haldol
Generic Name: (
haloperidol lactate)
Dosage Type: injection, solution Organization: ORTHO-McNEIL PHARMACEUTICAL, INC.
Rx Only
DESCRIPTION
Haloperidol is the first of the butyrophenone series of major
antipsychotics. The chemical designation is 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone
and it has the following structural formula:
HALDOL (haloperidol)
is available as a sterile parenteral form for intramuscular injection. The
injection provides 5 mg haloperidol (as the lactate) and lactic acid for pH
adjustment between 3.0 – 3.6.
ACTIONS
The precise mechanism of action has not been clearly established.
INDICATIONS
HALDOL (haloperidol) is indicated for use in the treatment
of schizophrenia.
HALDOL is indicated for the control
of tics and vocal utterances of Tourette's Disorder.
CONTRAINDICATIONS
HALDOL (haloperidol) is contraindicated in severe toxic central
nervous system depression or comatose states from any cause and in individuals
who are hypersensitive to this drug or have Parkinson's disease.
WARNINGS
Cardiovascular Effects
Cases of sudden death, QT-prolongation, and Torsades de Pointes have
been reported in patients receiving HALDOL. Higher than recommended doses
of any formulation and intravenous administration of HALDOL appear to be associated
with a higher risk of QT-prolongation and Torsades de Pointes. Although cases
have been reported even in the absence of predisposing factors, particular
caution is advised in treating patients with other QT-prolonging conditions
(including electrolyte imbalance [particularly hypokalemia and hypomagnesemia],
drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism,
and familial long QT-syndrome). HALDOL INJECTION IS NOT APPROVED FOR INTRAVENOUS
ADMINISTRATION. If HALDOL is administered intravenously, the ECG should be
monitored for QT prolongation and arrhythmias.
Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary,
dyskinetic movements may develop in patients treated with antipsychotic drugs.
Although the prevalence of the syndrome appears to be highest among the elderly,
especially elderly women, it is impossible to rely upon prevalence estimates
to predict, at the inception of antipsychotic treatment, which patients are
likely to develop the syndrome. Whether antipsychotic drug products differ
in their potential to cause tardive dyskinesia is unknown.
Both
the risk of developing tardive dyskinesia and the likelihood that it will
become irreversible are believed to increase as the duration of treatment
and the total cumulative dose of antipsychotic drugs administered to the patient
increase. However, the syndrome can develop, although much less commonly,
after relatively brief treatment periods at low doses.
There
is no known treatment for established cases of tardive dyskinesia, although
the syndrome may remit, partially or completely, if antipsychotic treatment
is withdrawn. Antipsychotic treatment, itself, however, may suppress (or
partially suppress) the signs and symptoms of the syndrome and thereby may
possibly mask the underlying process. The effect that symptomatic suppression
has upon the long-term course of the syndrome is unknown.
Given
these considerations, antipsychotic drugs should be prescribed in a manner
that is most likely to minimize the occurrence of tardive dyskinesia. Chronic
antipsychotic treatment should generally be reserved for patients who suffer
from a chronic illness that 1) is known to respond to antipsychotic drugs,
and, 2) for whom alternative, equally effective, but potentially less harmful
treatments are not available or appropriate.
In patients who do require chronic treatment, the smallest dose and the shortest
duration of treatment producing a satisfactory clinical response should be
sought. The need for continued treatment should be reassessed periodically.
If
signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics,
drug discontinuation should be considered. However, some patients may require
treatment despite the presence of the syndrome.
(For
further information about the description of tardive dyskinesia and its clinical
detection, please refer to ADVERSE REACTIONS.)
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to
as Neuroleptic Malignant Syndrome (NMS) has been reported in association with
antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle
rigidity, altered mental status (including catatonic signs) and evidence of
autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis,
and cardiac dysrhythmias). Additional signs may include elevated creatine
phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
The
diagnostic evaluation of patients with this syndrome is complicated. In arriving
at a diagnosis, it is important to identify cases where the clinical presentation
includes both serious medical illness (e.g., pneumonia, systemic infection,
etc.) and untreated or inadequately treated extrapyramidal signs and symptoms
(EPS). Other important considerations in the differential diagnosis include
central anticholinergic toxicity, heat stroke, drug fever and primary central
nervous system (CNS) pathology.
The management of NMS
should include 1) immediate discontinuation of antipsychotic drugs and other
drugs not essential to concurrent therapy, 2) intensive symptomatic treatment
and medical monitoring, and 3) treatment of any concomitant serious medical
problems for which specific treatments are available. There is no general
agreement about specific pharmacological treatment regimens for uncomplicated
NMS.
If a patient requires antipsychotic drug treatment
after recovery from NMS, the potential reintroduction of drug therapy should
be carefully considered. The patient should be carefully monitored, since
recurrences of NMS have been reported.
Hyperpyrexia
and heat stroke, not associated with the above symptom complex, have also
been reported with HALDOL.
Usage in Pregnancy
Rodents given 2 to 20 times the usual maximum human dose
of haloperidol by oral or parenteral routes showed an increase in incidence
of resorption, reduced fertility, delayed delivery and pup mortality. No teratogenic
effect has been reported in rats, rabbits or dogs at dosages within this range,
but cleft palate has been observed in mice given 15 times the usual maximum
human dose. Cleft palate in mice appears to be a nonspecific response to stress
or nutritional imbalance as well as to a variety of drugs, and there is no
evidence to relate this phenomenon to predictable human risk for most of these
agents.
There are no well controlled studies with HALDOL
(haloperidol) in pregnant women. There are reports, however, of cases of limb
malformations observed following maternal use of HALDOL along with other drugs
which have suspected teratogenic potential during the first trimester of pregnancy.
Causal relationships were not established in these cases. Since such experience
does not exclude the possibility of fetal damage due to HALDOL, this drug
should be used during pregnancy or in women likely to become pregnant only
if the benefit clearly justifies a potential risk to the fetus. Infants should
not be nursed during drug treatment.
Combined Use of HALDOL and Lithium
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 HALDOL. A causal
relationship between these events and the concomitant administration of lithium
and HALDOL 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.
General
A number of cases of bronchopneumonia, some fatal, have followed
the use of antipsychotic drugs, including HALDOL. It has been postulated that
lethargy and decreased sensation of thirst due to central inhibition may lead
to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore,
if the above signs and symptoms appear, especially in the elderly, the physician
should institute remedial therapy promptly.
Although
not reported with HALDOL, decreased serum cholesterol and/or cutaneous and
ocular changes have been reported in patients receiving chemically-related
drugs.
HALDOL may impair the mental and/or physical
abilities required for the performance of hazardous tasks such as operating
machinery or driving a motor vehicle. The ambulatory patient should be warned
accordingly.
The use of alcohol with this drug should
be avoided due to possible additive effects and hypotension.
PRECAUTIONS
HALDOL (haloperidol) should be administered cautiously to
patients:
- –
- with severe cardiovascular disorders, because
of the possibility of transient hypotension and/or precipitation of anginal
pain. Should hypotension occur and a vasopressor be required, epinephrine
should not be used since HALDOL may block its vasopressor activity and paradoxical
further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine
or norepinephrine should be used.
- –
- receiving anticonvulsant medications, with
a history of seizures, or with EEG abnormalities, because HALDOL may lower
the convulsive threshold. If indicated, adequate anticonvulsant therapy should
be concomitantly maintained.
- –
- with known allergies, or with a history of
allergic reactions to drugs.
- –
- receiving anticoagulants, since an isolated
instance of interference occurred with the effects of one anticoagulant (phenindione).
If concomitant antiparkinson medication is required, it
may have to be continued after HALDOL is discontinued because of the difference
in excretion rates. If both are discontinued simultaneously, extrapyramidal
symptoms may occur. The physician should keep in mind the possible increase
in intraocular pressure when anticholinergic drugs, including antiparkinson
agents, are administered concomitantly with HALDOL.
As
with other antipsychotic agents, it should be noted that HALDOL may be capable
of potentiating CNS depressants such as anesthetics, opiates, and alcohol.
In
a study of 12 schizophrenic patients coadministered haloperidoland rifampin,
plasma haloperidol levels were decreased by a mean of 70% and mean scores
on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other
schizophrenic patients treated with haloperidol and rifampin, discontinuation
of rifampin produced a mean 3.3-fold increase in haloperidol concentrations.
Thus, careful monitoring of clinical status is warranted when rifampin is
administered or discontinued in haloperidol-treated patients.
When
HALDOL is used to control mania in cyclic disorders, there may be a rapid
mood swing to depression.
Severe neurotoxicity (rigidity,
inability to walk or talk) may occur in patients with thyrotoxicosis who are
also receiving antipsychotic medication, including HALDOL.
No
mutagenic potential of haloperidol was found in the Ames Salmonella microsomal
activation assay. Negative or inconsistent positive findings have been obtained
in in vitro and in
vivo studies of effects of haloperidol on chromosome structure and
number. The available cytogenetic evidence is considered too inconsistent
to be conclusive at this time.
Carcinogenicity studies
using oral haloperidol were conducted in Wistar rats (dosed at up to 5 mg/kg
daily for 24 months) and in Albino Swiss mice (dosed up to 5 mg/kg daily for
18 months). In the rat study survival was less than optimal in all dose groups,
reducing the number of rats at risk for developing tumors. However, although
a relatively greater number of rats survived to the end of the study in high-dose
male and female groups, these animals did not have a greater incidence of
tumors than control animals. Therefore, although not optimal, this study does
suggest the absence of a haloperidol related increase in the incidence of
neoplasia in rats at doses up to 20 times the usual daily human dose for chronic
or resistant patients.
In female mice at 5 and 20 times
the highest initial daily dose for chronic or resistant patients, there was
a statistically significant increase in mammary gland neoplasia and total
tumor incidence; at 20 times the same daily dose there was a statistically
significant increase in pituitary gland neoplasia. In male mice, no statistically
significant differences in incidences of total tumors or specific tumor types
were noted.
Antipsychotic 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 potentialimportance 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 levels is unknown for most patients. An increase
in mammary neoplasms has been found in rodents after chronic administration
of antipsychotic 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.
There are
no well controlled studies with HALDOL (haloperidol) in pregnant women. There
are reports, however, of cases of limb malformations observed following maternal
use of HALDOL along with other drugs which have suspected teratogenic potential
during the first trimester of pregnancy. Causal relationships were not established
in these cases. Since such experience does not exclude the possibility of
fetal damage due to HALDOL, this drug should be used during pregnancy or in
women likely to become pregnant only if the benefit clearlyjustifies a potential
risk to the fetus. Infants should not be nursed during drug treatment.
Pediatric Use
Safety and effectiveness in pediatric patients have not been
established.
Geriatric Use
Clinical studies of haloperidol did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not consistently
identified differences in responses between the elderly and younger patients.
However, the prevalence of tardive dyskinesia appears to be highest among
the elderly, especially elderly women (see WARNNGS,
Tardive Dyskinesia). Also, the pharmacokinetics of haloperidol
in geriatric patients generally warrants the use of lower doses (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Cardiovascular Effects
Tachycardia, hypotension, and hypertension have been reported.
QT prolongation and/or ventricular arrhythmias have also been reported, in
addition to ECG pattern changes compatible with the polymorphous configuration
of torsade de pointes, and may occur more frequently with high doses and in
predisposed patients (see WARNINGS and PRECAUTIONS).
Cases
of sudden and unexpected death have been reported in association with the
administration of HALDOL. The nature of the evidence makes it impossible to
determine definitively what role, if any, HALDOL played in the outcome of
the reported cases. The possibility that HALDOL 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 antipsychotic drugs.
CNS Effects
Extrapyramidal Symptoms(EPS)
EPS during the administration of HALDOL (haloperidol) have
been reported frequently, often during the first few days of treatment, EPS
can be categorized generally as Parkinson-like symptoms, akathisia or dystonia
(including opisthotonos and oculogyric crisis). While all can occur at relatively
low doses, they occur more frequently and with greater severity at higher
doses. The symptoms may be controlled with dose reductions or administration
of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl
hydrochloride USP. It should be noted that persistent EPS have been reported;
the drug may have to be discontinued in such cases.
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 below 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 HALDOL.
Tardive Dyskinesia
As with all antipsychotic agents HALDOL has been associated
with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of
potentially irreversible, involuntary, dyskinetic movements, may appear in
some patients on long-term therapy or may occur 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 irreversible. The syndrome is characterized by rhythmical involuntary
movements of 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 and the trunk.
There
is no known effective treatment for tardive dyskinesia; antiparkinson 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, this syndrome may be masked.
It
has been reported that fine vermicular movement of the tongue may be an early
sign of tardive dyskinesia and if the medication is stopped at that time the
full syndrome may not develop.
Tardive Dystonia
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.
Other CNS Effects
Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness,
depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation
of psychotic symptoms including hallucinations, and catatonic-like behavioral
states which may be responsive to drug withdrawal and/or treatment with anticholinergic
drugs.
Body as a Whole
Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat
stroke have been reported with HALDOL. (See WARNINGS for
further information concerning NMS.)
Hematologic Effects
Reports have appeared citing the occurrence of mild and usually
transient leukopenia and leukocytosis, minimal decreases in red blood cell
counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has
rarely been reported to have occurred with the use of HALDOL, and then only
in association with other medication.
Liver Effects
Impaired liver function and/or jaundice have been reported.
Dermatologic Reactions
Maculopapular and acneiform skin reactions and isolated cases
of photosensitivity and loss of hair.
Endocrine Disorders
Lactation, breast engorgement, mastalgia, menstrual irregularities,
gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia, and
hyponatremia.
Gastrointestinal Effects
Anorexia, constipation, diarrhea, hypersalivation, dyspepsia,
nausea and vomiting.
Autonomic Reactions
Dry mouth, blurred vision, urinary retention, diaphoresis
and priapism.
Respiratory Effects
Laryngospasm, bronchospasm and increased depth of respiration.
Special Senses
Cataracts, retinopathy and visual disturbances.
Postmarketing Events
Hyperammonemia has been reported in a 5˝ year old child
with citrullinemia, an inherited disorder of ammonia excretion, following
treatment with HALDOL.
Cardiovascular Effects
OVERDOSAGE
Manifestations
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 manifest by muscular weakness or rigidity
and a generalized or localized tremor as demonstrated by the akinetic or agitans
types respectively. With accidental overdosage, hypertension rather than hypotension
occurred in a two-year old child. The risk of ECG changes associated with
torsades de pointes should be considered. (For further information regarding
torsades pointes, please refer to ADVERSE
REACTIONS.)
Treatment
Since there is no specific antidote, treatment is primarily
supportive. A patent airway must be established 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 intravenous fluids, plasma, or concentrated albumin, and vasopressor agents
such as metaraminol, phenylephrine and norepinephrine. Epinephrine should
not be used. In case of severe extrapyramidal reactions, antiparkinson medication
should be administered. ECG and vital signs should be monitored especially
for signs of Q-T prolongation or dysrhythmias and monitoring should continue
until the ECG is normal. Severe arrhythmias should be treated with appropriate
anti-arrhythmic measures.
DOSAGE AND ADMINISTRATION
There is considerable variation from patient to patient in
the amount of medication required for treatment. As with all drugs used to
treat schizophrenia, dosage should be individualized according to the needs
and response of each patient. Dosage adjustments, either upward or downward,
should be carried out as rapidly as practicable to achieve optimum therapeutic
control.
To determine the initial dosage, consideration
should be given to the patient's age, severity of illness, previous response
to other antipsychotic drugs, and any concomitant medication or disease state.
Debilitated or geriatric patients, as well as those with a history of adverse
reactions to antipsychotic drugs, may require less HALDOL (haloperidol). The
optimal response in such patients is usually obtained with more gradual dosage
adjustments and at lower dosage levels.
Parenteral medication,
administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt
control of the acutely agitated schizophrenic patient with moderately severe
to very severe symptoms. Depending on the response of the patient, subsequent
doses may be given, administered as often as every hour, although 4 to 8 hour
intervals may be satisfactory.
Controlled trials to
establish the safety and effectiveness of intramuscular administration in
children have not been conducted.
Parenteral drug products
should be inspected visually for particulate matter and discoloration prior
to administration, whenever solution and container permit.
Switchover Procedure
An oral form should supplant the injectable as soon as practicable.
In the absence of bioavailability studies establishing bioequivalence between
these two dosage forms the following guidelines for dosage are suggested.
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 12–24 hours following the last
parenteral dose.
HOW SUPPLIED
HALDOL® brand of haloperidol Injection (For
Immediate Release) 5 mg per mL (as the lactate) – NDC 0045-0255-01,
units of 10 × 1 mL ampuls.
Store HALDOL® haloperidol
Injection at controlled room temperature (15°– 30°C, 59°–86°F).
Protect from light. Do not freeze.
Manufactured by:
Janssen Pharmaceutica
N.V.
Beerse, Belgium
Distributed
by:
ORTHO-McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
August
2007
US-965834
©OMP
2005
US-965834
| HALDOL (haloperidol lactate) |
|
|
|
|
|
|
|
|
Revised: 08/2007ORTHO-McNEIL PHARMACEUTICAL, INC.