HALDOMEX

Haloperidol is a high potency first-generation (typical) antipsychotic and one of the most frequently used antipsychotic medications used worldwide.

While haloperidol has demonstrated pharmacologic activity at a number of receptors in the brain, 10 it exerts its antipsychotic effect through its strong antagonism of the dopamine receptor (mainly D2), particularly within the mesolimbic and mesocortical systems of the brain.

Haloperidol is indicated for the treatment of the manifestations of several psychotic disorders including schizophrenia, acute psychosis, Tourette syndrome, and other severe behavioural states.

It is also used off-label for the management of chorea associated with Huntington's disease and for the treatment of intractable hiccups as it is a potent antiemetic.

Dopamine-antagonizing medications such as haloperidol are though to improve psychotic symptoms and states that are caused by an over-production of dopamine, such as schizophrenia, which is theorized to be caused by a hyperdopaminergic state within the limbic system of the brain.

Use of the first-generation antipsychotics (including haloperidol) is considered highly effective for the management of the "positive" symptoms of schizophrenia including hallucinations, hearing voices, aggression/hostility, disorganized speech, and psychomotor agitation.

However, this class of drugs is also limited by the development of movement disorders induced by dopamine-blockade such as drug-induced parkinsonism, akathisia, dystonia, tardive dyskinesia, as well as other side effects including sedation, weight gain, and prolactin changes.

While there are limited high-quality studies comparing haloperidol to lower-potency first-generation antipsychotics such as Chlorpromazine, Zuclopenthixol, Fluphenazine, and Methotrimeprazine, haloperidol typically demonstrates the least amount of side effects within this class, but demonstrates a stronger disposition for causing extrapyramidal symptoms (EPS). 6, 7, 8 These other low‐potency antipsychotics are limited by their lower affinity for dopamine receptors, which requires a higher dose to effectively treat symptoms of schizophrenia.

In addition, they block many receptors other than the primary target (dopamine receptors), such as cholinergic or histaminergic receptors, resulting in a higher incidence of side effects such as sedation, weight gain, and hypotension.

Interestingly, in vivo pharmacogenetic studies have demonstrated that the metabolism of haloperidol may be modulated by genetically determined polymorphic CYP2D6 activity.

However, these findings contradict the findings from studies in vitro with human liver microsomes and from drug interaction studies in vivo.

Inter-ethnic and pharmacogenetic differences in haloperidol metabolism may possibly explain these observations.

First-generation antipsychotic drugs have largely been replaced with second.

• and third-generation (atypical) antipsychotics such as Risperidone, Olanzapine, Clozapine, Quetiapine, Aripiprazole, and Ziprasidone.

However, haloperidol use remains widespread and is considered the benchmark for comparison in trials of the newer generation antipsychotics.

The efficacy of haloperidol was first established in controlled trials in the 1960s.

Haloperidol is indicated for a number of conditions including for the treatment of schizophrenia, for the manifestations of psychotic disorders, for the control of tics and vocal utterances of Tourette's Disorder in children and adults, for treatment of severe behavior problems in children of combative, explosive hyperexcitability (which cannot be accounted for by immediate provocation).

Haloperidol is also indicated in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance.

Haloperidol should be reserved for these two groups of children only after failure to respond to psychotherapy or medications other than antipsychotics.

Use of the first-generation antipsychotics (including haloperidol) is considered highly effective for the management of the "positive" symptoms of schizophrenia including hallucinations, hearing voices, aggression/hostility, disorganized speech, and psychomotor agitation.

However, this class is limited by the development of movement disorders such as drug-induced parkinsonism, akathisia, dystonia, and tardive dyskinesia, and other side effects including sedation, weight gain, and prolactin changes.

Compared to the lower-potency first-generation antipsychotics such as Chlorpromazine, Zuclopenthixol, Fluphenazine, and Methotrimeprazine, haloperidol typically demonstrates the least amount of side effects within class, but demonstrates a stronger disposition for causing extrapyramidal symptoms (EPS). 6, 7, 8 Low‐potency medications have a lower affinity for dopamine receptors so that a higher dose is required to effectively treat symptoms of schizophrenia.

In addition, they block many receptors other than the primary target (dopamine receptors), such as cholinergic or histaminergic receptors, resulting in a higher incidence of side effects such as sedation, weight gain, and hypotension.

The balance between the wanted drug effects on psychotic symptoms and unwanted side effects are largely at play within dopaminergic brain pathways affected by haloperidol.

Cortical dopamine-D2-pathways play an important role in regulating these effects and include the nigrostriatal pathway, which is responsible for causing extrapyramidal symptoms (EPS), the mesolimbic and mesocortical pathways, which are responsible for the improvement in positive schizophrenic symptoms, and the tuberoinfundibular dopamine pathway, which is responsible for hyperprolactinemia.

A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol.

Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes.

Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance, drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome).

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs.

Clinical manifestations of

NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

5-hydroxytryptamine receptor 2C Antagonist D dopamine receptor Antagonist.

Haloperidol is a highly lipophilic compound and is extensively metabolized in humans, which may cause a large interindividual variability in its pharmacokinetics.

Studies have found a wide variance in pharmacokinetic values for Oral administered haloperidol with 1.7-6.1 hours reported for time to peak plasma concentration (tmax), 14.5-36.7 hours reported for half-life (t1⁄2), and 43.73 μg/L•h reported for AUC.

Haloperidol is well-absorbed from the gastrointestinal tract when ingested Oral, however, the first-pass hepatic metabolism decreases its oral bioavailability to 40-75%.

After intramuscular administration, the time to peak plasma concentration (tmax) is 20 minutes in healthy individuals or 33.8 minutes in patients with schizophrenia, with a mean half-life of 20.7 hours.

Bioavailability following intramuscular administration is higher than that for oral administration.

Administration of haloperidol decanoate (the depot form of haloperidol for long-term treatment) in sesame oil results in slow release of the drug for long-term effects.

The plasma concentrations of haloperidol gradually rise, reaching its peak concentration at about 6 days after the injection, with an apparent half-life of about 21 days.

Steady-state plasma concentrations are achieved after the third or fourth dose.

The apparent volume of distribution was found to range from 9.5-21.7 L/kg.

This high volume of distribution is in accordance with its lipophilicity, which also suggests free movement through various tissues including the blood-brain barrier.

Haloperidol is extensively metabolised in the liver with only about 1% of the administered dose excreted unchanged in urine.

In humans, haloperidol is biotransformed to various metabolites, including p-fluorobenzoylpropionic acid, 4-(4-chlorophenyl)-4-hydroxypiperidine, reduced haloperidol, pyridinium metabolites, and haloperidol glucuronide.

In psychiatric patients treated regularly with haloperidol, the concentration of haloperidol glucuronide in plasma is the highest among the metabolites, followed, in rank order, by unchanged haloperidol, reduced haloperidol and reduced haloperidol glucuronide.

The drug is thought to be metabolized primarily 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.

The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP) including CYP3A4 and CYP2D6, carbonyl reductase and uridine di-phosphoglucose glucuronosyltransferase enzymes.

The greatest proportion of the intrinsic hepatic clearance of haloperidol is performed by glucuronidation and followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation.

In studies of cytochrome-mediated disposition in vitro, CYP3A4 appears to be the major isoform of the enzyme responsible for the metabolism of haloperidol in humans.

The intrinsic clearance of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude.

This suggests that the same enzyme system is responsible for the above three metabolic reactions.

In vivo human studies on haloperidol metabolism have shown that the glucuronidation of haloperidol accounts for 50-60% of haloperidol biotransformation and that approximately 23% of the biotransformation was accounted for by the reduction pathway.

The remaining 20-30% ofthe biotransformation of haloperidol would be via N-dealkylation and pyridinium formation.

Hover over products below to view reaction partners Haloperidol 4-(4-chlorophenyl)-4-hydroxypiperidine Reduced haloperidol Haloperidol reduced pyridinium ion derivative Haloperidol pyridinium ion derivative Haloperidol glucuronide Haloperidol 1,2,3,6-tetrahydropyridine Haloperidol pyridinium ion derivative fluorobenzoylpropionic acid 4-(4-Chlorophenyl)-1--pyridinium (HPP+) p-Fluorobenzoylpropionic acid and 4-(4-chlorophenyl)-4-hydroxypiperidine.

In radiolabeling studies, approximately 30% of the radioactivity is excreted in the urine following a single oral administration of 14C-labelled haloperidol, while 18% is excreted in the urine as haloperidol glucuronide, demonstrating that haloperidol glucuronide is a major metabolite in the urine as well as in plasma in humans.

Following oral administration, the half-life was found to be 14.5-36.7 hours.

Following intramuscular injection, mean half-life was found to be 20.7 hours.

Following intravenous administration, the plasma or serum clearance (CL) was found to be 0.39-0.708 L/h/kg (6.5-11.8 ml/min/kg).

Following oral administration, clearance was found to be 141.65 L/h (range 41.34-335.80 L/h).

Haloperidol clearance after extravascular administration ranges from 0.9-1.5 l/h/kg, however this rate is reduced in poor metabolizers of C YP2D6 enzyme.

CYP2D6 enzyme activity may result in increased concentrations of haloperidol.

The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia 14.

Genetic polymorphism of

CYP2D6 has been demonstrated to be an important source of inter-patient variability in the pharmacokinetics of haloperidol and may affect therapeutic response and incidence of adverse effects.

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Acute oral toxicity (LD50): 71 mg/kg in rats MSDS.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Haloperidol is not approved for the treatment of patients with dementia-related psychosis.

Cases of sudden death, QT-prolongation, and Torsades de pointes have been reported in patients receiving haloperidol.

Higher than recommended doses of any formulation of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de pointes.

Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome).

A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.

However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered.

However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS). Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs.

Clinical manifestations of

NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc). and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of

NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

The patient should be carefully monitored, since recurrences of NMS have been reported.

Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with haloperidol.

Haloperidol tablets may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Usage in Pregnancy Pregnancy Nonteratogenic Effects

Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates.

These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Haloperidol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Rodents given to 20 times the usual maximum human dose of haloperidol by oral or parenteral routes showed an increase in incidence of resorption, reduced fertility, delayed delivery and pup mortality.

No teratogenic effect has been reported in rats, rabbits or dogs at dosages within this range, but cleft palate has been observed in mice given 15 times the usual maximum human does.

Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents.

There are no well controlled studies with haloperidol in pregnant women.

There are reports, however, of cases of limb malformations observed following maternal use of haloperidol along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy.

Causal relationships were not established in these cases.

Since such experience does not exclude the possibility of fetal damage due to haloperidol, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus.

Infants should not be nursed during drug treatment.

An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus haloperidol.

A causal relationship between these events and the concomitant administration of lithium and haloperidol has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear.

A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including haloperidol.

It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation.

Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly.

Although not reported with haloperidol, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs.

Haloperidol may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle.

The ambulatory patient should be warned accordingly.

The use of alcohol with this drug should be avoided due to possible additive effects and hypotension.

Haloperidol tablets are contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson's disease.

There is considerable variation from patient to patient in the amount of medication required for treatment.

As with all antipsychotic drugs, dosage should be individualized according to the needs and response of each patient.

Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control.

To determine the initial dosage, consideration should be given to the patient's age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state.

Children, debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less haloperidol.

The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels, as recommended below.

Clinical experience suggests the following recommendations

Oral Administration Initial Dosage Range Adults Moderate Symptomatology.

• 0.5 mg to 2 mg b.i.d. or t.i.d.

• 3 mg to 5 mg b.i.d. or t.i.d.

To achieve prompt control, higher doses may be required in some cases.

Patients who remain severely disturbed or inadequately controlled may require dosage adjustment.

Daily dosages up to 100 mg may be necessary in some cases to achieve an optimal response.

Infrequently, haloperidol has been used in doses above 100 mg for severely resistant patients; however, the limited clinical usage has not demonstrated the safety of prolonged administration of such doses.

The following recommendations apply to children between the ages of and 12 years (weight range 15 kg to 40 kg).

Haloperidol is not intended for children under 3 years old.

Therapy should begin at the lowest dose possible (0.5 mg per day).

If required, the dose should be increased by an increment of 0.5 mg at to 7 day intervals until the desired therapeutic effect is obtained.

The total dose may be divided, to be given b.i.d. or t.i.d.

• 0.05 mg/kg/day to 0.15 mg/kg/day Nonpsychotic Behavior.

• 0.05 mg/kg/day to 0.075 mg/kg/day Severely disturbed psychotic children may require higher doses.

In severely disturbed, non-psychotic children or in hyperactive children with accompanying conduct disorders, who have failed to respond to psychotherapy or medications other than antipsychotics, it should be noted that since these behaviors may be short lived, short term administration of haloperidol may suffice.

There is no evidence establishing a maximum effective dosage.

There is little evidence that behavior improvement is further enhanced in dosages beyond 6 mg per day. Maintenance Dosage Upon achieving a satisfactory therapeutic response, dosage should then be gradually reduced to the lowest effective maintenance level.

The oral form should supplant the injectable as soon as practicable.

In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested.

For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used.

Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover.

In this way, dosage adjustments, either upward or downward, can be quickly accomplished.

Depending on the patient's clinical status, the first oral dose should be given within to 24 hours following the last parenteral dose.

Tablets, USP are available containing 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg or 20 mg of haloperidol, USP.

The 0.5 mg tablets are white to off-white color, round, functionally scored tablets with notch, debossed with "LS" and "1" separated by score line on one side and score line on the other side.

They are available as follows

NDC 70756-001-11 bottles of 100 tablets with child-resistant closure NDC 70756-001-12 bottles of 1000 tablets The 1 mg tablets are light yellow to yellow color, round, functionally scored tablets with notch, debossed with "LS" and "2" separated by score line on one side and score line on the other side.

NDC 70756-002-11 bottles of 100 tablets with child-resistant closure NDC 70756-002-12 bottles of 1000 tablets The 2 mg tablets are light orange to orange color, round, functionally scored tablets with notch, debossed with "LS" and "3" separated by score line on one side and score line on the other side.

NDC 70756-003-11 bottles of 100 tablets with child-resistant closure NDC 70756-003-12 bottles of 1000 tablets The 5 mg tablets are light orange to orange color, round, functionally scored tablets with notch, debossed with "LS" and "4" separated by score line on one side and score line on the other side.

NDC 70756-004-11 bottles of 100 tablets with child-resistant closure NDC 70756-004-12 bottles of 1000 tablets The 10 mg tablets are light green to green color, round, functionally scored tablets, debossed with "LS" and "242" separated by score line on one side and plain on the other side.

NDC 70756-242-11 bottles of 100 tablets with child-resistant closure NDC 70756-242-12 bottles of 1000 tablets The 20 mg tablets are light blue to blue color, round, functionally scored tablets, debossed with "LS" and "236" separated by score line on one side and plain on the other side.

NDC 70756-236-11 bottles of 100 tablets with child-resistant closure NDC 70756-236-12 bottles of 1000 tablets Store at 20° to 25°C (68° to 77°F).

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Manufactured for

Lifestar Pharma LLC 1200 MacArthur Blvd.

Mahwah, NJ 07430 USA Made in India Revised: November 2024, V-05.