Version December 2023
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration, 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was approximately 4.5%, compared with a rate of approximately 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Haloperidol is not approved for the treatment of patients with dementia-related psychosis.
Dosage guidance:
Safety: IV administration is associated with dose-dependent QT prolongation at doses >2 mg and the risk of rare, but potentially fatal, cardiac arrhythmia; increased monitoring is necessary prior to and during administration (Ref).
Dosing: All doses are expressed as the equivalent amounts of haloperidol base. Although manufacturer's labeling includes a maximum dose of up to 100 mg/day, doses >30 mg/day are in general not recommended (Ref).
Clinical considerations: Concomitant IM or IV antiparkinsonism medications (eg, benztropine, diphenhydramine) may be useful for preventing acute dystonic reactions to short-acting IM/IV haloperidol (Ref).
Agitation/Aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia), substance intoxication, or other organic causes (off-label use): Note: Antipsychotics are appropriate when psychosis is suspected to be the primary cause of agitation/aggression (Ref). Avoid in suspected or confirmed intoxications with anticholinergic substances; other agents are used preferentially in some intoxications (eg, stimulants) or alcohol withdrawal. Depending on presentation, may combine with a benzodiazepine (Ref).
IM, IV (off-label route) (lactate injection): 2 to 10 mg; repeat dose every ≥15 minutes until acute symptoms are controlled; once acute symptoms are controlled, may repeat every 0.5 to 6 hours as needed; up to 30 mg/day (Ref).
Oral: 2 to 10 mg; repeat dose every 6 hours as needed; up to 30 mg/day. A lower initial dose of 0.5 to 1 mg may be sufficient for some patients (Ref).
Bipolar disorder:
Acute mania, episodes with mixed features and acute hypomania (either as monotherapy or as adjunctive therapy) (off-label use): Note: Haloperidol may worsen depressive symptoms. It is not recommended for the treatment of acute bipolar major depression or for maintenance in bipolar disorder (Ref).
Oral: Initial: 2 to 15 mg/day or 0.2 mg/kg/day (up to 15 mg/day), in 1 or 2 divided doses. May increase dose based on response and tolerability in increments of ≤5 mg as frequently as every 2 days up to 30 mg/day (Ref).
Delirium, hyperactive (treatment): Note: Nonpharmacologic interventions and treatment of underlying conditions are initial steps to prevent and manage delirium. Antipsychotics may be used as short-term adjunctive treatment if distressing symptoms (eg, agitation, anxiety, combative behavior) are present (Ref). Reassess daily for continued need; consider discontinuation and/or taper as symptoms resolve, especially at transitions of care to prevent unnecessary continuation of therapy (Ref).
ICU (off-label use): IV (off-label route), IM (lactate injection): Initial range: 0.5 to 20 mg depending on degree of agitation (mild: 0.5 to 2.5 mg; moderate: 2 to 5 mg; severe: 10 to 20 mg); if inadequate response, may repeat or increase bolus dose every 15 to 30 minutes until calm achieved, then administer a maintenance dose (~25% of total loading dose needed to achieve calm) every 6 to 12 hours if needed (Ref). Note: Continuous infusions have been used for refractory symptoms; regimens vary. One regimen includes an optional loading dose of 2.5 mg, followed by 0.5 to 2 mg/hour (Ref).
Non-ICU (off-label use): IM, IV (off-label route) (lactate injection), Oral: Initial: 0.5 to 1 mg; if needed, may repeat every 30 minutes until calm. Maximum 5 mg/day (Ref).
Nausea and vomiting in advanced or terminal illness (palliative care) (alternative agent) (off-label use): Note: Identify and treat potentially reversible causes; used in conjunction with other agents/treatments in bowel obstruction-associated symptoms (Ref).
IV, SubQ (off-label routes) (lactate injection), Oral: 0.5 to 2 mg every 6 to 8 hours; for nausea associated with bowel obstruction, may titrate up to 20 mg/day IV in divided doses if needed (Ref).
Continuous SubQ infusion (off-label route) (lactate injection): Typical range for initial treatment: 1 to 5 mg per 24 hours (Ref).
Postoperative nausea and vomiting, prevention, moderate- to high-risk patients (alternative agent) (off-label use): Note: In general, combined with one or more other prophylactic interventions.
IV (off-label route) (lactate injection): 0.5 to 2 mg as a single dose after induction of anesthesia or at the end of surgery (Ref).
Schizophrenia:
Oral, IM, IV (lactate injection; off-label route [IV]): Initial: 2 to 10 mg/day in 1 to 3 divided doses; adjust dose based on response and tolerability to a usual dose of 2 to 20 mg/day (typically ≤10 mg/day). Doses >30 mg/day are not recommended (Ref). Note: In a first psychotic episode, a lower dose (eg, 1 to 4 mg/day) may be sufficient (Ref).
IM (decanoate ER suspension): Note: Establish tolerability using oral haloperidol prior to initiating IM decanoate injection.
Regimen with overlapping of oral haloperidol:
Initial: 10 to 20 times the daily oral dose. If the initial dose conversion requires >100 mg ER injection, administer the dose in 2 injections with a maximum of 100 mg for first injection and the remainder given in 3 to 7 days. Maximum total initial dose: 450 mg.
Oral overlap: Following the first ER decanoate dose, taper the oral dose by ~25% at weekly intervals during the second or third month of decanoate treatment. Adjust oral dose and rate of tapering based on clinical response and tolerability (Ref).
Maintenance dose: Adjust dose based on response and tolerability; usual maintenance dose is 10 to 15 times the previous daily oral dose administered at 4-week intervals. Maximum dose: 450 mg every 4 weeks.
Alternative regimen without overlap of oral haloperidol: Note: Discontinue oral haloperidol immediately prior to the first injection when using this regimen.
Initial: 20 times the daily oral dose. If the initial dose conversion requires >100 mg ER injection, administer the dose in 2 injections with a maximum of 100 mg for the first injection and the remainder given in 3 to 7 days.
Maintenance dose: Reduce the ER decanoate dose during the second and third months (eg, by ~25% each month), then continue to adjust based on response and tolerability (Ref). Usual maintenance dose is 10 to 15 times the previous daily oral dose administered at 4-week intervals. Maximum dose: 450 mg every 4 weeks (Ref).
Tourette syndrome, management of tics (alternative agent): Oral: Initial: 1 to 2 mg/day in 1 to 3 divided doses; may increase dose based on response and tolerability in increments of 0.5 to 2 mg every 2 to 3 days up to 12 mg/day. Note: Although manufacturer's labeling includes a maximum dose of up to 100 mg/day, doses ≥12 mg/day are not recommended (Ref).
Dosing conversion:
IM (lactate injection) to oral: Use the total IM (as lactate) dose administered in the preceding 24 hours as an initial approximation of the total daily dose requirement for the oral formulation. Initiate the first oral dose within 12 to 24 hours of the last IM (as lactate) dose. Adjust dose based on response and tolerability. Note: Bioavailability of oral administration is about 60% to 70% relative to short-acting lactate injection; dose adjustment may be needed when switching from short-acting injection to oral (Ref).
Oral to IM (as decanoate): See Schizophrenia dosing.
Discontinuation of therapy:
Oral: In the treatment of chronic psychiatric disease, switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (ie, over several weeks to months) is advised to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (Ref).
Long-acting injectable: Switching to other treatments is generally advised if side effects are intolerable or treatment is not effective. However, if a patient insists on stopping treatment, gradual dose reduction to avoid withdrawal reactions is generally not needed with long-acting injectable antipsychotics. The risk of withdrawal symptoms from discontinuation of long-acting injectables is low because the rate of drug elimination is slow. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (Ref).
Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Ref). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: Mild to severe impairment: No dosage adjustment necessary (~1% of drug eliminated in urine) (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (large volume of distribution): No supplemental dose or dosage adjustment necessary (Ref); use with caution.
Peritoneal dialysis: Unlikely to be dialyzed (large volume of distribution): No dosage adjustment necessary (Ref); use with caution.
CRRT: Unlikely to be dialyzed (large volume of distribution): No dosage adjustment necessary (Ref).
PIRRT (eg, sustained low-efficiency diafiltration): Unlikely to be dialyzed (large volume of distribution): No dosage adjustment necessary (Ref).
There are no dosage adjustments provided in the manufacturer's labeling; however, haloperidol concentrations may increase in patients with hepatic impairment because it is primarily metabolized by the liver and protein binding may decrease.
Refer to adult dosing for indication-specific dosing. For hyperactive delirium or acute agitation, consider dosages in the lower initial range of recommended adult dosing (eg, 0.5 to 1 mg) and increase monitoring due to greater risks for adverse effects, including sedation and QTc prolongation (Ref). Dosages in the lower range of recommended adult dosing are generally sufficient with late-onset schizophrenia or psychosis (Ref).
(For additional information see "Haloperidol: Pediatric drug information")
Dosage guidance:
Dosing: Individualize dosing based on patient response. Gradually decrease dose to the lowest effective maintenance dosage once a satisfactory therapeutic response is obtained. Dosing presented as fixed (mg) dosing and weight-based (mg/kg) dosing; use caution when prescribing and dispensing.
Acute agitation: Limited data available:
Oral: Recommended for acute agitation in patients with suspected ethanol, benzodiazepine, or unknown intoxication, a known psychiatric disorder, hallucinations, or unknown etiology (Ref).
Weight-directed: Children and Adolescents: Oral: 0.025 to 0.075 mg/kg/dose; may repeat dose every 1 to 2 hours; not to exceed maximum daily dose: Patients ≤40 kg: 6 mg/day; patients >40 kg: 15 mg/day. In adults, usual total dose required is 10 to 20 mg (Ref).
Fixed dose: Oral: Children: 0.5 to 2 mg; Adolescents: 2 to 5 mg; may repeat dose every 1 to 2 hours; not to exceed maximum daily dose: Patients ≤40 kg: 6 mg/day; patients >40 kg: 15 mg/day. In adults, usual total dose required is 10 to 20 mg (Ref).
Parenteral: Recommended for acute agitation in patients with psychosis or mania, or suspected ethanol, benzodiazepine, or unknown intoxication, a known psychiatric disorder, hallucinations, or unknown etiology (Ref); if extrapyramidal symptoms (EPS) are a concern, consider concomitant diphenhydramine.
Weight-directed: Children and Adolescents: IM (lactate, immediate release): 0.025 to 0.075 mg/kg/dose; may repeat dose every 20 to 30 minutes; not to exceed maximum daily dose: Patients ≤40 kg: 6 mg/day; patients >40 kg: 15 mg/day. In adults, usual total dose required is 10 to 20 mg (Ref).
Fixed dose: Children and Adolescents: IM (lactate, immediate release): Children: 0.5 to 2 mg; Adolescents: 2 to 5 mg; may repeat dose every 20 to 30 minutes; not to exceed maximum daily dose: Patients ≤40 kg: 6 mg/day; patients >40 kg: 15 mg/day. In adults, usual total dose required is 10 to 20 mg (Ref).
Agitation (palliative care): Limited data available: Children ≥3 years and Adolescents: Oral: 0.01 mg/kg/dose 3 times daily as needed; to manage new-onset acute episode: 0.025 to 0.05 mg/kg once then may repeat 0.025 mg/kg/dose in one hour as needed (Ref).
Behavior disorders, nonpsychotic:
Note: For treatment of bipolar disorder (acute mania, nonpsychotic), haloperidol is not considered first line; initially second-generation antipsychotics and mood stabilizers are preferred (Ref). For management of disruptive behavior disorders without psychosis, therapy typically initiated with stimulants; haloperidol (first-generation antipsychotics) is no longer routinely used as initial therapy but may be necessary in refractory or complex cases (Ref).
Children ≥3 years and Adolescents: Limited data available in ages >12 years: Oral: Initial: 0.5 mg/day in 2 to 3 divided doses; may increase total daily dose by 0.5 mg every 5 to 7 days to usual maintenance range of 0.05 to 0.075 mg/kg/day in 2 to 3 divided doses; in the management of disruptive behavior disorders, a range of 0.5 to 10 mg/day has been suggested; maximum daily dose for patients 3 to 12 years of age and ≤40 kg: 6 mg/day in divided doses (children with severe, nonpsychotic disturbance did not show improvement with doses >6 mg/day); a maximum daily dose of 15 mg/day in divided doses has been suggested in adolescents with psychosis (Ref).
Delirium, critical care setting: Limited data available; optimal dose not established:
Note: Antipsychotics may be used as short-term adjunctive treatment; reassess frequently for continued need and consider taper/discontinuation as symptoms resolve (Ref). The administration of IV haloperidol is associated with QT prolongation and torsades de pointes; in adults without concomitant risk factors, this effect is dose dependent and was reported with cumulative IV doses ≥2 mg; in all patients, increased monitoring is necessary at baseline and during administration (Ref); ensure appropriate monitoring including extrapyramidal symptoms (EPS) effects.
Infants ≥3 months, Children, and Adolescents: IV (lactate, immediate release): Note: Reported experience in infants is very limited and suggests that lower doses may be required:
Loading dose: Note: Dosing is presented as a fixed dose (not a weight-based dose).
Weight 3.5 to <10 kg: IV: 0.05 mg (fixed dose) infused slowly over 30 to 45 minutes; may repeat twice for a maximum of 3 total doses (Ref).
Weight ≥10 kg: IV: 0.15 to 0.25 mg (fixed dose) infused slowly over 30 to 45 minutes; may repeat twice for a maximum of 3 total doses (Ref).
Maintenance dose: Note: Dosing is presented as weight-based dosing (ie, mg/kg/day) administered in divided doses:
Note: Use lowest effective dose, evaluate delirium symptoms daily, optimize nonpharmacologic treatments and discontinue/titrate therapy after clinical improvement and resolution (Ref):
Weight 3.5 to <10 kg: IV: Initial: 0.01 to 0.05 mg/kg/day in divided doses every 6 to 24 hours; may increase dose based on clinical response; higher doses have been associated with an increased incidence of EPS and sedation (Ref).
Weight ≥10 kg: IV: Initial: 0.05 to 0.5 mg/kg/day in divided doses every 6 to 24 hours; may increase dose based on clinical response; higher doses have been associated with an increased incidence of EPS and sedation; a maximum single pediatric dose is not defined in the literature; in adults, single doses of 10 mg are reserved for severe cases of delirium and up to 20 mg in some cases (Ref).
Psychotic disorders: Note: Not generally used as initial therapy for management of schizophrenia in pediatric patients; second-generation (atypical) antipsychotics typically preferred first line (Ref).
Children ≥3 years and Adolescents: Limited data available in ages >12 years: Oral: Initial: 0.5 mg/day in 2 to 3 divided doses; increase total daily dose by 0.5 mg every 5 to 7 days to usual maintenance range of 0.05 to 0.15 mg/kg/day in 2 to 3 divided doses; in pediatric schizophrenia efficacy trials (reported mean ages: 9 to 16 years), a mean dose range of 8 to 10 mg/day was reported; higher doses may be necessary in severe or refractory cases; maximum dose not established in children; in adolescents, maximum daily dose: 15 mg/day (Ref).
Tourette syndrome, tic disorder: Note: Compared to placebo, haloperidol is probably more likely than placebo to reduce tic severity; a higher risk of drug-induced movement disorders (compared to placebo) was observed in Tourette syndrome/tic trials with haloperidol; may be considered when treatment benefits outweigh risks (Ref).
Children ≥3 years and Adolescents: Oral: Initial: 0.25 to 0.5 mg/day in 2 to 3 divided doses; increase daily dose by 0.25 to 0.5 mg every 5 to 7 days to usual daily dose maintenance range of 1 to 4 mg/day in 2 to 3 divided doses has been reported (weight-directed maintenance per the manufacturer: 0.05 to 0.075 mg/kg/day in 2 to 3 divided doses); maximum daily dose: 15 mg/day; however, children with severe, nonpsychotic disturbance did not show improvement with doses >6 mg/day (Ref).
Discontinuation of psychosis therapy: Children and Adolescents: The manufacturer and American Academy of Child and Adolescent Psychiatry (AACAP), American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), National Institute for Health and Care Excellence (NICE), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (Ref); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic antipsychotics (Ref). When stopping antipsychotic therapy in patients with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months and the APA guidelines recommend reducing the dose by 10% each month (Ref). Continuing antiparkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Ref). When switching antipsychotics, three strategies have been suggested: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence supporting ideal switch strategies and taper rates is limited and results are conflicting (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥3 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling.
Hemodialysis/peritoneal dialysis: Supplemental dose is not necessary.
Children ≥3 years and Adolescents: There are no dosage adjustments provided in manufacturer's labeling.
Haloperidol commonly causes extrapyramidal symptoms (EPS), also known as drug-induced movement disorders, in all ages (Ref). Antipsychotics can cause 4 main EPS: Acute dystonia, drug-induced parkinsonism, akathisia, and tardive dyskinesia (Ref). EPS presenting as dysphagia, esophageal dysmotility, or pulmonary aspiration, have also been reported with antipsychotics, which may not be recognized as EPS (Ref).
Mechanism: EPS: Dose-related; due to antagonism of dopaminergic D2 receptors in nigrostriatal pathways; high levels of dopamine 2 receptor occupancy have been observed for haloperidol (Ref). Tardive dyskinesia: Time related (delayed); results from chronic exposure to dopamine 2 receptor antagonists leading to up-regulation of these receptors over time (Ref).
Onset:
Antipsychotics in general:
Acute dystonia: Rapid; in the majority of cases, dystonia usually occurs within the first 5 days after initiating antipsychotic therapy (and even with the first dose, particularly in patients receiving parenteral antipsychotics) or a dosage increase (Ref).
Drug-induced parkinsonism: Varied; onset may be delayed from days to weeks, with 50% to 75% of cases occurring within 1 month and 90% within 3 months of antipsychotic initiation, a dosage increase, or a change in the medication regimen (such as adding another antipsychotic agent or discontinuing an anticholinergic medication) (Ref).
Akathisia: Varied; may begin within several days after antipsychotic initiation but usually increases with treatment duration, occurring within 1 month in up to 50% of cases, and within 3 months in 90% of cases (Ref).
Tardive dyskinesia: Delayed; symptoms usually appear after 1 to 2 years of continuous exposure to a dopamine 2 receptor antagonist, and almost never before 3 months, with an insidious onset, evolving into a full syndrome over days and weeks, followed by symptom stabilization, and then a chronic waxing and waning of symptoms (Ref).
Esophageal dysfunction (associated with EPS): Varied; ranges from weeks to months following initiation (Ref)
Risk factors:
EPS (in general):
• Prior history of EPS (Ref)
• Higher doses (Ref)
• Specific antipsychotic: Haloperidol has a high propensity to cause EPS (Ref)
Acute dystonia:
• Males (Ref)
• Young age (Ref)
Drug-induced parkinsonism:
• Females (Ref)
• Older patients (Ref)
Akathisia:
• Higher antipsychotic dosages (Ref)
• Polypharmacy (Ref)
• Mood disorders (Ref)
• Females (Ref)
• Older patients (Ref)
Tardive dyskinesia:
• Age >55 year (Ref)
• Cognitive impairment (Ref)
• Concomitant treatment with anticholinergic medications (Ref)
• Diabetes (Ref)
• Diagnosis of schizophrenia or affective disorders (Ref)
• Female sex (Ref)
• Greater total antipsychotic exposure (especially first-generation antipsychotics) (Ref)
• History of extrapyramidal symptoms (Ref)
• Substance misuse or dependence (Ref)
• Race (White or African descent). Note: Although early literature supported race as a potential risk factor for tardive dyskinesia (Morgenstern 1993), newer studies have challenged this assertion (Ref).
Esophageal dysfunction (associated with EPS):
• Certain comorbidities such as neurologic degenerative disease, dementia, stroke, Parkinson disease, or myasthenia gravis (Ref)
• Older adults >75 years of age (may be risk factor due to age-related muscle atrophy, cognitive impairment, reduced esophageal peristalsis) (Ref)
Leukopenia, neutropenia, and thrombocytopenia have been reported rarely with haloperidol (Ref). Agranulocytosis and pancytopenia have also been reported very rarely (Ref).
Mechanism: Unclear and poorly understood (Ref).
Onset: Varied; in general, drug-induced neutropenia usually manifests after 1 or 2 weeks of exposure and agranulocytosis usually appears 3 to 4 weeks following initiation of therapy; however, the onset may be insidious (Ref).
Risk factors:
• History of drug-induced leukopenia/neutropenia or preexisting low WBC or absolute neutrophil count
• Older adults (Ref)
Haloperidol commonly causes hyperprolactinemia, which may lead to gynecomastia, galactorrhea not associated with childbirth, amenorrhea, sexual disorder, and infertility (Ref). Although long-term effects of antipsychotic-induced elevated prolactin levels have not been fully evaluated, some studies have also suggested a possible association between hyperprolactinemia and an increased risk for breast and/or pituitary tumors and osteopenia/osteoporosis (Ref).
Mechanism: Dose-related (although a dose response is not consistently observed) and possibly time-related; antagonism of dopamine D2 receptors in the tuberoinfundibular dopaminergic pathway which causes disinhibition of prolactin release resulting in hyperprolactinemia (Ref). Haloperidol has been shown to have a strong D2 receptor occupancy and antagonistic properties in the pituitary (Ref).
Onset: Varied; onset is typically within a few days or weeks following initiation or a dosage increase and usually persists throughout treatment (although partial tolerance may develop). Onset may also arise after long-term stable use (Ref).
Risk factors:
• Specific antipsychotic: Haloperidol is considered to be a prolactin-elevating antipsychotic with an intermediate to high risk for hyperprolactinemia (Ref)
• Higher doses (Ref)
• Females (particularly those of reproductive age) (Ref)
• Younger patients (Ref)
All antipsychotics are associated with metabolic syndrome, which is comprised of significant weight gain (increase of ≥7% from baseline), hyperglycemia, diabetes mellitus, dyslipidemia, and hypertension. Although metabolic abnormalities are usually associated with second-generation (atypical) antipsychotics, the syndrome also occurs in varying degrees with the first-generation (typical) antipsychotics, including haloperidol (Ref).
Mechanism: The mechanism for metabolic abnormalities and weight gain is not entirely understood and is likely multifactorial. Multiple proposed mechanisms, including actions at serotonin, dopamine, histamine, and muscarinic receptors, with differing effects explained by differing affinity of antipsychotics at these receptors (Ref).
Onset: Weight gain: Varied; antipsychotic-induced weight gain usually occurs rapidly in the initial period following initiation, then gradually decreases and flattens over several months with patients continuing to gain weight in the long term (Ref).
Risk factors:
Weight gain:
• Family history of obesity (Ref)
• Parental BMI (Ref)
• Children and adolescents (Ref)
• Rapid weight gain in the initial period: Younger age, lower baseline BMI, more robust response to antipsychotic and increase in appetite; rapid weight gain of >5% in the first month has been observed as the best predictor for significant long-term weight gain (Ref)
• Duration of therapy (although weight gain plateaus, patients continue to gain weight over time) (Ref)
• Schizophrenia, regardless of medication, is associated with a higher prevalence of obesity compared to the general population due to components of the illness such as negative symptoms, sedentary lifestyles, unhealthy diets (Ref)
• Specific antipsychotic: Haloperidol is usually associated with a low propensity for causing weight gain (Ref)
Lipid/glucose metabolism abnormalities:
• Specific antipsychotic: Haloperidol is usually associated with low risk of causing lipid and/or glucose metabolism abnormalities (Ref)
Older adults with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature (Ref). For haloperidol specifically, increased risk of mortality has also been observed with the cause of death varying and attributed to a number of causes including pneumonia, acute myocardial infarction, venous thromboembolism, stroke, hip fracture, and cardiac arrhythmias (Ref). Of note, haloperidol is not approved for the treatment of dementia-related psychosis.
Mechanism: Unknown; possible mechanisms include arrhythmia, cardiac arrest, and extrapyramidal effects that may increase the risk of falls, aspirations, and pneumonia. In addition, haloperidol has been found to induce apoptosis and cause neurotoxicity, which also may play a role (Ref).
Risk factors:
• Antipsychotic class (a higher risk of increased mortality has been observed for first-generation antipsychotics, and haloperidol specifically, compared to second-generation antipsychotics) (Ref)
• Higher antipsychotic dosage (Ref)
• Dementia-related psychosis (eg, Lewy body dementia, Parkinson disease dementia)
• Older adults
All antipsychotics have been associated with neuroleptic malignant syndrome (NMS) in all ages. First-generation antipsychotic-associated NMS seems to occur at a higher frequency, severity, and lethality compared to second-generation antipsychotic-associated NMS (Ref). There are numerous reports of NMS occurring with haloperidol, either as monotherapy or in combination with other medications (Ref).
Mechanism: Non-dose-related; idiosyncratic. Believed to be due to a reduction in CNS dopaminergic tone, along with the dysregulation of autonomic nervous system activity (Ref).
Onset: Varied; in general, most patients develop NMS within 2 weeks of initiating an antipsychotic or a dosage increase, and in some patients, prodromal symptoms emerge within hours of initiation; once the syndrome starts, the full syndrome usually develops in 3 to 5 days (Ref). However, there are many cases of NMS occurring months after stable antipsychotic therapy (Ref).
Risk factors:
Antipsychotics in general:
• Antipsychotic class: First-generation antipsychotics seem to have a higher risk of NMS compared to atypical antipsychotics (Ref)
• Specific antipsychotic: Potent agents such as haloperidol are thought to confer the greatest risk (Ref)
• Males (twice as likely to develop NMS compared to females) (Ref)
• Dehydration (Ref)
• High-dose antipsychotic treatment (Ref)
• Concomitant lithium or benzodiazepine (potential risk factors) (Ref)
• Catatonia (Ref)
• Polypharmacy (Ref)
• Pharmacokinetic interactions (Ref)
• IM administration (Ref)
• Rapid dosage escalation (Ref)
• Psychomotor agitation (Ref)
Haloperidol has been associated with a prolonged QT interval on ECG, torsades de pointes (TdP), and sudden cardiac death in all ages (Ref). In general, intravenous haloperidol is associated with a higher risk of QTc prolongation than the oral and IM route; however, the higher risk attributed to intravenous haloperidol has been questioned and recent evidence suggests it have been confounded by its use in medically ill patients with concomitant risk factors (Ref).
Mechanism: Haloperidol prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current (Ikr) (Ref).
Risk factors:
Drug-induced QTc prolongation/TdP (in general):
• Females (Ref)
• Age >65 years (Ref)
• Structural heart disease (eg, history of myocardial infarction or heart failure with a reduced ejection fraction) (Ref)
• History of drug-induced TdP (Ref)
• Genetic defects of cardiac ion channels (Ref)
• Congenital long QT syndrome (Ref)
• Baseline QTc interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 msec (Ref)
• Electrolyte disturbances (eg, hypokalemia, hypocalcemia, hypomagnesemia) (Ref)
• Bradycardia (Ref)
• Hepatic impairment (Ref)
• Kidney impairment (Ref)
• Co-administration of multiple medications (≥2) that prolong the QT interval or increase drug interactions that increase serum drug concentrations of QTc prolonging medications (Ref)
• Substance use (Ref)
Haloperidol may lower the seizure threshold and cause seizures rarely, although evidence is weak and limited (Ref).
Mechanism: Mechanism is unknown although a role of dopamine has been suggested (Ref).
Risk factors :
Antipsychotics in general:
• History of seizure activity (Ref)
• Concurrent use of drugs that lower seizure threshold (Ref)
• Rapid dose titration or sudden increase in dose (Ref)
• Slow drug metabolism (Ref)
• Metabolic factors (Ref)
• Drug-drug interactions (Ref)
• Organic brain disorders (Ref)
Antipsychotics have been associated with sexual disorders in both males and females. Antipsychotic treatment has been associated with effects on all phases of sexual activity (libido, arousal, and orgasm); however, many patients with schizophrenia experience more frequent sexual dysfunction, with or without antipsychotic treatment. The following adverse reactions have been observed with haloperidol: Decreased libido, erectile dysfunction, and orgasm abnormal (Ref).
Mechanism: Antipsychotic-induced sexual dysfunction has been attributed to many potential mechanisms, including dopamine receptor antagonism, dopamine D2 receptor antagonism in the hypothalamic infundibular system causing hyperprolactinemia, histamine receptor antagonism, cholinergic receptor antagonism, and alpha-adrenergic receptor antagonism (Ref). Of note, haloperidol is associated with a high propensity for elevating prolactin (Ref).
Risk factors:
• Hyperprolactinemia (although a correlation with sexual dysfunction has been observed, a relationship has not been confirmed) (Ref)
• Schizophrenia (the prevalence of antipsychotic-induced sexual dysfunction in patients with schizophrenia is high [~50% to 60% compared with 31% of men in the general population]) (Ref)
• Specific antipsychotic: Some studies have observed a high prevalence of sexual dysfunction with haloperidol (Ref)
Antipsychotics may impair the body's ability to regulate core body temperature, which may cause a potentially life-threatening heat stroke during predisposing conditions such a heat wave or strenuous exercise. There are also several case reports of potentially life-threatening hypothermia associated with haloperidol use (Ref).
Mechanism: Non-dose-related; idiosyncratic. Exact mechanism is unknown; however, body temperature is regulated by the hypothalamus with involvement of the dopamine, serotonin, and norepinephrine neurotransmitters. D2 antagonism may cause an increase in body temperature, while 5-HT2A (serotonin) receptor antagonism may cause a decrease in body temperature. In addition, antagonism of peripheral alpha-adrenergic receptors has also been suggested as a factor in the hypothermic effect, by inhibiting peripheral responses to cooling (vasoconstriction and shivering) (Ref).
Onset: Hypothermia: Varied; antipsychotic-induced hypothermia cases indicate a typical onset in the period shortly after initiation of therapy or a dosage increase (first 7 to 10 days) (Ref).
Risk factors:
Heat stroke:
• Psychiatric illness (regardless of medication use) (Ref)
• Dehydration (Ref)
• Strenuous exercise (Ref)
• Heat exposure (Ref)
• Concomitant medication possessing anticholinergic effects (Ref)
Hypothermia:
• In general, predisposing risk factors include: Older adults, cerebrovascular accident, preexisting brain damage, hypothyroidism, malnutrition, shock, sepsis, adrenal insufficiency, diabetes, disability, burns, exfoliative dermatitis benzodiazepine use, polypharmacy, alcohol intoxication, immobility, kidney or liver failure (Ref)
• Schizophrenia (regardless of antipsychotic use) (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Nervous system: Extrapyramidal reaction, parkinsonism
1% to 10%:
Gastrointestinal: Abdominal pain, constipation, sialorrhea, xerostomia
Nervous system: Akathisia, akinesia, drowsiness, dystonia, headache, hypertonia, tremor
Neuromuscular & skeletal: Bradykinesia, hyperkinetic muscle activity
Ophthalmic: Oculogyric crisis
<1%:
Cardiovascular: Hypotension, orthostatic hypotension, tachycardia
Dermatologic: Acneiform eruption
Endocrine & metabolic: Heavy menstrual bleeding, weight gain
Genitourinary: Dysmenorrhea, mastalgia
Local: Injection-site reaction
Nervous system: Cogwheel rigidity, dizziness, mask-like face, restlessness, sedated state, trismus
Neuromuscular & skeletal: Dyskinesia, hypokinesia, muscle rigidity, muscle twitching, torticollis
Ophthalmic: Blurred vision, nystagmus disorder
Frequency not defined:
Dermatologic: Diaphoresis
Endocrine & metabolic: Hyperglycemia, hyponatremia, increased libido, menstrual disease
Gastrointestinal: Anorexia, diarrhea, dyspepsia
Genitourinary: Breast engorgement, impotence, lactation
Nervous system: Anxiety, euphoria, lethargy, psychotic symptoms (exacerbation), vertigo
Ophthalmic: Cataract, retinopathy, visual disturbance
Respiratory: Increased depth of respiration
Postmarketing:
Cardiovascular: Edema, extrasystoles (Mehta 1979), hypertension, prolonged QT interval on ECG (Douglas 2000), torsades de pointes (O’Brien 1999, Tisdale 2020), ventricular arrhythmia (Mehta 1979), ventricular fibrillation (Douglas 2000), ventricular tachycardia
Dermatologic: Alopecia, exfoliative dermatitis, hyperhidrosis, maculopapular rash, pruritus, skin photosensitivity, skin rash, urticaria (Balai 2017)
Endocrine & metabolic: Amenorrhea (Bobes 2003), decreased libido (Bobes 2003), galactorrhea not associated with childbirth (Bobes 2003), gynecomastia (Bobes 2003), heatstroke, hyperammonemia, hyperprolactinemia (Crawford 1997), hypoglycemia (Couto 2019), SIADH, weight loss
Gastrointestinal: Cholestasis, dysphagia (Dziewas 2007), nausea, vomiting
Genitourinary: Erectile dysfunction (Bobes 2003), orgasm abnormal (Bobes 2003), priapism, sexual disorder (Bobes 2003), urinary retention
Hematologic & oncologic: Agranulocytosis (Jurivich 1987), anemia, leukocytosis (Youniss 2021), leukopenia (Cutler 1979), lymphocytosis with monocytosis, neutropenia (Şahan 2019), pancytopenia (Remelli 2020), thrombocytopenia (Remelli 2020)
Hepatic: Acute hepatic failure, hepatic insufficiency, hepatitis, jaundice
Hypersensitivity: Anaphylaxis, angioedema (Masiran 2017, Muzyk 2012), facial edema (Balai 2017), hypersensitivity angiitis (Lee 1999), hypersensitivity reaction
Local: Abscess at injection site
Nervous system: Agitation, confusion, depression, dystonic reaction (laryngeal) (Christodoulou 2005), hyperthermia (Bach 1985), hypothermia (Harada 1994), insomnia, motor dysfunction, neonatal withdrawal (Sexson 1989), neuroleptic malignant syndrome (Seitz 2009), opisthotonus, seizure (Bloechlinger 2015)
Neuromuscular & skeletal: Laryngospasm, rhabdomyolysis (Marsh 1995), tardive dyskinesia (Correll 2004), tardive dystonia
Respiratory: Bronchopneumonia, bronchospasm (Sethna 1991), dyspnea, exacerbation of asthma (can be severe) (Kuo 2022), laryngeal edema, pulmonary aspiration (Dziewas 2007)
Miscellaneous: Fever (Youniss 2021)
Hypersensitivity to haloperidol or any component of the formulation; Parkinson disease; severe CNS depression; coma; dementia with Lewy bodies
Canadian labeling: Additional contraindications (not in US labeling): Significant depressive states; previous spastic diseases; young children
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with severe cardiovascular disease because of the possibility of transient hypotension and/or precipitation of angina pain.
• Bipolar disorder: Use with caution in patients with bipolar disorder; when used to control mania, there may be a rapid mood swing to depression. Haloperidol does not possess antidepressant effects (Cipriani 2006).
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Mehrizi 2012).
• Parkinson disease: Haloperidol is contraindicated in patients with Parkinson disease; these patients are reported to be more sensitive to antipsychotic medications and use may result in severe extrapyramidal symptoms, confusion, sedation, and falls.
• Thyroid dysfunction: Avoid in thyrotoxicosis; severe neurotoxicity (rigidity, inability to walk or talk) may occur with use.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• Sesame oil: Some decanoate products may contain sesame oil.
Other warnings/precautions:
• Discontinuation of therapy: When discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).
• Parenteral administration: Hypotension may occur, particularly with parenteral administration. Although the short-acting form (lactate) is used clinically intravenously, the IV use of the injection is not an FDA-approved route of administration; the decanoate form should never be administered intravenously.
For the management of delirium in pediatric patients, intravenous haloperidol has been widely studied for efficacy and has been frequently used due to lower sedative effects and rapid onset of action; however, its use is associated with adverse effects (Harrison 2006; Slooff 2014; Turkel 2014). Newer atypical antipsychotics have shown similar efficacy with less adverse effects and are being utilized more frequently. Intravenous haloperidol for delirium may be considered in patients that are unresponsive to an atypical agent or who require intravenous therapy; ECG monitoring could be considered (Turkel 2014).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Concentrate, Oral, as lactate [strength expressed as base]:
Generic: 2 mg/mL (5 mL, 15 mL, 120 mL)
Solution, Intramuscular, as decanoate [strength expressed as base]:
Haldol Decanoate: 50 mg/mL (1 mL); 100 mg/mL (1 mL) [contains benzyl alcohol, sesame oil]
Generic: 50 mg/mL (1 mL, 5 mL); 100 mg/mL (1 mL, 5 mL)
Solution, Injection, as lactate [strength expressed as base]:
Haldol: 5 mg/mL (1 mL [DSC])
Generic: 5 mg/mL (1 mL, 10 mL)
Solution, Injection, as lactate [strength expressed as base, preservative free]:
Generic: 5 mg/mL (1 mL)
Tablet, Oral:
Generic: 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg
Yes
Concentrate (Haloperidol Lactate Oral)
2 mg/mL (per mL): $0.84 - $0.88
Solution (Haldol Decanoate Intramuscular)
50 mg/mL (per mL): $104.49
100 mg/mL (per mL): $199.19
Solution (Haloperidol Decanoate Intramuscular)
50 mg/mL (per mL): $7.56 - $33.70
100 mg/mL (per mL): $15.12 - $61.78
Solution (Haloperidol Lactate Injection)
5 mg/mL (per mL): $0.48 - $7.19
Tablets (Haloperidol Oral)
0.5 mg (per each): $0.33 - $0.89
1 mg (per each): $0.46 - $1.07
2 mg (per each): $0.63 - $1.25
5 mg (per each): $0.69 - $1.29
10 mg (per each): $0.53 - $2.01
20 mg (per each): $1.56 - $3.62
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Concentrate, Oral, as lactate [strength expressed as base]:
Generic: 2 mg/mL ([DSC])
Solution, Intramuscular:
Generic: 5 mg/mL (1 mL, 10 mL)
Solution, Intramuscular, as decanoate [strength expressed as base]:
Generic: 100 mg/mL (1 mL, 5 mL)
Solution, Injection, as lactate [strength expressed as base]:
Generic: 5 mg/mL (1 mL)
Tablet, Oral:
Generic: 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg [DSC]
Injection oil (decanoate): The decanoate injectable formulation should be administered IM only, do not administer decanoate IV. A 21-gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. Z-track injection techniques are recommended to limit leakage after injections (Ref). Experts recommend administering in the gluteal muscle by deep IM injection, however haloperidol by deltoid injection has been studied with positive results (Ref).
Injection solution (lactate): The lactate injectable formulation may be administered IM or IV (off-label route). Rate of IV administration not well defined; rates of a maximum of 5 mg/minute (Ref) and 0.125 mg/kg over 1 to 2 minutes (Ref) have been reported. Note: IV administration has been associated with QT prolongation and the manufacturer recommends ECG monitoring for QT prolongation and arrhythmias. Consult individual institutional policies and procedures prior to administration. Subcutaneous administration has also been reported (usually in the palliative care setting), either as intermittent administration or as a continuous subcutaneous infusion (Ref).
Oral: Administer with food or milk to decrease GI distress. Avoid skin contact with oral suspension or solution; may cause contact dermatitis.
Parenteral:
IM: Lactate (immediate release): May be administered undiluted IM.
IV: Infusion or IVPB: Lactate (immediate release): May be administered undiluted (5 mg/mL), or diluted in D5W. Rate of IV administration is not well defined but should be slow; in pediatric delirium patients, loading doses have been administered over 30 to 45 minutes (Ref); in adults, rates of a maximum of 5 mg/minute (Ref) and 0.125 mg/kg (in 10 mL NS) over 1 to 2 minutes (Ref) have been reported. Note: The administration of IV haloperidol is associated with QT prolongation and torsades de pointes; in adults without concomitant risk factors, this effect is dose dependent and was reported with cumulative IV doses ≥2 mg; in all patients, increased monitoring is necessary at baseline and during administration (Ref). Consult individual institutional policies and procedures prior to administration.
Behavioral disorders, nonpsychotic (tablet, concentrate): Treatment of severe behavioral problems in children with combative, explosive hyperexcitability that cannot be accounted for by immediate provocation. Reserve for use in these children only after failure to respond to psychotherapy or medications other than antipsychotics.
Hyperactivity (tablet, concentrate): Short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggression, mood lability, or poor frustration tolerance. Reserve for use in these children only after failure to respond to psychotherapy or medications other than antipsychotics.
Schizophrenia:
IM lactate: Treatment of schizophrenia.
IM decanoate: Treatment of patients with schizophrenia who require prolonged parenteral antipsychotic therapy.
Tablet, concentrate: Treatment of manifestations of psychotic disorders such as schizophrenia.
Tourette syndrome, management of tics (tablet, concentrate): Control of tics and vocal utterances in Tourette syndrome in adults and children.
Agitation/Aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia), substance intoxication, or other organic causes; Bipolar disorder (acute mania, episodes with mixed features or acute hypomania); Chemotherapy-induced breakthrough nausea and vomiting; Delirium, hyperactive (treatment); Nausea and vomiting in advanced or terminal illness (palliative care); Postoperative nausea and vomiting, prevention, moderate- to high-risk patients
Haldol may be confused with Halcion, Halog, Stadol
Beers Criteria: Antipsychotics are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years and older due to an increased risk of cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Antipsychotics may be appropriate for schizophrenia, bipolar disorder, other mental health conditions, or short-term use as antiemetic during chemotherapy but should be given in the lowest effective dose for the shortest duration possible. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2019]). Note: Updates for the American Geriatrics Society 2023 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults are in process.
KIDs List: Dopamine antagonists, when used in pediatric patients <18 years of age, are identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list; use should be avoided in infants and used with caution in children and adolescents due to risk of acute dystonia (dyskinesia), and with intravenous administration an increased risk of respiratory depression, extravasation, and death (strong recommendation; moderate quality of evidence) (PPA [Meyers 2020]).
Haldol [US and multiple international markets] may be confused with Halotestin brand name for fluoxymesterone [Great Britain]
Substrate of CYP1A2 (minor), CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Agents With Seizure Threshold Lowering Potential: May enhance the adverse/toxic effect of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy
Amiodarone: May enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Amisulpride (Oral): May enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy
Anti-Parkinson Agents (Dopamine Agonist): May diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible. If antipsychotic use is necessary, consider using atypical antipsychotics such as clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification
ARIPiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Asenapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Benperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brexpiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy
Cabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combination
Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
CarBAMazepine: May decrease the serum concentration of Haloperidol. Risk C: Monitor therapy
Cariprazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Chlorprothixene: Anticholinergic Agents may enhance the anticholinergic effect of Chlorprothixene. Risk C: Monitor therapy
Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Risk X: Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Clothiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
CloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Haloperidol. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase the serum concentration of Haloperidol. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Haloperidol. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Haloperidol. Risk C: Monitor therapy
Dabrafenib: Haloperidol may enhance the QTc-prolonging effect of Dabrafenib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Domperidone: Haloperidol may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy
DroPERidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of DroPERidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
EPINEPHrine (Systemic): Haloperidol may diminish the vasoconstricting effect of EPINEPHrine (Systemic). Management: Consider alternatives to this combination and monitor for reduced epinephrine efficacy, and possible paradoxical effects (ie, hypotension), when combined. Use of alternative vasopressor agents (eg, phenylephrine, metaraminol, norepinephrine) is preferred. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fluorouracil Products: Haloperidol may enhance the QTc-prolonging effect of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Flupentixol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
FluPHENAZine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
FluvoxaMINE: May increase the serum concentration of Haloperidol. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor therapy
Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Risk X: Avoid combination
Glycopyrrolate (Systemic): May decrease the serum concentration of Haloperidol. Management: Consider avoiding concurrent use of glycopyrrolate and haloperidol.Monitor patients closely for signs/symptoms of reduced clinical response to haloperidol if concurrent use with glycopyrrolate is required. Risk D: Consider therapy modification
Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy
Homochlorcyclizine: May enhance the anticholinergic effect of Haloperidol. Homochlorcyclizine may enhance the CNS depressant effect of Haloperidol. Homochlorcyclizine may increase the serum concentration of Haloperidol. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Iloperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Indomethacin: May enhance the CNS depressant effect of Haloperidol. Risk C: Monitor therapy
Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Risk C: Monitor therapy
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Levoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid combination
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Risk X: Avoid combination
Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Loxapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Loxapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Lumateperone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Lurasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modification
Methadone: Haloperidol may enhance the CNS depressant effect of Methadone. Haloperidol may enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation or those taking IV haloperidol may be at even higher risk. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Methyldopa: Haloperidol may enhance the adverse/toxic effect of Methyldopa. Risk C: Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for extrapyramidal symptoms and excessive sedation may be increased. Risk C: Monitor therapy
Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Risk C: Monitor therapy
Molindone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor therapy
OLANZapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Ondansetron: May enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paliperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Pentamidine (Systemic): Haloperidol may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Periciazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Perphenazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Pimozide: May enhance the QTc-prolonging effect of Haloperidol. Risk X: Avoid combination
Pipamperone [INT]: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pipamperone [INT]. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Risk X: Avoid combination
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor therapy
Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combination
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid combination
Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Prochlorperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Promazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Promethazine: May enhance the anticholinergic effect of Haloperidol. Promethazine may enhance the CNS depressant effect of Haloperidol. Promethazine may increase the serum concentration of Haloperidol. Risk C: Monitor therapy
QT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
QT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of Haloperidol. Haloperidol may enhance the serotonergic effect of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome/serotonin toxicity (SS/ST) or NMS when these agents are combined. Patients with additional risk factors for QTc prolongation or SS/ST may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Antipsychotics (Moderate Risk): May enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome/serotonin toxicity (SS/ST) or NMS when these agents are combined. Patients with additional risk factors for QTc prolongation or SS/ST may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-Prolonging Inhalational Anesthetics (Moderate Risk): Haloperidol may enhance the QTc-prolonging effect of QT-Prolonging Inhalational Anesthetics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Miscellaneous Agents (Highest Risk): May enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Quinolone Antibiotics (Moderate Risk): Haloperidol may enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): Haloperidol may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk) may increase the serum concentration of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Haloperidol may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QUEtiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of QUEtiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy
Quinidine (Non-Therapeutic): May enhance the QTc-prolonging effect of QT-prolonging CYP2D6 Substrates. Quinidine (Non-Therapeutic) may increase the serum concentration of QT-prolonging CYP2D6 Substrates. Risk X: Avoid combination
Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination
RisperiDONE: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Saquinavir: May enhance the QTc-prolonging effect of Haloperidol. Risk X: Avoid combination
Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider therapy modification
Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Sertindole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sertindole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy
Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Risk X: Avoid combination
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for NMS and extrapyramidal symptoms may be increased. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Thioridazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thioridazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Thiothixene: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Risk X: Avoid combination
Tobacco (Smoked): May decrease the serum concentration of Haloperidol. Risk C: Monitor therapy
Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Risk C: Monitor therapy
Trifluoperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Triptorelin: Hyperprolactinemic Agents may diminish the therapeutic effect of Triptorelin. Risk X: Avoid combination
Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Urea Cycle Disorder Agents: Haloperidol may diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Haloperidol may increase plasma ammonia concentrations and thereby increase the doses of Urea Cycle Disorder Agents needed to maintain concentrations in the target range. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
Haloperidol may increase prolactin serum concentrations, leading to decreased fertility in males and females (Drobnis 2017; Larsen 2015). When antipsychotic treatment is initiated for the first time in a patient planning to become pregnant, an agent other than haloperidol may be preferred (Larsen 2015).
Haloperidol crosses the placenta in humans (Newport 2007). Although haloperidol has not been found to be a major human teratogen, an association with limb malformations following first trimester exposure in humans cannot be ruled out (ACOG 2008; Diav-Citrin 2005). Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization. If needed, the minimum effective maternal dose should be used in order to decrease the risk of EPS (ACOG 2008).
Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of haloperidol may be altered. If treatment with haloperidol is required during pregnancy, regular therapeutic drug monitoring (eg, every 3 months) is recommended (Larsen 2015; Schoretsanitis 2020; Westin 2018).
Haloperidol is preferred when a first-generation antipsychotic is needed in pregnant patients. If needed, the minimum effective maternal dose should be used in order to decrease the risk of extrapyramidal symptoms (ACOG 2008; Raffi 2019; WFSBP [Hasan 2015]).
Haloperidol is present in breast milk.
Haloperidol has been detected in the plasma and urine of breastfeeding infants (Whalley 1981; Yoshida 1999). Adverse events have been reported in some infants exposed to haloperidol via breast milk (Larsen 2015; Uguz 2019). Gynecomastia and galactorrhea are known side effects with the use of haloperidol. Breastfeeding is not recommended by the manufacturer. Some guidelines do not recommend initiating haloperidol in patients who are breastfeeding (Larsen 2015). Other guidelines note that if a first-generation antipsychotic is required, haloperidol is preferred; infants should be monitored for adverse events (WFSBP [Hasan 2015]).
Mental status; vital signs (as clinically indicated); ECG (as clinically indicated and with off-label intravenous administration); weight, height, BMI, waist circumference (baseline; at every visit for the first 6 months; quarterly with stable antipsychotic dose); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia); electrolytes and liver function (annually and as clinically indicated); fasting plasma glucose level/ HbA1c (baseline, then yearly; in patients with diabetes risk factors or if gaining weight repeat 4 months after starting antipsychotic, then yearly); lipid panel (baseline; repeat every 2 years if LDL level is normal; repeat every 6 months if LDL level is >130 mg/dL); changes in menstruation, libido, development of galactorrhea, erectile and ejaculatory function (at each visit for the first 12 weeks after the antipsychotic is initiated or until the dose is stable, then yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 6 months; high-risk patients every 3 months); visual changes (inquire yearly); ocular examination (yearly in patients >40 years; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004); fall risk (baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk); signs and symptoms of NMS (mental status changes, fever, muscle rigidity, and/or autonomic instability).
Additional monitoring parameters with IV administration: ECG (prior to administration and regularly [eg, daily] during administration to detect emerging QTc interval prolongation; consider continuous ECG, especially if patient has risk factors for QTc prolongation, the baseline ECG reveals a prolonged QTc, or cumulative doses of ≥2 mg are needed) (Drew 2010) some experts recommend continuous cardiac monitoring during administration and for 2 to 3 hours after administration (Jibson 2019); serum electrolytes (especially potassium and magnesium, prior to administration and throughout therapy).
Schizophrenia:
Timing of serum samples: Draw trough just before next dose (Hiemke 2018).
Therapeutic reference range: 1 to 10 ng/mL (SI: 2.66 to 26.6 nmol/L) (Hiemke 2018). Note: Dosing should be based on therapeutic response as opposed to serum concentrations; however, therapeutic drug monitoring can be used to confirm adherence (APA [Keepers 2020]).
Laboratory alert level: Variable; levels ranging from 15 ng/mL (SI: 39.9 nmol/L) to 50 ng/mL (SI: 133 nmol/L) have been identified as supratherapeutic and resulting in toxicity (Darby 1995; Hiemke 2018).
Haloperidol is a butyrophenone antipsychotic that nonselectively blocks postsynaptic dopaminergic D2 receptors in the brain (Richelson 1999; Risch 1996).
Onset of action: Lactate:
IM: Agitation: Initial effects within 15 minutes with mean time to sedation 24.8 to 28.3 minutes (Isenberg 2015; Klein 2018; Nobay 2004).
IV: Sedation: 3 to 20 minutes (Jacobi 2002); Peak effect: Sedation: ~30 minutes (Forsman 1976; Jacobi 2002; Magliozzi 1985).
Oral:
Bipolar disorder, acute mania: Oral and IR injection: Initial effects may be observed within days of treatment with continued improvements over 1 to 2 weeks (Goikolea 2013; Tohen 2000; Welten 2016).
Schizophrenia: Oral: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).
Duration: Lactate (dose dependent):
IM: Sedation: Mean: 126.5 minutes (Nobay 2004).
IV: Sedation: Reported range: 3 to 24 hours (Magliozzi 1985).
Distribution:
IV: Vz: 9.5 to 21.7 L/kg (Kudo 1999).
Oral: Vz/F: 52.6 ± 14.5 L/kg (Kudo 1999).
Protein binding: 88.4% to 92.5% (Kudo 1999).
Metabolism: Hepatic: 50% to 60% glucuronidation (inactive); 23% CYP3A4-mediated reduction to inactive metabolites (some back-oxidation to haloperidol); and 20% to 30% CYP3A4-mediated N-dealkylation, including minor oxidation pathway to toxic pyridinium derivative (Kudo 1999).
Bioavailability: Oral: 60% to 70% (Kudo 1999).
Half-life elimination:
Decanoate: 21 days.
Lactate:
IM: 20 hours (Kudo 1999).
IV: 14 to 26 hours (Kudo 1999).
Oral: 14 to 37 hours (Kudo 1999).
Time to peak, serum:
Decanoate: 6 days.
Lactate:
IM: 20 minutes (Kudo 1999).
Oral: 2 to 6 hours (Kudo 1999).
Excretion: Urine (30%, 1% as unchanged drug) (Kudo 1999).
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