Haloperidol

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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)

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

Pharmacology

Mechanism of Action

Haloperidol is a butyrophenone antipsychotic that nonselectively blocks postsynaptic dopaminergic D₂ receptors in the brain (Richelson 1999; Risch 1996).

Pharmacokinetics/Pharmacodynamics

Distribution

IV: V_z: 9.5 to 21.7 L/kg (Kudo 1999).

Oral: V_z/F: 52.6 ± 14.5 L/kg (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).

Excretion

Urine (30%, 1% as unchanged drug) (Kudo 1999).

Onset of Action

Lactate:

IM: Sedation: Mean: 28.3 minutes (Nobay 2004).

IV: Sedation: 3 to 20 minutes (Jacobi 2002).

Peak effect: Lactate: IV: Sedation: ~30 minutes (Forsman 1976; Jacobi 2002; Magliozzi 1985).

Time to Peak

Decanoate: 6 days.

Lactate:

IM: 20 minutes (Kudo 1999).

Oral: 2 to 6 hours (Kudo 1999).

Duration of Action

Lactate (dose dependent):

IM: Sedation: Mean: 126.5 minutes (Nobay 2004).

IV: Sedation: 3 to 24 hours (Magliozzi 1985).

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).

Protein Binding

88.4% to 92.5% (Kudo 1999).

Use: Labeled Indications

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, IM lactate): Control of tics and vocal utterances in Tourette syndrome in adults and children.

Use: Off Label

Agitation/Aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia), substance intoxication, or other organic causesbyes

Data from a meta-analysis of randomized trials support the use of IM haloperidol in the treatment of agitation and/or aggression due to psychosis. Use in combination with promethazine has better evidence than monotherapy; evidence for greater efficacy when used in combination with lorazepam and midazolam is more limited Ostinelli 2017. Data from an open-label clinical study and 2 retrospective studies suggest that haloperidol (oral, IM, and IV) may be beneficial for the treatment of acute agitation in the emergency setting Clinton 1987, MacDonald 2012, Wilson 2012b.

Based on the National Institute for Health and Care Excellence (NICE) guidelines for the short-term treatment of violence and aggression in mental health, health, and community settings, IM haloperidol is recommended in combination with IM promethazine for acute agitation in adults without evidence of cardiovascular disease (including a prolonged QT interval) NICE 2015.

Bipolar disorder (acute manic or mixed episodes or acute hypomania)byes

Data from a meta-analysis of randomized trials support the use of haloperidol for patients experiencing manic or mixed episodes and shows a faster onset of action compared to second-generation antipsychotics Goikolea 2013.

Based on the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines for the management of patients with bipolar disorder, haloperidol is recommended as monotherapy or adjunctive therapy to antimanic therapy for the management of acute manic or mixed episodes if first-line options are not effective or tolerated CANMAT [Yatham 2018]. Based on the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders update on the treatment of acute mania and the CANMAT/ISBD guidelines for the management of patients with bipolar disorder, limited evidence exists for the treatment of hypomania; however, based on clinical experience, treatment should be the same as mania and clinicians should consider antipsychotics, such as haloperidol, and/or antimanic agents CANMAT [Yatham 2018], WFSBP [Grunze 2009]. Based on the British Association for Psychopharmacology (BAP) evidence-based guidelines for treating bipolar disorders, long-acting haloperidol injections may be considered during the maintenance phase of treatment if adherence is erratic or injection is preferred BAP [Goodwin 2016]; however, some experts limit haloperidol maintenance use because of increased risks for movement disorders and bipolar major depression Stovall 2019.

Chemotherapy-induced breakthrough nausea and vomitingcyes

Based on the American Society of Clinical Oncology antiemetic guidelines for chemotherapy-induced nausea and vomiting (CINV), dopamine antagonists may be given for breakthrough episodes of CINV Basch 2011. Clinical experience also suggests the utility of haloperidol in managing breakthrough episodes of CINV in adults Lohr 2008.

Delirium, hyperactive (treatment)byes

Data from a large, prospective, randomized trial evaluating IV haloperidol, IV ziprasidone, and placebo in medical or surgical ICU patients with delirium did not show a benefit with pharmacologic treatment on the duration of delirium and coma; there was no difference in survival, length of ICU stay, or length of hospital stay Girard 2018.

Based on the Society of Critical Care Medicine guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU (ie, the PADIS guidelines), nonpharmacologic management and treatment of underlying conditions should be implemented as the initial steps to reduce delirium. Antipsychotics (both typical and atypical) are not recommended for the prevention or treatment of delirium in the ICU except in patients who are experiencing distressing symptoms of delirium (eg, agitation, anxiety). In that case, short-term use of antipsychotics (typical or atypical) may be administered until the symptoms resolve SCCM [Devlin 2018].

Nausea and vomiting in advanced or terminal illness (palliative care)cyes

Data from a limited number of patients studied (in an uncontrolled study and a retrospective study) suggest that haloperidol (lactate) may be beneficial for the management of nausea and vomiting in advanced or terminal illness Hardy 2010, Mercadante 1995.

Based on the Multinational Association of Supportive Care in Cancer and European Society for Medical Oncology (MASCC/ESMO) 2016 guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients, haloperidol is considered a second-line antiemetic in the management of nausea and vomiting in advanced cancer. MASCC/ESMO 2016 updated consensus recommendations for management of nausea and vomiting in advanced cancer also recommend haloperidol as an alternative antiemetic agent; for nausea and vomiting due to bowel obstruction, haloperidol should be administered in combination with octreotide.

Postoperative nausea and vomiting, prevention, moderate- to high-risk patientsbyes

Data from a meta-analysis of randomized, blinded trials support the use of IM and IV haloperidol in the prevention of postoperative nausea and vomiting Büttner 2004.

Based on the Society for Ambulatory Anesthesia consensus guidelines for the management of postoperative nausea and vomiting, haloperidol is effective and recommended to prevent postoperative nausea and vomiting.

Contraindications

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

Dosage and Administration

Dosing: Adult

Note: Dose: Although manufacturer's labeling includes a maximum dose of up to 100 mg/day, doses >30 mg/day are in general not recommended (APA [Lehman 2004]; Moore 2019). 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 (Drew 2010; Jibson 2019; Meyer-Massetti 2010). Formulations: Available as oral tablets (as base), an oral solution and short-acting injection (as lactate), and an ER suspension for IM injection (as decanoate). All doses are expressed as the equivalent amounts of haloperidol base.

Agitation/Aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia) (labeled use), substance intoxication (off-label use), or other organic causes (off-label use): Note: Antipsychotics are appropriate when psychosis is suspected to be the primary cause of agitation/aggression (WFSBP [Hasan 2012]; Wilson 2012a). 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 (Moore 2019; Suh 2019; Wilson 2012a).

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 (Clinton 1987; Klein 2018; MacDonald 2012; Moore 2019; Ostinelli 2017; Wilson 2012a; Wilson 2012b).

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 (Moore 2019).

Bipolar disorder:

Acute manic or mixed episodes 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 (Stovall 2019).

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 (Goikolea 2013; McElroy 1996; Sachs 2002; Stovall 2019).

Chemotherapy-induced breakthrough nausea and vomiting (alternative therapy) (off-label use): Note: May be used as an adjunct to standard antiemetic regimens for breakthrough nausea/vomiting (Hesketh 2019; Lohr 2008).

Oral, IV (off-label route) (lactate injection): 0.5 to 1 mg every 6 hours as needed (Lohr 2008).

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 (SCCM [Devlin 2018]). Reassess daily for continued need; consider discontinuation and/or taper as symptoms resolve, especially at transitions of care to prevent unnecessary continuation of therapy (D’Angelo 2019; Marshall 2016; Tietze 2019).

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 hours if needed (Tesar 1988; Tietze 2019). 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 (Reade 2009).

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 (Francis 2019; Maneeton 2013).

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 (Del Fabbro 2019).

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. (Del Fabbro 2019; Harman 2019).

Continuous SubQ infusion (off-label route) (lactate injection): Typical range for initial treatment: 1 to 5 mg per 24 hours (Glare 2008; Mercadante 2019).

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 at the end of surgery (Büttner 2004; Feinleib 2019; Gan 2014).

Schizophrenia:

Oral, IM, IV (lactate injection): 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 (Rosenheck 2003; Stroup 2019a; WFSBP [Hasan 2013]). Note: In a first psychotic episode, a lower dose (eg, 1 to 4 mg/day) may be sufficient (WFSBP [Hasan 2013]).

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 (Lauriello 2019; McEvoy 2006).

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. (Ereshefsky 1990; Ereshefsky 1993). 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 (manufacturer's labeling).

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 (AAN [Pringsheim 2019]).

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 (Jibson 2019).

Oral to IM (as decanoate): See Schizophrenia dosing.

Discontinuation of therapy: Gradual dose reduction is advised to avoid withdrawal symptoms (ie, insomnia, headache, GI symptoms) unless discontinuation is due to significant adverse effects. In general, when discontinuing antipsychotic therapy for a chronic psychiatric disorder (eg, schizophrenia, bipolar disorder), decreasing the dose very gradually over weeks to months (eg, reducing the dose by 10% per month) with close monitoring is suggested to allow for detection of prodromal symptoms of disease recurrence (APA [Lehman 2004]; CPA 2005).

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 (Cerovecki 2013; Remington 2005; Takeuchi 2017). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Post 2019; Stroup 2019b).

Dosing: Geriatric

Refer to adult dosing. Consider use of lower doses and increased monitoring due to greater risks for adverse effects, including QTc prolongation.

Dosing: Pediatric

Note: Dosing should be individualized based on patient response. Gradually decrease dose to the lowest effective maintenance dosage once a satisfactory therapeutic response is obtained.

Note: Dosing presented as fixed (mg) dosing and weight-based (mg/kg) dosing; use caution when prescribing and dispensing.

Behavior disorders, nonpsychotic:

Children 3 to 12 years weighing 15 to 40 kg: Oral: Initial: 0.5 mg/day in 2 to 3 divided doses; may increase 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. Maintenance range calculates to a fixed dose of 0.75 to 3 mg/day in divided doses; maximum dose not established; children with severe, nonpsychotic disturbance may require higher doses; however, no improvement has been shown with doses >6 mg/day.

Children >40 kg and Adolescents: Limited data available: Oral: 0.5 to 15 mg/day in 2 to 3 divided doses; begin at lower end of the range and may increase as needed (no more frequently than every 5 to 7 days); maximum daily dose: 15 mg/day. Note: Higher doses may be necessary in severe or refractory cases (Kliegman 2011).

Delirium: Limited data available; optimal dose not established; Note: Reported experience in infants is very limited and suggests that lower doses may be required. Infants ≥3 months, Children, and Adolescents: IV (lactate, immediate release): Loading dose: 0.15 to 0.25 mg/dose infused slowly over 30 to 45 minutes (Schieveld 2007); maintenance dose: 0.05 to 0.5 mg/kg/day in divided doses (Brown 1996; Schieveld 2007); a retrospective review of 27 patients (ages: 3 months to 17 years) using this dosing showed the signs/symptoms of delirium responded well to treatment in all patients; however, two patients experienced dystonic reactions (Schieveld 2007). In a small case-series, loading doses of 0.025 to 0.1 mg/kg/dose administered every 10 minutes until sedation achieved (reported total haloperidol loading dose: 0.09 to 0.25 mg/kg total) followed by maintenance doses of 0.06 to 0.45 mg/kg/day in divided doses every 6 to 8 hours were described (n=5; age range: 9 months to 16 years); infants (n=2) were noted to require lower doses (total loading dose: 0.09 to 0.1 mg/kg total; maintenance: 0.015 to 0.025 mg/kg/dose every 6 hours); one patient experienced a dystonic reaction (Harrison 2002)

Psychotic disorders:

Children 3 to 12 years weighing 15 to 40 kg: Oral: Initial: 0.5 mg/day in 2 to 3 divided doses; increase 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 (maintenance range calculates to a fixed dose of 0.75 to 6 mg/day in divided doses); higher doses may be necessary in severe or refractory cases; maximum dose not established; in adolescents, the maximum daily dose is 15 mg/day (Kliegman 2011)

Children >40 kg and Adolescents: Limited data available: Oral: 0.5 to 15 mg/day in 2 to 3 divided doses; begin at lower end of the range and may increase as needed (no more frequently than every 5 to 7 days); maximum daily dose: 15 mg/day (Kliegman 2011; Willner 1969). Note: Higher doses may be necessary in severe or refractory cases (Kliegman 2011).

Agitation (acute); psychosis: Limited data available: Infants, Children, and Adolescents: IM, IV (lactate, immediate release): 0.05 to 0.15 mg/kg; may be repeated hourly as needed; maximum dose: 5 mg/dose (Hegenbarth 2008)

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 (Kliegman 2011)

Tourette syndrome:

Children 3 to 12 years weighing 15 to 40 kg: Oral:

Manufacturer's labeling: Initial: 0.5 mg/day in 2 to 3 divided doses; increase by 0.25 to 0.5 mg every 5 to 7 days to usual maintenance of 0.05 to 0.075 mg/kg/day in 2 to 3 divided doses (maintenance range calculates to a fixed dose of 0.75 to 3 mg/day in divided doses); maximum dose not established; however, no improvement has been shown with doses >6 mg/day in patients with nonpsychotic disturbances

Alternate dosing: Limited data available: Initial: 0.25 to 0.5 mg/day in 2 to 3 divided doses titrated to a usual daily dose range of 1 to 4 mg/day (Roessner 2011; Scahill 2006)

Children weighing >40 kg and Adolescents: Limited data available: Oral: 0.25 to 15 mg/day in 2 to 3 divided doses; begin at lower end of the range and may increase as needed (no more frequently than every 5 to 7 days) (Kleigman 2011; Roessner 2011); usual dose range: 1 to 4 mg/day (Roessner 2011; Scahill 2006); maximum dose not established; however, no improvement has been shown with doses >6 mg/day in patients with nonpsychotic disturbances

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 (AACAP [McClellan 2007]; APA [Lehman 2004]; Cerovecki 2013; CPA 2005; NICE 2013; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). 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 (APA [Lehman 2004]; CPA 2005). Continuing antiparkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). 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 (Cerovecki 2013; Remington 2005).

Administration

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 (Baweja 2012; Gillespie 2013; McEvoy 2006). Experts recommend administering in the gluteal muscle by deep IM injection, however haloperidol by deltoid injection has been studied with positive results (Baweja 2012; Gillespie 2013; McEvoy 2014; Sassa 2002; Yasuhara 2012).

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 (Forsman 1976; Lerner 1979) and 0.125 mg/kg over 1 to 2 minutes (Holley 1983; Magliozzi 1985) 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 (Glare 2008; Hardy 2010; Mercadante 1995).

Storage

Concentrate, tablets: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Dispense in a tight, light-resistant container. Do not freeze concentrate.

Solution for injection, decanoate: Store at 15°C to 30°C (59°F to 86°F). Protect from light. Do not refrigerate or freeze.

Solution for injection, lactate: Store at 15°C to 30°C (59°F to 86°F). Protect from light. Do not refrigerate or freeze.

Solution for injection, lactate (preservative free): Store at 20°C to 25°C (68°F to 77°F). Protect from light. Do not freeze.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. 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. Consider therapy modification

Amisulpride: Antipsychotic Agents may enhance the adverse/toxic effect of Amisulpride. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Avoid combination

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Management: Avoid concomitant therapy if possible and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

ARIPiprazole: May enhance the QTc-prolonging effect of Haloperidol. ARIPiprazole may diminish the therapeutic effect of Haloperidol. Haloperidol may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph. Aripiprazole dose adjustment may not be required when used as adjunctive therapy for major depressive disorder. Consider therapy modification

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Haloperidol. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. 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. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

CloBAZam: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dacomitinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. 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. 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. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Fexinidazole [INT]: Haloperidol may enhance the QTc-prolonging effect of Fexinidazole [INT]. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

FLUoxetine: May enhance the QTc-prolonging effect of Haloperidol. FLUoxetine may increase the serum concentration of Haloperidol. Monitor therapy

FluvoxaMINE: May increase the serum concentration of Haloperidol. Management: Monitor for increased haloperidol concentrations/effects when patients are receiving fluvoxamine, particularly when fluvoxamine dose is 150 mg/day or greater. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Glycopyrrolate (Systemic): May decrease the serum concentration of Haloperidol. Management: Monitor patients closely for signs/symptoms of reduced clinical response to haloperidol if concurrent use with glycopyrrolate is required. When possible, consider avoiding concurrent use. Consider therapy modification

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. 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. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Imatinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). 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 anticonvulsants. 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 anticonvulsants. 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 anticonvulsants. Consider therapy modification

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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. 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. Consider therapy modification

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. 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. 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. 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 adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Haloperidol. Specifically including drowsiness and confusion. Monitor therapy

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. 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. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

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. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. 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). 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. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Perhexiline: CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Pimozide: May enhance the QTc-prolonging effect of Haloperidol. Avoid combination

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. Avoid combination

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. 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. Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

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. Monitor therapy

QT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

QT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

QT-prolonging Antidepressants (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. Monitor therapy

QT-prolonging Antipsychotics (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. Exceptions: Pimozide. 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. 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. 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. Consider therapy modification

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. 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. 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. 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. Exceptions: Domperidone. 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. 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. Monitor therapy

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Avoid combination

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Saquinavir: May enhance the QTc-prolonging effect of Haloperidol. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

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. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. 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. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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. Consider therapy modification

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Tobacco (Smoked): May decrease the serum concentration of Haloperidol. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. 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. 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. Consider therapy modification

Adverse Reactions

>10%: Central nervous system: Extrapyramidal reaction (lactate: 51%; oral: <1%), parkinsonism (decanoate: 31%; lactate and oral: <1%)

1% to 10%:

Central nervous system: Dystonia (lactate: 7%; decanoate and oral: <1%), hypertonia (lactate: 7%; decanoate and oral: <1%), drowsiness (lactate: 5%; decanoate and oral: <1%), akathisia (decanoate: 3%; lactate and oral: <1%), headache (decanoate: 3%; lactate and oral: <1%)

Gastrointestinal: Constipation (lactate: 4%; decanoate and oral: <1%), abdominal pain (decanoate: 3%), xerostomia (≤2%), sialorrhea (≤1%)

Neuromuscular & skeletal: Hyperkinetic muscle activity (lactate: 10%), tremor (3% to 8%), bradykinesia (lactate: 4%), akinesia (decanoate: 3%)

Ophthalmic: Oculogyric crisis (decanoate: 6%; lactate: <1%)

Frequency not defined:

Central nervous system: Anxiety, euphoria, lethargy, psychotic symptoms (exacerbation), vertigo

Dermatologic: Diaphoresis

Endocrine & metabolic: Hyperglycemia, hyponatremia, increased libido, menstrual disease

Gastrointestinal: Anorexia, diarrhea, dyspepsia

Genitourinary: Breast engorgement, impotence, lactation

Ophthalmic: Cataract, retinopathy, visual disturbance

Respiratory: Increased depth of respiration

<1%, postmarketing, and/or case reports: Abnormal hepatic function tests, abscess at injection site, acneiform eruption, acute hepatic failure, agitation, agranulocytosis, akathisia, alopecia, amenorrhea, anaphylaxis, anemia, angioedema, blurred vision, bronchopneumonia, bronchospasm, cardiac arrhythmia, cholestasis, cogwheel rigidity, confusion, decreased libido, depression, dizziness, dyskinesia, dysmenorrhea, dyspnea, edema, erectile dysfunction, exfoliative dermatitis, extrasystoles, facial edema, galactorrhea not associated with childbirth, gynecomastia, heatstroke, heavy menstrual bleeding, hepatic insufficiency, hepatitis, hyperammonemia, hyperhidrosis, hyperprolactinemia, hyperpyrexia, hypersensitivity angiitis, hypersensitivity reaction, hypertension, hyperthermia, hypoglycemia, hypokinesia, hypotension, hypothermia, injection site reaction, insomnia, jaundice, laryngeal edema, laryngospasm, leukocytosis, leukopenia, lymphocytosis with monocytosis, maculopapular rash, mask-like face, mastalgia, motor dysfunction, muscle rigidity, muscle twitching, nausea, neonatal withdrawal, neuroleptic malignant syndrome, neutropenia, nystagmus, opisthotonus, orthostatic hypotension, pancytopenia, priapism, prolonged Q-T interval on ECG, pruritus, restlessness, rhabdomyolysis, sedated state, seizure, SIADH, skin photosensitivity, skin rash, tachycardia, tardive dyskinesia, tardive dystonia, thrombocytopenia, torsades de pointes, torticollis, trismus, urinary retention, urticaria, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, vomiting, weight gain, weight loss

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: Cases of sudden death, QT prolongation, and torsades de pointes have been reported with haloperidol use; risk may be increased with doses exceeding recommendations and/or intravenous administration (off-label route) of intramuscular lactate injection. Use with caution or avoid use in patients with electrolyte abnormalities (eg, hypokalemia, hypomagnesemia), hypothyroidism, familial long QT syndrome, concomitant medications which may augment QT prolongation, or any underlying cardiac abnormality which may also potentiate risk. Prior to initiation of intravenous therapy, obtain a baseline ECG. Consider continuous ECG monitoring, especially if the patient has risk factors for QTc prolongation, the baseline ECG reveals a prolonged QTc, or cumulative doses of ≥2 mg are needed. Monitor electrolyte concentrations throughout therapy. If the baseline QTc interval increases by 20% to 25%, increases >500 msec, or if T-waves flatten or U-waves develop on the ECG, reduce the dosage or consider alternative therapy (Hassaballa 2003; Meyer-Massetti 2010).
• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. Relative to other neuroleptics, haloperidol has a low potency of cholinergic blockade (Richelson 1999).
• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm³.
• 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).
• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (ie, Alzheimer disease), particularly in patients >75 years of age (Herzig 2017; Maddalena 2004).
• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia. Risk of dystonia (and possibly other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.
• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability. Complete fall risk assessments at baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk.
• Hyperprolactinemia: May increase prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.
• Hypersensitivity: Hypersensitivity reactions (including anaphylactic reactions, angioedema, exfoliative dermatitis, hypersensitivity vasculitis, rash, urticaria, face edema, laryngeal edema, bronchospasm, and laryngospasm) have been reported.
• Neuroleptic malignant syndrome (NMS): Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability. Following recovery from NMS, reintroduction of drug therapy should be carefully considered; if an antipsychotic agent is resumed, allow at least 2 weeks to elapse after recovery before rechallenge, consider a lower potency antipsychotic and monitor closely for the reemergence of NMS (Strawn 2007).
• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use that may predispose to hypotension/bradycardia). Relative to other neuroleptics, the risk of orthostatic hypotension is low (APA [Lehman 2004]).
• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects (Kwok 2005; Martinez 2002).

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).
• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Avoid the first-line use of oral haloperidol in elderly patients with dementia-related psychosis due to a greater risk of harm relative to other antipsychotics (APA [Reus 2016]). Haloperidol is not approved for the treatment of dementia-related psychosis. Haloperidol is contraindicated in patients with dementia with Lewy bodies; these patients are reported to be more sensitive to antipsychotic medications and use may result in severe extrapyramidal symptoms, confusion, sedation, and falls.
• 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.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, EEG abnormalities, or concurrent anticonvulsant therapy; haloperidol may lower the seizure threshold.
• Thyroid dysfunction: Avoid in thyrotoxicosis; severe neurotoxicity (rigidity, inability to walk or talk) may occur with use.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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.

Other warnings/precautions:

• Discontinuation of therapy: When discontinuing antipsychotic therapy, the manufacturer and the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA 2005; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life, and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or 2 episodes within 5 years (APA [Lehman 2004]).
• Parenteral administration: Hypotension may occur, particularly with parenteral administration. Risk of QT prolongation, torsade de pointes, and sudden death appear to be increased with intravenous administration, particularly at higher doses. 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.

Monitoring Parameters

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/ HbA_1c (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).

Additional monitoring parameters with IV administration: ECG (prior to administration and regularly [eg, daily] during administration to detect emerging QTc interval prolongation) (Drew 2010); serum potassium and magnesium (prior to administration); continuous cardiac monitoring (during administration and 2 to 3 hours after administration) (Drew 2010; Jibson 2019).

Pregnancy

Pregnancy Considerations

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).

Patient Education

What is this drug used for?

• It is used to treat schizophrenia.
• It is used to treat Tourette's syndrome.
• It is used to treat problems with how one acts.
• It is used to treat mood problems.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Fatigue
• Anxiety
• Constipation
• Dry mouth
• Increased saliva
• Nausea
• Vomiting
• Diarrhea
• Lack of appetite
• Acne
• Agitation
• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Chest pain
• Cough
• Shortness of breath
• Wheezing
• Abnormal movements
• Twitching
• Change in balance
• Difficulty swallowing
• Difficulty speaking
• Severe dizziness
• Passing out
• Tremors
• Difficulty moving
• Rigidity
• Unable to pass urine
• Severe loss of strength and energy
• Bruising
• Bleeding
• Vision changes
• Severe headache
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Low sodium like headache, difficulty focusing, trouble with memory, confusion, weakness, seizures, or change in balance.
• Sensing things that seem real but are not
• Seizures
• Mood changes
• Behavioral changes
• Enlarged breasts
• Involuntary eye movement
• Sexual dysfunction
• Decreased sex drive
• Menstrual changes
• Nipple discharge
• Fast heartbeat
• Abnormal heartbeat
• Neuroleptic malignant syndrome like fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot.
• Tardive dyskinesia like unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; or puffing cheeks.
• Erection that lasts more than 4 hours
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.