Haldol LA (Haloperidol Decanoate)

HALDOL® LA

Janssen-Ortho

Haloperidol Decanoate

Antipsychotic

Action And Clinical Pharmacology: Haloperidol decanoate, an ester derivative of haloperidol obtained from condensation of haloperidol with decanoic acid possesses the antipsychotic properties of haloperidol. When it is administered as an i.m. depot in sesame oil, esterases present in blood and tissues hydrolyze haloperidol decanoate to provide a slow release of the active neuroleptic haloperidol from the depot into the systemic circulation. The onset of action occurs within a few days after injection and the therapeutic effect continues for 2 to 4 weeks, although adequate control is frequently maintained with 1 injection every 4 weeks. Careful supervision is required throughout treatment due to the variations in individual patient response.

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

Pharmacokinetics: The pharmacokinetics of haloperidol decanoate were studied in chronic psychotic patients receiving monthly injections for up to 2 years. The initial dose was based on the observation that the bioavailability of oral haloperidol is 60 to 70%, corresponding to a monthly dose of haloperidol decanoate of about 20 times the daily oral dose. Patients were switched abruptly from their previous oral maintenance medication and plasma levels of haloperidol were measured at fixed intervals after injections. At the end of the first 4-week period, plasma haloperidol levels were similar to steady state levels attained with oral administration; however, the levels immediately following injection were considerably higher. Accumulation of plasma levels was observed for the first 3 to 6 months, after which a steady state was reached at levels about 2 to 3 times higher than in the first month of treatment.

Depending on the dose (25 to 400 mg equivalents of haloperidol), at the end of injection period steady state levels ranged from about 1 to 13 ng/mL; this range of blood levels is similar to that found in patients administered oral haloperidol.

Plasma haloperidol levels were also measured in patients who first received haloperidol decanoate in the 50 mg eq/mL concentration and subsequently were given the 100 mg eq/mL concentration. No significant differences in plasma levels were observed.

The half-life has been estimated at about 3 weeks. Haloperidol is metabolized in the liver and excreted in urine and feces.

Indications And Clinical Uses: Is of value in the management of manifestations of chronic schizophrenia.

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 children have not been established; therefore, haloperidol decanoate is contraindicated in this age group.

Pregnancy and Lactation: Haloperidol decanoate 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 decanoate 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 decanoate-treated women.

Manufacturers’ Warnings In Clinical States: Rare cases of sudden death have been reported in psychiatric patients receiving antipsychotic drugs, including haloperidol decanoate. Since QT-prolongation has been observed during haloperidol decanoate treatment, it is advised 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 withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described above 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 decanoate. Caution is advised in patients suffering from epilepsy and in conditions predisposing to convulsions (e.g., 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. Caution is also advised in patients with pheochromocytoma and conditions predisposing to epilepsy, such as alcohol withdrawal and brain damage.

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 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 together with other anticoagulants.

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

Enhanced CNS effects have been reported when haloperidol is used in combination with methyldopa. Haloperidol inhibits the metabolization of tricyclic antidepressants, thereby increasing plasma levels of these drugs.

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 concomitant antiparkinson medication is required, it may have to be continued for at least a couple of weeks after the last Haldol LA injection due to the very long half-life of haloperidol decanoate.

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.

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 patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. However, neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of these drugs and mammary tumorigenesis: the available evidence is considered too limited to be conclusive at this time.

It is recommended that patients being considered for haloperidol decanoate therapy be initially put on oral haloperidol to exclude the possibility of an unexpected adverse sensitivity to haloperidol.

As with all antipsychotic agents, haloperidol decanoate 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.

In pharmacokinetic studies mild to moderately increased haloperidol decanoate levels have been reported when haloperidol was given concomitantly with the following drugs: quinidine, buspirone, fluoxetine. It may be necessary to reduce the haloperidol decanoate dosage.

Occupational Hazards: 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 decanoate 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 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.

Agranulocytosis and thrombocytopenia have rarely been reported with the use of haloperidol, and then only in association with other medication.

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, 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, weight gain, constipation, diarrhea and hypersalivation have been reported.

Miscellaneous: Other untoward effects which may be 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, have also been reported.

Symptoms And Treatment Of 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: severe extrapyramidal reactions; hypotension; or 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, please refer to 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 or 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 antiarrhythmic measures.

Dosage And Administration: Haloperidol decanoate is administered by deep i.m. injection, preferably in the gluteus maximus. This drug is not for i.v. use.

As a long-acting, depot neuroleptic, it has been found useful in the maintenance management of chronic schizophrenic patients who have been stabilized with short-acting medication, and who might benefit from transfer to longer acting injectable therapy. The changeover to haloperidol decanoate should aim at maintaining a clinical outcome similar to or better than that obtained with previous therapy in patients who cannot be relied upon to take oral medication regularly.

It is suggested that previous antipsychotic medication be discontinued before instituting therapy with haloperidol decanoate. Continuous supervision is required during the initial period of dosage adjustment in order to minimize the risk of overdosage or insufficient suppression of psychotic symptoms before the next injection. Supplemental oral haloperidol may be required in diminishing dosage during this period.

The selection of the initial dose of haloperidol decanoate should be based on the patient’s symptomatology and previous oral neuroleptic dosage. A ratio of 20:1 of haloperidol decanoate to oral haloperidol appears to produce comparable steady state plasma levels of haloperidol with both dosage forms. However, control of psychotic symptoms has also been achieved with doses based on lower ratios (10 to 15 times the daily maintenance dose of oral haloperidol). In order to reduce the possible occurrence of adverse effects, it is advisable to initiate therapy with haloperidol decanoate at lower doses and adjust the dose upwards as needed. There is limited experience with patients transferred to haloperidol decanoate from other oral neuroleptics. If such a transfer is deemed desirable, it is suggested that the patient be converted initially from the previous antipsychotic medication to oral haloperidol in order to exclude the possibility of an unexpected adverse sensitivity to haloperidol.

The average duration of action of haloperidol decanoate is 4 weeks. However, the frequency of administration and the dosage must be individually determined for each patient. The dose should not be increased with the intent of prolonging the interval between injections beyond 4 weeks, since higher doses may increase the incidence of extrapyramidal symptoms and other adverse effects. Occasional patients may require higher dosages and/or shorter injection intervals, such as 3 or even 2 weeks.

Clinical experience with haloperidol decanoate at doses greater than 300 mg has been limited and much lower doses are usually adequate to achieve symptom control. In order to minimize the possible occurrence of serious and potentially irreversible adverse effects, the lowest neuroleptic dosage should be used which is consistent with effective management of the patient.

After appropriate dosage adjustment is achieved, regular reassessment is considered essential to allow additional adjustments which will ensure that the lowest effective individual doses are used.

Geriatrics and Debilitated Patients: Lower initial doses and more gradual titration are recommended in elderly and debilitated patients.

Patients who require higher doses of haloperidol decanoate and/or those who complain of discomfort with a large injection volume may be administered haloperidol decanoate 100 mg eq/mL in preference to haloperidol decanoate 50 mg eq/mL.

As with all oily injections it is important to insure, by aspiration before injection, that inadvertent intravascular injection does not occur.

A dry syringe and a dry 5 cm needle of 21 gauge should be used for patients with a normal amount of body fat. Obese patients should be injected with a 6.5 cm needle in order to ensure that the injection goes into muscle.

Availability And Storage: 50 mg/mL: Each mL of slightly amber, slightly viscous solution contains: haloperidol 50 mg (haloperidol decanoate 70.52 mg). Nonmedicinal ingredients: benzyl alcohol and sesame oil. Ampuls of 1 mL. Multidose vials of 5 mL.

100 mg/mL: Each mL of slightly amber, slightly viscous solution contains: haloperidol 100 mg (haloperidol decanoate 141.04 mg). Nonmedicinal ingredients: benzyl alcohol and sesame oil. Ampuls of 1 mL. Multidose vials of 5 mL.

Store at controlled room temperature (15 to 30°C). Do not refrigerate or freeze. Protect from light. Keep in carton until empty.

HALDOL® LA Janssen-Ortho Haloperidol Decanoate Antipsychotic

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