The P-I-E-N-O Parkinsn's List Drug Database
haloperidol / HaldolTM , SerenaceTM
HIGH RISK
Description: Haloperidol is a high-potency antipsychotic that is structurally related to droperidol. Haloperidol is indicated for the symptomatic treatment of psychotic disorders, to control tics and vocal utterances of Tourette's syndrome, and for the treatment of severe behavioral problems in children, manifested as impulsive, combative, or explosive hyperexcitability, that are unresponsive to behavioral or counseling therapy. Haloperidol may be effective in some cases of infantile autism and is commonly used in Huntington's disease to reduce disabling choreiform movements. Haloperidol appears to be at least as effective as phenothiazines for treating chemotherapy-induced nausea and vomiting; however, further research is needed. Haloperidol decanoate is a long-lasting intramuscular injection used for chronic schizophrenia or other chronic psychotic disorders. Haloperidol was originally approved by the FDA in 1967.
Mechanism of Action: Haloperidol blocks postsynaptic dopamine receptors (DA) in the mesolimbic system and increases dopamine turnover by blockade of the DA somatodendritic autoreceptor. After approximately 12 weeks of chronic therapy, depolarization blockade of dopamine tracts occur. The decrease in dopamine neurotransmission has been found to correlate with the antipsychotic effects. This DA-blockade is also responsible for the potent extrapyramidal effects observed with this drug. Dopamine blockade in the chemoreceptor trigger zone accounts for the antiemetic effects. Haloperidol possesses extremely weak anticholinergic and ›-adrenergic receptor blocking effects. Blockade of ›A-adrenergic receptors produces sedation; muscle relaxation; and cardiovascular effects such as hypotension, reflex tachycardia, and minor changes in ECG patterns.
Pharmacokinetics: Formulations of haloperidol include oral tablet or solution, the rapid-acting IM lactate, or long-lasting IM decanoate. Following oral administration, haloperidol is well absorbed from the GI tract. First-pass metabolism in the liver reduces the bioavailability to approximately 60%. Bioavailability of the IM lactate formulation is 75%. Peak plasma concentrations after oral administration are achieved within 2-6 hours. Following IM injection of haloperidol lactate, peak plasma concentrations occur in 10-20 minutes, with maximum therapeutic action occurring within 30-45 minutes. Following IM injection of haloperidol decanoate, peak plasma concentrations are achieved after about 7 days.
Distribution of haloperidol is extensive, demonstrating three- compartment pharmacokinetics following IV injection. It is 92% plasma protein-bound, predominately to ›A-acid glycoprotein. It is unknown if haloperidol crosses the placenta; however, it is distributed into breast milk. Haloperidol decanoate dissolved in sesame oil is given by deep intramuscular injection, which is released extremely slowly into the circulation. After release, hydrolysis by plasma and/or tissue esterases to haloperidol and decanoic acid occurs almost instantaneously.
Haloperidol is extensively metabolized in the liver through N- dealkylation to inactive metabolites. Reduction to hydroxyhaloperidol, an active metabolite, also occurs. Haloperidol appears to exhibit extensive enterohepatic circulation. The elimination half-life of the oral dosage averages 24 hours. Apparent half-lives of IM haloperidol lactate and decanoate are 21 hours and 21 days, respectively. About 40% of a dose of haloperidol is excreted renally within 5 days, with 1% appearing as unchanged drug. Approximately 15% is eliminated through biliary excretion. Dosage reductions in the presence of renal impairment do not appear necessary; however, an increased risk for adverse reactions such as hypotension and sedation exists.
A 2 mg haloperidol oral dose would be equivalent to 100 mg chlorpromazine, the prototype antipsychotic. At steady state (after 3 months on the same dose), 10 mg haloperidol decanoate injection given every 28 days would be equivalent to 100 mg of oral chlorpromazine given daily.
CONTRAINDICATIONS/PRECAUTIONS: Haloperidol should be used with extreme caution in patients with thyrotoxicosis or hyperthyroidism. Antipsychotic agents can cause severe extrapyramidal symptoms such as dystonias or rigidity. Laryngospasm can prevent breathing and could be life- threatening. Therefore haloperidol should be used with caution in patients with pulmonary disease.
Patients with hypocalcemia may be at an increased risk for having dystonic reactions. Therefore, haloperidol should be used with caution in this patient population.
Rarely, haloperidol causes hypotension or precipitates angina; therefore, it should be used with extreme caution in patients with cardiac disease.
Haloperidol is classified as pregnancy category C. Two cases of limb reduction malformations have been reported after haloperidol use during the first trimester of pregnancy; however, a causal relationship to the drug has not been established. Haloperidol should be used during pregnancy only when the benefits outweigh the potential risks to the fetus. Haloperidol is excreted into breast milk. Adverse effects to the nursing infant, if any, remain unknown. Therefore, use of haloperidol in breast-feeding women should occur only when a benefit-to-risk assessment shows that it is clearly needed.
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. In addition, haloperidol can suppress the symptoms of these disorders, if they are present. Haloperidol is contraindicated in patients who are in a coma or who exhibit severe toxic CNS depression.
Patients with a history of hepatic encephalopathy secondary to cirrhosis may be at an increased risk for potentiation of haloperidol's CNS effects. Although preexisting hepatic disease does not appear to increase the probability of jaundice occurring in patients receiving antipsychotic agents, haloperidol should be used with caution in this patient population.
Children with acute illnesses, including varicella-zoster infections, CNS infections, measles, gastroenteritis, or dehydration, may be more susceptible to developing extrapyramidal symptoms, particularly dystonias.
Hematologic reactions have been reported following administration of antipsychotic agents. Although these reactions are quite rare, haloperidol should be used with caution in patients with preexisting hematological disease. If sore throat or other signs or symptoms of infection occur, obtain a complete blood count and consider discontinuing haloperidol treatment.
Some oral formulations of haloperidol (1, 5, 10 mg tablets) can contain tartrazine dye. Allergic reactions, including an asthmatic episode, can occur in patients with known tartrazine dye hypersensitivity. Bronchospasm frequently occurs in patients with aspirin hypersensitivity.
Patients receiving anticonvulsant agents or who have a history of a seizure disorder, epilepsy, or EEG abnormalities should be monitored carefully during therapy with haloperidol due to its slight lowering of seizure threshold. High doses and large changes in haloperidol doses should be avoided in patients with a known history of seizures. Haloperidol does not increase, and actually can decrease, intraocular pressure. Angle closure glaucoma, however, can be worsened due to the anticholinergic effects of haloperidol or concomitant antiparkinsonian agent; therefore, it should be used with caution in patients with preexisting angle closure glaucoma.
Haloperidol should be used cautiously in patients with prostatic hypertrophy. The anticholinergic effects of haloperidol or concomitant antiparkinsonian agent can worsen urinary retention.
Haloperidol is contraindicated in patients with Parkinson's disease. The dopamine blockade from haloperidol will dramatically worsen the preexisting Parkinson's disease, possibly incapacitating the patient.
Haloperidol can disrupt the hypothalamic mechanism for temperature regulation. Patients should therefore avoid exposure to extreme temperature variations to prevent developing hyperthermia or hypothermia.
Antipsychotics stimulate the release of prolactin and should be used extremely cautiously in patients who have a history of breast carcinoma.
Tobacco smoking can reduce the plasma concentrations of haloperidol to an average of 67% compared with those of nonsmokers taking the same dose. Plasma concentrations of haloperidol should be monitored and linear dosage adjustments made in patients who start or stop smoking. DRUG INTERACTIONS: Haloperidol can potentiate the actions of other CNS depressants such as opiate agonists, barbiturates, ethanol, or general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Carbamazepine is a potent inducer of the cytochrome P-450 mixed- function oxidase system. Concomitant use of carbamazepine can reduce the plasma concentrations of haloperidol by an average of 50%. Plasma concentrations of haloperidol should be monitored and linear dosage adjustments made in patients receiving carbamazepine. Limited data suggest that rifampin can also increase the metabolism and/or reduce the bioavailability of haloperidol. Patient response, adverse effects, and plasma haloperidol concentrations should be monitored following addition or deletion of rifampin during treatment with haloperidol. Although no data are available, it is likely that barbiturates may also enhance haloperidol elimination, however, it is not necessary to avoid this combination.
Although a causal relationship has not been established, an encephalopathic syndrome can occur when haloperidol is administered to patients whose lithium serum concentrations are "1.2 mEq/L. This syndrome is characterized by weakness, lethargy, fever, confusion, extrapyramidal symptoms, leukocytosis, and elevated BUN. Additive extrapyramidal effects also have been noted in patients receiving both agents at normal concentrations. Not all patients receiving this drug combination develop this reaction. Lithium levels should be monitored closely during concomitant therapy with haloperidol.
Haloperidol reportedly interfered with the anticoagulant effects of phenindione in one patient. Therefore, careful monitoring is recommended during concomitant administration of haloperidol with oral anticoagulants.
In general, neuroleptics should be used cautiously with antihypertensive agents due to the possibility of additive hypotension. Hypotension developed in an elderly woman 2.5 hours after she received clonidine, furosemide, and haloperidol although it could be determined which agent or agents contributed most to this hypotension. Concurrent administration of haloperidol and methyldopa has been reported to result in dementia in some cases. The clinical importance of this interaction has not been established, but caution is advised during simultaneous use of these agents. In addition, haloperidol may inhibit the antihypertensive effects of guanethidine.
Elevated haloperidol serum concentrations and symptoms of haloperidol excess were observed when fluvoxamine was added to a regimen of haloperidol and benztropine in four patients with schizophrenia. Although data are limited, fluvoxamine should be used cautiously in patients receiving haloperidol. In a single patient, fluoxetine appeared to provoke haloperidol-induced extrapyramidal reactions. Until more data are available, both fluvoxamine and fluoxetine should be used cautiously in patients receiving haloperidol.
Patients taking haloperidol can have reduced pressor response to phenylephrine, metaraminol, or norepinephrine, but these agents are preferred over epinephrine if a vasopressor agent is required in patients receiving haloperidol. The ›-adrenergic effects of epinephrine can be blocked during concurrent administration of some neuroleptics, possibly resulting in a paradoxical condition called "epinephrine reversal." Epinephrine reversal can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction. The vasoconstrictive properties of dopamine infusion can also be decreased due to the ›-adrenergic blocking capability of neuroleptics. Dopamine infusions intended to improve renal perfusion can be ineffective due to haloperidol's dopamine receptor blockade. Since haloperidol has less ›-antagonistic properties than chlorpromazine, haloperidol may be less likely to predispose patients to this pharmacologic response.
Haloperidol, a dopamine receptor antagonist, is a pharmacologic antagonist to dopamine agonists such as levodopa, bromocriptine, or pergolide. Haloperidol can antagonize the actions of these drugs. Limited data, however, suggest that there could be therapeutic benefits from the addition of levodopa to haloperidol therapy in a small number of refractory schizophrenic patients.
Anticholinergic symptoms can be additive if haloperidol is used with atropine, benztropine, dicyclomine, tricyclic antidepressants, or some HA-blockers such as diphenhydramine. Limited data suggest that haloperidol may also inhibit the metabolism of some tricyclic antidepressants, however, the clinical significance of this is uncertain.
ADVERSE REACTIONS: Extrapyramidal symptoms (EPS) occur frequently during treatment with haloperidol and appear to be the result of blockade at the DA-receptor. These symptoms occur with greater severity and frequency during high-dose therapy. Extrapyramidal symptoms are categorized as dystonia, akathisia (subjective and objective motor restlessness), and parkinsonism. Parkinsonian symptoms are more common in the elderly, whereas children most often develop dystonic reactions, which can be worsened by acute infections or severe dehydration. Dystonic reactions are seen during the first week of treatment. Akathisia and parkinsonian symptoms usually develop several days to weeks into therapy. Dystonia and pseudoparkinsonism usually are easily treated with concomitant benztropine, diphenhydramine, lorazepam, or amantadine. A tardive dystonia can also develop during threrapy with haloperidol. This dystonia is characterized by a delayed onset of choreic or dystonic movements. It can be persistent and potentially irreversible. Akathisia may respond to dosage reduction or concomitant administration of a benzodiazepine (usually lorazepam) or propranolol. In rare patients, haloperidol will need to be discontinued and an alternate antipsychotic used instead. Haloperidol is the antipsychotic most likely to cause EPS.
Neuroleptic malignant syndrome (NMS) can occur in patients receiving haloperidol. NMS is characterized by hyperthermia, severe extrapyramidal dysfunction, alterations in consciousness, altered mental status, and autonomic instability. Increased serum creatine phosphokinase (CPK), acute renal failure, and leukocytosis also have occurred. NMS does not appear to be dose- related. Severe cases have resulted in death occurring 3-30 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.
Tardive dyskinesia can develop during long-term therapy or following discontinuation of haloperidol, and occurs more frequently in elderly women. Tardive dyskinesia (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. Routine (at 3- to 6-month intervals) monitoring of movement disorders is considered the standard practice when using haloperidol. If signs or symptoms of TD develop, haloperidol use should be reevaluated and possibly discontinued.
Drowsiness is a CNS effect that can occur during initial treatment with haloperidol. Tolerance usually develops with continued therapy. Other CNS effects reported less frequently include agitation, anxiety, confusion, depression, euphoria, hallucinations, headache, insomnia, restlessness, vertigo and cerebral edema. Seizures can occur and are of special significance in patients who have preexisting seizure disorders or EEG abnormalities.
Sexual dysfunction can be seen with haloperidol including impotence and ejaculation dysfunction (painful ejaculation). Antipsychotic agents increase serum prolactin concentrations. Evidence is limited as to the possible connection between increased serum prolactin and breast cancer. Some patients have reported menstrual irregularity, and noticed changes in the breast with reports of gynecomastia, mastalgia, and galactorrhea.
Pigmentary retinopathy can occur, with or without pigmentary changes in the skin. Symptoms of blurred vision, difficulty with nighttime vision, or defective color vision should be investigated promptly. Wearing protective dark glasses can reduce the possibility of developing this reaction. The drug has been associated with frequent ocular changes including deposition of fine particles in the lens and cornea, which can lead to visual impairment.
Concomitant administration of anticholinergic antiparkinsonian drugs, antidepressants, or other anticholinergic agents can increase the possibility of anticholinergic effects such as blurred vision, xerostomia, mydriasis, nausea/vomiting, urinary retention, and constipation. Other gastrointestinal effects with haloperidol include anorexia, hypersalivation, diarrhea and dyspepsia.
Hypothermia and hyperthermia have been reported and may result from haloperidol's effect on the hypothalamic control of temperature regulation. Tolerance to these effects can develop, but avoidance of predisposing factors is advisable, such as extremes of temperature, exercise, hot baths, and saunas. Hyperpyrexia and heat stroke unrelated to NMS have occurred.
Hematologic disturbances that have been reported following haloperidol administration include leukopenia, leukocytosis, and anemia. Agranulocytosis has occurred rarely but was associated with other concomitant treatment.
Melanosis has been observed to occur following prolonged therapy with other antipsychotics. Changes in skin pigmentation are generally restricted to areas of the body exposed to sunlight. Photosensitivity can result, and patients should be warned either to keep out of the sun or to use effective sunscreens (SPF 15+) on exposed areas of the body. Withdrawal 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.
Pneumonia has occurred with haloperidol. This problem may result from dehydration, hemoconcentration, and reduced pulmonary ventilation, which are secondary to decreased thirst and lethargy due to CNS depression.
Liver impairment in the form of cholestasis with jaundice has been reported rarely with administration of haloperidol.
Adverse cardiovascular reactions that have occurred during haloperidol therapy include hypotension, hypertension, ventricular tachycardia, QT prolongation on ECG, and other cardiac arrhythmias including torsade de pointes.I Cardiac arrhythmias such as torsade de pointes secondary to antipsychotic therapy have mainly been associated with thioridazineI and haloperidol.
The majority of patients do not experience problems if antipsychotic therapy is abruptly terminated. However, some patients on maintenance therapy have transient dyskinetic symptoms after abrupt withdrawal. These symptoms resemble a tardive dyskinesia, but are not prolonged. It has not been determined if gradual withdrawal of haloperidol will eliminate this possibility, but it would seem prudent to do so until further evidence is obtained.
PATIENT INFORMATION:
What do haloperidol tablets do?
Haloperidol (HaldolTM ) helps to treat schizophrenia. Haloperidol can help you to keep in touch with reality and reduce your mental problems. Haloperidol can help to control tics and vocal outbursts in patients with Tourette's syndrome and treat behavioral problems in children with severe conduct disorders (hyperactivity, mood swings, aggressive behavior, or difficulty maintaining attention). Generic haloperidol tablets are available.
What should my doctor, dentist, or pharmacist know before I take haloperidol?
They need to know if you have any of these conditions:
How should I take this medicine?
Take haloperidol tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. If haloperidol upsets your stomach you can take it with food. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.
Special precautions for use in children:
This medicine is not for children under 3 years old.
Elderly patients over age 65 years may have a stronger reaction to this medicine and need smaller doses.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose and space remaining doses through the rest of the day. Do not take double or extra doses.
What other medicines can interact with haloperidol?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking haloperidol?
Serious side effects with haloperidol include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with haloperidol include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take haloperidol?
Visit your doctor for regular checks on your progress. It may be several weeks before you see the full effects of haloperidol. Do not suddenly stop taking haloperidol. You may need to gradually reduce the dose. Only stop taking haloperidol on your doctor's advice.
You may get dizzy or drowsy. Do not drive, use machinery, or do anything that needs mental alertness until you know how haloperidol affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can increase dizziness and drowsiness. Avoid alcoholic drinks. You can get a hangover effect the morning after a bedtime dose.
Do not treat yourself for colds, diarrhea or allergies. Ask your doctor or pharmacist for advice, some nonprescription medicines may increase possible side effects.
Your mouth may get dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water will help. Be careful when brushing and flossing your teeth to avoid mouth infections or damage to your gums. See your dentist regularly.
If you are going to have surgery tell your doctor or dentist that you are taking haloperidol.
Avoid extreme heat or cold. Haloperidol can stop you sweating and increase your body temperature. It can also make your body unable to stand extreme cold. Avoid hot baths and saunas. Be careful about exercising especially in hot weather. Dress warmly in cold weather and do not stay out long in the cold.
Haloperidol may make you more sensitive to sun or ultraviolet light. Keep out of the sun, or wear protective clothing outdoors and use a sunscreen (at least SPF 15). Do not use sun lamps, or sun tanning beds or booths. To protect your eyes wear sunglasses even on cloudy days.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Protect from light. Keep container tightly closed. Throw away any unused medicine after the expiration date.
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