Medications: Haldol^® – haloperidol

Haloperidol is indicated for use in the management of manifestations of psychotic disorders.

Haloperidol is indicated for the control of tics and vocal utterances of Tourette’s Disorder in children and adults. Haloperidol is effective for the treatment of severe behavior problems in children of combative, explosive hyperexcitability (which cannot be accounted for by immediate provocation).

Haloperidol is also effective 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.

DOSAGE AND ADMINISTRATION

Oral Administration
INITIAL DOSAGE RANGE

Adults

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.

Children

The following recommendations apply to children between the ages of 3 and 12 years (weight range 15 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 5 to 7 day intervals until the desired therapeutic effect is obtained. (see chart below).

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

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 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.

• Cardiovascular Effects: Tachycardia, hypotension, and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes and may occur more frequently with high doses and in predisposed patients (see WARNINGS and PRECAUTIONS).
• CNS Effects:
  • EXTRAPYRAMIDAL SYMPTOMS (EPS) — EPS during the administration of haloperidol have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases.
  • Dystonia: Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
  • WITHDRAWAL EMERGENT NEUROLOGICAL SIGNS: Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases, the dyskinetic movements are indistinguishable from the syndrome described below under ” TARDIVE DYSKINESIA” except for duration. It is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs but until further evidence becomes available, it seems reasonable to gradually withdraw use of haloperidol.
  • TARDIVE DYSKINESIA: As with all antipsychotic agents, haloperidol has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and, in some patients, appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk.
  • TARDIVE DYSTONIA: Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible.
• OTHER CNS EFFECTS: Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs.
• Body as a Whole: Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with haloperidol (see WARNINGS for further information concerning NMS).
• Hematologic Effects: Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of haloperidol, and then only in association with other medication.
• Liver Effects: Impaired liver function and/or jaundice have been reported.
• Dermatologic Reactions: Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair.
• Endocrine Disorders: Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia.
• Gastrointestinal Effects: Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting.
• Autonomic Reactions: Dry mouth, blurred vision, urinary retention, diaphoresis and priapism.
• Respiratory Effects: Laryngospasm, bronchospasm and increased depth of respiration.
• Special Senses: Cataracts, retinopathy and visual disturbances.
• Postmarketing Events: Hyperammonemia has been reported in a 5½ year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with haloperidol.

Haloperidol is 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.

WARNINGS AND PRECAUTIONS:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• Cardiovascular Effects: Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol.
• Tardive Dyskinesia
• Neuroleptic Malignant Syndrome (NMS)
• Falls: Haloperidol may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.
• Usage in Pregnancy: Haloperidol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Combined Use of Haloperidol and Lithium: 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 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.
• 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 use of alcohol with this drug should be avoided due to possible additive effects and hypotension.
• Leukopenia, Neutropenia and Agranulocytosis: In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including haloperidol tablets USP. Agranulocytosis (including fatal cases) has also been reported.
• Pediatric use: Safety and effectiveness in pediatric patients have not been established.
• Geriatric use: The pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses.
• Haloperidol should be administered cautiously to patients: a) with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since haloperidol may block its vasopressor activity and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used. b) receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because haloperidol may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained. c) with known allergies, or with a history of allergic reactions to drugs. d) receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione).
• The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with haloperidol.
• As with other antipsychotic agents, it should be noted that haloperidol may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol.
• Careful monitoring of clinical status is warranted when rifampin is administered or discontinued in haloperidol-treated patients.
• When haloperidol is used to control mania in cyclic disorders, there may be a rapid mood swing to depression.
• Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including haloperidol.
• Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients.

Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of plasma levels). The risks of using haloperidol in combination with other drugs have been evaluated as described below.

Pharmacodynamic Interactions:

Since QTc interval-prolongation has been observed during HALDOL treatment, caution is advised when prescribing to a patient with QT-prolongation conditions or to patients receiving medications known to prolong the QTc-interval (see WARNINGS, Cardiovascular Effects). Examples include (but are not limited to): Class 1A antiarrhythmics (e.g., procainamide, quinidine, disopyramide); Class 3 antiarrhythmics (e.g., amiodarone, sotalol); and other drugs such as citalopram, erythromycin, levofloxacin, methadone, and ziprasidone. Caution is advised when HALDOL is used in combination with drugs known to cause electrolyte imbalance (e.g., diuretics or corticosteroids because hypokalemia, hypomagnesemia, and hypocalcemia are risk factors for QT prolongation. Haloperidol may impair the antiparkinson effects of levodopa and other dopamine agonists. If concomitant antiparkinson medication is required, it may have to be continued after HALDOL is discontinued because of the difference in excretion rates. If both are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with HALDOL. As with other antipsychotic agents, it should be noted that haloperidol may be capable of potentiating CNS depressants such as anesthetics, opioids, and alcohol.

Pharmacokinetic Interactions:

Drugs that May Increase Haloperidol Plasma Concentrations: Haloperidol is metabolized by several routes. The major pathways are glucuronidation and ketone reduction. The cytochrome P450 enzyme system is also involved, particularly CYP3A4 and, to a lesser extent, CYP2D6. Inhibition of these routes of metabolism by another drug or a decrease in CYP2D6 enzyme may result in increased haloperidol concentrations. The effect of CYP3A4 inhibition and of decreased CYP2D6 enzyme activity may be additive. The haloperidol plasma concentrations increased when a CYP3A4 and/or CYP2D6 inhibitor was coadministered with haloperidol. Examples include:

• CYP3A4 inhibitors – alprazolam; itraconazole, ketoconazole, nefazodone ritonavir.
• CYP2D6 inhibitors – chlorpromazine; promethazine; quinidine; paroxetine, sertraline, venlafaxine.
• Combined CYP3A4 and CYP2D6 inhibitors – fluoxetine, fluvoxamine; ritonavir.

Increased haloperidol plasma concentrations may result in an increased risk of adverse events, including QTc interval prolongation (see WARNINGS – Cardiovascular Effects). Increases in QTc have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It is recommended that patients who take haloperidol concomitantly with such medicinal products be monitored for signs or symptoms of increased or prolonged pharmacologic effects of haloperidol, and the HALDOL dose be decreased as deemed necessary.

Valproate: Sodium valproate, a drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations.

Drugs that May Decrease Haloperidol Plasma Concentrations: Coadministration of haloperidol with potent enzyme inducers of CYP3A4 may gradually decrease the plasma concentrations of haloperidol to such an extent that efficacy may be reduced. Examples include (but are not limited to): carbamazepine, phenobarbital, phenytoin, rifampin, St John’s Wort (Hypericum, perforatum).

Rifampin: In a study of 12 patients with schizophrenia coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other patients with schizophrenia treated with oral haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations.

Carbamazepine: In a study in 11 patients with schizophrenia coadministered haloperidol and increasing doses of carbamazepine, haloperidol plasma concentrations decreased linearly with increasing carbamazepine concentrations. During combination treatment with inducers of CYP3A4, it is recommended that patients be monitored and the HALDOL dose increased as deemed necessary. After withdrawal of the CYP3A4 inducer, the concentration of haloperidol may gradually increase and therefore it may be necessary to reduce the dose of HALDOL.

Effect of Haloperidol on Other Drugs: Haloperidol is an inhibitor of CYP2D6. Plasma concentrations of CYP2D6 substrates (e.g., tricyclic antidepressants such as desipramine or imipramine) may increase when they are co-administered with haloperidol.

In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reaction would be manifest by muscular weakness or rigidity and a generalized or localized tremor as demonstrated by the akinetic or agitans types respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. (For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS).

Treatment: Gastric lavage or induction of emesis should be carried out immediately followed by administration of activated charcoal. Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures.