What are the potential drug interactions with Haldol (haloperidol)?

Haloperidol Drug Interactions

Haloperidol has clinically significant drug interactions primarily through CYP3A4 metabolism, QT prolongation risk, and CNS depressant effects—avoid strong CYP3A4 inducers (carbamazepine, rifampin, phenytoin, phenobarbital) and strong inhibitors (fluvoxamine), use caution with other QT-prolonging agents, and avoid combining with CNS depressants including alcohol. 1, 2, 3

Critical Contraindications and High-Risk Combinations

Strong CYP3A4 Inducers - AVOID

• Carbamazepine, phenobarbital, phenytoin, and rifampin decrease haloperidol levels by 50-80% and require dose-correction factors of 2-5, making them clinically problematic combinations that should be avoided. 2, 3
• Rifampin specifically decreased plasma haloperidol levels by a mean of 70% in schizophrenic patients, with corresponding worsening of psychiatric symptoms; discontinuation of rifampin produced a 3.3-fold increase in haloperidol concentrations. 1
• If these combinations cannot be avoided, haloperidol doses may need to be increased 2-5 fold, with careful clinical monitoring required. 3

Strong CYP Inhibitors - AVOID OR USE EXTREME CAUTION

• Fluvoxamine should be avoided as it significantly increases haloperidol levels through CYP3A4 and CYP2D6 inhibition. 3
• Combinations of CYP3A4 and CYP2D6 inhibitors should be avoided due to additive effects on haloperidol metabolism. 3
• Promethazine should be avoided due to significant inhibitory effects. 3
• Fluoxetine lacks long-term studies but appears to increase haloperidol levels; use with caution and monitor closely. 3
• Valproate may act as a moderate inhibitor (dose-correction factor 0.6), requiring potential haloperidol dose reduction. 3

Cardiac Interactions - QT Prolongation Risk

QT-Prolonging Medications

• Haloperidol causes mean QT prolongation of 7 ms at usual doses, placing it in the moderate-risk category among antipsychotics. 4
• IV haloperidol carries an FDA non-black box warning due to deaths associated with high doses and IV administration; intramuscular dosing is the preferred parenteral route. 4
• Coadministration with other QT-prolonging medications increases risk of torsades de pointes and sudden death. 4
• Obtain baseline ECG before initiating therapy, especially when combining with other QT-prolonging agents. 5
• Avoid epinephrine for hypotension as haloperidol may block its vasopressor activity and cause paradoxical further blood pressure lowering; instead use metaraminol, phenylephrine, or norepinephrine. 1

High-Risk Cardiac Scenarios

• Use cautiously in patients with severe cardiovascular disorders due to risk of transient hypotension and precipitation of anginal pain. 1
• Monitor patients with electrolyte abnormalities (hypokalemia, hypomagnesemia), bradycardia, or concomitant medications that prolong QT interval. 4

CNS Depressant Interactions

Alcohol and Sedatives

• Haloperidol potentiates CNS depressants including anesthetics, opiates, and alcohol; alcohol use should be avoided due to possible additive effects and hypotension. 1
• Combination with benzodiazepines (lorazepam) showed enhanced efficacy for agitation but requires monitoring for excessive sedation. 4

Anticonvulsants

• Administer cautiously to patients receiving anticonvulsant medications, with history of seizures, or with EEG abnormalities, as haloperidol may lower the convulsive threshold. 1
• Maintain adequate anticonvulsant therapy concomitantly if indicated. 1

Anticholinergic Interactions

• Concomitant anticholinergic drugs (including antiparkinson agents) may increase intraocular pressure when administered with haloperidol. 1
• If antiparkinson medication is required for extrapyramidal symptoms, it may need to be continued after haloperidol discontinuation due to different excretion rates. 1
• Simultaneous discontinuation of both medications may precipitate extrapyramidal symptoms. 1

Lithium Combination - Special Warning

• An encephalopathic syndrome (weakness, lethargy, fever, tremulousness, confusion, extrapyramidal symptoms, leukocytosis, elevated enzymes) followed by irreversible brain damage has occurred in patients treated with lithium plus haloperidol. 1
• Monitor patients receiving combined therapy closely for early evidence of neurological toxicity and discontinue promptly if signs appear. 1

Other Significant Interactions

Anticoagulants

• An isolated instance of interference with phenindione (anticoagulant) effects has been reported; monitor anticoagulation parameters if used concomitantly. 1

Smoking

• Smoking appears to be a weak inducer of haloperidol metabolism with a dose-correction factor of 1.2, potentially requiring modest dose increases in smokers. 3

Haloperidol as Perpetrator

• Haloperidol is a weak CYP2D6 inhibitor and may affect metabolism of CYP2D6 substrates, though clinical significance is limited in most patients. 2, 3

Monitoring Recommendations

• Complete blood count monitoring is required in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia during the first few months of therapy. 1
• Discontinue haloperidol at first sign of WBC decline without other causative factors. 1
• Monitor for extrapyramidal symptoms (acute dystonia, akathisia, Parkinsonian syndrome), which occur more frequently with haloperidol than benzodiazepines (20% incidence in studies). 4
• Assess fall risk due to somnolence, postural hypotension, and motor instability, particularly in elderly patients or those with predisposing conditions. 1