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Special Alerts
Antipsychotics: Newborn Extrapyramidal and Withdrawal Symptoms with Third Trimester Exposure (Update)
June 2011
The U.S. Food and Drug Administration (FDA) and Health Canada have updated or are in the process of updating the pregnancy sections of their respective prescribing information for antipsychotics to contain detailed information about nonteratogenic effects following maternal use during pregnancy. 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 vary in severity and may be self-limiting (subsiding within hours or days) or require hospitalization. In the cases reported to the FDA, concomitant use of other medications (known to precipitate withdrawal symptoms) may have contributed to the effects, although in some cases, antipsychotic medication use was the only contributing factor for the EPS and withdrawal symptoms.
Women who are taking antipsychotics should not stop them if they become pregnant (abrupt discontinuation is not recommended), but should notify their healthcare provider. Women taking antipsychotics who intend to become pregnant should discuss treatment concerns with their healthcare provider. Any adverse effects noted in newborns should be reported in the U.S. to the FDA's Medwatch program (1-800-332-1088 or https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm) or in Canada to Health Canada's Canada Vigilance Program (1-866-234-2345 or http://www.hc-sc.gc.ca/dhp-mps/medeff/index-eng.php).
For additional information, please refer to:
U.S.: http://www.fda.gov/Drugs/DrugSafety/ucm243903.htm#aihp
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_78-eng.php
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(ha loe PER i dole)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of schizophrenia; control of tics and vocal utterances of Tourette's disorder in children and adults; severe behavioral problems in children
Use: Unlabeled
Treatment of nonschizophrenia psychosis; may be used for the emergency sedation of severely-agitated or delirious patients; adjunctive treatment of ethanol dependence; postoperative nausea and vomiting (alternative therapy); psychosis/agitation related to Alzheimer's dementia
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events were observed in animal studies. Haloperidol crosses the placenta. There are case reports of limb malformations following first trimester exposure in humans. 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 self-limiting or require hospitalization.
Lactation
Enters breast milk/not recommended (AAP rates “of concern”; AAP 2001 update pending)
Breast-Feeding Considerations
Haloperidol is found in breast milk and has been detected in the plasma and urine of nursing infants. Developmental decline was observed in 3 nursing infants following maternal use of haloperidol in combination with chlorpromazine. Breast engorgement, gynecomastia, and lactation are known side effects with the use of haloperidol.
Contraindications
Hypersensitivity to haloperidol or any component of the formulation; Parkinson's disease; severe CNS depression; coma
Warnings/Precautions
Boxed warnings:
• Dementia: See “Disease-related concerns” below.
Concerns related to adverse effects:
• Altered cardiac conduction: May alter cardiac conduction and prolong QT interval; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics, but risk may be increased with doses exceeding recommendations and/or intravenous administration (unlabeled route). 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. Monitor ECG closely for dose-related QT effects. Adverse effects of decanoate may be prolonged.
• 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.
• 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, pre-existing 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 <1000/mm3.
• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer's disease).
• 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.
• 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.
• 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 which may predispose to hypotension/bradycardia).
• Pigmentary retinopathy: Antipsychotics have been associated with pigmentary retinopathy.
• Sedation: May be sedating, use with caution in disorders where CNS depression is a feature; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with severe cardiovascular disease.
• Dementia: [U.S. 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.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; condition may be exacerbated by cholinergic blockade.
• Parkinson's disease: Use is contraindicated in patients with Parkinson's disease; they may be more sensitive to adverse effects.
• Renal impairment: Use with caution in patients with renal impairment.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.
• Thyroid dysfunction: Avoid in thyrotoxicosis.
Concurrent drug therapy issues:
• Antiemetic effects: May mask toxicity of other drugs or conditions (eg, intestinal obstruction, Reye's syndrome, brain tumor) due to antiemetic effects.
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• Elderly: Use caution in the elderly; increased risk of tardive dyskinesia, particularly in elderly women.
Dosage form specific issues:
• Tartrazine: Some tablets contain tartrazine.
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 I.V. use of the injection is not an FDA-approved route of administration; the decanoate form should never be administered intravenously.
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
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (moderate), CYP3A4 (moderate)
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. Risk D: Consider therapy modification
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotics. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Amphetamines: Antipsychotics may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy
Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy
Anti-Parkinson's Agents (Dopamine Agonist): Antipsychotics (Typical) may enhance the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Anti-Parkinson's Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotics (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's agents. Risk D: Consider therapy modification
ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole systemic exposure/affects with concomitant use of a moderate CYP3A4 inhibitor. Decrease aripiprazole dose to 25% of the usual dose in patients receiving both a CYP3A4 and a CYP2D6 inhibitor (regardless of potencies). Risk C: Monitor therapy
ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Budesonide (Systemic, Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic, Oral Inhalation). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor. This interaction is likely less severe with orally inhaled budesonide. Monitor patients closely for signs/symptoms of corticosteroid excess. Risk D: Consider therapy modification
CarBAMazepine: May increase the metabolism of Haloperidol. Risk D: Consider therapy modification
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
ChlorproMAZINE: May enhance the QTc-prolonging effect of Haloperidol. ChlorproMAZINE may increase the serum concentration of Haloperidol. Haloperidol may increase the serum concentration of ChlorproMAZINE. 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). Risk D: Consider therapy modification
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: 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. Risk C: Monitor therapy
Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: A lower starting dose of eplerenone (25 mg once daily for adults) is recommended in patients with hypertension who are also taking drugs that are moderate inhibitors of CYP3A4. Risk D: Consider therapy modification
Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Risk D: Consider therapy modification
FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients extra closely for several days following initiation of the combination, and fentanyl dosage reductions should be made as appropriate. Risk D: Consider therapy modification
Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy
FLUoxetine: May enhance the QTc-prolonging effect of Haloperidol. FLUoxetine may increase the serum concentration of Haloperidol. Management: Consider alternatives to this combination when available. If the combination is used, monitor for evidence of QTc prolongation and increased systemic haloperidol concentrations/effects. Risk D: Consider therapy modification
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. Risk C: Monitor therapy
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Indacaterol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Decrease ivacaftor dose to 150 mg daily in patients also receiving moderate CYP3A4 inhibitors. Risk D: Consider therapy modification
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Lithium formulations: May enhance the neurotoxic effect of Antipsychotics. Lithium formulations may decrease the serum concentration of Antipsychotics. Specifically noted with chlorpromazine. Risk C: Monitor therapy
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Risk D: Consider therapy modification
Methylphenidate: Antipsychotics may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotics. Risk X: Avoid combination
Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Haloperidol. Specifically including drowsiness and confusion. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QUEtiapine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Quinagolide: Antipsychotics may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy
QuiNIDine: Haloperidol may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may increase the serum concentration of Haloperidol. Risk D: Consider therapy modification
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Risk C: Monitor therapy
Saxagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Saxagliptin. Risk C: Monitor therapy
Serotonin Modulators: Antipsychotics may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy
Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Risk D: Consider therapy modification
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination
Toremifene: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Toremifene. The risk for potentially dangerous arrhythmias may be increased. Risk X: Avoid combination
Vandetanib: QTc-Prolonging Agents may enhance the arrhythmogenic effect of Vandetanib. Risk X: Avoid combination
Vemurafenib: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Vemurafenib. Risk X: Avoid combination
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Storage
Protect oral dosage forms from light. Haloperidol lactate injection should be stored at controlled room temperature; do not freeze or expose to temperatures >40°C. Protect from light; exposure to light may cause discoloration and the development of a grayish-red precipitate over several weeks. Stability of standardized solutions is 38 days at room temperature (24°C).
Reconstitution
Haloperidol lactate may be administered IVPB or I.V. infusion in D5W solutions. NS solutions should not be used due to reports of decreased stability and incompatibility.
Standardized dose: 0.5-100 mg/50-100 mL D5W.
Compatibility
Stable in D5W; variable stability (consult detailed reference) in D51/4NS, LR, 1/2NS, NS.
Y-site administration: Compatible: Amifostine, amsacrine, bivalirudin, cimetidine, cisatracurium, cladribine, dexmedetomidine, dobutamine, docetaxel, dopamine, doxorubicin liposome, etoposide phosphate, famotidine, fenoldopam, fentanyl, filgrastim, fludarabine, gemcitabine, granisetron, hetastarch in lactate electrolyte injection (Hextend®), hydromorphone, lidocaine, linezolid, lorazepam, melphalan, methadone, nitroglycerin, norepinephrine, ondansetron, oxaliplatin, paclitaxel, pemetrexed, phenylephrine, propofol, quinupristin/dalfopristin, remifentanil, sufentanil, tacrolimus, teniposide, theophylline, thiotepa, tigecycline, vinorelbine. Incompatible: Allopurinol, amphotericin B cholesteryl sulfate complex, cefepime, dexamethasone sodium phosphate, fluconazole, foscarnet, furosemide, gallium nitrate, heparin, ketorolac, piperacillin/tazobactam, sargramostim. Variable (consult detailed reference): Aztreonam, metoclopramide, midazolam, morphine, nitroprusside.
Compatibility in syringe: Compatible: Buprenorphine with glycopyrrolate, lorazepam, sufentanil. Incompatible: Diphenhydramine, heparin, hydroxyzine, ketorolac, morphine. Variable (consult detailed reference): Benztropine, hydromorphone, scopolamine.
Mechanism of Action
Haloperidol is a butyrophenone antipsychotic which blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones; believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis
Pharmacodynamics/Kinetics
Onset of action: Sedation: I.M., I.V.: 30-60 minutes
Duration: Decanoate: 2-4 weeks
Distribution: Vd: 8-18 L/kg
Protein binding: 90%
Metabolism: Hepatic: 50% to 60% glucuronidation (inactive); 23% CYP3A4-mediated reduction to inactive metabolites (some back-oxidation to haloperidol); and 20% to 30% CYP3A4-mediated N-dealkylation, including minor oxidation pathway to toxic pyridinium derivative (Kudo, 1999)
Bioavailability: Oral: 60% to 70%
Half-life elimination: 18 hours; Decanoate: 21 days
Time to peak, serum: Oral: 2-6 hours; I.M.: 20 minutes; Decanoate: 7 days
Excretion: Urine (30%, 1% as unchanged drug); feces (15%)
Dosage
Children: 3-12 years (15-40 kg): Oral:
Initial: 0.5 mg/day given in 2-3 divided doses; increase by 0.5 mg every 5-7 days; maximum: 0.15 mg/kg/day
Usual maintenance:
Nonpsychotic disorders, Tourette's disorder: 0.05-0.075 mg/kg/day in 2-3 divided doses
Psychotic disorders: 0.05-0.15 mg/kg/day in 2-3 divided doses
Children 6-12 years: Sedation/psychotic disorders: I.M. (as lactate): 1-3 mg/dose every 4-8 hours to a maximum of 0.15 mg/kg/day; convert to oral therapy as soon as able
Adults:
Psychosis:
Oral: 0.5-5 mg 2-3 times/day; usual maximum: 30 mg/day
I.M. (as lactate): 2-5 mg every 4-8 hours as needed
I.M. (as decanoate): Initial: 10-20 times the daily oral dose administered at 4-week intervals
Maintenance dose: 10-15 times initial oral dose; used to stabilize psychiatric symptoms
Delirium in the intensive care unit (unlabeled use, unlabeled route; Jacobi, 2002): I.V.: Initial: 2-10 mg depending on degree of agitation; if inadequate response, may repeat bolus dose (with sequential doubling of initial bolus dose) every 15-30 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. Note: QTc prolongation may occur with cumulative doses ≥35 mg and torsade de pointes has been reported with single doses of ≥20 mg. The optimal dose and regimen of haloperidol for the treatment of severe agitation and/or delirium has not been established.
Rapid tranquilization of severely-agitated patient (unlabeled use): Administer every 30-60 minutes:
Oral: 5-10 mg
I.M. (as lactate): 5 mg
Average total dose (oral or I.M.) for tranquilization: 10-20 mg
Postoperative nausea and vomiting (PONV) (unlabeled use): I.M., I.V.: 0.5-2 mg (Gan, 2007)
Elderly: Nonpsychotic patient, dementia behavior (unlabeled use): Initial: Oral: 0.25-0.5 mg 1-2 times/day; increase dose at 4- to 7-day intervals by 0.25-0.5 mg/day; increase dosing intervals (twice daily, 3 times/day, etc) as necessary to control response or side effects
Hemodialysis/peritoneal dialysis: Supplemental dose is not necessary
Administration: Oral
Dilute the oral concentrate with water or juice before administration. Note: Avoid skin contact with oral medication; may cause contact dermatitis.
Administration: I.M.
The decanoate injectable formulation should be administered I.M. only; do not give decanoate I.V.
Administration: I.V.
Decanoate: Do not administer I.V.
Lactate: May be administered I.V. (unlabeled route) or I.M.
Administration: I.V. Detail
pH: 3.0-3.6
Monitoring Parameters
Vital signs; lipid profile, fasting blood glucose/Hgb A1c; BMI; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS); ECG (with off-label intravenous administration)
Reference Range
Therapeutic: 5-20 ng/mL (SI: 10-40 nmol/L) (psychotic disorders - less for Tourette's and mania)
Toxic: >42 ng/mL (SI: >84 nmol/L)
Patient Education
It may take 2-3 weeks to achieve desired results. Dilute oral concentration with water or juice. Avoid alcohol. Maintain adequate hydration, unless instructed to restrict fluid intake. Avoid skin contact with medication; may cause contact dermatitis (wash immediately with warm, soapy water). You may experience excess drowsiness, restlessness, dizziness, blurred vision, nausea, vomiting, constipation, postural hypotension, urinary retention, or decreased perspiration. Report persistent CNS effects (eg, trembling fingers, altered gait or balance, excessive sedation, seizures, unusual movements, anxiety, abnormal thoughts, confusion, personality changes), chest pain, palpitations, rapid heartbeat, severe dizziness, unresolved urinary retention or changes in urinary pattern, vision changes, skin rash or yellowing of skin, respiratory difficulty, or worsening of condition.
Geriatric Considerations
Many elderly patients receive antipsychotic medications for inappropriate nonpsychotic behavior. Before initiating antipsychotic medication, the clinician should investigate any possible reversible cause; any stress or stress from any disease can cause acute “confusion” or worsening of baseline nonpsychotic behavior. Most commonly acute changes in behavior are due to increases in drug dose or addition of new drug to regimen; fluid electrolyte loss; infections; and changes in environment.
Any changes in disease status in any organ system can result in behavior changes.
In the treatment of agitated, demented, elderly patients, authors of meta-analysis of controlled trials of the response to the traditional antipsychotics (phenothiazines, butyrophenones) in controlling agitation have concluded that the use of neuroleptics results in a response rate of 18%. Clearly neuroleptic therapy for behavior control should be limited with frequent attempts to withdraw the agent given for behavior control.
Clinical studies of haloperidol did not include sufficient numbers of subjects ≥65 years of age to determine whether they respond differently from younger subjects. Other reported clinical experience has not consistently identified differences between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women. Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments:
Delirium in the ICU Patient: Set goals for control of delirium. Haloperidol has not been studied in well-controlled trials enrolling ICU patients with acute delirium or agitation. In September 2007, the FDA and Johnson and Johnson informed healthcare providers about an increased risk of QT prolongation, torsade de pointes (TdP), and sudden death associated with haloperidol use, particularly high dose, intravenous administration (unlabeled use). Case-control studies indicate a dose-response between intravenous haloperidol and TdP. Even when used at recommended doses, cardiac arrhythmias have occurred. Caution or avoidance of haloperidol is advised in patients with predisposing risk factors including 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. In addition, ECG monitoring is recommended with off-label intravenous use of haloperidol.
Haloperidol may cause extrapyramidal symptoms. It is the most frequently implicated antipsychotic associated with neuroleptic malignant syndrome.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation). Orthostatic hypotension, and nasal congestion are possible; since the drug is a dopamine antagonist, extrapyramidal symptoms of the TMJ are a possibility.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Manufacturer's information states that haloperidol may block vasopressor activity of epinephrine. This has not been observed during use of epinephrine as a vasoconstrictor in local anesthesia. Haloperidol is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.
Dental Comment
Haloperidol is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Haloperidol is considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.
Mental Health: Comment
Haloperidol is a high-potency antipsychotic. Older antipsychotic medications (chlorpromazine, haloperidol), which do not meet specific criteria for “atypical” antipsychotics, are often referred to as typical antipsychotics. They are associated with the troubling side effect, EPS. However, it is commonly believed that in order for a drug to treat psychosis, it must block dopamine is some manner.
Common side effects include sedation and neuroleptic effect (reduced initiative, interest in the environment, and display of emotion or affect). All typical antipsychotics are considered to be equally effective if given in equipotent doses. An inverse relationship exists between intrinsic antimuscarinic activity and propensity to cause extrapyramidal side effects. If dystonia or pseudoparkinsonism occurs, antiparkinsonian agents should be considered. If akathisia occurs, beta-blockers (eg, propranolol), benzodiazepines, or antiparkinsonian agents should be considered. Tardive dyskinesia (TD) secondary to typical antipsychotics has an estimated incidence of 3% to 5% per year for the first 5 years of treatment. After this time period, the incidence is estimated to be 2% to 3% per year. Prevalence rates are ~15% to 20%. Female gender and age constitute risk factors for TD. Indeed, prevalence rates have been reported to be as high as 70% in elderly females. No specific treatment exists for TD, however, patients are often initiated on/switched to an atypical antipsychotic because of their lower incidence to cause TD and hopes of suppression.
Typical antipsychotics are usually only indicated for schizophrenia, but are generally effective for mania and psychosis and/or behavioral syndromes secondary to other mental conditions. Nonpsychiatric uses include Tourette's syndrome, Huntington's disease, and occasionally, intractable hiccups, pruritus, nausea, and vomiting.
These drugs are thought to exert their antipsychotic activity by blocking dopamine D2 receptors in the mesolimbic dopaminergic pathway. Side effects are often related to their ability to antagonize dopamine receptors in the nigrostriatal and tuberoinfundibular pathways.
Long-acting dosage form is useful in patients nonadherent to treatment.
Coadministration of two or more antipsychotics does not generally improve clinical response and may increase the potential for adverse effects.
In 2008, the FDA issued a warning regarding increased mortality risk with typical and atypical antipsychotic drugs when used in elderly patients with dementia-related psychosis.
Nursing: Physical Assessment/Monitoring
With I.M. or I.V. use, monitor for hypotension and cardiac irregularities. Initiate at lower doses and taper dosage slowly when discontinuing.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, oil, as decanoate [strength expressed as base]: 50 mg/mL (1 mL, 5 mL); 100 mg/mL (1 mL, 5 mL)
Haldol® Decanoate: 50 mg/mL (1 mL); 100 mg/mL (1 mL) [contains benzyl alcohol, sesame oil]
Injection, solution, as lactate [strength expressed as base]: 5 mg/mL (1 mL, 10 mL)
Haldol®: 5 mg/mL (1 mL)
Solution, oral, as lactate [strength expressed as base, concentrate]: 2 mg/mL (5 mL, 15 mL, 120 mL)
Tablet, oral: 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg
Pricing: U.S. (www.drugstore.com)
Solution (Haloperidol Decanoate)
100 mg/mL (1): $50.99
100 mg/mL (5): $225.98
Tablets (Haloperidol)
0.5 mg (90): $16.99
1 mg (90): $19.99
2 mg (90): $20.99
5 mg (90): $25.99
10 mg (60): $72.99
20 mg (60): $124.99
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International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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