HALOPERIDOL
DESCRIPTION:
Haloperidol is the first of the butyrophenone series of major tranquilizers. The
chemical designation is 4-(4-(p-chlorophenyl)-4-hydroxy- piperidino)-4'-
fluorobutyrophenone.
.
ACTIONS/CLINICAL PHARMACOLOGY:
The precise mechanism of action has not been clearly established.
INDICATIONS AND USAGE:
HALIDOL haloperidol is indicated for use in the management of manifestations of
psychotic disorders.
HALIDOL is indicated for the control of tics and vocal utterances of Tourette's
Disorder in children and adults.
HALIDOL is effective for the treatment of severe behavior problems in children of
combative, explosive hyperexcitability (which cannot be accounted for by
immediate provocation). HALIDOL is also effective in the short-term treatment of
hyperactive children who show excessive motor activity with accompanying conduct
disorders consisting of some or all of the following symptoms: impulsivity,
difficulty sustaining attention, aggressivity, mood lability and poor
frustration tolerance. HALIDOL should be reserved for these two groups of
children only after failure to respond to psychotherapy or medications other
than antipsychotics.
CONTRAINDICATIONS:
HALIDOL 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:
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treatment is withdrawn.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 HALIDOL.
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 non-specific 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 HALIDOL haloperidol in pregnant women.
There are reports, however, of cases of limb malformations observed following
maternal use of HALIDOL 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 HALIDOL, 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 HALIDOL 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 HALIDOL. A causal relationship
between these events and the concomitant administration of lithium and HALIDOL
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 HALIDOL. 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 HALIDOL, decreased serum cholesterol and/or cutaneous
and ocular changes have been reported in patients receiving chemically-related
drugs.
HALIDOL 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:
HALIDOL 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 HALIDOL 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 HALIDOL 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 HALIDOL 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 HALIDOL.
As with other antipsychotic agents, it should be noted that HALIDOL may be
capable of potentiating CNS depressants such as anesthetics, opiates, and
alcohol.
When HALIDOL 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
HALIDOL.
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 at
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
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 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.
DRUG INTERACTIONS:
COMBINED USE OF HALIDOL 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 HALIDOL. A causal relationship
between these events and the concomitant administration of lithium and HALIDOL
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.
HALIDOL 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 HALIDOL 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 HALIDOL may lower the convulsive threshold. If indicated,
adequate anticonvulsant therapy should be concomitantly maintained.
--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 HALIDOL 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 HALIDOL.
As with other antipsychotic agents, it should be noted that HALIDOL may be
capable of potentiating CNS depressants such as anesthetics, opiates, and
alcohol.
(See Also WARNINGS and PRECAUTIONS)
ADVERSE REACTIONS:
CNS EFFECTS:
Extrapyramidal Symptoms (EPS)--EPS during the administration of HALIDOL
(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 HALIDOL.
Tardive Dyskinesia--As with all antipsychotic agents HALIDOL 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 HALIDOL. (See WARNINGS for further information
concerning NMS.)
CARDIOVASCULAR EFFECTS: Tachycardia, hypotension, hypertension and ECG changes
including prolongation of the Q-T interval and ECG pattern changes compatible
with the polymorphous configuration of torsades de pointes.
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 HALIDOL, 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.
OTHER: Cases of sudden and unexpected death have been reported in association
with the administration of HALIDOL. The nature of the evidence makes it
impossible to determine definitively what role, if any, HALIDOL played in the
outcome of the reported cases. The possibility that HALIDOL 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.
POSTMARKETING EVENTS: Hyperammonemia has been reported in a 5 1/2 year old child
with citrullinemia, an inherited disorder of ammonia excretion, following
treatment with HALIDOL.
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 de pointes,
please refer to ADVERSE REACTIONS.)
TREATMENT
Gastric lavage or induction of emesis should be carried out immediately followed
by administration of activated charcoal. 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 antipsychotic drugs, 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. Children, debilitated or geriatric
patients, as well as those with a history of adverse reactions to antipsychotic
drugs, may require less HALIDOL haloperidol. The optimal response in such
patients is usually obtained with more gradual dosage adjustments and at lower
dosage levels, as recommended below.
Clinical experience suggests the following recommendations:
ORAL ADMINISTRATION
Initial Dosage Range
Adults
------------------------------------------------------------------------------------------------------------------------------------
Moderate Symptomatology 0.5 mg to 2.0 mg
b.i.d. or t.i.d.
----------------------------------------------------------------------------------------------------------------------------------
Severe Symptomatology 3.0 mg to 5.0 mg
b.i.d. or t.i.d.
------------------------------------------------------------------------------------------------------------------------------------
To achieve prompt control, higher doses may be required in some cases.
-----------------------------------------------------------------------------------------------------------------------------------
Geriatric or Debilitated Patients 0.5 mg to 2.0 mg
b.i.d. or t.i.d.
---------------------------------------------------------------------------------------------------------------------------------
Chronic or Resistant Patients 3.0 mg to 5.0 mg
b.i.d. or t.i.d.
---------------------------------------------------------------------------------------------------------------------------------
PATIENTS WHO REMAIN SEVERELY DISTURBED OR INADEQUATELY CONTROLLED MAY REQUIRE
DOSAGE ADJUSTMENT. DAILY DOSAGES UP TO 100 MG MAY BE NECESSARY IN SOME CASES
TO ACHIEVE AN OPTIMAL RESPONSE. INFREQUENTLY, HALIDOL HAS BEEN USED IN DOSES
ABOVE 100 MG FOR SEVERELY RESISTANT PATIENTS; HOWEVER, THE LIMITED CLINICAL
USAGE HAS NOT DEMONSTRATED THE SAFETY OF PROLONGED ADMINISTRATION OF SUCH
DOSES.
---------------------------------------------------------------------------------------------------------------------------------------------------
Children
The following recommendations apply to children between the ages of 3 and 12
years (weight range 15 to 40 kg). HALIDOL is not intended for children under 3
years old. Therapy should begin at the lowest dose possible (0.5 mg per day). If
required, the dose should be increased by an increment of 0.5 mg at 5 to 7 day
intervals until the desired therapeutic effect is obtained. (See chart below).
The total dose may be divided, to be given b.i.d. or t.i.d.
----------------------------------------------------------------------------------------------------------------------------------------------------
Psychotic Disorders 0.05 mg/kg/day to
0.15 mg/kg/day
--------------------------------------------------------------------------------------------------------------------------------------------------
Non-Psychotic Behavior 0.05 mg/kg/day to
Disorders and Tourette's Disorder 0.075 mg/kg/day
--------------------------------------------------------------------------------------------------------------------------------------------------
SEVERELY DISTURBED PSYCHOTIC CHILDREN MAY REQUIRE HIGHER DOSES. IN SEVERELY
DISTURBED, NON-PSYCHOTIC CHILDREN OR IN HYPERACTIVE CHILDREN WITH
ACCOMPANYING CONDUCT DISORDERS, WHO HAVE FAILED TO RESPOND TO PSYCHOTHERAPY
OR MEDICATIONS OTHER THAN ANTIPSYCHOTICS, IT SHOULD BE NOTED THAT SINCE THESE
BEHAVIORS MAY BE SHORT-LIVED, SHORT-TERM ADMINISTRATION OF HALIDOL MAY
SUFFICE. THERE IS NO EVIDENCE ESTABLISHING A MAXIMUM EFFECTIVE DOSAGE. THERE
IS LITTLE EVIDENCE THAT BEHAVIOR IMPROVEMENT IS FURTHER ENHANCED IN DOSAGES
BEYOND 6 MG PER DAY.
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MAINTENANCE DOSAGE
Upon achieving a satisfactory therapeutic response, dosage should then be
gradually reduced to the lowest effective maintenance level.
INTRAMUSCULAR ADMINISTRATION
Adults
Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is
utilized for prompt control of the acutely agitated 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
The 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.
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