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Haloperidol

Pronunciation

Pronunciation

(ha loe PER i dole)

Index Terms

  • Haloperidol Decanoate
  • Haloperidol Lactate

Dosage Forms

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

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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

Brand Names: U.S.

  • Haldol
  • Haldol Decanoate

Pharmacologic Category

  • First Generation (Typical) Antipsychotic

Pharmacology

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

Distribution

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

Oral: Vz/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)

Time to Peak

Decanoate: 6 days

Lactate:

IM: 20 minutes (Kudo 1999)

Oral: 2 to 6 hours (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)

Protein Binding

88.4% to 92.5% (Kudo 1999)

Use: Labeled Indications

Behavioral disorders (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.

Psychotic disorders (tablet, concentrate): Management of manifestations of psychotic disorders.

Schizophrenia:

IM, lactate: Treatment of schizophrenia.

IM, decanoate: Treatment of patients with schizophrenia who require prolonged parenteral antipsychotic therapy.

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

Use: Unlabeled

Emergency sedation of severely-agitated or delirious patients; treatment of ICU delirium; adjunctive treatment of ethanol dependence; Huntington's disease; postoperative nausea and vomiting (alternative therapy)

Contraindications

Hypersensitivity to haloperidol or any component of the formulation; Parkinson disease; severe CNS depression; coma

Dosage

Children and Adolescents:

Behavior disorders, nonpsychotic:

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; maximum dose not established; children with severe, nonpsychotic disturbance may require higher doses; however, no improvement has been shown with doses >6 mg/day.

>40 kg and Adolescents (off-label dose): 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).

Psychosis:

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; 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)

>40 kg and Adolescents (off-label dose): 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).

Tourette syndrome:

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 0.5 mg every 5 to 7 days to usual maintenance of 0.05 to 0.075 mg/kg/day in 2 to 3 divided doses; maximum dose not established; however, no improvement has been shown with doses >6 mg/day in patients with nonpsychotic disturbances

Alternate dosing: 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)

>40 kg and Adolescents (off-label dose): 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

Adults:

Psychosis:

Manufacturer’s labeling: Oral: 0.5 to 5 mg 2 to 3 times daily; adjust dose based on response and tolerability. According to the manufacturer, daily dosages up to 100 mg may be necessary in some cases to achieve an optimal response; infrequently, doses >100 mg have been used in severely treatment resistant patients. Recommended dose range for schizophrenia: 5 to 20 mg/day (APA [Lehman 2004)].

Schizophrenia:

IM (as lactate): 2 to 5 mg; subsequent doses may be administered as often as every 60 minutes, although 4- to 8-hour intervals may be satisfactory.

IM (as decanoate): Note: Establish tolerance to oral haloperidol prior to changing to IM decanoate injection.

Initial: 10 to 20 times the daily oral dose. The initial dose should not exceed 100 mg regardless of previous antipsychotic requirements. If the initial dose conversion requires >100 mg, administer the dose in 2 injections (maximum of 100 mg for first injection) separated by 3 to 7 days.

Oral haloperidol ≤10 mg/day, elderly, or debilitated: Initiate dose at 10 to 15 times the daily oral dose.

Oral haloperidol >10 mg/day or high risk of relapse: Initiate dose at 20 times the daily oral dose

Maintenance dose: 10 to 15 times the previous daily oral dose or 50 to 200 mg; administer doses at 4-week intervals (Buchanan 2009; Hasan 2013)

Oral overlap: Following initial dose, taper the oral dose and discontinue after the first 2 or 3 injections (McEvoy 2006).

Alternative dosing regimen:

Loading dose regimen: Initial: 20 times the previous daily oral dose, divide total dose and give every 3 to 7 days, do not exceed 250 mg per injection; discontinue oral haloperidol prior to first injection. Reduce the dose by 25% each month, depending on clinical response, in months 2 to 4, and establish the maintenance dose.

Usual maintenance dose: 200 mg per month (Ereshefsky 1993).

Tourette syndrome: Oral: 0.5 to 5 mg 2 to 3 times daily; adjust dose based on response and tolerability. Tourette Canada Guidelines recommend a dosing range of 0.5 to 3 mg/day (Pringsheim 2012) and European Society for the Study of Tourette Syndrome recommend a dosing range of 0.25 to 15 mg/day (Roessner 2011). According to the manufacturer, daily dosages up to 100 mg may be necessary in some cases to achieve an optimal response; infrequently doses >100 mg have been used in severely treatment resistant patients.

Chemotherapy-induced nausea and vomiting (off-label use): Breakthrough nausea/vomiting: Adults: Oral, IV (off-label route): 0.5 to 1 mg every 6 hours as needed (Lohr 2008)

Delirium in the intensive care unit, treatment (off-label use): Note: The optimal dose and regimen of haloperidol for the treatment of severe agitation and/or delirium has not been established. Currently, there are no studies evaluating the role of haloperidol on duration or severity of delirium. Haloperidol has been used for symptomatic treatment (severe agitation) of delirious patients. Current guidelines do not advocate use of haloperidol for the treatment or prevention of delirium due to insufficient evidence (Barr 2013).

IV (off-label route): Initial: 0.5 to 10 mg depending on degree of agitation; if inadequate response, may repeat bolus dose (with sequential doubling of initial bolus dose) every 15 to 30 minutes until calm achieved, then administer 25% of the last bolus dose every 6 hours; monitor ECG and QTc interval. After the patient is controlled, haloperidol therapy should be tapered over several days. This strategy is based upon expert opinion; efficacy and safety have not been formally evaluated (Tesar 1988).

Note: Continuous infusions have also been used with doses in the range of 0.5 to 2 mg/hour with an optional loading dose of 2.5 mg (Reade 2009).

Delirium in the intensive care unit (patients at high risk of delirium), prevention (off-label use): Note: The optimal dose and regimen of haloperidol for prevention of ICU delirium has not been established. Current guidelines do not advocate use of haloperidol for the treatment or prevention of delirium due to insufficient evidence (Barr 2013). Haloperidol may decrease the incidence of delirium (Van den Boogaard 2013; Wang 2012).

IV (off-label route): 0.5 mg followed by a continuous infusion of 0.1 mg/hour for 12 hours (Wang 2012) or 0.5 to 1 mg every 8 hours (Van den Boogaard 2013)

Phencyclidine psychosis (off-label use): IM, IV (off-label route), Oral: 5 mg (Giannini 1984; MacNeal 2012). Note: Additional data may be necessary to further define the role of haloperidol in this condition.

Postoperative nausea and vomiting (PONV), prevention (off-label use): IM, IV (off-label route): 0.5 to 2 mg (Gan 2014)

Rapid tranquilization (agitation/aggression/violent behavior) (off-label use): IM (as lactate): 2.5 to 10 mg (Clinton 1987; MacDonald 2012; Powney 2012; Wilson 2012)

Elderly:

Psychosis: Oral: 0.5 to 2 mg 2 to 3 times daily; adjust dose based on response and tolerability. Maximum dosage per manufacturer’s labeling: 100 mg/day. Recommended dose range for schizophrenia: 5 to 20 mg/day (APA [Lehman 2004)].

Psychosis/agitation related to Alzheimer disease and other dementias (off-label use): Initial: Oral: 0.25 to 0.5 mg/day (APA [Rabins 2007]; slowly increase dose based on response and tolerability every 4 to 7 days in increments of 0.25 to 1 mg (De Deyn 1999; Devanand 1998); usual maximum dose of 2 mg/day (APA [Rabins 2007]; Doses up to 6 mg/day in 1 to 2 divided doses were evaluated in clinical trials (Lonergan 2002).

Dosage adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

Haloperidol lactate may be administered IVPB or IV infusion in D5W solutions. NS solutions should not be used due to reports of decreased stability and incompatibility.

Usual concentration range: 0.5 to 100 mg/50 to 100 mL D5W.

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. Administer in the gluteal muscle by deep IM injection; Z-track injection techniques are recommended to limit leakage after injections (Baweja 2012; Gillespie 2013; McEvoy 2006).

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 (Lerner 1979) and 0.125 mg/kg (in 10 mL NS) over 1 to 2 minutes (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.

Compatibility

Stable in D5W.

Y-site administration: Incompatible with allopurinol, amphotericin B cholesteryl sulfate complex, cefepime, dexamethasone sodium phosphate, fluconazole, foscarnet, furosemide, gallium nitrate, heparin, ketorolac, lansoprazole, magnesium sulfate, piperacillin/tazobactam, sargramostim.

Compatibility in syringe: Incompatible with benztropine, cyclizine, dexamethasone, sodium phosphate, diphenhydramine hydrochloride, heparin, hydromorphone hydrochloride, hydroxyzine hydrochloride, ketorolac.

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. 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

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

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

Amisulpride: Antipsychotic Agents may enhance the adverse/toxic effect of Amisulpride. Avoid combination

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

Analgesics (Opioid): Anticholinergic Agents may enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Exceptions: Levocabastine (Nasal). Monitor therapy

Anti-Parkinson's 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's Agents (Dopamine Agonist). 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's agents. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. 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

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. Monitor therapy

Brimonidine (Topical): 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 increase the metabolism of Haloperidol. Consider therapy modification

ChlorproMAZINE: May enhance the QTc-prolonging effect of Haloperidol. Haloperidol may increase the serum concentration of ChlorproMAZINE. ChlorproMAZINE may increase the serum concentration of Haloperidol. Management: Consider alternatives to combined treatment with these agents. If combined treatment cannot be avoided, monitor for signs and symptoms of prolonged QTc interval (e.g. arrhythmias). Consider therapy modification

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

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Monitor therapy

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

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

CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Monitor therapy

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

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. 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. Monitor therapy

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. 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

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

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

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. Monitor therapy

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

Glycopyrrolate: 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

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

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Hydrocodone: CNS Depressants may enhance the CNS depressant effect of Hydrocodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. 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

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

Metoprolol: CYP2D6 Inhibitors may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification

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 enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

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

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

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

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

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

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

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

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

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

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

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. 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

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

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

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

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

QuiNIDine: Haloperidol may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may increase the serum concentration of Haloperidol. Avoid combination

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

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

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

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to 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

Serotonin Modulators: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. 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

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrahydrocannabinol: 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 Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide Diuretics. Monitor therapy

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. 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

Frequency not defined.

Cardiovascular: Abnormal T waves with prolonged ventricular repolarization, arrhythmia, hyper-/hypotension, QT prolongation, sudden death, tachycardia, torsade de pointes

Central nervous system: Agitation, akathisia, altered central temperature regulation, anxiety, confusion, depression, drowsiness, dystonic reactions, euphoria, extrapyramidal reactions, headache, insomnia, lethargy, neuroleptic malignant syndrome (NMS), pseudoparkinsonian signs and symptoms, restlessness, seizure, tardive dyskinesia, tardive dystonia, vertigo

Dermatologic: Alopecia, contact dermatitis, hyperpigmentation, photosensitivity (rare), pruritus, rash

Endocrine & metabolic: Amenorrhea, breast engorgement, galactorrhea, gynecomastia, hyper-/hypoglycemia, hyponatremia, lactation, mastalgia, menstrual irregularities, sexual dysfunction

Gastrointestinal: Anorexia, constipation, diarrhea, dyspepsia, hypersalivation, nausea, vomiting, xerostomia

Genitourinary: Priapism, urinary retention

Hematologic: Agranulocytosis (rare), leukopenia, leukocytosis, neutropenia, anemia, lymphomonocytosis

Hepatic: Cholestatic jaundice, obstructive jaundice

Ocular: Blurred vision

Respiratory: Bronchospasm, laryngospasm

Miscellaneous: Diaphoresis, heat stroke

ALERT: U.S. Boxed Warning

Increased mortality in elderly patients with dementia-related psychosis:

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.

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 (Hassballa 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 (APA [Lehman 2004]).

• 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; use with caution in patients at risk of pneumonia (ie, Alzheimer disease) (Maddalena 2004).

• Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, 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 (APA [Lehman 2004]). Risk of tardive dyskinesia and potential for irreversibility may be increased in elderly patients (particularly women), prolonged therapy, and higher total cumulative dose; antipsychotics may also mask signs/symptoms of tardive dyskinesia. Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

• Hyperprolactinemia: May increase prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.

• 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, monitor closely for NMS.

• 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 anginal 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. Haloperidol is not approved for the treatment of dementia-related psychosis.

• Glaucoma: Use with caution in patients with narrow-angle glaucoma; condition may be exacerbated by cholinergic blockade (APA [Lehman 2004]).

• Parkinson disease: Use is contraindicated in patients with Parkinson disease; these patients may be more sensitive to adverse effects (APA [Lehman 2004]).

• 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.

Special populations:

• Elderly: Use in patients with dementia is associated with an increased risk of mortality and cerebrovascular accidents; avoid antipsychotic use for behavioral problems associated with dementia unless alternative nonpharmacologic therapies have failed and patient may harm self or others. In addition, use may cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria). Increased risk for developing tardive dyskinesia, particularly elderly women.

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:

• 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/ 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).

ICU delirium: Monitor either the Confusion Assessment Method for the ICU (CAM-ICU) or the Intensive Care Delirium Screening Checklist (ICDSC)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. 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 [EPS]) 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 selflimiting 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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, anxiety, constipation, dry mouth, nausea, vomiting, diarrhea, lack of appetite, headache, agitation, or insomnia. Have patient report immediately to prescriber abnormal movements, twitching, change in balance, dysphagia, difficulty speaking, severe dizziness, passing out, tremors, difficulty moving, rigidity, urinary retention, loss of strength and energy, brusing, bleeding, vision changes, hallucinations, seizures, mood changes, enlarged breasts, sexual dysfunction, amenorrhea, nipple discharge, signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; and puffing cheeks) or priapism (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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