HALOPERIDOL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May administer with food to minimize GI irritation.
Oral Liquid Formulations
Oral concentrate solution:
-The concentrate can be administered directly from the calibrated pipette, or the solution can be mixed with a beverage or food prior to administration. However, the concentrate may precipitate if mixed with coffee or tea.
-Avoid skin contact with solution during administration as contact dermatitis may occur.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Verify selection of proper injectable product prior to administration.

Instructions for opening injection ampules:
-Lightly tap the top of the ampule until all of the fluid moves to the bottom of the ampule.
-Hold the ampule between index finger and thumb with colored point (located at the base of the neck of the ampule) facing you.
-Position index finger of the other hand to support the neck of the ampule. Position the thumb so that it covers the colored point and is parallel to the colored ring (located above the colored point).
-Keeping the thumb on the colored point and with the index fingers close together, apply firm pressure on the colored point in the direction of the arrow to snap the ampule open.
Intravenous Administration
IV Push* or Intermittent IV infusion* (haloperidol lactate immediate-release injection solution only):
-IV administration of the lactate injection is not approved by the FDA in any population. Therefore, benefit to risk should be carefully assessed. Higher than recommended doses of any haloperidol formulation and IV administration appear to be associated with a higher risk of QT prolongation and torsade de pointes.
-If haloperidol is administered IV, the ECG should be closely monitored for QT prolongation and arrhythmias.
-SLOW IV push/infusion over several minutes is recommended to decrease the risk of hypotension, oversedation, extrapyramidal effects, and other adverse effects. Slow IV infusion over 30 to 45 minutes has also been reported for loading dose administration.
-Carefully monitor efficacy and tolerability (sedation or other adverse effects) periodically for the first several days. Switch to oral therapy, if needed, as soon as practical.
-When switching parenteral therapy to oral therapy, and depending on the patient's clinical status, the first oral dose should be given within 12-24 hours following the last parenteral dose.

Intramuscular Administration
Haloperidol lactate immediate-release injection solution*:
-NOTE: Haloperidol lactate injection is not FDA-approved for use in children or adolescents for any indication.
-Administer by intramuscular (IM) injection.
-The parenteral dose administered in the preceding 24 hours may be used to approximate the total daily dose required for subsequent parenteral treatment.
-Carefully monitor efficacy and tolerability (sedation or other adverse effects) periodically for the first several days.
-When switching parenteral therapy to oral therapy, and depending on the patient's clinical status, the first oral dose should be given within 12-24 hours following the last parenteral dose.

Haloperidol decanoate depot injection in oil*:
-NOTE: Haloperidol decanoate injection is not FDA-approved for use in children or adolescents for any indication.
-Do NOT administer intravenously. Administer by deep intramuscular (IM) injection ONLY.
-The volume per injection site should not exceed 3 ml.
-A 21 gauge needle is recommended.

Extrapyramidal symptoms (EPS) occur more frequently during treatment with high potency antipsychotics such as haloperidol than low potency antipsychotics such as chlorpromazine and appear to be the result of blockade at the D2-receptor. EPS may be categorized as dystonic reaction, akathisia, or pseudoparkinsonism (e.g., decreased motor activity, resting tremor or pill-rolling, cogwheel rigidity, increased salivation, and postural abnormalities). Dystonic reactions usually occur within the first 24 to 96 hours of treatment, and may manifest as torticollis with or without throat tightness, difficulty swallowing or breathing, oculogyric crisis, or protrusion of the tongue. Risk factors include younger age (especially young males), and the use of large dosages. Dystonia is more likely to occur with high potency than low potency antipsychotics. Akathisia usually develops several days to weeks into therapy. Akathisia may respond to dosage reduction or concomitant administration of a benzodiazepine or a beta-blocker. Pseudoparkinsonism usually occurs 1 to 2 weeks after initiation of antipsychotic therapy. Risk factors for pseudoparkinsonism include increasing age and female gender. For reasons that are unclear, EPS appear to be less common with intravenous administration of haloperidol than with oral or IM administration. EPS, including hyperkinesis (10.2%), tremor (8.1%), hypertonia (7.4%), dystonia (6.7%), and bradykinesia (4.2%), were reported during adult clinical trials for oral haloperidol. Pseudoparkinsonism (30.6%) including cogwheel rigidity and masked facies, oculogyric crisis (5.6%), akinesia (2.8%), akathisia (2.8%), and tremor (2.8%) were reported during adult clinical trials for IM haloperidol. Muscle twitching, akathisia, dyskinesia, dystonic reaction (e.g., oculogyric crisis, torticollis, trismus), hypertonia, nystagmus, and pseudoparkinsonism (e.g., cogwheel rigidity, masked facies, muscle rigidity, hypokinesis) have been reported in adult patients receiving oral or injectable haloperidol during clinical trials. Opisthotonus and tardive dystonia have been reported with postmarketing use. Reversible extrapyramidal symptoms (e.g., hypertonia, tremor) have been reported after delivery in neonates exposed to antipsychotics during the third trimester. These effects have varied in severity ranging from self-limited to requiring intensive care unit stays and prolonged hospitalization.

Clinical trial data and postmarketing reports indicate that leukopenia, neutropenia, eosinophilia, anemia (e.g., hemolytic anemia, aplastic anemia), thrombocytopenia, thrombocytopenic purpura, pancytopenia, and agranulocytosis have occurred during the use of antipsychotic agents. Hematologic disturbances that have been reported after haloperidol administration include mild and usually transient leukopenia or leukocytosis, tendency toward lymphomonocytosis, minimal decreases in red blood cell counts, and anemia. Agranulocytosis has occurred rarely and was associated with concomitant treatment. Monitor complete blood count (CBC) frequently during the first few months of therapy in patients with a history of drug-induced leukopenia or neutropenia or clinically significant low white blood cell (WBC) count. Discontinue treatment if a clinically significant decline in WBC occurs in the absence of an identifiable cause. Carefully monitor patients with clinically significant neutropenia for fever and other signs of infection; treat promptly if such signs and symptoms occur. Discontinue haloperidol in patients with severe neutropenia (ANC less than 1,000/mm3) and follow the patient's WBC until recovery.

Neuroleptic malignant syndrome (NMS) has been reported during adult clinical trials of haloperidol. NMS is characterized by hyperpyrexia, severe extrapyramidal dysfunction, alterations in consciousness, altered mental status, and autonomic instability. Increased serum creatine phosphokinase (CPK), acute renal failure, and myoglobinuria (rhabdomyolysis) may also occur. NMS does not appear to be dose-related. Severe cases can result in death, which usually occurs 3 to 30 days after onset of the syndrome. Several predisposing factors can contribute to the development of NMS including heat stress, physical exhaustion, dehydration, organic brain disease, and use of the long-acting depot formulation. NMS occurs more frequently in young men. Haloperidol should be immediately discontinued and appropriate supportive therapy initiated as soon as symptoms of NMS are discovered. Hyperpyrexia, heat intolerance, and heat stroke, not associated with NMS, have also been reported with haloperidol. Rhabdomyolysis has been reported during postmarketing use of haloperidol, although incidence and causality have not been established.

Tardive dyskinesia (TD) can develop during long-term therapy or after discontinuation of haloperidol. TD is characterized by involuntary movements of the perioral region (tongue, mouth, jaw, eyelids, or face) or choreoathetoid movements in the extremities. The incidence of TD may be higher in patients with bipolar disorder than with schizophrenia. Some cases are irreversible. While contradictory evidence exists, it has been suggested that the likelihood of developing TD increases with prolonged treatment and cumulative doses. Although TD also has been reported to occur after short periods of time and with low dosages. If signs or symptoms of TD develop, haloperidol use should be reevaluated and possibly discontinued. Fine vermicular movement of the tongue may be an early sign of TD and discontinuation of haloperidol at that time may prevent advancement to the full syndrome. A tardive dystonia can also develop during therapy with haloperidol, and is unrelated to tardive dyskinesia. This dystonia is characterized by a delayed onset of choreic or dystonic movements. It can be persistent and potentially irreversible. Occasionally, haloperidol will need to be discontinued and an alternate antipsychotic used. Routine (at 3- to 6-month intervals) monitoring for movement disorders is considered standard practice when using antipsychotics.

Drowsiness is a CNS effect that can occur during initial treatment with haloperidol; however, drowsiness is less likely to occur with high potency antipsychotics such as haloperidol than low potency antipsychotics such as chlorpromazine. Tolerance usually develops with continued therapy. Somnolence (5.3% or less), headache (2.8%), dizziness, sedation, and restlessness were reported during adult clinical trials. Agitation, confusion, depression, and insomnia have been reported with postmarketing use. Other reported CNS effects include anxiety, euphoria, lethargy, vertigo, exacerbation of psychotic symptoms including hallucinations and catatonic-like behavioral states, and seizures. Seizures are of special significance in patients who have preexisting seizure disorders or EEG abnormalities. Because drowsiness is a possible side effect of haloperidol, advise patients to use caution when engaging in activities or tasks that require mental alertness until they know how the drug affects them.

Central dopamine blockade by antipsychotics can lead to elevations in prolactin levels (e.g., hyperprolactinemia), which can affect reproductive or sexual functioning. Increased levels of prolactin can cause galactorrhea, gynecomastia, menstrual irregularity, infertility (e.g., anovulation in females), and sexual dysfunction. Amenorrhea, galactorrhea, dysmenorrhea, menorrhagia, and breast discomfort (mastalgia) have been reported in adult patients during clinical trials. Priapism, urinary retention, and gynecomastia have been reported with postmarketing use. Chronic hyperprolactinemia may result in loss of bone density (osteopenia) in both males and females. Evidence is limited as to the possible connection between increased serum prolactin and breast cancer.

Haloperidol has been associated with adverse ocular effects including cataracts, retinopathy (unspecified), blurred vision, and other types of visual impairment. Pigmentary retinopathy (retinal pigment changes with or without pigmentary changes in the skin) has occurred during therapy with other antipsychotics such as phenothiazines. Due to the potential for serious ocular effects, investigate symptoms of blurred vision, difficulty with nighttime vision, or defective color vision promptly in patients receiving haloperidol.

Constipation (4.2% or less), abdominal pain (2.8%), xerostomia (1.8% or less), hypersalivation (1.2% or less), and weight gain have been reported during adult clinical trials of haloperidol. Nausea, vomiting, and weight loss have been reported with postmarketing use. Some GI effects, such as xerostomia and constipation, are generally due to the anticholinergic effects of antipsychotics. Impaired liver function, including cases of acute hepatic failure, hepatitis, cholestasis, jaundice, and elevated hepatic enzymes have also been reported. Weight gain is considered a class effect of antipsychotics and can be significant. In some cases, weight gain may be associated with antipsychotic-induced increases in prolactin levels or H-1 antagonism. In one safety and efficacy study, 22.7% of haloperidol-treated patients experienced a weight gain of at least 7% of baseline body weight compared to 61.5% of olanzapine-treated patients. Dysphagia, with possible aspiration of gastric contents, can occur during antipsychotic use. This adverse effect may increase the incidence of aspiration pneumonia in certain patient populations. Monitor patients with dysphagia or who are at risk for aspiration closely while receiving haloperidol.

As with all injectable medications, an injection site reaction can occur after administration of injectable haloperidol formulations. Local tissue reactions may include symptoms such as injection site pain, swelling, redness, and/or induration. Injection site abscess has been reported with postmarketing use of haloperidol depot injections. The adverse effect data for use of long-acting injectable antipsychotic agents, including depot haloperidol injections, are not extensive in pediatric patients due to off-label use.

Hypersensitivity reactions have been reported during haloperidol administration including anaphylactoid reactions, angioedema, exfoliative dermatitis, hypersensitivity vasculitis, rash, urticaria, facial edema, laryngeal edema, laryngospasm, and bronchospasm. Several cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including haloperidol. Bronchopneumonia may result from dehydration, hemoconcentration, and reduced pulmonary ventilation secondary to decreased thirst and/or lethargy due to CNS depression.

Blockade of alpha-1-adrenergic receptors by antipsychotics may produce cardiovascular effects such as hypotension, sinus tachycardia, and changes in ECG patterns. Hypotension, orthostatic hypotension, and sinus tachycardia have been reported in adult patients during clinical trials. Edema, ventricular fibrillation, QT prolongation, torsade de pointes (TdP), ventricular tachycardia, extrasystoles, and sudden death have been reported with postmarketing use. According to the FDA, at least 28 cases of QT prolongation and TdP have been documented. Higher than recommended doses of any formulation and intravenous (IV) administration appear to be associated with an increased risk of QT prolongation and TdP. Although predisposed patients may be at higher risk, cases have been reported in patients without risk factors. Haloperidol lactate injection is not FDA-approved for IV administration; if IV use is required, monitor the ECG for QT prolongation and arrhythmias. Haloperidol decanoate should not be administered intravenously.

Hyperglycemia and hypoglycemia have been reported during haloperidol administration, although the frequencies are unknown. Hyperglycemia and diabetes mellitus, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with antipsychotics. Consider the possibility of impaired glucose tolerance in patients receiving haloperidol who develop symptoms of hyperglycemia or diabetes, such as excess thirst, polyuria, polyphagia, and weakness. Consider discontinuation of haloperidol therapy if symptoms are severe. Other laboratory abnormalities that have been reported include one postmarketing case of hyperammonemia in a child with citrullinemia.

Thirst and polydipsia have been reported during treatment with antipsychotics. Polydipsia may be psychogenic in nature or a result of antipsychotic-induced metabolic complications such as diabetes; therefore, careful evaluation is recommended. Hyponatremia can develop from polydipsia with can progress to water intoxication, with symptoms such as confusion, lethargy, psychosis, and in severe cases, seizures or death. Some data suggest antipsychotic-induced hyponatremia is most likely the result of syndrome of inappropriate antidiuretic hormone (SIADH). SIADH has been reported with postmarketing haloperidol use.

If possible, avoid abrupt discontinuation of haloperidol. Some patients on maintenance therapy have transient dyskinetic symptoms after abrupt withdrawal of immediate-release formulations. These symptoms resemble tardive dyskinesia but are not prolonged. It has not been determined if gradual withdrawal of haloperidol will eliminate this possibility, but it is reasonable to gradually taper haloperidol when possible. Other discontinuation symptoms of antipsychotics have included nausea, vomiting, anorexia, excessive sweating, headache, insomnia, restlessness, anxiety, and agitation. A neonatal abstinence syndrome has been reported in neonates postmarketing after the use of haloperidol in pregnant women.

Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving haloperidol should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, or dehydration). A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. Thermoregulation is multi-factorial; however, the dopaminergic system appears to have a primary role, and serotonin may also have modulatory activity (5-HT2a receptors). Most cases of hypothermia associated with antipsychotics have occurred in conjunction with other potential precipitating factors such as hypothyroidism, sepsis, organic brain injury, or environmental temperature. Hypothermia appears to occur more frequently during initiation of antipsychotic therapy or after dose increases.

Acneiform rash, maculopapular rash, alopecia, diaphoresis, and photosensitivity have been reported in patients receiving oral or injectable haloperidol. Although photosensitivity is rare, it is advisable to caution patients about sun exposure and the use of sunscreen. Skin hyperpigmentation has occurred after prolonged therapy with phenothiazine antipsychotics; changes in skin pigmentation are generally restricted to areas of the body exposed to sunlight. Discontinuation of the drug can reverse the effects, and the clinician needs to decide whether therapy should be continued if pigmentary changes occur. Contact dermatitis has occurred when some antipsychotic liquids remain on the skin; precautions to avoid contact should be taken, and any inadvertent spillage should be washed off immediately.

The American Psychiatric Association does not recommend the maintenance use of antipsychotic medications, such as haloperidol, as first-line therapy for children and adolescents with any diagnosis other than psychotic disorders. Routine use in clinical circumstances that are not endorsed by available clinical practice guidelines or FDA-approval should be questioned. Antipsychotics may be unnecessary when they are prescribed without a comprehensive assessment, accurate diagnosis, and initial trial of non-pharmacologic interventions (e.g., family-based, behavioral and environmental interventions). For some young patients, the use of antipsychotic medication may be an appropriate choice if the clinical benefits are judged to outweigh any potential harm (e.g., weight gain, metabolic or cardiovascular adverse reactions). Antipsychotics should not be prescribed for any indication without appropriate initial evaluation and ongoing monitoring. Routine use of multiple concurrent antipsychotics is discouraged.

Haloperidol use is contraindicated in anyone with a known hypersensitivity to the drug or components of the drug product. Hypersensitivity reactions have included anaphylactic reactions and angioedema.

Various adverse cardiovascular effects have been associated with haloperidol administration such as transient hypotension, precipitation of angina, QT prolongation, torsade de pointes (TdP), and sudden death. Haloperidol decanoate IM injection, which is formulated in sesame oil, should NEVER be given by intravenous administration. Haloperidol lactate injection solution is not FDA approved for intravenous (IV) administration; however, clinically, haloperidol lactate has been used IV for control of acute agitation or related behavioral symptoms, particularly in the intensive care setting. According to the FDA, at least 28 cases of QT prolongation and torsade de pointes (TdP) have been documented in the medical literature. These events appear to be dose-related and have frequently occurred in association with higher than recommended dosages or during IV administration; fatalities have been reported in some cases. Due to the severity of these cardiac events, ECG monitoring is recommended during IV administration. Haloperidol administration has also been associated with transient hypotension and precipitation of angina; use caution in patients with preexisting hypotension or angina. Antipsychotics may cause orthostatic hypotension, which could lead to falls with the potential for fractures and other injuries. Complete a fall risk assessment upon antipsychotic initiation in patients with conditions, diseases, or taking concurrent medications that could exacerbate orthostasis and recurrently during long-term therapy in at-risk patients. Use haloperidol with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, abnormally low body temperature, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Haloperidol should be used with caution in patients with hematological disease. Hematologic effects including leukopenia, neutropenia, and agranulocytosis have been associated with antipsychotic use. A history of drug-induced leukopenia or neutropenia or pre-existing low white blood cell (WBC) count may increase the likelihood of developing hematologic effects during treatment with an antipsychotic medication. Patients with a history of clinically significant low WBC count or drug-induced leukopenia/neutropenia should have frequent complete blood count (CBC) assessments during the first few months of treatment. Discontinuation of the antipsychotic should be considered if a clinically significant decline in WBC occurs in the absence of an identifiable cause. Patients with clinically significant neutropenia should be closely monitored for fever and infection, and appropriate medical intervention should be instituted if necessary. Haloperidol should be discontinued in patients with severe neutropenia (ANC less than 1,000/mm3); ongoing medical care is recommended until the symptoms resolve.

Because haloperidol can cause CNS depression, it is contraindicated in patients who are in a coma or who exhibit severe CNS depression. Severe adverse CNS reactions induced by haloperidol may appear similar to neurologic symptoms of CNS disorders such as encephalitis, Reye's syndrome, encephalopathy, meningitis, and tetanus.

Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotics. Regular evaluation for movement disorders is recommended (e.g., AIMS, DISCUS). Factors associated with a greater susceptibility to tardive dyskinesia include an age above 55 years, female gender, white or African ethnicity, presence of a mood disorder, intellectual disability, CNS injury, prior or current akathisia, significant parkinsonism, or acute dystonic reaction. The rate of tardive dyskinesia in adults treated with a first generation antipsychotic appears to be at least 3 times that observed with second generation antipsychotics. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotics administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief periods at low doses or may arise after drug discontinuation. Antipsychotics may suppress the signs and symptoms of tardive dyskinesia and thereby mask the underlying process; however, the syndrome may also remit partially or completely if the antipsychotic is withdrawn. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. If signs and symptoms of tardive dyskinesia appear, haloperidol discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

Antipsychotics can cause motor instability, which may lead to falls with the potential for fractures and other injuries. Complete a fall risk assessment when initiating an antipsychotic in patients with diseases (e.g., neurological disease), conditions, or concurrent medication use that could exacerbate motor and sensory instability. A fall risk assessment is also recommended recurrently in at-risk patients on long-term antipsychotic therapy. Haloperidol is contraindicated in patients with Parkinson's disease or dementia with Lewy bodies; these patients have an increased sensitivity to antipsychotic medication. Manifestations of such increased sensitivity may include severe extrapyramidal symptoms, confusion, sedation, and falls. Additionally, haloperidol may impair the antiparkinson effects of levodopa and other dopamine agonists. Parkinson's disease is very rare in pediatric patients; when it does occur, there is usually a family history of the illness.

Haloperidol can impair cognitive and motor skills. Pediatric patients and their caregivers should be informed about the potential hazards involved with the patient participating in activities requiring coordination and concentration, such as driving or operating machinery, during use of haloperidol. Somnolence, orthostatic hypotension, and motor and sensory instability have also been reported with the use of antipsychotics; such effects may lead to falls and related injuries. Assess the risk of falls during treatment initiation and periodically throughout therapy in patients with diseases, conditions, or concurrent medications that could exacerbate these effects. Given the primary CNS effects of haloperidol, caution should be used during coadministration with other CNS depressants and alcohol. Ethanol ingestion may further impair cognitive and motor skills and patients should be advised to avoid use of alcoholic beverages.

Patients with a seizure disorder, history of seizures, or electroencephalogram (EEG) abnormalities should be monitored carefully during therapy with haloperidol because antipsychotics can lower the seizure threshold. High doses and rapid dose changes should be avoided in patients with a known history of seizures.

Pediatric patients with dysphagia or who are at risk for aspiration should be closely monitored while receiving haloperidol. Antipsychotics have been associated with esophageal dysmotility and aspiration of gastric contents, which may increase the incidence of aspiration pneumonia in susceptible patient populations.

Monitor patients with pre-existing pulmonary disease closely when haloperidol is used. Several cases of pneumonia, some fatal, have followed the use of antipsychotic drugs, including haloperidol. It has been theorized that lethargy and decreased sensation of thirst due to central inhibition may lead to a dehydrated state, hemoconcentration, and reduced pulmonary ventilation. If signs and symptoms of pneumonia develop, an evaluation should be promptly initiated.

Use haloperidol with caution in patients with hepatic disease. Haloperidol concentrations may increase in patients with hepatic impairment because it is primarily metabolized in the liver and protein binding may decrease. Lower initial doses and slower titration are advisable; however, specific guidelines are not available.

Although not reported with haloperidol, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs. The anticholinergic effects of haloperidol are minimal; however, concomitant use of anticholinergic drugs (e.g., benztropine) to treat extrapyramidal symptoms may increase the likelihood of increased intraocular pressure.

The anticholinergic effects of haloperidol are minimal. However, haloperidol has been reported to cause urinary retention, which may be more likely to occur in susceptible individuals. Co-use of an anticholinergic medication (e.g., benztropine) to treat extrapyramidal symptoms with haloperidol may increase the risk for urinary retention.

Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are receiving an antipsychotic agent such as haloperidol.

Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving haloperidol should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, dehydration). A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. Thermoregulation is multi-factorial; however, the dopaminergic system appears to have a primary role, and serotonin may also have modulatory activity (5-HT2a receptors). Most cases of hypothermia associated with antipsychotics have occurred in conjunction with other potential precipitating factors such as hypothyroidism, sepsis, organic brain injury, or environmental temperature. Hypothermia appears to occur more frequently during initiation of antipsychotic therapy or after dose increases. Of note, hypothermia may increase the risk of prolonging the QT interval.

Haloperidol can cause hyperprolactinemia, likely due to central dopamine (D2) receptor antagonism. Elevations in prolactin may result in endocrine abnormalities in pediatric patients, including changes in menstruation in females or breast enlargement in males. Close monitoring for adverse endocrine effects is advisable during use of haloperidol in pediatric patients. Some human breast cancers may be prolactin-dependent and therefore haloperidol should be used cautiously in those who have a history of breast cancer; however, breast cancer in pediatric patients (male or female) is extremely rare.

Tobacco smoke contains polycyclic aromatic hydrocarbons that induce hepatic cytochrome P450 (CYP450) microsomal enzymes. There is some evidence to suggest that tobacco smoking accelerates the metabolism of haloperidol. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, the sudden cessation of tobacco smoking may result in a reduced clearance of haloperidol, despite the initiation of a nicotine replacement product. Monitor patients carefully when changes in smoking status occur.

In general, short-term antipsychotic therapy is not associated with symptoms related to abrupt discontinuation; however, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In some cases, the dyskinetic movements are not distinguishable from tardive dyskinesia except for duration. Other discontinuation symptoms of antipsychotics include nausea, vomiting, anorexia, diaphoresis, headache, insomnia, restlessness, anxiety, and agitation. It is not known if a gradual taper reduces the rate of withdrawal-emergent neurological signs, but until further evidence becomes available, it is reasonable to gradually withdraw haloperidol when clinically feasible. Carefully observe patients for symptom exacerbation and dyskinetic movements after drug discontinuation.

Neonates with in utero exposure to antipsychotics in the third trimester have experienced adverse events such as extrapyramidal effects, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder. These effects have varied in severity ranging from self-limited to requiring intensive care unit stays and prolonged hospitalization. In addition, there are reports of limb malformations in neonates following maternal use of haloperidol in combination with other drugs which have suspected teratogenic potential during the first trimester of pregnancy.

Description: Haloperidol is a high-potency conventional antipsychotic that is structurally related to droperidol. Oral haloperidol is indicated in patients 3 years and older for the treatment of schizophrenia, severe behavioral problems associated with oppositional defiant disorder or other disruptive behavioral disorders, attention-deficit hyperactivity disorder (ADHD) in patients who show excessive motor activity with accompanying conduct disorders, and to treat tics and vocal utterances of Tourette's syndrome. The American Academy of Neurology practice guideline states that haloperidol is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; however, there is insufficient evidence to determine the efficacy of haloperidol relative to other antipsychotics used to treat tics. Oral haloperidol has been used off label to treat irritability associated with autistic disorder; however, due to the risk of extrapyramidal effects, haloperidol is generally reserved for children who have not responded to or are intolerant to atypical antipsychotics. Haloperidol immediate-release injection is used off-label in children and adolescents for delirium and agitation in select scenarios. However, IV administration of haloperidol lactate injectable solution is not FDA-approved and IV use is associated with an increased risk of QT prolongation and torsade de pointes (TdP); ECG monitoring is recommended if the drug is used by this route. The safety and efficacy of haloperidol decanoate depot injection have not been established in pediatric patients. Compared to low potency conventional antipsychotics, high potency conventional agents have a higher risk of extrapyramidal symptoms and a lower risk of anticholinergic effects, sedation, and orthostatic hypotension. Due to the adverse effect profile of conventional antipsychotics, atypical antipsychotics have become the drugs of choice for treating most pediatric disorders requiring an antipsychotic. As with all antipsychotics, periodic evaluation for new or worsening tardive dyskinesia is highly recommended.

For the treatment of schizophrenia:
Oral dosage:
Children less than 3 years and Children weighing less than 15 kg: Safety and efficacy have not been established.
Children 3 to 12 years and weighing 15 to 40 kg: 0.5 mg/day PO initially; may administer in 2 or 3 divided doses. If clinically warranted, the dose may be increased by 0.5 mg increments at 5 to 7 day intervals until the desired therapeutic effect is obtained. The usual dose range is 0.05 to 0.15 mg/kg/day PO; severe cases may require higher doses. A maximum effective dose has not been established; however, there is little evidence that behavior improvement is further enhanced with dosages above 6 mg/day PO. After a therapeutic response is achieved, the dosage should be slowly reduced to the lowest effective maintenance dose.
Adolescents: 0.5 to 5 mg/day PO; may administer in 2 or 3 divided doses. Although a pediatric dose for children and adolescents weighing more than 40 kg is not specified, FDA-approved labeling recommends 0.5 to 2 mg PO 2 to 3 times per day as an initial dose for adult patients with moderate symptomatology, or 3 to 5 mg PO 2 to 3 times per day for adult patients with severe, chronic, or treatment-resistant symptoms. Higher doses may be required in some cases to achieve prompt control. Patients who remain severely disturbed or inadequately controlled may require dosage adjustment. Adult Max: 100 mg/day for severe refractory cases. After a therapeutic response is achieved, the dosage should be slowly reduced to the lowest effective maintenance dose.

For the treatment of tics and vocal utterances associated with Tourette's syndrome or chronic tic disorders*:
Oral dosage:
Children 3 to 12 years and weighing 15 to 40 kg: 0.25 to 0.5 mg/day PO initially, slowly titrated by 0.25 to 0.5 mg increments at 5 to 7 day intervals until the desired therapeutic effect is obtained. The daily dosage may be given in 2 or 3 divided doses. FDA approved labeling states the usual dose range is 0.05 to 0.075 mg/kg/day PO; this coincides closely with the usual dose range of 1 to 4 mg/day PO that clinical guidelines suggest. Max: 15 mg/day PO. After a therapeutic response is achieved, gradually reduce to the lowest effective maintenance dose. The American Academy of Neurology practice guideline states that haloperidol is probably more likely than placebo to reduce tic severity; however, there is insufficient evidence to determine the efficacy of haloperidol relative to other antipsychotics used to treat tics.
Adolescents: 0.25 to 0.5 mg/day PO initially, slowly titrated by 0.25 to 0.5 mg increments at 5 to 7 day intervals until the desired therapeutic effect is obtained. The daily dosage may be given in 2 or 3 divided doses. Clinical guidelines suggest a usual dosage range of 1 to 4 mg/day PO. Max for those 40 kg or less: 15 mg/day PO. Although a dose for adolescents more than 40 kg is not specified, FDA-approved labeling recommends 0.5 to 2 mg PO 2 to 3 times per day as an initial dose for adults with moderate symptomatology, or 3 to 5 mg PO 2 to 3 times per day for adults with severe, chronic, or treatment-resistant symptoms. After a therapeutic response is achieved, gradually reduce to the lowest effective maintenance dose. The American Academy of Neurology practice guideline states that haloperidol is probably more likely than placebo to reduce tic severity; however, there is insufficient evidence to determine the efficacy of haloperidol relative to other antipsychotics used to treat tics.

For the treatment of severe behavioral problems associated with oppositional defiant disorder or other disruptive behavioral disorders, or for the treatment of attention-deficit hyperactivity disorder (ADHD) in pediatric patients who show excessive motor activity with accompanying conduct disorders:
Oral dosage:
Children less than 3 years and Children weighing less than 15 kg: Safety and efficacy have not been established.
Children 3 to 12 years and weighing 15 to 40 kg: 0.5 mg/day PO initially; may administer in 2 or 3 divided doses. If clinically warranted, the dose may be increased by 0.5 mg increments at 5 to 7 day intervals until the desired therapeutic effect is obtained. The usual dose range is 0.05 to 0.075 mg/kg/day PO. A maximum effective dose has not been established; however, there is little evidence that behavior improvement is further enhanced with dosages above 6 mg/day PO. Patients should be assessed periodically to determine the need for continued therapy; short-term treatment may be sufficient in some patients.

For the treatment of irritability associated with autistic disorder*:
Oral dosage:
Children less than 3 years*: Safety and efficacy have not been established.
Children* and Adolescents* 3 years and older: Data are limited. In one small study of children 10 years of age and older, haloperidol was initiated at 0.25 mg/day PO at bedtime and titrated over 1 week to 0.5 mg PO twice daily. Thereafter, the dose was adjusted as clinically indicated. The mean daily dose was 1.3 mg and the range was 1 to 1.5 mg/day PO. In a separate study enrolling children 2.6 to 7.2 years of age, the optimal dose was 1.7 mg/day PO. Haloperidol was associated with significant improvement in withdrawal and stereotypy in children 4.5 years and older. Data from clinical trials assessing dyskinesias in young children (2 to 8 years of age) receiving long-term treatment (e.g., 6 months) with haloperidol indicate that tardive dyskinesia or withdrawal dyskinesias have occurred in approximately 20% to 34% of patients. The majority of cases have been withdrawal dyskinesias which were reversible. Due to the risk of extrapyramidal effects, haloperidol is generally reserved for children who have not responded to or are intolerant to therapy with an atypical antipsychotic.

For the treatment of delirium* in the pediatric intensive care unit (PICU):
Intravenous dosage*:
Children and Adolescents: Limited data available, particularly in young children. A loading dose of 0.15 to 0.25 mg IV given slowly over 30 to 45 minutes, followed by a maintenance dose of 0.05 to 0.5 mg/kg/24 hours IV (divided and given every 8 hours) has been described in several case reports/series (n = 39; age range: 3 months to 17 years). One small case series (n = 6; age range: 9 to 15 years) reported no loading dose but a modal individual maintenance dose of 0.5 mg IV. Maximum dose is unclear in pediatric patients. Do not exceed 20 mg/day, the FDA-approved maximum parenteral dose in adults. Treatment of delirium often consisted of psychosocial, environmental, and, if warranted, pharmaceutical intervention. In general, IV haloperidol was reserved for patients with psychomotor agitation that was acutely threatening to their health. Pharmaceutical intervention lasted from a few hours to days and, in most cases, was stopped or tapered off during hospitalization or subsequently in an outpatient setting. Discontinue pharmacotherapy as soon as the acute phase of delirium has resolved. Haloperidol lactate injection is not FDA-approved for intravenous (IV) administration. Cases of QT prolongation and torsade de pointes (TdP) have occurred, including fatalities, during IV use. ECG monitoring is recommended during IV administration.

For the treatment of acute agitation*:
Intramuscular dosage (haloperidol lactate):
Children and Adolescents weighing 15 to 40 kg: 0.025 to 0.075 mg/kg/dose (Usual dose: 0.5 to 2 mg/dose) IM every 20 to 30 minutes as needed. Consider one-fourth to one-half of the usual daily dose if the child is currently taking haloperidol and it is not the usual dose time. Max: 6 mg/day.
Children and Adolescents weighing more than 40 kg: 0.025 to 0.075 mg/kg/dose (Usual dose: 2 to 5 mg/dose) IM every 20 to 30 minutes as needed. Consider one-fourth to one-half of the usual daily dose if the child is currently taking haloperidol and it is not the usual dose time. Max: 15 mg/day.
Oral dosage:
Children and Adolescents weighing 15 to 40 kg: 0.025 to 0.075 mg/kg/dose (Usual dose: 0.5 to 2 mg/dose) PO every hour as needed. Consider one-fourth to one-half of the usual daily dose if the child is currently taking haloperidol and it is not the usual dose time. Max: 6 mg/day.
Children and Adolescents weighing more than 40 kg: 0.025 to 0.075 mg/kg/dose (Usual dose: 2 to 5 mg/dose) PO every hour as needed. Consider one-fourth to one-half of the usual daily dose if the child is currently taking haloperidol and it is not the usual dose time. Max: 15 mg/day.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 2 years or weighing less than 15 kg: Safety and efficacy have not been established.
3 to 12 years and weighing 15 to 40 kg: 0.15 mg/kg/day PO for most indications; severely psychotic children may require higher doses (suggested Max: 6 mg/day PO for non-psychotic behaviors); 15 mg/day PO for Tourette's syndrome; safe and effective use of haloperidol injections has not been established (adult haloperidol lactate Max: 20 mg/day IM).
-Adolescents
Weighing 40 kg or less: 0.15 mg/kg/day PO for most indications; severely psychotic patients may require higher doses (suggested Max: 6 mg/day PO for non-psychotic behaviors); 15 mg/day PO for Tourette's syndrome; safe and effective use of haloperidol injections has not been established (adult haloperidol lactate Max: 20 mg/day IM).
Weighing more than 40 kg: 15 mg/day PO for Tourette's syndrome; there is no stated maximum dosage for adolescents with other indications; dosages more than 15 mg/day PO are rarely needed in adults but severely disturbed psychotic adults may require higher dosages; adult dosages up to 100 mg/day PO have been used in severe refractory cases; safe and effective use of haloperidol injections has not been established (adult haloperidol lactate Max: 20 mg/day IM).

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; however, reduced dosages or avoidance is advisable in patients with significant hepatic impairment. Haloperidol is extensively metabolized in the liver.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: The precise mechanism of haloperidol, a conventional antipsychotic, is unknown; however, the therapeutic effect in treating the positive symptoms of schizophrenia (e.g., hallucinations, delusions) is thought to occur from blockade of central postsynaptic dopamine (D2) receptors in the mesolimbic pathway. By antagonizing dopamine in all areas of the brain, conventional antipsychotics are effective for treating the positive symptoms of schizophrenia, but can cause a variety of adverse effects. In addition, therapeutic effects on the negative symptoms (e.g., social withdrawal, blunted affect) and cognitive symptoms of schizophrenia relate to increased dopamine activity in the prefrontal cortex which may, in part, account for the general lack of improvement in these symptoms observed with D2 blockers such as conventional agents. Antipsychotics appear to have neuroplastic effects, including synaptic plasticity (remodeling of synapses and development of new neuron connections) and neurogenesis (new neuron development), which may partially explain the delay in some therapeutic effects of antipsychotics. Induction of synaptic plasticity has been well-documented with haloperidol in the striatum, where the highest concentration of D2 receptors exist.

In the nigrostriatal pathway, antipsychotic-induced dopamine blockade can lead to pseudoparkinsonism and other extrapyramidal symptoms (e.g., dystonic reactions, akathisia). Dopamine receptor blockade in the tuberoinfundibular tract results in prolactin release, which can lead to adverse effects related to hyperprolactinemia such as weight gain and menstrual irregularity. Haloperidol has a negligible affinity for muscarinic receptors, resulting in only weak anticholinergic effects. Haloperidol also has a weak affinity for alpha1 and H1 receptors, minimizing the likelihood of orthostatic hypotension, dizziness, reflex tachycardia, and sedation compared to many other antipsychotics.

Pharmacokinetics: Haloperidol is administered orally, intramuscularly, and intravenously (immediate-release lactate injection only). Of note, injectable formulations are not FDA-approved for intravenous administration; if the immediate-release lactate injection is administered intravenously, the ECG should be monitored for QT prolongation and arrhythmias. Haloperidol is approximately 90% plasma protein-bound but distributes freely into various tissues, particularly the globus pallidus. Apparent volume of distribution is 9.5 to 21.7 L/kg, or 1,260 L for body weight between 56 to 92 kg. Haloperidol is metabolized by several routes, including glucuronidation. Extensive metabolism to inactive metabolites occurs in the liver through N-dealkylation via CYP3A4 (primary) and CYP2D6. Reduction to hydroxyhaloperidol, an active metabolite, also occurs. About 30% of a dose of haloperidol is excreted renally, with 1% appearing as unchanged drug. Approximately 15% is eliminated through biliary excretion. The elimination half-life for immediate-release products ranges between 12 to 37 hours (reported average: 16 hours) in adult patients.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, and CYP1A2 (minor)
CYP2D6 and CYP3A4 are the primary CYP isoenzymes involved in the metabolism of haloperidol, although limited data suggest that CYP1A2 may also play a role. Inhibition of one or more of these metabolic pathways may result in increased haloperidol concentrations and the potential for QT prolongation. Mild to moderate increases in haloperidol concentrations have been reported during concomitant use of haloperidol and substrates or inhibitors of CYP3A4 or CYP2D6. Significant reductions in haloperidol concentrations have occurred with the use of some enzyme-inducing drugs and tobacco. In addition to the concern of drug-drug interactions, slow metabolizers of CYP2D6 appear to be at increased risk of experiencing extrapyramidal symptoms and other adverse events due to delayed clearance of the drug. The impact of haloperidol on CYP2D6 and CYP3A4 is unclear. Some pharmacokinetic data suggest that haloperidol may inhibit CYP2D6 and CYP3A4; however, other data suggest that the risk of clinically significant inhibition is low. Because the strength of inhibition is not clear, use caution when co-administering haloperidol with drugs that are metabolized by CYP3A4 or CYP2D6.


-Route-Specific Pharmacokinetics
Oral Route
After oral administration in adults, systemic absorption occurs in 60 to 90 minutes. First-pass metabolism in the liver, and potentially other factors, reduces the bioavailability of haloperidol to 40% to 70%, with an average of approximately 60%. There is a wide variance in the reported mean values for Tmax (1.7 to 6.1 hours). Wide intersubject variation in Cmax, AUC, and clearance values has been reported after a single 5 mg oral dose of haloperidol administered to 28 healthy adult males; mean values were calculated as Cmax = 1.41 +/- 0.69 ng/mL (range: 0.65 to 2.19, coefficient variation [CV] 48.7%), AUC = 43.73 +/- 26.6 ng/L x hour (range: 14.89 to 120.96, CV 58.54%), and CL = 141.65 +/- 60.57 L/hour (range: 41.34 to 335.8 L/hour, CV 42.76%).

Intravenous Route
Immediate-release lactate injection
When used intravenously, peak plasma concentrations are obtained almost immediately after injection and decrease rapidly for about 1 hour during the distribution phase before reaching the elimination phase, where plasma concentrations decrease more slowly. Of note, this formulation is not FDA-approved for intravenous administration.

Intramuscular Route
Immediate-release lactate injection
In adults, peak plasma concentrations occur in 20 to 40 minutes after intramuscular administration.

Decanoate depot injection
Administration of haloperidol decanoate in sesame oil results in slow and sustained release of the drug. In adults, peak plasma concentrations are achieved after about 6 days and decrease thereafter. Steady state is achieved after the third or fourth dose. The apparent half-life of haloperidol decanoate is about 3 weeks. Although the pharmacokinetics of haloperidol decanoate are linear for doses less than 450 mg, parameters can vary between patients.


-Special Populations
Hepatic Impairment
Haloperidol concentrations may increase in hepatically impaired patients because it is extensively metabolized in the liver and protein binding may decrease.