Action And Clinical Pharmacology: Haloperidol is a butyrophenone 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.
As with other neuroleptics, 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.
Pharmacokinetics: 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.
Indications And Clinical Uses: 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.
Contra-Indications: In comatose states and in the presence of CNS depression due to alcohol or other depressant drugs. It is also contraindicated in patients with severe depressive states, previous spastic diseases, lesions of the basal ganglia, and in Parkinson’s syndrome, except in the case of dyskinesias due to levodopa treatment. It should not be used in patients known to be sensitive to the drug, nor in senile patients with pre-existing Parkinson-like symptoms.
Children: Safety and effectiveness in young children have not been established; therefore, haloperidol is contraindicated in this age group.
Pregnancy and Lactation: Haloperidol has shown no significant increase in fetal anomalies in large population studies. There have been isolated case reports of birth defects following fetal exposure to haloperidol in combination with other drugs. It should, therefore, not be administered 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. Extrapyramidal symptoms have been observed in breast-fed infants of haloperidol-treated women.
Manufacturers’ Warnings In Clinical States: Rare cases of sudden death have been reported in psychiatric patients receiving antipsychotic drugs, including haloperidol. Since QT-prolongation has been observed during haloperidol treatment, it is advisable to be cautious in patients with QT-prolonging conditions (QT-syndrome, hypokalemia, drugs known to prolong QT).
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 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 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.
In rare cases, the following symptoms were reported during the concomitant use of lithium and haloperidol: encephalopathy, extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, brain stem disorder, acute brain syndrome and coma. Most of these symptoms were reversible; it remains unclear whether this represents a distinct clinical entity. Nonetheless, it is advised that in patients who are treated concomitantly with lithium and haloperidol, therapy should be stopped immediately if such symptoms occur.
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, judgment 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.
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.
It has been reported that seizures can be triggered by haloperidol. Caution is advised in patients suffering from epilepsy and in conditions predisposing to convulsions such as alcohol withdrawal and brain damage.
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.
Haloperidol has lowered the level of cholesterol in the serum and liver of monkeys. An accumulation of desmosterol has been observed in the serum of rats given repeated 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 an 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, it is advisable that 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, the drug should be discontinued 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 have been reported when haloperidol is used in combination with methyldopa.
As with all antipsychotic agents, haloperidol should not be used alone where depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist.
If concomitant antiparkinson medication is required, it may have to be continued after stopping haloperidol if its excretion is faster than that of haloperidol in order to avoid the development or aggravation of extrapyramidal symptoms.
Haloperidol inhibits the metabolization of tricyclic antidepressants, thereby increasing plasma levels of these drugs.
In pharmacokinetic studies, mild to moderately increased haloperidol levels have been reported when haloperidol was given concomitantly with the following drugs: quinidine, busipirone, fluoxetine. It may be necessary to reduce the haloperidol dosage.
When prolonged treatment with enzyme-inducing drugs such as carbamazepine, phenobarbital, rifampin 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 such drugs, it will be necessary to reduce the dosage of haloperidol.
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, previously controlled by antiparkinson agents, 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 in 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 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.
Occupational Hazards: Effects on driving ability and use of machinery: Some degree of sedation or impairment of alertness may occur, particularly with higher doses and at the start of treatment and may be potentiated by alcohol. Patients should be advised not to drive or operate machinery during treatment, until their susceptibility is known.
Adverse Reactions: Neurological effects are the most common.
Extrapyramidal Symptoms: In common with all neuroleptics, extrapyramidal symptoms may occur, e.g., tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia. 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 inter-patient 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.
Antiparkinson drugs of the anticholinergic type may be prescribed as required, but should not be prescribed routinely as a preventive measure.
Tardive Dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or may appear after drug therapy has been discontinued. 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. The manifestations may be permanent in some patients.
The syndrome may be masked when treatment is reinstituted, when the dosage is increased or when a switch is made to a different antipsychotic drug. Treatment should be discontinued as soon as possible.
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, depressive reactions, and toxic confusional states are the more common effects encountered. Drowsiness, lethargy, stupor and catalepsy, confusion, restlessness, agitation, anxiety, euphoria, vertigo, grand mal seizures, and exacerbation of psychotic symptoms, including hallucinations, have also been reported.
Cardiovascular: Tachycardia, hypertension, and ECG changes including ventricular arrhythmias and/or 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 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, erectile dysfunctions, peripheral edema, excessive perspiration or salivation, heartburn, and body temperature disregulation 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 and thrombocytopenia have rarely been reported with the use of haloperidol, and then only in association with other medication. Impairment of liver function (jaundice or hepatitis, most often cholestatic) has been reported rarely. One case of photosensitization is known and isolated cases of idiosyncratic cutaneous involvement have been observed.
Endocrine: Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinemia, which may cause galactorrhea, gynecomastia and oligo- or amenorrhea. Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido and changes in blood sugar levels and very rare cases of Syndrome of Inappropriate ADH Secretion 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.
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, generalized muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure). Hyperthermia is often an early sign of this syndrome. 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, has also been reported.
Overdosage: 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 manifest by muscular weakness or rigidity and a generalized or localized tremor as demonstrated by the akinetic or agitans types respectively.
In extreme cases, the patient would appear comatose with respiratory depression and hypotension that could be severe enough to produce a shock-like state. The risk of ventricular arrhythmias, possibly associated with QT-prolongation, should be considered. (For further information regarding torsades de pointes, see Adverse Effects.)
Treatment: Since there is no specific antidote, treatment is primarily supportive but gastric lavage or induction of emesis is advised (unless the patient is obtunded, comatose or convulsing) followed by administration of activated charcoal. For comatose patients, 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 i.v. fluids, plasma, or concentrated albumin, and vasopressor agents such as norepinephrine. Epinephrine should not be used since it may cause profound hypotension in the presence of haloperidol. In case of severe extrapyramidal reactions, antiparkinson 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 anti-arrhythmic measures.
Dosage And Administration: 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, dosage should then be reduced 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 is best obtained if therapy is initiated at a lower dosage level and titration is more gradual.
Parenteral: When symptoms are severe or rapid control is desired, haloperidol may be administered i.m. 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.
Clinical experience has shown that it is seldom necessary to employ dosages greater than 4 to 6 mg t.i.d. However, 30 to 40 mg daily may be required in severely disturbed patients who remain inadequately controlled by lower doses, and 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 2 mg t.i.d. or q.i.d.
Children: The safety and effectiveness of i.m. administration in children have not been established.
Elderly or Debilitated Patients: Lower doses are recommended in these patients since they may be more sensitive to the drug. Initially, 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.
The oral dosage form should supplant the injectable as soon as practicable. 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.
Availability And Storage: Each mL ampul contains: haloperidol 5 mg (as a lactate). Nonmedicinal ingredients: lactic acid sufficient to adjust the pH within the range of 3.0 to 3.6, methylparaben, propylparaben and water. Do not dilute with sterile saline. Ampuls of 1 mL, units of 10. Store at controlled room temperature (15 to 30°C). Protect from light. Do not freeze.
HALDOL® Janssen-Ortho Haloperidol Antipsychotic
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