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haloperidol 10 mg tablet

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Uses

Schizophrenia

Haloperidol is used orally and parenterally for the symptomatic management of psychotic disorders (i.e., schizophrenia). Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to improve symptoms between episodes and to minimize the risk of recurrent acute episodes. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia and generally are effective in all subtypes of the disorder and subgroups of patients. Conventional antipsychotic agents, such as haloperidol, generally are considered to exhibit similar efficacy in treating acute psychotic symptoms, although they vary in their potency and adverse effect profile. Haloperidol is a high-potency antipsychotic that has been shown to be effective in the management of acute and stable phases of schizophrenia, but is frequently associated with extrapyramidal reactions such as akathisia, dystonia, or parkinsonian symptoms, even at low dosages.

Results of short-term studies indicate that oral haloperidol is more effective than placebo and equally or less effective than atypical antipsychotics in the treatment of positive (e.g., delusions, hallucinations) and negative symptoms (e.g., withdrawal from social interaction, blunted emotional expression) of schizophrenia. However, in one clinical study, haloperidol was less effective than the atypical antipsychotic agent risperidone in preventing relapse in adult outpatients with clinically active schizophrenia or schizoaffective disorders who were assigned to receive either drug for a minimum of 1 year. In this study, approximately 40% of patients in the study who received usual dosages of haloperidol had relapsed by the end of the study compared with approximately 25% of those receiving usual dosages of risperidone.

Because atypical antipsychotics appear to be at least as effective in the treatment of positive symptoms and possibly more effective in the treatment of negative symptoms of schizophrenia and have fewer extrapyramidal reactions, some clinicians prefer use of atypical antipsychotics rather than conventional antipsychotics, such as haloperidol, for the management of schizophrenia, except in stable patients who have had good response to conventional antipsychotics without major adverse effects, in patients who require IM therapy, which is not yet available for some atypical antipsychotics, and for the acute management of aggression/violence in some patients, particularly those requiring long-acting (depot) parenteral preparations. However, patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.

The long-acting decanoate ester of haloperidol is used parenterally principally in patients requiring prolonged antipsychotic therapy (e.g., patients with chronic schizophrenic disorder). Parenteral antipsychotic therapy with a long-acting preparation may be particularly useful in patients with a history of poor compliance. In addition, long-acting antipsychotic preparations may be useful in patients with suspected GI malabsorption or variable GI absorption of the drug. The principal disadvantage of long-acting parenteral antipsychotics is the inability to terminate the drug's action when severe adverse reactions occur. Long-acting antipsychotic preparations should not be used in the acute management of severely agitated patients. Generally, patients should be stabilized on antipsychotic medication prior to conversion to haloperidol decanoate therapy and should have previously received and tolerated a shorter-acting haloperidol preparation so that the possibility of an unexpected adverse reaction that potentially could not be readily reversed following the decanoate can be minimized. For further information on the use of antipsychotic agents in the symptomatic treatment of schizophrenia,

Tourette's Syndrome

Haloperidol is used orally and parenterally for the control of tics and vocal utterances of Tourette's syndrome (Gilles de la Tourette's syndrome) in children and adults. Haloperidol generally has been considered the drug of choice for the management of Tourette's syndrome and pimozide has been an effective alternative in some patients who have an inadequate response to or do not tolerate haloperidol. Because limited data suggest that pimozide may be more effective than haloperidol in reducing tics and pimozide appears to be better tolerated than haloperidol, some clinicians and experts prefer the use of pimozide in patients with Tourette's syndrome.

In children with tic disorders (e.g., Tourette's syndrome) and comorbid attention deficit hyperactivity disorder (ADHD) in whom stimulants alone cannot control tics, haloperidol may be used concomitantly with a stimulant.

Delirium

Antipsychotic agents, mainly haloperidol, have been used in the management of delirium.

General Considerations

Delirium is principally a disturbance of consciousness, attention, cognition, and perception but also may affect sleep, psychomotor activity, and emotions. It is a common psychiatric illness among medically compromised patients, particularly hospitalized patients, and may be a harbinger of substantial morbidity and mortality.

Prevalence and Course

The prevalence of delirium in hospitalized medically ill patients ranges from 10-30%; in those who are elderly, delirium ranges up to 40%. Up to 25% of hospitalized cancer patients and 30-40% of hospitalized patients with acquired immunodeficiency syndrome (AIDS) develop delirium. Up to about 50% of postoperative patients develop delirium, and up to 80% of terminally ill patients develop it near death. EEG abnormalities, mainly generalized slowing, have fairly good sensitivity for aiding in the diagnosis of delirium, but the absence of such changes does not rule out the diagnosis. Prodromal manifestations may progress to full-blown delirium over 1-3 days; the duration of delirium generally ranges from less than a week to more than 2 months, but typically does not exceed 10-12 days. Symptoms persist for up to 30 days or longer in up to 15% of patients, and frequently persist for longer than 1 month in geriatric patients. Although most patients recover fully, delirium may progress to stupor, coma, seizures, and death, particularly if untreated. Full recovery is less likely in geriatric patients and patients with AIDS, possibly because of underlying dementia in both populations.

Underlying general medical conditions associated with delirium include CNS disorders (e.g., head trauma, seizures, postictal state, vascular or degenerative disease), metabolic disorders (e.g., renal or hepatic failure, anemia, hypoxia, hypoglycemia, thiamine deficiency, endocrinopathy, fluid or electrolyte imbalance, acid-base imbalance), cardiopulmonary disorder (myocardial infarction, congestive heart failure, cardiac arrhythmia, shock, respiratory failure), and systemic illness (e.g., substance intoxication or withdrawal, infection, cancer, severe trauma, sensory deprivation, temperature dysregulation, postoperative state).

Management

Overview

Clinicians should undertake an essential array of psychiatric management tasks designed to provide immediate interventions for urgent general medical conditions, identify and treat the etiology of delirium, ensure safety of the patient and others in contact with the patient, and improve the patient's functioning. Environmental (e.g., varying light levels in intensive care units to heighten awareness about time of day and reduce the perception of timelessness) and supportive interventions (e.g., to deal with disorientation, to assure the patient that manifestations are temporary and reversible and do not reflect a persistent psychiatric disorder) also generally are offered to patients with delirium and are designed to reduce factors that may exacerbate delirium, to reorient patients, and to provide support. Patients may have life-threatening medical conditions that require therapeutic intervention even before a specific or definitive cause of the delirium is determined. The goal of diagnosis is to identify potentially reversible causes of delirium and prevent complications through prompt treatment of these specific disorders. Psychiatric management is essential and should be undertaken for all patients with delirium. Somatic interventions principally consist of drug therapy. The choice of somatic intervention will depend on the specific features of the patient's clinical condition, the underlying etiology of the delirium, and any associated comorbid conditions.

Drug Therapy

Antipsychotic agents often are the drugs of choice for the management of delirium. Although other drugs (e.g., phenothiazines, droperidol) have been used, haloperidol generally is considered the antipsychotic of choice for most patients with delirium because of its relatively low risk of anticholinergic activity and of sedative and hypotensive effects. In addition, haloperidol has been studied most extensively, although few studies have used standardized definitions of delirium or reliable and valid delirium symptom rating measures to assess symptom severity before and after initiation of treatment. For drugs other than haloperidol, there have been no large, prospective studies that included a control. Evidence of efficacy for such alternative therapies, including second-generation antipsychotic agents (e.g., olanzapine, quetiapine, risperidone, ziprasidone), is principally from small case series, case reports, or open-label studies. In addition, interpretation of findings from many such case presentations is difficult because of use of nonstandardized delirium definitions and/or informal measures of delirium symptom severity. In general, evidence of the efficacy of antipsychotics, including haloperidol, in the management of delirium comes from numerous case reports and uncontrolled studies. However, evidence from a randomized, double-blind, comparator-drug controlled study (haloperidol, chlorpromazine, and lorazepam) in patients with AIDS that employed standardized clinical measures of delirium demonstrated clinical superiority of antipsychotic agents compared with benzodiazepines. Statistically significant improvement in the Delirium Rating Scale was evident after 2 days in patients receiving haloperidol or chlorpromazine but not in the lorazepam group (mean decreases in the score [i.e., improvement] were 8, 8.5, and 1, respectively). The symptomatic improvement in delirium occurred quickly among patients receiving antipsychotic therapy, usually before initiation of interventions directed at the medical etiologies of delirium.

Although various antipsychotic agents may be given orally, IM, or IV, IV administration is considered most effective in emergency situations or where oral access is limited. In addition, some evidence indicates that IV administration of antipsychotic agents may be associated with less severe extrapyramidal effects.

Special Precautions

Antipsychotic agents, particularly IV haloperidol, used in the management of delirium have been associated with lengthening of the QT interval, possibly leading to atypical ventricular tachycardia (torsades de pointes), ventricular fibrillation, and sudden death. The manufacturer of Haldol and the US Food and Drug Administration (FDA) state that although injectable haloperidol is approved only for IM injection and not for IV administration, there is considerable evidence from the medical literature that IV administration of the drug is a relatively common, unlabeled (''off-label'') clinical practice, principally for the treatment of severe agitation in intensive care units, and recommend ECG monitoring in any patient receiving the drug IV. Many clinicians also recommend that baseline and periodic or continuous ECG monitoring be performed with special attention paid to the length of the QTc interval. Prolongation of the QTc interval to greater than 450 msec or to greater than 15-25% over that in previous ECGs may warrant telemetry, a cardiology consultation, and dose reduction or discontinuance. Serum concentrations of magnesium and potassium also should be monitored at baseline and periodically in critically ill patients, especially those with baseline QTc intervals of 440 msec or longer, those receiving other drugs known to increase the QT interval, and those who have electrolyte disorders. Limited evidence suggests that the incidence of torsades de pointes in patients receiving haloperidol IV is about 0.4-3.6%, but may increase to greater than 10% at relatively high IV doses (e.g., 35 mg or more over 24 hours).(See Cautions: Cardiovascular Effects and also see Cautions: Precautions and Contraindications.)

Disruptive Behavior Disorder and Attention Deficit Hyperactivity Disorder

Haloperidol is used orally for the treatment of severe behavioral problems in children marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and for the short-term treatment of hyperactive children who exhibit excessive motor activity with accompanying conduct disorders that are manifested as impulsive behavior, difficulty sustaining attention, aggression, mood lability, and/or poor frustration tolerance. However, the possible risks of tardive dyskinesia, withdrawal dyskinesia, and other extrapyramidal reactions should be considered. Some experts currently recommend use of haloperidol only for the treatment of comorbid tics in children with attention deficit hyperactivity disorder (ADHD). Some clinicians recommend routine administration of the Abnormal Involuntary Movement Scale (AIMS) to all children receiving antipsychotic agents.

Nausea and Vomiting

Haloperidol also has been used in the prevention and control of severe nausea and vomiting (e.g., cancer chemotherapy-induced emesis). Based on limited data, haloperidol appears to be as effective as phenothiazines in the prevention of cancer chemotherapy-induced emesis. Additional studies are required to determine the efficacy of haloperidol in the prevention and control of severe nausea and vomiting.

Dosage and Administration

Administration

Haloperidol is administered orally. Haloperidol lactate is administered orally or by IM injection, and haloperidol decanoate is administered by IM injection. Pending accumulation of further data to establish safety and efficacy, IM administration of haloperidol lactate or decanoate in children is not recommended by the manufacturers. Haloperidol lactate also has been administered by IV injection or infusion. Haloperidol decanoate injection should not be administered IV.

Haloperidol decanoate should be administered by deep IM injection into the gluteal region using a 21-gauge needle. The manufacturers of haloperidol decanoate state that the maximum volume of haloperidol decanoate should not exceed 3 mL per IM injection site.

Haloperidol lactate and decanoate injections should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Dosage

Dosage of haloperidol lactate and the decanoate is expressed in terms of haloperidol.

There is considerable interindividual variation in optimum dosage requirements of haloperidol, and dosage must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage. Dosage should be increased more gradually in children and in debilitated, emaciated, or geriatric patients. Because of the risk of adverse reactions associated with cumulative effects of butyrophenones, patients with a history of long-term therapy with haloperidol and/or other antipsychotic agents should be evaluated periodically to determine whether maintenance dosage could be decreased or drug therapy discontinued.

Oral Dosage

For the symptomatic management of psychotic disorders or Tourette's disorder in adults with moderate symptomatology and in geriatric or debilitated patients, the manufacturers state that the usual initial oral dosage of haloperidol is 0.5-2 mg administered 2 or 3 times daily. To achieve prompt control, higher initial dosages may be required in some patients. Subsequent dosage should be carefully adjusted according to the patient's tolerance and therapeutic response. Dosage during prolonged maintenance therapy should be kept at the lowest effective level.

For the symptomatic management of psychotic disorders or Tourette's disorder in adults with severe symptomatology and/or chronic or resistant disorders, the manufacturers state that the usual initial oral dosage of haloperidol is 3-5 mg administered 2 or 3 times daily. To achieve prompt control, higher initial dosages may be required in some patients. Subsequent dosage should be carefully adjusted according to the patient's tolerance and therapeutic response. Dosage during prolonged maintenance therapy should be kept at the lowest effective level.

Similarly, the American Psychiatric Association (APA) recommends oral haloperidol dosages ranging from 5-20 mg daily in the treatment of adults with schizophrenia. The APA states that determining the optimal dosage of antipsychotic agents during the acute phase of schizophrenia is complicated because there usually is a delay between initiation of therapy and full therapeutic response. An initial response to antipsychotic therapy may take 2-4 weeks and up to 6 months or longer may be needed for a full or optimal response.

Patients who remain severely disturbed or inadequately controlled despite receiving recommended dosages of haloperidol may require dosage adjustment. Some manufacturers state that oral haloperidol dosages up to 100 mg daily may be necessary in some cases to achieve an optimal response. In addition, these manufacturers further state that haloperidol has been used infrequently in dosages exceeding 100 mg daily in severely resistant disorders in adults, but that the limited use has not demonstrated the safety of prolonged administration of such high dosages of the drug. However, extensive clinical experience suggests that higher-dosage haloperidol regimens (i.e., those exceeding 20-40 mg daily) are unlikely to be more effective or result in a faster clinical response in the majority of patients with schizophrenia, including in those with refractory or chronic schizophrenia, and supports the use of more moderate dosage regimens (i.e., from 4 mg daily up to 15-20 mg daily) in such patients. In addition, high-dosage haloperidol regimens are more likely to be associated with unacceptable short- and long-term adverse effects (see Cautions).

The usual initial oral dosage of haloperidol in children 3-12 years of age and weighing 15-40 kg is 0.5 mg daily given in 2 or 3 divided doses. Subsequent dosage may be increased by 0.5 mg daily at 5- to 7-day intervals, depending on the patient's tolerance and therapeutic response.

For the symptomatic management of psychotic disorders in children 3-12 years of age, the usual oral dosage range is 0.05-0.15 mg/kg daily given in 2 or 3 divided doses; however, severely disturbed psychotic children may require higher dosages. Dosage during prolonged maintenance therapy should be kept at the lowest possible effective level; once an adequate response has been achieved, dosage should be gradually reduced and subsequently adjusted according to the patient's therapeutic response and tolerance.

For the management of non-psychotic behavioral problems and for the control of Tourette's disorder in children 3-12 years of age, the usual oral dosage range is 0.05-0.075 mg/kg daily given in 2 or 3 divided doses. Unlike psychotic disorders for which prolonged therapy is usually required, non-psychotic or hyperactive behavioral problems in children may be acute, and short-term administration of haloperidol may be adequate. A maximum effective dosage of haloperidol for the management of behavioral problems in children has not been established; however, the manufacturers state that there is little evidence that improvement in behavior is further enhanced at dosages greater than 6 mg daily.

IM Dosage

Haloperidol Lactate

For the prompt control of acutely agitated patients with moderately severe to very severe symptoms, the usual initial adult IM dose of haloperidol lactate is 2-5 mg (of haloperidol) given as a single dose. Depending on the response of the patient, this dose may be repeated as often as every hour; however, IM administration of haloperidol lactate every 4-8 hours may be adequate to control symptoms in some patients.

Oral therapy should replace short-acting parenteral therapy as soon as possible. Depending on the patient's clinical status, the first oral dose should be given within 12-24 hours following administration of the last parenteral dose of haloperidol lactate. Since bioavailability studies to establish bioequivalence between oral and parenteral dosage forms of haloperidol have not been conducted to date, the manufacturers suggest that the parenteral dosage administered during the preceding 24 hours be used for initial approximation of the total daily oral dosage required. Since this dosage is only an initial estimate, patients being switched from parenteral haloperidol lactate therapy to oral therapy should be closely monitored, particularly for clinical signs and symptoms of efficacy, sedation, and adverse effects, for the first several days following initiation of oral therapy. Subsequent dosage may be increased or decreased according to the patient's tolerance and therapeutic response, using the lowest possible effective dosage.

Haloperidol Decanoate

For patients requiring prolonged antipsychotic therapy (e.g., patients with chronic schizophrenic disorder), the long-acting haloperidol decanoate injection may be considered. If the decanoate is used, the patient's condition should initially be stabilized with an antipsychotic agent prior to attempting conversion to haloperidol decanoate. In addition, if the patient is receiving an antipsychotic agent other than haloperidol, it is recommended that the patient initially be converted to oral haloperidol therapy in order to minimize the risk of an unexpected adverse reaction to the drug, which might not be readily reversible following use of the decanoate.

The initial IM dose of haloperidol decanoate should be based on the patient's clinical history, physical condition, and response to previous antipsychotic therapy. To determine the minimum effective dosage, haloperidol decanoate therapy has been initiated at low initial doses and gradually titrated upward as necessary. A precise formula for converting from oral haloperidol to IM haloperidol decanoate dosage has not been established, but an initial adult dose 10-20 times the previous daily dose of oral haloperidol, not exceeding 100 mg (regardless of previous antipsychotic dosage requirements), is suggested, although limited clinical experience suggests that a lower initial dosage of the decanoate may be adequate. If conversion requires an initial dosage of haloperidol decanoate higher than 100 mg daily, such dosage should be administered in 2 injections (i.e., administering a maximum initial dose of 100 mg followed by the balance in 3-7 days). However, some clinicians have converted therapy to the decanoate using a higher initial dosage.

Lower initial IM dosages (e.g., 10-15 times the previous daily dose of oral haloperidol) and more gradual upward titration of haloperidol administered as the decanoate salt are recommended for patients who are geriatric, debilitated, or stabilized on low oral dosages (e.g., up to the equivalent of 10 mg daily of oral haloperidol). Higher initial IM dosages (e.g., 20 times the previous daily dosage of oral haloperidol) should be considered for patients who are stabilized on high oral dosages of antipsychotic agents, those who are at risk of relapse, and those who are tolerant to oral haloperidol, with downward titration on succeeding injections.

Haloperidol decanoate usually has been administered IM at monthly intervals (i.e., every 4 weeks), but individual response may dictate the need for adjusting the dosing interval as well as the dose.

The maintenance dosage of haloperidol decanoate must be individualized with upward or downward dosage titration based on clinical response. The usual adult maintenance IM dosage is 10-15 times the previous daily dosage of oral haloperidol for adult patients depending on the clinical response of the patient.

Close clinical observation is required during dosage titration in order to minimize the risk of overdosage and of emergence of psychotic manifestations prior to the next dose. If supplemental antipsychotic therapy is necessary during periods of dosage titration or for control of acute exacerbations of psychotic manifestations, a short-acting haloperidol preparation should be used. Experience with haloperidol decanoate dosages exceeding 450 mg (of haloperidol) monthly is limited.

IV Dosage

Haloperidol Lactate

The optimum dosage of haloperidol (administered as haloperidol lactate) for the treatment of delirium has not been established. However, initiation of IV haloperidol with dosages of 1-2 mg every 2-4 hours in adults has been suggested. Lower IV dosages (e.g., 0.25-0.5 mg every 4 hours) have been suggested for geriatric patients with delirium; severely agitated adults may require titration to higher dosages. Although single IV doses up to 50 mg or total daily dosages of 500 mg have been reported in adults, the risk of adverse effects, particularly prolongation of the QT interval and torsades de pointes, must be considered.(See Uses: Delirium and also see Cautions: Cardiovascular Effects and Cautions: Precautions and Contraindications.) Some evidence suggests that the risk of torsades de pointes increases at total daily dosages of 35-50 mg or more. In patients requiring multiple IV injections of the drug to control delirium (e.g., more than eight 10-mg doses in 24 hours or more than 10 mg/hour for more than 5 consecutive hours), consideration can be given to continuous IV infusion of haloperidol; in such patients, an initial 10-mg dose followed by an infusion of 5-10 mg/hour has been suggested. If agitation persists, repeat 10-mg IV doses at 30-minute intervals, accompanied by a 5 mg/hour increase in the infusion rate, can be considered. ECG should be determined at baseline and periodically or continuously thereafter, with special attention paid to possible prolongation of the QT interval, and dosage should be reduced or the drug discontinued if clinically important QT prolongation (e.g., 15-25% or more over baseline) occurs or the QTc exceeds 450 msec.

Cautions

Haloperidol shares the toxic potentials of phenothiazines, and the usual precautions of phenothiazine therapy should be observed. The overall incidence of adverse effects associated with haloperidol is similar to that associated with piperazine-derivative phenothiazines.

Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of mortality.(See Cautions: Geriatric Precautions.)

Nervous System Effects

The most frequent adverse effects of haloperidol involve the CNS.

Extrapyramidal Reactions

Extrapyramidal reactions occur frequently with haloperidol, especially during the first few days of therapy. In most patients, these reactions consist of parkinsonian symptoms (e.g., marked drowsiness and lethargy, drooling or hypersalivation, fixed stare), which are mild to moderate in severity and are usually reversible following discontinuance of the drug. Other adverse neuromuscular reactions have been reported less frequently, but are often more severe, and include feelings of motor restlessness (i.e., akathisia), tardive dystonia, and dystonic reactions (e.g., hyperreflexia, opisthotonos, oculogyric crisis, torticollis, trismus). Generally, the occurrence and severity of most extrapyramidal reactions are dose related, since they occur at relatively high dosages and disappear or become less severe following a reduction in dosage; however, severe extrapyramidal reactions have reportedly occurred at relatively low dosages. Most patients respond rapidly to treatment with an anticholinergic antiparkinsonian drug (e.g., benztropine, trihexyphenidyl). If persistent extrapyramidal reactions occur, haloperidol therapy may have to be discontinued.

Neuroleptic malignant syndrome (NMS) may occur in patients receiving haloperidol or other antipsychotic therapy. NMS is potentially fatal and requires immediate discontinuance of the drug and initiation of intensive symptomatic and supportive care. For additional information on NMS,

Tardive Dyskinesia

Like other antipsychotic agents (e.g., phenothiazines), haloperidol has been associated with persistent dyskinesias. Tardive dyskinesia may occur in some patients during long-term administration of haloperidol or it may occur following discontinuance of the drug. The risk of developing tardive dyskinesia appears to be greater in geriatric patients receiving high dosages of the drug, especially females. The symptoms are persistent, and in some patients appear to be irreversible. Tardive dyskinesia is characterized by rhythmic involuntary movements of the tongue, face, mouth, or jaw (e.g., protrusion of the tongue, puffing of cheeks, chewing movements, puckering of the mouth), which sometimes may be accompanied by involuntary movements of the extremities and/or trunk. Although not clearly established, the risk of developing the syndrome and the likelihood that it will become irreversible may increase with the duration of therapy and total cumulative dose of antipsychotic agent(s) administered; however, the syndrome may occur, although much less frequently, after relatively short periods of treatment with low dosages. There is no proven or uniformly effective treatment for tardive dyskinesia; antiparkinsonian agents do not alleviate and tend to exacerbate the symptoms of this syndrome. If possible, antipsychotic agents should be discontinued if signs or symptoms of tardive dyskinesia occur. The syndrome may partially or completely remit if antipsychotic agents are discontinued, although some patients may require many months for improvement. Tardive dyskinesia may be masked if therapy is reinstituted, dosage is increased, or therapy with another antipsychotic agent is initiated. The effect that masking of the symptoms may have on the long-term course of the syndrome is not known. Fine vermicular movement of the tongue may be an early sign of the syndrome; prompt discontinuance of haloperidol after this sign occurs may prevent development of the syndrome.

In general, abrupt withdrawal of antipsychotic agents following short-term administration is not associated with adverse effects; however, transient dyskinetic signs have occurred following abrupt withdrawal in patients receiving prolonged maintenance therapy with haloperidol. In some patients, the dyskinetic movements are indistinguishable, except on the basis of their duration, from tardive dyskinesia. It is not known whether gradual withdrawal of antipsychotic agents reduces the incidence of withdrawal-emergent neurologic signs; however, if haloperidol therapy must be discontinued, gradual withdrawal of the drug is recommended, if possible, pending further accumulation of data.

Other Nervous System Effects

Tardive dystonia, not associated with tardive dyskinesia, has occurred in patients receiving haloperidol. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, often is persistent, and potentially can become irreversible.

Other adverse nervous system effects of haloperidol include insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, and tonic-clonic seizures. Exacerbation of psychotic symptoms (including hallucinations and catatonic-like behavior), which may subside following discontinuance of therapy or treatment with anticholinergic agents, has also been reported.

Adverse anticholinergic effects of haloperidol include dry mouth (xerostomia), blurred vision, constipation, urinary retention, and diaphoresis. Priapism has also occurred.

Hematologic Effects

Mild and usually transient leukopenia/neutropenia and leukocytosis have been reported in patients receiving antipsychotic agents, including haloperidol. Agranulocytosis (including fatal cases) has also been reported rarely in patients receiving haloperidol, but only when combined with other drugs. Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia.(See Cautions: Precautions and Contraindications.) Other adverse hematologic effects associated with haloperidol include anemia, minimal decreases in erythrocyte count, and a tendency toward lymphomonocytosis.

Endocrine and Metabolic Effects

Moderate engorgement of the breast with lactation has occurred in some females receiving haloperidol. Galactorrhea, mastalgia, menstrual irregularities, gynecomastia, increased libido, impotence, hyperglycemia, hypoglycemia, and hyponatremia have also occurred in some patients. Antipsychotic agents increase serum prolactin concentrations. (See Cautions: Mutagenicity and Carcinogenicity.) Although not reported to date with haloperidol, the manufacturers caution that decreases in serum cholesterol concentration have occurred in patients receiving chemically related drugs.

Cardiovascular Effects

Tachycardia, hypotension, hypertension, ECG changes (including those compatible with QT-interval prolongation and the polymorphous configuration of torsades de pointes), and sudden death have been reported in patients receiving haloperidol. The US Food and Drug Administration (FDA) states that there have been at least 28 case reports of QT-interval prolongation and torsades de pointes, including some that were fatal, in patients receiving the drug IV. In addition, FDA states that case-control studies have demonstrated a dose-dependent relationship between IV haloperidol dosage and subsequent development of torsades de pointes. A postmarketing analysis of a worldwide safety database revealed 229 reports of QT-interval prolongation and torsades de pointes with oral or parenteral haloperidol; many of these cases were confounded by concomitant administration of drugs known to prolong the QT interval or medical conditions associated with QT-interval prolongation. The reports included 73 cases of torsades de pointes, 11 of which were fatal. In 8 out of 11 fatal cases, haloperidol was administered IV in various dosages. In another postmarketing analysis of adverse cardiovascular events associated with haloperidol decanoate, 13 cases of torsades de pointes, QT-interval prolongation, ventricular arrhythmias, and/or sudden death were identified.

FDA states that it is not possible to estimate the frequency with which QT-interval prolongation or torsades de pointes occurs following administration of haloperidol based on these case reports alone. However, use of higher than recommended doses of any haloperidol formulation and IV administration of the drug appear to be associated with an increased risk of these effects. Many of the reported cases of QT-interval prolongation and torsades de pointes have occurred in patients receiving relatively high dosages of IV haloperidol (e.g., exceeding 35 mg daily); however, such effects also have been reported in patients receiving lower IV dosages or oral therapy. Although cases of sudden death, torsades de pointes, and QT-interval prolongation have been reported even in the absence of predisposing factors, FDA, the manufacturer of Haldol, and some clinicians state that particular caution is advised when using any formulation of haloperidol in patients who have other QT-interval prolonging conditions, including electrolyte imbalance (particularly hypokalemia and hypomagnesemia), underlying cardiac abnormalities, hypothyroidism, or familial long QT syndrome, or those who are concomitantly taking medications known to prolong the QT interval.(See Uses: Delirium, see Cautions: Precautions and Contraindications, and also see Acute Toxicity: Manifestations.) FDA states that clinicians should consider this cardiovascular risk information when making individual treatment decisions for their patients.

Cases of sudden and unexpected death have been reported in haloperidol-treated patients. The nature of the evidence makes it impossible to determine definitively what role, if any, haloperidol played in the outcome of the cases reported to date. Although the possibility that haloperidol played a causative role in these deaths cannot be excluded, it should be kept in mind that sudden and unexpected death may occur in psychotic patients when they remain untreated or when they are treated with other antipsychotic medications.

Other Adverse Effects

Impaired liver function and/or jaundice, maculopapular and acneiform dermatologic reactions, photosensitivity, alopecia, anorexia, diarrhea, hypersalivation, dyspepsia, nausea, vomiting, cataracts, retinopathy, and visual disturbances have also been reported.

Hyperpyrexia and heat stroke, not associated with neuroleptic malignant syndrome (see Extrapyramidal Reactions in Cautions: Nervous System Effects), have been reported in some patients receiving haloperidol.

Laryngospasm, bronchospasm, and increased depth of respiration have occurred in patients receiving haloperidol. Bronchopneumonia, resulting in fatalities in some patients, has occurred following the use of antipsychotic agents, including haloperidol. It has been suggested that lethargy and decreased thirst, resulting from central inhibition, may cause dehydration, hemoconcentration, and reduced pulmonary ventilation.

Hyperammonemia following haloperidol treatment has been reported in at least one child with citrullinemia, an inherited disorder of ammonia excretion.

Precautions and Contraindications

Haloperidol shares the toxic potentials of other antipsychotic agents (e.g., phenothiazines), and the usual precautions associated with therapy with these agents should be observed.

Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of mortality.(See Cautions: Geriatric Precautions.)

Patients should be warned that haloperidol may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Patients also should be warned that haloperidol may enhance their response to alcohol, barbiturates, or other CNS depressants.

Because of the possibility of transient hypotension and/or precipitation of angina, haloperidol should be used with caution in patients with severe cardiovascular disorders. If hypotension occurs, metaraminol, norepinephrine, or phenylephrine may be used; epinephrine should not be used since haloperidol causes a reversal of epinephrine's vasopressor effects and a further lowering of blood pressure.

Since haloperidol may lower the seizure threshold, the drug should be used with caution in patients receiving anticonvulsant agents and in those with a history of seizures or EEG abnormalities. Adequate anticonvulsant therapy should be maintained during administration of haloperidol.

The manufacturers state that haloperidol should be used with caution in patients with known allergies or with a history of allergic reactions to drugs.

When concomitant therapy with an antiparkinsonian drug is necessary to manage haloperidol-induced extrapyramidal symptoms, it may be necessary to continue the antiparkinsonian drug for a period of time after discontinuance of haloperidol in order to prevent emergence of these symptoms.

The manufacturers caution that when haloperidol is used to control mania in patients with bipolar disorder, there may be a rapid mood swing to depression.

Haloperidol should be used with caution in patients with thyrotoxicosis since severe neurotoxicity (e.g., rigidity, inability to walk or talk) may occur in these patients during therapy with an antipsychotic agent.

Cases of leukopenia and neutropenia have been reported in patients receiving antipsychotic agents, including haloperidol; agranulocytosis (including fatal cases) has also been reported.(See Cautions: Hematologic Effects.) Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their complete blood count monitored frequently during the first few months of therapy and haloperidol should be discontinued at the first sign of a decline in the leukocyte count in the absence of other causative factors. Haloperidol-treated patients with neutropenia should be carefully monitored for fever or other signs or symptoms of infection and be treated promptly should such signs and symptoms occur. Patients with severe neutropenia (absolute neutrophil count less than 1000/mm) should discontinue haloperidol and have their leukocyte count followed until recovery.

Care should be taken to avoid skin contact with haloperidol lactate oral solution and injection, since contact dermatitis has occurred rarely.

Cases of sudden death, QT-interval prolongation, and torsades de pointes have been reported in patients receiving haloperidol.(See Uses: Delirium and also see Cautions: Cardiovascular Effects.) Use of higher than recommended doses of any haloperidol formulation and IV administration of the drug appear to be associated with an increased risk of QT-interval prolongation and torsades de pointes. Although these effects have been reported in the absence of predisposing factors, haloperidol should be used with particular caution in patients with other conditions that prolong the QT interval, including electrolyte imbalance (particularly hypokalemia and hypomagnesemia), underlying cardiac abnormalities, hypothyroidism, and familial long QT syndrome, as well as in those concurrently receiving other drugs known to prolong the QT interval. In addition, ECG monitoring is recommended whenever haloperidol is administered IV.(See Uses: Delirium.)

Haloperidol is contraindicated in patients with severe toxic CNS depression or in those who are comatose from any cause. Haloperidol also is contraindicated in patients who are hypersensitive to the drug and in those with parkinsonian syndrome.

Pediatric Precautions

Safety and efficacy of haloperidol decanoate or lactate injection in children have not been established, and safety and efficacy of other haloperidol preparations in children younger than 3 years of age have not been established. Hyperammonemia was reported during postmarketing surveillance in a 5.5-year-old child with citrullinemia, an inherited disorder of ammonia excretion, following haloperidol therapy.

Geriatric Precautions

Clinical studies of haloperidol did not include sufficient numbers of geriatric patients 65 years of age and older to determine whether this age group responds differently from younger adults. Other reported clinical experience has not consistently identified differences in responses between geriatric and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among geriatric patients, particularly elderly women. In addition, the pharmacokinetics of haloperidol generally warrant the use of reduced dosages in geriatric patients.(See Dosage and Administration: Dosage.)

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of mortality. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in those receiving placebo. Although the causes of death were varied in these trials, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Subsequently, 2 observational, epidemiologic studies have indicated that, similar to atypical antipsychotic agents, treatment with conventional antipsychotic agents may increase mortality; the causes of death were not reported in the first study, and cancer and cardiac disease were the causes of death with the highest relative risk in the second study. However, the extent to which these findings of increased mortality in observational studies may be attributed to the antipsychotic agent as opposed to certain patient characteristics remains unclear.

The US Food and Drug Administration (FDA) currently advises clinicians that antipsychotic agents, including haloperidol, are not FDA labeled for the treatment of dementia-related psychosis. The FDA further advises clinicians that no drugs currently are approved for the treatment of dementia-associated psychosis and that other management options should be considered in patients with this disorder. The decision whether to prescribe antipsychotic agents ''off-label'' in the treatment of dementia symptoms is left to the discretion of the clinician. Clinicians who prescribe antipsychotic agents for geriatric patients with dementia-related psychosis should discuss the increased mortality risk with patients, their families, and their caregivers. In addition, patients currently receiving antipsychotic agents for dementia-associated symptoms should not abruptly stop taking the drugs; caregivers and patients should discuss any possible concerns with their clinician. For additional information on the use of antipsychotic agents for dementia-associated psychosis and other behavioral disturbances, , , and also .

Mutagenicity and Carcinogenicity

Haloperidol did not exhibit mutagenic potential in the Ames test. Negative or inconsistent positive findings have been reported in in vitro and in vivo studies on the effects of conventional preparations of haloperidol on chromosome structure and number. However, the available cytogenetic evidence is considered too inconsistent to be conclusive at this time.

Although an increase in mammary neoplasms has been found in rodents following long-term administration of prolactin-stimulating antipsychotic agents, no clinical or epidemiologic studies conducted to date have shown an association between long-term administration of these drugs and mammary tumorigenesis in humans. Current evidence is considered too limited to be conclusive, and further study is needed to determine the clinical importance in most patients of elevated serum prolactin concentrations associated with antipsychotic agents. Since in vitro tests indicate that approximately one-third of human breast cancers are prolactin dependent, haloperidol should be used with caution in patients with previously detected breast cancer.

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in humans, 2 cases of limb malformations (e.g., phocomelia) have occurred in offspring of women who were given haloperidol concurrently with other potentially teratogenic drugs during the first trimester of pregnancy; these teratogenic effects have not been directly attributed to haloperidol. Haloperidol has been shown to be teratogenic and fetotoxic in animals at dosages 2-20 times the usual maximum human dosage.

Neonates exposed to antipsychotic agents, including haloperidol, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported in these neonates to date include agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored. Symptoms were self-limiting in some neonates, but varied in severity; some infants required intensive care unit support and prolonged hospitalization. For further information on extrapyramidal and withdrawal symptoms in neonates, .

Haloperidol should be used during pregnancy or in women likely to become pregnant only when the potential benefits justify the possible risks to the fetus.

Fertility

The effect of haloperidol on fertility in humans is not known. Impotence, increased libido, priapism, and menstrual irregularities have occurred in some individuals during haloperidol therapy.

Lactation

Haloperidol is distributed into milk. The manufacturers warn that nursing should not be undertaken by women receiving haloperidol.

Drug Interactions

CNS Depressants

Haloperidol may be additive with, or may potentiate the action of, other CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol. When haloperidol is used concomitantly with other CNS depressants, caution should be used to avoid excessive sedation.

Lithium

Although most patients receiving lithium and an antipsychotic agent (e.g., haloperidol, phenothiazines) concurrently do not develop unusual adverse effects, an acute encephalopathic syndrome occasionally has occurred, especially when high serum lithium concentrations were present. Patients receiving such combined therapy should be observed for evidence of adverse neurologic effects; treatment should be promptly discontinued if such signs or symptoms appear.

Anticoagulants

Haloperidol has been reported to antagonize the anticoagulant activity of phenindione in one patient. Further study is needed to determine the clinical importance of this interaction.

Rifampin

Concomitant oral therapy with rifampin and haloperidol in schizophrenic patients resulted in a mean 70% decrease in plasma haloperidol concentrations and decreased antipsychotic efficacy. Following discontinuance of rifampin in other schizophrenic patients treated with oral haloperidol, mean haloperidol concentrations increased 3.3-fold. Careful monitoring of clinical status and appropriate dosage adjustment are warranted whenever rifampin is initiated or discontinued in patients stabilized on haloperidol.

Drugs with Anticholinergic Effects

The manufacturers caution that increases in intraocular pressure may occur in patients receiving anticholinergic drugs, including antiparkinsonian agents, concurrently with haloperidol.

Drugs that Prolong QT Interval

Cases of QT-interval prolongation and torsades de pointes have been reported in patients receiving haloperidol. Patients receiving higher than recommended dosages of any haloperidol preparation and those receiving the drug IV appear to be at a higher risk of developing these adverse effects. (See Uses: Deliriumand see also Cautions: Cardiovascular Effects.) Particular caution is advised when oral or parenteral haloperidol is used in patients concurrently receiving other drugs that prolong the QT interval.

Methyldopa

Dementia has reportedly occurred in several patients who received haloperidol and methyldopa concomitantly. Although the clinical importance of this possible interaction has not been determined, patients should be carefully observed for adverse psychiatric symptoms if the drugs are used concurrently.

Pharmacokinetics

Absorption

Haloperidol is well absorbed from the GI tract following oral administration, but appears to undergo first-pass metabolism in the liver. Oral bioavailability of the drug has been reported to average 60%. The drug may undergo some enterohepatic circulation. Peak plasma concentrations of haloperidol occur within 2-6 hours following oral administration. Following IM administration of haloperidol lactate, peak plasma haloperidol concentrations occur within 10-20 minutes and peak pharmacologic action occurs within 30-45 minutes; in acutely agitated patients, control of psychotic manifestations may become apparent within 30-60 minutes, with substantial improvement often occurring within 2-3 hours. Haloperidol concentrations are detectable in plasma for several weeks following administration of a single dose of the drug.

Esterification of haloperidol results in slow and gradual release of haloperidol decanoate from fatty tissues, thus prolonging the duration of action; administration of the ester in a sesame oil vehicle further delays the rate of release. Following IM administration of haloperidol decanoate, plasma haloperidol concentrations are usually evident within 1 day and peak concentrations generally occur within about 6-7 days (range: 1-9 days). Steady-state plasma haloperidol concentrations are usually reached in approximately 3 months following once-monthly IM injection of the decanoate. In one group of patients receiving 20-400 mg monthly, data adjusted to 100-mg monthly doses suggested mean trough plasma haloperidol concentrations of 2 ng/mL after the first dose and of 4 ng/mL at steady state; accumulation during 24 months of therapy was not apparent. Within the usual dosage range, plasma haloperidol concentrations following IM administration of the decanoate are approximately proportional and linearly related to dosage; however, there is considerable interindividual and intraindividual variation in plasma concentrations attained with a given dosage.

Distribution

Distribution of haloperidol into human body tissues and fluids has not been fully characterized. Following administration of haloperidol in animals, the drug is distributed mainly into the liver, with lower concentrations being distributed into the brain, lungs, kidneys, spleen, and heart.

Haloperidol is about 92% bound to plasma proteins.

Haloperidol is distributed into milk.

Elimination

Although the exact metabolic fate has not been clearly established, it appears that haloperidol is principally metabolized in the liver. The drug appears to be metabolized principally by oxidative N-dealkylation of the piperidine nitrogen to form fluorophenylcarbonic acids and piperidine metabolites (which appear to be inactive), and by reduction of the butyrophenone carbonyl to the carbinol, forming hydroxyhaloperidol. Limited data suggest that the reduced metabolite, hydroxyhaloperidol, has some pharmacologic activity, although its activity appears to be less than that of haloperidol. Urinary metabolites in rats include p-fluorophenaceturic acid, β-p-fluorobenzoylpropionic acid, and several unidentified acids.

Haloperidol and its metabolites are excreted slowly in urine and feces. Approximately 40% of a single oral dose of haloperidol is excreted in urine within 5 days. About 15% of an oral dose of the drug is excreted in feces via biliary elimination. Small amounts of the drug are excreted for about 28 days following oral administration.

Following IM administration of haloperidol decanoate, the esterified compound is initially distributed into fatty tissue stores, from which the drug is then slowly and gradually released and subsequently undergoes hydrolysis by plasma and/or tissue esterases to form haloperidol and decanoic acid. Subsequent distribution, metabolism, and excretion of haloperidol appears to be similar to those of orally administered drug. Following IM administration of the decanoate, the drug has an apparent elimination half-life of approximately 3 weeks.

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