Haloperidol

Brand name: Haldol

Drug monograph

Contents
 Pharmacology
 Indications
 Contraindications
 Warnings
 Precautions
 Adverse Effects
 Overdose
 Dosage
 Supplied
 Research

Pharmacology
Antipsychotic

Haloperidol is a butyropherone derivative with antipsychotic properties that has been

considered particularly effective in the management of hyperactivity, agitation, and
mania. Haloperidol is an effective neuroleptic and also possesses antiemetic properties; it
has a marked tendency to provoke extrapyramidal effects and has relatively weak alpha-
adrenolytic properties. It may also exhibit hypothermic and anorexiant effects and
potentiate the action of barbiturates, general anesthetics, and other CNS depressant drugs.

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The mechanism of action of haloperidol has not been entirely elucidated, but has been
attributed to the inhibition of the transport mechanism of cerebral monoamines,
particularly by blocking the impulse transmission in dopaminergic neurons.

Peak plasma levels of haloperidol occur within 2 to 6 hours of oral dosing and about 20
minutes after i.m. administration. The mean plasma (terminal elimination) half-life has
been determined as 20.7+/-4.6 (SD) hours, and although excretion begins rapidly, only 24
to 60% of ingested radioactive drug is excreted (mainly as metabolites in urine, some in
feces) by the end of the first week, and very small but detectable levels of radioactivity
persist in the blood and are excreted for several weeks after dosing. About 1% of the
ingested dose is recovered unchanged in the urine.

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Indications
Haloperidol is indicated in the management of manifestations of acute and chronic
psychosis, including schizophrenia and manic states. It may also be of value in the
management of aggressive and agitated behavior in patients with chronic brain syndrome
and mental retardation and in the symptomatic control of Gilles de la Tourette's
syndrome.

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Contraindications
Comatose states and CNS depression due to alcohol or other depressant drugs; severe
depressive states; previous spastic diseases; lesions of the basal ganglia; Parkinson's
syndrome, except in the case of dyskinesias due to levodopa treatment; sensitivity to
haloperidol; senile patients with pre-existing Parkinson-like symptoms.

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Children:
Safety and effectiveness in young children have not been established; therefore,
haloperidol is contraindicated in this age group.

Pregnancy and Lactation:

Safety for use in pregnancy and lactation has not been established; do not administer to
women of childbearing potential or nursing mothers unless, in the opinion of the
physician, the expected benefits of the drug outweigh the potential hazard to the fetus or
child. Haloperidol is excreted in breast milk.

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Warnings
Tardive Dyskinesia:
Tardive dyskinesia is known to occur in patients treated with neuroleptics with
antipsychotic properties and other drugs with substantial neuroleptic activity. Although
the dyskinetic syndrome may remit partially or completely if the medication is
withdrawn, it is irreversible in some patients. At the present time there is uncertainty as to
whether neuroleptic drugs differ in their potential to cause tardive dyskinesia.

Since there is a significant prevalence in this syndrome associated with the use of
neuroleptic drugs, and since there is no known effective treatment, chronic use of these
drugs should generally be restricted to patients for whom neuroleptics are known to be
effective and for whom there is no alternative therapy available with better risk
acceptability. If manifestations of tardive dyskinesia are detected during the use of a
neuroleptic, the drug should be discontinued.

The risk of a patient developing tardive dyskinesia and of the syndrome becoming
irreversible appear to increase with the duration of treatment and the total amount of
drugs administered, although, in some instances, tardive dyskinesia may develop after
relatively short periods of treatment at low doses. The risk of developing tardive

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dyskinesia may, therefore, be minimized by reducing the dose of the neuroleptic drug
used and its duration of administration, consistent with the effective management of the
patient's condition. Continued use of neuroleptics should be periodically reassessed.

Withdrawal Emergent Neurological Signs:

Generally, patients receiving short-term therapy experience no problems with abrupt
discontinuation of antipsychotic drugs. However, some patients on maintenance treatment
experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the
dyskinetic movements are indistinguishable from the syndrome described under Tardive
Dyskinesia except for duration. It is not known whether gradual withdrawal of
antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent
neurological signs but until further evidence becomes available it seems reasonable to
gradually withdraw use of antipsychotic drugs.

An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness

and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN
and FBS, followed by irreversible brain damage) has occurred in a few patients treated
with lithium plus haloperidol. A causal relationship between these events and the
concomitant administration of lithium and haloperidol has not been established; however,
patients receiving such combined therapy should be monitored closely for early evidence
of neurological toxicity and treatment discontinued promptly if such signs appear.

Elderly or debilitated patients receiving the drug should be carefully observed for
lethargy and a decreased sensation of thirst due to central inhibition which might lead to
dehydration and reduced pulmonary ventilation and could result in complications, such as
terminal bronchopneumonia.

Occupational Hazards:
Although haloperidol is a relatively nonsedating neuroleptic, sedation may occur in some
patients. Therefore, physicians should be aware of this possibility and caution patients
about the danger of participating in activities requiring complete mental alertness,

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judgement and physical coordination, such as driving and operating dangerous
machinery.

Haloperidol may prolong the hypnotic action of barbiturates and may potentiate the
effects of alcohol and other CNS depressant drugs such as anesthetics and narcotics;
caution should therefore be exercised when it is used with agents of this type and
adjustments in their dosage may be required.

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Precautions
Administration to patients with severe cardiac involvement should be guarded, despite
the fact that haloperidol is well tolerated by patients with cardiac insufficiency and that it
has been used with favorable results to maintain the cardiovascular function of patients
with excitive crises. In very rare instances, it has been felt that haloperidol was
contributory to the precipitation of attacks in angina prone patients. Moderate
hypotension may occur with parenteral administration or excessive oral doses of
haloperidol; however, vertigo and syncope occur only rarely.

Haloperidol may lower the convulsive threshold and has been reported to trigger seizures
in previously controlled known epileptics. When instituting haloperidol therapy in these
patients, adequate anticonvulsant medication should be maintained concomitantly.

As with other antipsychotic agents, haloperidol should be administered cautiously to

patients with severe impairment of liver or kidney function, and to patients with known
allergies or history of allergies to other neuroleptic drugs. Caution is also advised in
patients with pheochromocytoma and conditions predisposing to epilepsy, such as alcohol
withdrawal and brain damage.

Haloperidol has lowered cholesterol concentrations in the serum and liver of monkeys.
An accumulation of desmosterol has been observed in the serum of rats given repeated

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high doses (10 mg/kg) of haloperidol. In man, mild transient decreases in serum
cholesterol were reported in preliminary studies. However, in a study involving a group
of schizophrenic patients on extended medication, significant lowering of serum
cholesterol was not observed with haloperidol, and there was no accumulation of
desmosterol or 7-dehydrocholesterol. A significant lowering of cholesterol together with
accumulation of another sterol (possibly 7-dehydrocholesterol) has been reported in
patients receiving a chemically related drug (trifluperidol), and skin and eye changes
(ichthyosis and cataracts) have occurred clinically with another butyrophenone
derivative. Skin and eye changes have not been observed in patients receiving
haloperidol. However, all patients receiving haloperidol for a prolonged period of time
should be carefully observed for any changes in the skin and eyes. If such changes are
seen, discontinue the drug promptly.

Drug Interactions:
Haloperidol has been reported to interfere with the anticoagulant properties of
phenindione in an isolated case, and the possibility should be kept in mind of a similar
effect occurring when haloperidol is used with other anticoagulants.

Haloperidol may antagonize the action of epinephrine and other sympathomimetic agents
and reverse the blood pressure-lowering effects of adrenergic-blocking agents, such as
guanethidine.

Enhanced CNS effects may occur when haloperidol is used in combination with
methyldopa.

Haloperidol inhibits the metabolization of tricyclic antidepressants, thereby increasing

plasma levels of these drugs. This may result in increased tricyclic antidepressant toxicity
(anticholinergic effects, cardiovascular toxicity, lowering of seizure threshold).

When prolonged carbamazepine treatment is added to haloperidol therapy, this results in

a significant reduction of haloperidol plasma levels. Therefore, during combination
treatment, the haloperidol dose should be adjusted, when necessary. After stopping
carbamazepine, it will be necessary to reduce the dosage of haloperidol.

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Haloperidol may impair the antiparkinson effects of levodopa.

If an antiparkinson agent is used concomitantly with haloperidol, both drugs should not
be discontinued simultaneously, since extrapyramidal symptoms may occur due to the
slower excretion rate of haloperidol.

The physician should keep in mind the possibility of an increase in intraocular pressure
when anticholinergic drugs, including antiparkinson agents, are administered
concomitantly with haloperidol.

When haloperidol is used to control mania in cyclic disorders, there may be a rapid mood
swing to depression.

The antiemetic action of haloperidol may obscure signs of toxicity due to overdosage of
other drugs or mask the symptoms of some organic diseases, such as brain tumor or
intestinal obstructions.

Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with
thyrotoxicosis who are also receiving antipsychotic medication, including haloperidol.

Carcinogenicity studies in mice (18 months) and rats (24 months) showed a significant
increase in mammary gland neoplasia and total tumor incidence in female mice at 1.25
and 5 mg/kg/day and in pituitary gland neoplasia in female mice at 5 mg/kg. A significant
dose related increase in pituitary gland hyperplasia was observed in female rats at 1.25
and 5 mg/kg/day. The potential significance of these findings to man is not known.

Neuroleptic drugs elevate prolactin levels; 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, which are presumed to be linked to elevated prolactin
levels, the clinical significance of elevated serum prolactin levels is unknown for most

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patients. An increase in mammary neoplasms has been found in rodents after chronic
administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies
conducted to date, however, 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.

FD and C Yellow No. 5 (tartrazine) may cause allergic-type reactions (including

bronchial asthma) in certain susceptible individuals. Although the overall incidence of
tartrazine sensitivity in the general population is low, it is frequently seen in patients who
also have ASA hypersensitivity. Tartrazine is contained in the 1, 5 and 10 mg haloperidol
tablets.

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Adverse Effects
Neurological:
Neuromuscular (extrapyramidal) effects such as Parkinson-like symptoms, akathisia,
dyskinesia, dystonia, hyperreflexia, rigidity, opisthotonos, and, occasionally, oculogyric
crisis are the most frequently reported side effects associated with the administration of
haloperidol. Headache, vertigo and cerebral seizures have also been reported. The
extrapyramidal reactions are usually dose related in occurrence and severity and, as a
rule, tend to subside when the dose is reduced or the drug is temporarily discontinued.

However, considerable interpatient variability exists, and, although some individuals may
tolerate higher than average doses of haloperidol, severe extrapyramidal reactions,
necessitating discontinuation of the drug, may occur at relatively low doses.
Administration of an antiparkinson agent is usually, but not always, effective in
preventing or reversing neuromuscular reactions associated with haloperidol.

Tardive dyskinesias:
As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-

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term therapy or may appear after drug therapy has been discontinued. The risk appears to
be greater in elderly patients on high dose therapy, especially females. The symptoms are
persistent and in some patients appear to be irreversible. The syndrome is characterized
by rhythmical, involuntary movements of the tongue, face, mouth or jaw (e.g. protrusion
of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these
may be accompanied by involuntary movements of extremities.

There is no known effective treatment for tardive dyskinesia; antiparkinsonism agents

usually do not alleviate the symptoms of this syndrome. It is suggested that all
antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to
reinstitute treatment, or increase the dosage of the agent, or switch to a different
antipsychotic agent, the syndrome may be masked. The physician may be able to reduce
the risk of this syndrome by minimizing the unnecessary use of neuroleptic drugs and
reducing the dose or discontinuing the drug, if possible, when manifestations of this
syndrome are recognized, particularly in patients over the age of 50. It has been reported
that fine vermicular movements of the tongue may be an early sign of the syndrome and
if the medication is stopped at that time the syndrome may not develop.

Tardive dystonia, not associated with the above syndrome, has also been reported.
Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is
often persistent, and has the potential of becoming irreversible.

Behavioral:
Insomnia, depressive reactions, and toxic confusional states are the more common effects
encountered. Drowsiness, lethargy, stupor and catalepsy, confusion, restlessness,
agitation, anxiety, euphoria, and exacerbation of psychotic symptoms, including
hallucinations, have also been reported.

Cardiovascular:
Tachycardia, hypertension and ECG changes including prolongation of the QT interval
and ECG pattern changes compatible with the polymorphous configurations of torsades
de pointes have been reported. Hypotension has occurred, but severe orthostatic

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hypotension has not been reported. However, should it occur, supportive measures,
including i.v. vasopressors such as norepinephrine, may be required. Epinephrine should
not be used, since haloperidol may block the vasoconstrictor effects of this drug.

Autonomic:
Dry mouth, blurred vision, urinary retention, incontinence, diaphoresis and priapism have
been reported.

Allergic and Toxic:

The overall incidence of significant hematologic changes in patients on haloperidol has
been low. Occasionally there have been reports of mild and usually transient leukopenia
and leukocytosis, decreases in blood cell counts, anemia, and a tendency toward
lymphomonocytosis. Agranulocytosis has rarely been reported with the use of
haloperidol, and then only in association with other medication. Impairment of liver
function (jaundice or hepatitis) has been reported rarely. One case of photosensitization is
known and isolated cases of idiosyncratic cutaneous involvement have been observed.

Endocrine:
Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia,
impotence, increased libido and changes in blood sugar concentrations have been
reported.

Gastrointestinal:
Heartburn, nausea, vomiting, anorexia, weight loss, constipation, diarrhea and
hypersalivation have been reported.

Miscellaneous:
Other untoward effects encountered include peripheral edema, hypocholesterolemia,
alopecia, laryngospasm, bronchospasm and increased depth of respiration and stasis
pneumonia. Hyperammonemia has been reported in a 5 1/2 year old child with
citrullinemia, an inherited disorder of ammonia excretion, following treatment with
haloperidol.

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Cases of sudden and unexpected death have been reported in association with the
administration of haloperidol. The nature of the evidence makes it impossible to
determine definitively what role, if any, haloperidol played in the outcome of the reported
cases. The possibility that haloperidol caused death cannot, of course, be excluded, but it
is to be kept in mind that sudden and unexpected death may occur in psychotic patients
when they go untreated or when they are treated with other neuroleptic drugs.

Neuroleptic Malignant Syndrome:

As with other neuroleptic drugs, a symptom complex sometimes referred to as
neuroleptic malignant syndrome (NMS) has been reported. Cardinal features of NMS are
hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and
evidence of autonomic instability (irregular pulse or blood pressure). Additional signs
may include elevated CPK, myoglobinuria (rhabdomyolysis), and acute renal failure.
NMS is potentially fatal, requires intensive symptomatic treatment and immediate
discontinuation of neuroleptic treatment.

Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also
been reported.

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Overdose
Symptoms:
In general, the symptoms of overdosage would be an exaggeration of known
pharmacologic effects and adverse reactions, the most prominent of which would be: (1)
severe extrapyramidal reactions, (2) hypotension, or (3) sedation. The patient would
appear comatose with respiratory depression and hypotension which could be severe
enough to produce a shock-like state. The extrapyramidal reaction would be manifested
by muscular weakness or rigidity and a generalized or localized tremor as demonstrated

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by the akinetic or agitans types respectively. The risk of ECG changes associated with
torsades de pointes should be considered (see Adverse Effects).

Treatment:
Gastric lavage or induction of emesis should be carried out immediately followed by
administration of the universal antidote. Since there is no specific antidote, treatment is
primarily supportive. Establish a patent airway by use of an oropharyngeal airway or
endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory
depression may be counteracted by artificial respiration and mechanical respirators.
Hypotension and circulatory collapse may be counteracted by use of i.v. fluids, plasma,
or concentrated albumin, and vasopressor agents such as norepinephrine. Epinephrine
should not be used. In case of severe extrapyramidal reactions, antiparkinsonian
medication should be administered. ECG and vital signs should be monitored especially
for signs of QT prolongation or dysrhythmias and monitoring should continue until the
ECG is normal. Severe arrhythmias should be treated with appropriate antiarrhythmic
measures.

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Dosage
Initial dosage should be individualized through consideration of severity of symptoms,
age, weight, health, previous response to neuroleptic drugs and concomitant disease
states. It is important initially to increase dosage adequately until symptoms are
controlled or side effects requiring lowering the dosage or discontinuing the drug are
encountered. When a satisfactory therapeutic response is achieved, reduce dosage
gradually to the lowest effective maintenance level.

Patients with previous adverse responses to other neuroleptic drugs, children and the
elderly or debilitated may require less haloperidol. The optimal response in such patients

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is best obtained if therapy is initiated at a lower dosage level and titration is more
gradual.

Oral:
1 to 2 mg 2 or 3 times daily, initially, followed by upward adjustment as tolerated until
the desired effect is achieved or limiting side effects appear. Clinical experience has
shown that it is seldom necessary to employ dosages greater than 4 to 6 mg 3 times daily.
However, 30 to 40 mg daily may be required in severely disturbed patients who remain
inadequately controlled by lower doses. Up to 100 mg daily has been used occasionally
in particularly resistant patients. Nevertheless, the safety of prolonged administration of
the higher doses has not been established. After a therapeutic response has been achieved,
dosages should be gradually adjusted downwards until a schedule providing adequate
maintenance is reached. Maintenance dosages are commonly in the range of 1 to 2 mg 3
or 4 times daily.

Children, debilitated and geriatric patients:

Lower doses are recommended in these patients since they may be more sensitive to the
drug.

Initial daily doses ranging from 0.5 to 1.5 mg (0.25 to 0.5 mg, 2 or 3 times a day) should
be employed. Upward adjustment of these doses should be made gradually; maximum
and maintenance doses should be individualized and are generally lower in this type of
patient.

Parenteral:
When symptoms are severe or rapid control is desired, administer haloperidol by i.m.
route. Dosages in the range of 2.5 to 5 mg are recommended, and should be employed on
a prn basis until the desired effect is achieved. Administration every 4 to 6 hours is
sufficient in most cases, although for resistant patients the dosage may be repeated as
often as every hour if required. Parenteral administration of high doses may be
accompanied by rapid appearance of extrapyramidal effects as control of
symptomatology is achieved.

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Children:
The safety and effectiveness of i.m. administration in children have not been established.

The oral dosage form should supplant the injectable as soon as practical. For an initial
approximation of the total daily dose required, the parenteral dose administered in the
preceding 24 hours may be used. Since this dose is only an initial estimate, it is
recommended that careful monitoring of clinical signs and symptoms, including clinical
efficacy, sedation, and adverse effects be carried out periodically for the first several days
following the initiation of switchover. In this way, dosage adjustments, either upward or
downward, can be quickly accomplished. Depending on the patient's clinical status, the
first oral dose should be given within 12 to 24 hours following the last parenteral dose.

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Supplied
Ampuls:
Each mL of clear colorless solution contains: Haloperidol 5 mg, methylparaben 1.8 mg,
propylparaben 0.2 mg in water and lactic acid sufficient to adjust the pH within the range
of 3.2 to 3.6. Do not dilute with sterile saline. Ampuls of 1 mL, units of 10 and 100.

Solution:
Each mL of clear, colorless, odorless, tasteless solution contains: Haloperidol 2 mg. Also
contains methylparaben USP 2 mg/mL. Sodium-free. Dropper bottles of 100 mL
(droppers calibrated 1 mg in 0.5 mL) and bottles of 500 mL.

Tablets:
Each round, scored, uncoated tablet, biconcave with beveled edges, embossed McNEIL
on one side, contains: Haloperidol 500 mcg (white, marked 1/2 on the reverse side), 1 mg
(yellow, marked 1 on the reverse side), 2 mg (pink, marked 2 on the reverse side), 5 mg
(green, marked 5 on the reverse side), 10 mg (aqua, marked 10 on the reverse side) or 20
mg (salmon, marked 20 on the reverse side). Energy: 500 mcg: 0.459 kJ (0.109 kcal); 1

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mg: 0.448 kJ (0.106 kcal); 2 mg: 0.432 kJ (0.103 kcal); 5 mg: 0.447 kJ (0.106 kcal); 10
mg: 0.845 kJ (0.202 kcal); 20 mg: 0.490 kJ (0.117 kcal). Sodium-free (500 mcg).
Sodium: <1 mmol (<1 mg)/1, 2, 5, 10 and 20 mg tablets. Also contains tartrazine (1, 5
and 10 mg). Bottles of 100 (500 mcg, 1, 2, 5, 10 and 20 mg); bottles of 1000 (500 mcg, 1,
2 and 5 mg).

All tablets are gluten-free, lactose-free and metabisulfite-free.

Dispense tablets and oral solution in a tight light-resistant container.

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Research
The research information is available separately on Internet Mental Health.

Note: This information is from a Canadian monograph. There can be differences in

indications, dosage forms and warnings for this drug in other countries.

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Internet Mental Health (www.mentalhealth.com) copyright © 1995-2005 by Phillip W.

Long, M.D.

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