increase in haloperidol concentrations 4
• CYP3A4 is the major isoform responsible for haloperidol metabolism, explaining these interactions 5
• Smoking appears to be a weak inducer requiring a dose-correction factor of 1.2 3

Strong Inhibitors (Avoid or Significantly Reduce Haloperidol Dose)

Fluvoxamine, promethazine, and combinations of CYP3A4 and CYP2D6 inhibitors should be avoided due to risk of excessive haloperidol accumulation. 3

• Valproate may be an inhibitor requiring a dose-correction factor of 0.6 3
• Limited long-term data exists for fluoxetine to provide a reliable dose correction factor 3
• Haloperidol itself is a weak CYP2D6 inhibitor, potentially affecting metabolism of other drugs 3

Interactions with Other Antipsychotics

When combining haloperidol with quetiapine, both drugs prolong QTc interval, requiring baseline and periodic ECG monitoring. 6

• Haloperidol and risperidone do not significantly affect each other's pharmacokinetics 7
• Thioridazine significantly increases oral clearance of quetiapine by 68%, potentially requiring higher quetiapine doses 7
• Monitor for orthostatic hypotension, particularly with quetiapine, which carries higher risk of transient orthostasis 6
• While quetiapine may mitigate haloperidol's extrapyramidal effects, monitor for dystonic reactions, akathisia, and parkinsonism, especially if haloperidol doses exceed 2 mg/day 6

CNS Depressant Interactions

Haloperidol potentiates CNS depressants including anesthetics, opiates, and alcohol, requiring dose adjustments and close monitoring. 4

• Assess for excessive sedation and respiratory depression when combining with any CNS depressant 6
• The combination increases risk compared to single agents 2

Cardiovascular Drug Interactions

If hypotension occurs requiring a vasopressor, do not use epinephrine; instead use metaraminol, phenylephrine, or norepinephrine. 4

• Haloperidol may block epinephrine's vasopressor activity, causing paradoxical further lowering of blood pressure 4
• Administer cautiously to patients with severe cardiovascular disorders due to possibility of transient hypotension and/or precipitation of anginal pain 4

Anticoagulant Interactions

Monitor anticoagulation closely, as isolated instances of interference with anticoagulant effects (phenindione) have been reported. 4

Anticonvulsant Considerations

Administer cautiously to patients receiving anticonvulsant medications, as haloperidol may lower the convulsive threshold. 4

• Maintain adequate anticonvulsant therapy concomitantly if indicated 4

Anticholinergic Drug Interactions

If concomitant antiparkinson medication is required, it may need to be continued after haloperidol discontinuation due to different excretion rates. 4

• Keep in mind possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with haloperidol 4
• If both haloperidol and antiparkinson medication are discontinued simultaneously, extrapyramidal symptoms may occur 4

Hematologic Monitoring Requirements

Patients with preexisting low white blood cell count or history of drug-induced leukopenia/neutropenia should have complete blood count monitored frequently during the first few months of therapy. 4

• Discontinue haloperidol at the first sign of WBC decline in the absence of other causative factors 4
• Patients with severe neutropenia (absolute neutrophil count < 1,000/mm³) should discontinue haloperidol and have WBC followed until recovery 4