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Haloperidol (Systemic)


VA CLASSIFICATION
Primary: CN709
Secondary: CN900; GA609

Commonly used brand name(s): Apo-Haloperidol; Haldol; Haldol Decanoate; Haldol LA; Novo-Peridol; PMS Haloperidol; Peridol.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antipsychotic—

antidyskinetic (Gilles de la Tourette's syndrome; Huntington's chorea)—

antiemetic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Psychotic disorders (treatment)—Haloperidol is indicated for the management of the manifestations of acute and chronic psychotic disorders {18} {20} including schizophrenia , manic states, and drug-induced psychoses, such as steroid psychosis {02}. It may also be useful in the management of aggressive and agitated patients, including patients with organic mental syndrome or mental retardation. Haloperidol decanoate, a long-acting parenteral form, is intended for maintenance use in the management of patients requiring prolonged parenteral therapy, as in chronic schizophrenia . {01}

Behavior problems, severe (treatment)—Haloperidol is effective in the treatment of children with severe behavior problems of apparently unprovoked, combative, explosive hyperexcitability {18} {20}. It is also effective in the short-term treatment of hyperactivity in children who show excessive motor activity with accompanying conduct disorders such as aggressiveness, impulsiveness, easy frustration, short attention span, and/or rapid mood fluctuations {18}. In these two groups of children, haloperidol should be tried only in patients who fail to respond to psychotherapy or other non-neuroleptic medication {18}.

Gilles de la Tourette"s syndrome (treatment)—Haloperidol is used to control tics and vocalizations of Tourette"s syndrome in children and adults {18} {20}.

[Autism, infantile (treatment)]1—Haloperidol has been used to reduce abnormal behaviors, such as withdrawal, stereotypy, abnormal object relationships, fidgetiness, hyperactivity, negativism, angry affect, and labile affect, and may improve learning, in some patients with autism {03}.

[Chorea, Huntington"s {08} (treatment)]1—Because of its strong extrapyramidal effects, haloperidol is used to reduce disabling choreiform movements in Huntington"s disease {02}.

[Nausea and vomiting, cancer chemotherapy–induced (prophylaxis and treatment)]1— Haloperidol is used as a second-line agent to control nausea and vomiting associated with antineoplastic therapy and surgery {02}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Pharmacological effects of haloperidol are similar to the effects of piperazine-derivative phenothiazines, which include acetophenazine, fluphenazine, perphenazine, prochlorperazine, and trifluoperazine.


Physicochemical characteristics:

Chemical group—
    A butyrophenone derivative {18} {19} {20}.
Molecular weight—
    Haloperidol: 375.87
    Haloperidol decanoate: 530.12


Other characteristics
    Haloperidol oral solution: pH 2.75–3.75.
    Haloperidol injection: pH 3.0–3.8.

Mechanism of action/Effect:

Although the complex mechanism of the therapeutic effect is not clearly established {18} {20}, haloperidol is known to produce a selective effect on the central nervous system (CNS) by competitive blockade of postsynaptic dopamine (D 2) receptors in the mesolimbic dopaminergic system and an increased turnover of brain dopamine to produce its tranquilizing effects. With subchronic therapy, depolarization blockade, or diminished firing rate of the dopamine neuron (decreased release) along with D 2 postsynaptic blockade results in the antipsychotic action. {54}

The long-acting decanoate form acts as a pro-drug, slowly and steadily releasing haloperidol from the vehicle.


Other actions/effects:

Blockade of dopamine receptors in the nigrostriatal dopamine pathway produces extrapyramidal motor reactions; blockade of dopamine receptors in the tuberoinfundibular system decreases growth hormone release and increases prolactin release by the pituitary. There is also some blockade of alpha-adrenergic receptors of the autonomic system.

Absorption:

Oral—60% {24} {25} {28}.

Distribution:

The volume of distribution of haloperidol at steady state (Vd SS) is 18 L per kg {24} {26}.

Protein binding:

Very high (92%) {24} {46}.

Biotransformation:

Hepatic; extensive {26}.

Half-life:


Haloperidol, Elimination:

Oral: 24 hours (range, 12 to 37 hours) {25} {27} {28} {30}.

Intramuscular: 21 hours (range, 17 to 25 hours) {27} {30}.

Intravenous: 14 hours {25} {26} {27} {30} (range, 10 to 19 hours {25} {26}).



Haloperidol decanoate, Elimination:

Approximately 3 weeks (single {54} or multiple doses) {01} {04} {44} {45} {46}.


Time to peak plasma concentration

Oral—3 to 6 hours {20} {28} {29} {30}.

Intramuscular—10 to 20 minutes {20} {30}.

Long-acting intramuscular—3 to 9 days, although variable. May occur on first day in some patients, notably the elderly. {01} {04} {45} {46}

Therapeutic plasma concentration

4 to 20 nanograms per mL (0.01 to 0.05 micromoles per L) {24} {44}.

Elimination:


Renal {20}
        About 40% of a single oral dose is excreted in the urine within 5 days, 1% of which is unchanged drug {24}. A mean clearance value of 12 mL per kg per minute has been reported {26}.



Biliary {20}
        15% of an oral dose is excreted in the feces by biliary elimination.



Precautions to Consider

Carcinogenicity/Tumorigenicity

Neuroleptic drugs (including haloperidol) elevate prolactin concentrations; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin concentrations is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. However, neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. {18} {19} {20} {24}

Mutagenicity

Haloperidol decanoate—No mutagenic potential was found in the Ames Salmonella microsomal activation assay {01} {19}.

Pregnancy/Reproduction
Fertility—
Animal reproduction studies have shown decreased fertility with doses 2 to 20 times the usual maximum human dose of haloperidol.

Pregnancy—

For haloperidol

Adequate studies in humans have not been done {18} {19}. However, there have been some reports of limb malformations with maternal use of haloperidol along with other drugs of suspected teratogenicity during the first trimester {18} {19}.

Some rodent studies have shown an increase in incidence of fetal resorption, delayed delivery, and neonatal death with doses 2 to 20 times the usual maximum human dose of haloperidol {18}. Cleft palate has been observed in a study with mice given 15 times the human dose of haloperidol {18}.



For haloperidol decanoate

Adequate studies in humans have not been done.

Studies in rats given up to three times the usual maximum human dose showed an increase in incidence of fetal resorption, fetal mortality, and neonatal mortality {01} {19}.

FDA Pregnancy Category C {01} {19}.


Breast-feeding

Haloperidol is distributed into breast milk {19} {46}. Animal studies have shown that haloperidol is distributed into milk in quantities sufficient to cause sedation and motor function impairment in the nursing offspring. Breast-feeding during haloperidol therapy is not recommended.

Pediatrics

Haloperidol is not recommended for use in children up to 3 years of age. Children are highly susceptible to the extrapyramidal side effects, especially dystonias {15}, of haloperidol.


Geriatrics


Geriatric patients tend to develop higher plasma concentrations of haloperidol because of changes in distribution due to decreases in lean body mass, total body water, and albumin, and often an increase in total body fat composition {09}. These patients usually require lower initial dosage and a more gradual titration of dose.

Elderly patients appear to be more prone to orthostatic hypotension and exhibit an increased sensitivity to the anticholinergic and sedative effects of haloperidol. In addition, they are more prone to develop extrapyramidal side effects, such as tardive dyskinesia and parkinsonism. The symptoms of tardive dyskinesia are persistent, difficult to control, and, in some patients, appear to be irreversible. The symptoms may be masked during long-term treatment, but may appear if haloperidol is discontinued. There is no known effective treatment. Careful observation during haloperidol therapy for early signs of tardive dyskinesia and reduction of dosage or discontinuation of medication may prevent a more severe manifestation of the syndrome.


It has been suggested that elderly patients receive half the usual adult dose. Patients with organic mental syndrome or acute confusional states should initially receive one-third to one-half the usual adult dose {10}, with the dose being increased no more frequently than every 2 or 3 days, and preferably at intervals of 7 to 10 days. A periodic attempt should be made to discontinue medication as soon as the patient improves {09}.


Dental

The peripheral anticholinergic effects of haloperidol may decrease or inhibit salivary flow, especially in middle-aged or elderly patients, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

Extrapyramidal reactions induced by haloperidol will result in increased motor activity of the head, face, and neck. Occlusal adjustments, bite registrations, and treatment for bruxism may be made less reliable. {11}

The leukopenic and thrombocytopenic effects of haloperidol may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol{18}{20} or
» CNS depression–producing medications, other{18}{19}{20}{22}{23}{28} (see Appendix II )    (concurrent use with haloperidol may result in increased CNS and respiratory depression and increased hypotensive effects {15})

    (concurrent use with haloperidol may potentiate alcohol intoxication {15})


Amphetamines{21}{22}{59}    (concurrent use may decrease stimulant effects of amphetamines due to alpha-adrenergic blockade by haloperidol; also, the antipsychotic effects of haloperidol may be reduced when amphetamines and haloperidol are used concurrently)


Anticholinergics or other medications with anticholinergic activity (see Appendix II ){21}{22}{23}{44} or
Antidyskinetic agents{18}{19}{20} or
Antihistamines    (concurrent use with haloperidol may intensify anticholinergic side effects, especially those of confusion, hallucinations, nightmares, and increased intraocular pressure, because of secondary anticholinergic effects of haloperidol; also, patients should be advised to report occurrence of gastrointestinal problems since paralytic ileus may occur with concurrent therapy; in addition, antipsychotic effectiveness of haloperidol may be decreased because of reduced gastrointestinal absorption; dosage adjustments may be necessary)


Anticoagulants{18}{20}{21}{22}{28}{59} , coumarin- or indandione-derivative    (concurrent use with haloperidol may either increase or decrease anticoagulant activity; although the clinical significance has not been determined, caution is recommended )


Anticonvulsants, including barbiturates{18}{19}{20}{21}{22}{23}{44}{59}    (concurrent use with haloperidol may cause a change in the pattern and/or frequency of epileptiform seizures; dosage adjustments of anticonvulsants may be necessary; serum concentrations of haloperidol may be significantly reduced)


Antidepressants, tricyclic{21}{22}{23}{59} or
Maprotiline{33}{34}{59} or
Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, or selegiline or
Trazodone    (concurrent use with haloperidol may prolong and intensify the sedative and anticholinergic effects of either these medications or haloperidol)


Bromocriptine{35}    (concurrent use with haloperidol may increase serum prolactin concentrations and interfere with effects of bromocriptine; dosage adjustment of bromocriptine may be necessary)


Bupropion{36}{37}{38}    (concurrent use of bupropion with haloperidol may lower the seizure threshold and increase the risk of major motor seizures)


Diazoxide{22}{39}    (concurrent use antagonizes the inhibition of insulin release by diazoxide)


Dopamine    (concurrent use may antagonize peripheral vasoconstriction produced by high doses of dopamine because of the alpha-adrenergic blocking action of haloperidol)


Ephedrine{17}    (concurrent use may decrease the pressor response to ephedrine)


» Epinephrine{17}{20}{59}    (concurrent use may block the alpha-adrenergic effects of epinephrine, possibly resulting in severe hypotension and tachycardia)


» Extrapyramidal reaction–causing medications, other (see Appendix II )    (concurrent use with haloperidol may increase the severity and frequency of extrapyramidal effects)


Fluoxetine{40}{41}{59}    (caution in concurrent use of fluoxetine with haloperidol is recommended because of a potentially increased risk of CNS side effects, particularly extrapyramidal reactions {52} {60} {61})


Guanadrel or
Guanethidine{20}{21}{22}{23}{59}    (concurrent use with haloperidol may decrease the hypotensive effects of these agents because of displacement from and inhibition of uptake into alpha-adrenergic neurons)


» Levodopa{22}{59} or
Pergolide{42}    (concurrent use may decrease the therapeutic effects of these agents because of blockade of dopamine receptors by haloperidol)


» Lithium{18}{19}{20}{21}{22}{23}{28}{44}    (lithium is frequently used concurrently with haloperidol during the first week or two of treatment for acute manic episodes; lithium alone may be adequate thereafter, although some patients may continue to need both {02}; however, concurrent use with haloperidol has been associated with irreversible neurological toxicity and brain damage, especially in patients with organic mental syndrome or other CNS impairment, although this interaction has been reported only with high doses {16} {52}; extrapyramidal symptoms may be increased by haloperidol's enhancement of dopamine blockade; patients should be monitored closely during concurrent use; dosage adjustments or discontinuation of treatment may be necessary)

    (admixture of the liquid forms of lithium and haloperidol may result in precipitation of free haloperidol)


Metaraminol    (concurrent use with haloperidol usually decreases, but does not reverse or completely block, the pressor response to metaraminol, because of the alpha-adrenergic blocking action of haloperidol)


Methoxamine    (prior administration of haloperidol may decrease the pressor effect and duration of action of methoxamine because of the alpha-adrenergic blocking action of haloperidol)


Methyldopa{20}{21}{22}{23}{59}    (concurrent use with haloperidol may cause unwanted mental effects such as disorientation and slowed or difficult thought processes)


Phenylephrine    (prior administration of haloperidol may decrease the pressor response to phenylephrine because of the alpha-adrenergic blocking action of haloperidol)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
ECG    (prolongation of the Q-T interval and changes compatible with configuration of torsades de pointes may occur {62} {63})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» CNS depression, toxic, drug-induced, severe{18}{19}{20}    (may be potentiated)


Risk-benefit should be considered when the following medical problems exist
Alcoholism, active    (CNS depression may be potentiated; risk of heat stroke may be increased {15})


» Cardiovascular disease, severe, especially angina{18}{19}{20}    (transient hypotension and anginal pain may be provoked)


» Epilepsy{18}{19}{20}    (seizure threshold may be lowered)


Glaucoma or predisposition to{18}{19}{20}    (may be potentiated because of secondary anticholinergic effects of haloperidol)


Hepatic function impairment{18}{19}{20}    (metabolism may be altered)


Hyperthyroidism or thyrotoxicosis{18}{19}{20}    (severe neurotoxicity such as rigidity and inability to walk or talk may result)


» Parkinson's disease{18}{19}{20}{53}    (may be potentiated)


Pulmonary insufficiency, such as asthma, emphysema, or acute pulmonary infections    (potentiation of breathing impairment may possibly lead to “silent pneumonias”)


Renal function impairment{20}    (excretion may be altered; more applicable to higher dosage since renal clearance of unchanged drug is relatively low)


» Sensitivity to haloperidol    (patients with known allergies or with a history of allergic reactions to other medications may also be sensitive to haloperidol {01} {18} {19} {20})


» Urinary retention{18}{19}{20}    (may be potentiated)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood cell counts and differential in patients with sore throat and fever or infections    (may be required during high-dose or prolonged therapy when symptoms of infection develop; if significant cellular depression occurs, medication should be discontinued and appropriate therapy initiated; rechallenge in recovered patients will usually cause a recurrence of agranulocytosis {15})


Careful observation for early signs of dehydration, such as lethargy and decreased sensation of thirst    (recommended at periodic intervals, especially in elderly or debilitated persons, for prevention of bronchopneumonia)


Careful observation for early symptoms of tardive dyskinesia    (recommended at periodic intervals, especially in the elderly and patients on high or extended maintenance dosage; since there is no known effective treatment if syndrome should develop, haloperidol should be discontinued, if clinically feasible, at earliest signs, usually fine, worm-like movements of the tongue, to stop further development)


Careful observation for early symptoms of tardive dystonia    (recommended at periodic intervals; since there is no known effective treatment if syndrome should develop, haloperidol should be discontinued, if clinically feasible, at the earliest signs)


Careful observation for signs of overdose or insufficient dosing with haloperidol decanoate    (recommended during initial dosing adjustments; since haloperidol decanoate slowly increases to steady state plasma concentration over 2 to 4 months, accumulation to excessive levels may occur; if psychotic symptoms reappear before next dose, therapy can be supplemented with short-acting forms of haloperidol {01})


Hepatic function determinations    (may be required at periodic intervals during high-dose or prolonged therapy or if jaundice or grippe-like symptoms occur, to detect liver function impairment)




Side/Adverse Effects

Note: A few cases of sudden and unexpected death have been reported in patients who were receiving haloperidol therapy. However, there is no definite evidence that haloperidol is a causative factor. {18} {19}
Children are highly susceptible to extrapyramidal effects.
Geriatric and debilitated patients are more prone to develop extrapyramidal side effects and orthostatic hypotension and usually require a lower initial dosage and a more gradual titration of dose.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Akathisia (restlessness or need to keep moving)
    
dystonic extrapyramidal effects{18}{19}{20} (muscle spasms of face, neck, and back; tic-like or twitching movements; twisting movements of body; inability to move eyes; weakness of arms and legs)
    
parkinsonian extrapyramidal effects{18}{19}{20} (difficulty in speaking or swallowing; loss of balance control; mask-like face; shuffling walk; stiffness of arms or legs; trembling and shaking of hands and fingers)

Note: Akathisia may appear within first 6 hours after dose; often indistinguishable from psychotic agitation; differentiation with benztropine may improve haloperidol-induced akathisia but not psychotic agitation. {08}
Dystonic extrapyramidal effects appear most often in children and young adults and early in treatment; may subside within 24 to 48 hours after drug has been discontinued.
Parkinsonian extrapyramidal effects are more frequent in the elderly; symptoms may be seen in the first few days of treatment or after prolonged treatment, and can recur after even a single dose.


Incidence less frequent
    
Allergic reaction{18}{19} (red and raised, or acne-like skin rash)
    
anticholinergic effects{18}{19}{20} (difficult urination; hallucinations)
    
CNS effect{18}{19}{20} (hallucinations)
    
decreased thirst, or unusual tiredness or weakness
    
orthostatic hypotension{18}{19} (dizziness, lightheadedness, or fainting)
    
persistent tardive dyskinesia{18}{19}{20} (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements; uncontrolled movements of the arms and legs)

Note: Decreased thirst or unusual tiredness or weakness may precede dehydration, hemoconcentration, reduced pulmonary ventilation, and bronchopneumonia; occur most often in elderly or debilitated patients {18} {19} {20}.
Tardive dyskinesia is more frequent in elderly patients, women, and patients with brain damage {15}; initially dose related, but may increase with long-term treatment and total cumulative dose; may persist after discontinuation of haloperidol {18} {19} {20}.


Incidence rare
    
Agranulocytosis{18}{19}{20} (sore throat and fever; unusual bleeding or bruising)
    
heat stroke{18}{19}{20} (hot, dry skin; inability to sweat; muscle weakness; confusion)
    
obstructive jaundice{18}{19}{20} (yellow eyes or skin)
    
neuroleptic malignant syndrome (NMS){18}{19}{20} (difficult or unusually fast breathing; fast heartbeat or irregular pulse; high fever; high or low [irregular] blood pressure; increased sweating; loss of bladder control; severe muscle stiffness; seizures; unusual tiredness or weakness; unusually pale skin)
    
tardive dystonia{18}{54}{55}{56} (increased blinking or spasms of eyelid; unusual facial expressions or body positions; uncontrolled twisting movements of neck, trunk, arms, or legs)

Note: Heat stroke, caused by haloperidol-induced suppression of central and peripheral temperature regulation in the hypothalamus {12}, may occur during environmental conditions of high heat and high humidity. The effectiveness of sweating as a cooling mechanism may be reduced by humid conditions and by the anticholinergic effects of haloperidol, used alone or in combination with other anticholinergic medications such as nonprescription cold medications or antihistamines. Adequate interior temperature control (air conditioning) must be maintained for institutionalized patients during hot weather because of the increased risk of heat stroke and NMS. {13} Patients should be advised to avoid exertion, stay in cool areas, and avoid dehydration and other anticholinergic medications. {15}
NMS may occur at any time during neuroleptic therapy, but is more commonly seen soon after start of therapy, or after patient has switched from one neuroleptic to another, during combined therapy with another psychotropic medication, or after a dosage increase. Along with the overt signs of skeletal muscle rigidity, hyperthermia, autonomic dysfunction, and altered consciousness, differential diagnosis may reveal leukocytosis (9500 to 26,000 cells per cubic millimeter), elevated liver function test values, and elevated creatine kinase (CK). {12}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Blurred vision{18}{19}{20}
    
changes in menstrual period{18}{19}{20}
    
constipation{18}{19}{20}
    
dryness of mouth{18}{19}{20}
    
swelling or soreness in breasts in females{18}{19}{20}
    
unusual secretion of milk{18}{19}{20}
    
weight gain

Incidence less frequent
    
Decreased sexual ability{18}{19}{20}
    
drowsiness{18}{19}{20}
    
increased sensitivity of skin to sun{18}{19}
    
nausea or vomiting{18}{19}{20}



Those indicating the need for medical attention if they occur after the medication is discontinued
    
Withdrawal emergent dyskinesia{18}{19}{20} (trembling of fingers and hands; uncontrolled, repetitive movements of mouth, tongue, and jaw)—more frequent in elderly patients, women, and patients with brain damage{15}




Overdose
For specific information on the agents used in the management of haloperidol overdose, see:
   • Albumin Human (Systemic) monograph;
   • Benztropine in Antidyskinetics (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Diphenhydramine in Antihistamines (Systemic) monograph; and/or
   • Norepinephrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
In general, symptoms of overdose may be an exaggeration of adverse effects. Patient would appear comatose with respiratory depression and hypotension severe enough to produce a shock-like state.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Severe breathing difficulty {18} {19}
    
dizziness {18} {19}
    
severe drowsiness or comatose state {18} {19}
    
severe muscle trembling, jerking, stiffness, or uncontrolled movements {18} {19} {20}
    
severe tiredness or weakness {18} {19}


Treatment of overdose
Treatment is essentially symptomatic and supportive.


To decrease absorption:
Inducing emesis or initiating gastric lavage, immediately followed by administration of activated charcoal {18} {20}.



Specific treatment:
Counteracting hypotension and circulatory collapse by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as norepinephrine. Epinephrine should not be used since it may cause paradoxical hypotension. {18} {19} {20}

Administering benztropine or diphenhydramine to manage severe extrapyramidal reactions {18} {19} {20}.



Monitoring:
Monitoring ECG for signs of Q-T prolongation or torsades de pointes . Severe arrhythmias should be treated with appropriate antiarrhythmic measures. {62} {63}



Supportive care:
Establishing a patent airway {18} {19} {20}.

Mechanically assisting respiration, if necessary {18} {19} {20}.

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Note: Dialysis is not effective in removing excessive systemic haloperidol.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Haloperidol (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to haloperidol

Pregnancy—Reports of limb malformations after maternal use of haloperidol with other drugs of suspected teratogenicity during first trimester; animal reproduction studies have shown a decrease in fertility, increased incidence of fetal resorption, delayed delivery, and neonatal death with very high doses





Breast-feeding—Distributed into breast milk; animal studies have shown sedation, impaired motor function in nursing offspring; not recommended for use during breast-feeding





Use in children—Children are more prone to extrapyramidal symptoms, especially dystonias






Use in the elderly—Elderly patients are more likely to develop extrapyramidal, anticholinergic, hypotensive, and sedative effects; reduced dosage recommended





Dental—Haloperidol-induced blood dyscrasias may result in infections, delayed healing, and bleeding; dry mouth may cause caries, candidiasis, periodontal disease, and discomfort; increased motor activity of face, head, and neck may interfere with some dental procedures
Other medications, especially alcohol, other CNS depression–producing medications, epinephrine, other extrapyramidal reaction–producing medications, levodopa, or lithium
Other medical problems, especially severe cardiovascular disease, severe CNS depression, Parkinson's disease, allergies, epilepsy, or urinary retention

Proper use of this medication
Taking with food or milk to reduce gastrointestinal irritation

Proper administration of oral liquid form:

• Using special dropper


• Mixing with water or a beverage such as orange juice, apple juice, tomato juice, or cola; not mixing with tea or coffee


» Importance of not taking more or less medication than the amount prescribed

» Compliance with therapy; may require several weeks of therapy to obtain desired effects

» Proper dosing
Missed dose: Taking as soon as possible; taking any remaining doses for that day at regularly spaced intervals; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress of therapy

» Checking with physician before discontinuing medication; gradual dosage reduction may be needed

» Avoiding use of alcoholic beverages or other CNS depressants during therapy

» Possible drowsiness or dizziness; caution when driving, using machinery, or doing things requiring alertness {18} {19} {20}

Possible dizziness or lightheadedness: caution when getting up suddenly from a lying or sitting position

» Possible heat stroke: caution during exercise, hot baths, or hot weather {06}

Avoiding the use of over-the-counter medications for colds or allergies, to prevent increased anticholinergic effects and risk of heat stroke {15}

» Caution if any kind of surgery, dental treatment, or emergency treatment is required; telling physician or dentist in charge about taking haloperidol because of possible drug interactions or blood dyscrasias {15}

Possible skin photosensitivity; avoiding unprotected exposure to sun; using protective clothing; using a sun block product that includes protection against both UVA-caused photosensitivity reactions and UVB-caused sunburn reactions; avoiding use of sunlamp, tanning bed, or tanning booth {15}

Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

If taking liquid form, avoiding contact with skin (to prevent contact dermatitis)

Observing precautions for up to 6 {14} weeks with long-acting parenteral form


Side/adverse effects
» Stopping medication and notifying physician immediately if symptoms of neuroleptic malignant syndrome (NMS) appear

Extrapyramidal effects are more likely to occur in children, the elderly, and debilitated patients

Notifying physician as soon as possible if early symptoms of tardive dyskinesia appear

Possibility of withdrawal symptoms

Signs of potential side effects, especially akathisia, dystonias, parkinsonism, allergic reaction, anticholinergic effects, CNS effect, decreased thirst, unusual tiredness or weakness, orthostatic hypotension, tardive dyskinesia or dystonia, blood dyscrasias, heat stroke, obstructive jaundice, and neuroleptic malignant syndrome (NMS)


General Dosing Information
See also Patient monitoring .

Dosage must be individualized by titration from the lower dose range {18}. After a favorable response is noted (usually within 3 weeks), the proper maintenance dosage should be determined by gradually decreasing to the lowest level of therapeutic dosage that will maintain an adequate clinical response {20}.

The antiemetic effect of haloperidol may mask signs of drug toxicity or may obscure diagnosis of conditions in which the primary symptom is nausea {20}.

When extended therapy is discontinued, a gradual reduction in haloperidol dosage over several weeks is recommended, since abrupt withdrawal may cause some patients on high or long-term dosage to experience withdrawal-emergent neurological symptoms.

Avoid skin contact with haloperidol oral solution; contact dermatitis has been reported {64}.

For oral dosage forms only
Because undiluted haloperidol concentrated oral solution may irritate mucous membranes, the dose should be diluted with water or beverages having a pH less than 4 (such as orange juice, apple juice, tomato juice, or cola). The dilution should be prepared immediately prior to administration to prevent precipitation. If mixed with coffee, tea, or lithium citrate syrup, free haloperidol will precipitate. {64} {65}

For long-acting dosage form only
Patients being considered for haloperidol decanoate therapy should be first converted to oral haloperidol from any other neuroleptic they may have been taking to prevent unexpected adverse sensitivity to haloperidol.

Variations in patient response may require adjustments of dose and dosing intervals {18}. Each patient must be carefully supervised to determine the optimal dosing interval and lowest effective dose, depending on patient's response, age, physical condition, symptoms, severity of illness, and drug history {15}.

Effects of the extended-action injectable form may last up to 6 weeks in some patients. The side effects information and precautions apply during this period of time.

Diet/Nutrition
Haloperidol tablets may be taken with food or a full glass (240 mL) of water or milk if necessary to lessen gastrointestinal irritation.

To prevent mucosal irritation, haloperidol oral solution should be diluted in water or beverages such as orange juice, apple juice, tomato juice, or cola immediately prior to administration {64}.

For treatment of adverse effects


Neuroleptic malignant syndrome (NMS):
Treatment is essentially symptomatic and supportive and includes the following

   • Discontinuing haloperidol immediately. Neuroleptic malignant syndrome after injection of long-acting haloperidol decanoate may be difficult to treat because of this dosage form's long half-life.
   • Hyperthermia—Administering antipyretics (aspirin or acetaminophen); using cooling blanket.
   • Dehydration—Restoring fluids and electrolytes.
   • Cardiovascular instability—Monitoring blood pressure and cardiac rhythm closely.
   • Hypoxia—Administering oxygen; considering airway insertion and assisted ventilation.
   • Muscle rigidity—Dantrolene sodium may be administered (100 to 300 mg per day in divided doses; 1.25 to 1.5 mg per kg of body weight, intravenously). Bromocriptine (5 to 7.5 mg every eight hours) has been used to reverse hyperpyrexia and muscle rigidity. {06}



Parkinsonism, severe:
Many authorities advise that the only appropriate treatment of extrapyramidal symptoms is reduction of the antipsychotic dosage, if possible. Oral antidyskinetic agents such as trihexyphenidyl, 2 mg three times per day, or benztropine, may be effective in treating more severe parkinsonism and acute motor restlessness but are used sparingly, and then usually for no longer than 3 months. Extrapyramidal symptoms may reappear if both haloperidol and the antidyskinetic agent are discontinued simultaneously. The antidyskinetic agent may have to be continued after haloperidol is discontinued because of different excretion rates. Milder effects may be treated by adjusting dosage. {05}



Akathisia:
May be treated with antiparkinsonian medications, or with propranolol (30 to 120 mg per day), nadolol (40 mg per day), pindolol (5 to 60 mg per day) {43} {50} {51} {52}, lorazepam (1 or 2 mg two or three times a day), or diazepam (2 mg two or three times a day {02} {06} {50} {53}).



Dystonia:
Acute dystonic postures or oculogyric crisis may be relieved by parenteral administration of benztropine (2 mg intramuscularly); or diphenhydramine (50 mg intramuscularly); or diazepam (5 to 7.5 mg intravenously), to be followed by oral antidyskinetic medication for one or two days to prevent recurrent dystonic episodes. Dosage adjustments of haloperidol may control these effects, and discontinuation of haloperidol may reverse severe symptoms in weeks to months.



Tardive dyskinesia or tardive dystonia:
No known effective treatment. Dosage of haloperidol should be lowered or medication discontinued, if clinically feasible, at earliest signs of tardive dyskinesia or tardive dystonia, to prevent possible irreversible effects.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

HALOPERIDOL ORAL SOLUTION USP

Usual adult and adolescent dose
Antipsychotic; antidyskinetic
Oral, 500 mcg (0.5 mg) to 5 mg two or three times a day initially, the dosage being gradually adjusted as needed and tolerated {18}.


Usual adult prescribing limits
100 mg a day {18} {20}.

Usual pediatric dose
Psychotic disorders
Children younger than 3 years of age: Safety and efficacy have not been established {18}.

Children 3 to l2 years of age or 15 to 40 kg of body weight: Oral, initially 50 mcg (0.05 mg) per kg of body weight a day (in two or three divided doses), the daily dose being increased as needed and tolerated by 500-mcg (0.5 mg) increments at five- to seven-day intervals up to a total of 150 mcg (0.150 mg) per kg of body weight a day {18}.

Nonpsychotic behavior disorders and Tourette's syndrome
Children younger than 3 years of age: Safety and efficacy have not been established {18}.

Children 3 to l2 years of age or 15 to 40 kg of body weight: Oral, initially 50 mcg (0.05 mg) per kg of body weight a day (in two or three divided doses), the daily dose being increased as needed and tolerated by 500-mcg (0.5 mg) increments at five- to seven-day intervals up to a total of 75 mcg (0.075 mg) per kg of body weight a day {18}. Alternatively, some clinicians recommend that, in the treatment of Tourette's syndrome, the initial daily dose be administered at bedtime to avoid daytime sedation {49}.

[Infantile autism]1
Children younger than 3 years of age: Safety and efficacy have not been established {18}.

Children 3 to l2 years of age or 15 to 40 kg of body weight: Oral, 25 mcg (0.025 mg) per kg of body weight a day, up to 50 mcg (0.05 mg) per kg of body weight a day.


Note: There is little evidence that pediatric dosages exceeding 6 mg a day produce additional improvement in behavior {18} or in tics {49}.


Usual geriatric dose
Oral, 500 mcg (0.5 mg) to 2 mg two or three times a day, the dosage being increased gradually as needed and tolerated {18}.

Note: The dose for debilitated patients is the same as the geriatric dose {18}.


Strength(s) usually available
U.S.—


2 mg per mL (Rx) [Haldol (methylparaben)][Generic]

Canada—


2 mg per mL (Rx) [Apo-Haloperidol] [Novo-Peridol] [Peridol] [PMS Haloperidol][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing.

Incompatibilities:
Insoluble precipitate of haloperidol is formed when mixed with coffee, tea or lithium citrate syrup.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.

Note: Avoid skin contact with liquid forms of this medication; contact dermatitis has been reported.
Each dose must be diluted in water or a beverage such as orange juice, apple juice, tomato juice, or cola, immediately prior to administration.
Provide patient with specially marked dosage dropper and explain use if necessary.



HALOPERIDOL TABLETS USP

Usual adult and adolescent dose
See Haloperidol Oral Solution USP .

Usual adult prescribing limits
See Haloperidol Oral Solution USP .

Usual pediatric dose
See Haloperidol Oral Solution USP .

Usual geriatric dose
See Haloperidol Oral Solution USP .

Strength(s) usually available
U.S.—


500 mcg (0.5 mg) (Rx) [Haldol][Generic]


1 mg (Rx) [Haldol (tartrazine)][Generic]


2 mg (Rx) [Haldol][Generic]


5 mg (Rx) [Haldol (tartrazine)][Generic]


10 mg (Rx) [Haldol (tartrazine)][Generic]


20 mg (Rx) [Haldol][Generic]

Canada—


500 mcg (0.5 mg) (Rx) [Apo-Haloperidol] [Haldol] [Novo-Peridol] [Peridol (scored)][Generic]


1 mg (Rx) [Apo-Haloperidol] [Haldol (tartrazine)] [Novo-Peridol] [Peridol (scored)][Generic]


2 mg (Rx) [Apo-Haloperidol] [Haldol (metabisulfite)] [Novo-Peridol] [Peridol (scored)][Generic]


5 mg (Rx) [Apo-Haloperidol] [Haldol (tartrazine)] [Novo-Peridol] [Peridol (scored)][Generic]


10 mg (Rx) [Apo-Haloperidol] [Haldol (tartrazine)] [Novo-Peridol] [Peridol (scored)][Generic]


20 mg (Rx) [Haldol (metabisulfite)] [Novo-Peridol][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Parenteral Dosage Forms

HALOPERIDOL INJECTION USP

Usual adult and adolescent dose
Acute psychosis
Intramuscular, 2 to 5 mg initially, the dosage being repeated at one-hour intervals if necessary, or at four- to eight-hour intervals if symptoms are satisfactorily controlled {18}.

Note: For the rapid control of acute psychosis or delirium, haloperidol has also been administered intravenously, in doses of 0.5 to 50 mg {30} {31} at a rate of 5 mg per minute {31}, the dose being repeated as needed at 30-minute intervals {30} {31}. Alternatively, the dose of haloperidol can be diluted in 30 to 50 mL of compatible intravenous fluid and administered over 30 minutes {30}.



Usual adult prescribing limits
Intramuscular: 100 mg daily {18}.

Usual pediatric dose
Safety and efficacy have not been established {18}.

Strength(s) usually available
U.S.—


5 mg per mL (Rx) [Haldol (methylparaben 1.8 mg) (propylparaben 0.2 mg) (lactic acid)][Generic]

Canada—


5 mg per mL (Rx) [Haldol (methylparaben 1.8 mg) (propylparaben 0.2 mg) (lactic acid)][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Incompatibilities:
Haloperidol injection may be precipitated by phenytoin or heparin {31}.


HALOPERIDOL DECANOATE INJECTION

Note: The dosing of haloperidol decanoate injection is expressed in terms of haloperidol base (not the decanoate).


Usual adult and adolescent dose
Chronic psychosis
Intramuscular, initially 10 to 15 times the previous daily oral dose of haloperidol, up to a maximum initial dose of 100 mg (base), at monthly intervals, the dosing interval and dose being adjusted as needed and tolerated {19}.


Note: Administration is by deep intramuscular injection {19} into gluteal region using Z-track technique {45}. A 2-inch long, 21-gauge {19} needle is recommended.
The maximum volume per injection site should not exceed 3 mL {19}.


Usual adult prescribing limits
300 mg (base) per month {19}.

Note: Monthly doses as high as 900 mg (base) have been reported {45} {52} {54}.


Usual pediatric dose
Safety and efficacy have not been established {19}.

Strength(s) usually available
U.S.—


50 mg (base) (70.52 mg of haloperidol decanoate) per mL (Rx) [Haldol Decanoate (benzyl alcohol 1.2%) (sesame oil)][Generic]{66}


100 mg (base) (141.04 mg of haloperidol decanoate) per mL (Rx) [Haldol Decanoate (benzyl alcohol 1.2%) (sesame oil)][Generic]{66}

Canada—


50 mg (base) (70.52 mg of haloperidol decanoate) per mL (Rx) [Haldol LA (benzyl alcohol 15 mg/mL)]


100 mg (base) (141.04 mg of haloperidol decanoate) per mL (Rx) [Haldol LA (benzyl alcohol 15 mg/mL)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing. Do not refrigerate.

Note: Not to be administered intravenously {19}.




Revised: 08/24/1998



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Haldol Decanoate package insert (McNeil) 1986.
  1. Panelist comment.
  1. Anderson LT, Campbell M, Grega DM, et al. Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms. Am J Psychiatry 1984 Oct; 141 (10): 1195-202.
  1. Jann MW, Ereshefsky L, Saklad SR. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinetics 1985; 10: 315-53.
  1. Textbook of Medicine—Wyngaarden and Smith, 1985.
  1. USP DI, 1987, Molindone (Systemic) monograph.
  1. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 28th ed. London: The Pharmaceutical Press, 1982.
  1. Panelist comment—8/87.
  1. From Phenothiazines (Systemic), USP DI 1989. Reference is: Drug Therapy for the Elderly 2(5): 25-30, 1987. Neuroleptics in the treatment of the confused elderly patient. From N Eng J Med 1983; 308: 134-8, 194-9. Thompson TL, et al. Psychotropic drug use in the elderly (2 parts).
  1. From Phenothiazines (Systemic), USP DI 1989. Reference is: Lamy P, Zuckerman IH. Pharmacologic considerations in the treatment of Alzheimer's disease. The Maryland Pharmacist 1987 Mar; 63(3): 10-2.
  1. Panelist comment on Phenothiazines monograph, USP DI, 1988.
  1. Rewording, etc., from Phenothiazines (Systemic), USP DI 89. Reference is: Birkhimer LJ, deVane CL. The neuroleptic malignant syndrome: Presentation and treatment. Drug Intell Clin Pharm 1984; 18: 462-5.
  1. Panelist comment on Phenothiazines monograph, USP DI—6/88.
  1. Panelist comment on Phenothiazines monograph, USP DI—6/88.
  1. Phenothiazines monograph, USP DI—5/89.
  1. Comment from Review—1988.
  1. Bronchodilators, Adrenergic monograph, USP DI—5/89.
  1. Haldol (McNeil—US) package insert, Rev 6/3/87, Rec 11/29/88.
  1. Haldol Decanoate Injection (McNeil—US) package insert, Rev 2/15/89, Rec 10/30/89.
  1. Haloperidol (Kenral—Canada) product monograph, Rev 2/20/89, Rec 3/22/90.
  1. Hansten PD, Horn JR. Drug interactions. 6th ed. Philadelphia: Lea & Febiger, 1989.
  1. Shinn AF, Shrewsbury RP. EDI, Evaluation of drug interactions. 3rd ed. St Louis: Mosby, l985.
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  1. Cressman WA, Bianchine JR, Slotnick VB, et al. Plasma level profile of haloperidol in man following intramuscular administration. Eur J Clin Pharmacol 1974; 7: 99-103.
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  1. Moore DP. Rapid treatment of delirium in critically ill patients. Am J Psychiatry 1977 Dec; 132(12): 1431-2.
  1. Adams S, Fernandez F. Intravenous use of haloperidol. Hospital Pharmacy 1987 Mar; 22: 306-7.
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  1. Reviewer comment, 10/89.
  1. Bryant SG, Brown CS. Current concepts in clinical therapeutics: Major affective disorders, Part 1. Therapy review. Clin Pharm 1986; 5: 304-18.
  1. Panel consensus (Maprotiline monograph), 5/91.
  1. Parlodel (Bromocriptine) product monograph, PDR 1991: 1958-60.
  1. Wellbutrin (Bupropion) product monograph, PDR 1991: 807-10.
  1. Wellbutrin package insert, Rev 10/89, Rec 2/91.
  1. Panel comment (on Bupropion monograph), 10/30/90.
  1. Proglycem (Diazoxide) product monograph (Schering) CPS 1988: 749.
  1. Prozac (Fluoxetine-Lilly) product monograph, December 30, 1987.
  1. Panel comment (on Fluoxetine monograph), 7/89.
  1. Permax (Pergolide) product monograph, PDR 1991: 1259-61.
  1. Reviewer comment, 11/89.
  1. Froemming JS, Lam YW, Jann MW, Davis CM. Pharmacokinetics of haloperidol. Clin Pharmacokinet 1989 Dec; 17(6): 396-423.
  1. Hemstrom CA, Evans RL, Lobeck FG. Haloperidol decanoate: a depot antipsychotic. Drug Intell Clin Pharm 1988 Apr; 22: 290-5.
  1. Beresford R, Ward A. Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis. Drugs 1987; 33: 31-49.
  1. Stewart RB, Karas B, Springer PK. Haloperidol excretion in human milk. Am J Psychiatry 1980 Jul; 137(7): 849-50.
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  1. Panel comment, 10/91.
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  1. Panel comment, 10/91.
  1. Panel comment, 10/91.
  1. Reviewers responses to monograph revision, 10/3/91.
  1. Panel comment, 10/91.
  1. Reviewers responses to Psychiatric Disease Advisory Panel Memo #6 of 9/16/91.
  1. Wojcik JD, Falk WE, Fink JS, et al. A review of 32 cases of tardive dystonia. Am J Psychiatry 1991 Aug; 148(8): 1055-9.
  1. Burke RE, Kang UJ. Tardive dystonia: clinical aspects and treatment. In: Jankovic J Tolosae, editor. Facial Dyskinesias, Advances in Neurology. New York: Raven Press, 1988; 49: 199-210.
  1. Kang UJ, Burke RE, Fahn S. Natural history and treatment of tardive dystonia. Movement Disorders. 1986; 1: 193-208.
  1. Watsky EJ, Salzman C. Psychotropic Drug Interactions. Hosp Community Psychiatry 1991 Mar; 42(3): 247-56.
  1. Tate JL. Extrapyramidal symptoms in a patient taking haloperidol and fluoxetine. [Letter]. Am J Psychiatry 1989 Mar; 146(3): 399-400.
  1. Brod TM. Fluoxetine and extrapyramidal symptoms. [Letter]. Am J Psychiatry 1989 Oct; 146(10): 1353.
  1. Haldol decanoate package insert (McNeil—US), Rev 12/30/91, Rec 9/11/92.
  1. Haldol package insert (McNeil—US), Rev 12/29/91, Rec 9/11/92.
  1. Personal communication, Medical Information, Ortho-McNeil, 5/22/95.
  1. Panelist comment, 5/88 and 7/88.
  1. Haloperidol decanoate injection package insert (Fujisawa—US), Rev 12/96, Rec 2/98.
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