Orap (Pimozide)





Action And Clinical Pharmacology: Pimozide is a diphenylbutylpiperidine derivative with neuroleptic properties that has been found to be useful in the management of chronic schizophrenic patients. It is relatively non-sedating and can be administered in a single daily dosage.

It is assumed that the basic mechanism of action of pimozide is related to its action on central aminergic receptors. It appears to have a selective ability to block central dopaminergic receptors, although it affects norepinephrine turnover at higher doses. The extrapyramidal effects typical of other neuroleptic agents are seen also with pimozide, but it appears to have fewer autonomic effects. As with other neuroleptics, endocrine effects and ECG changes have also been reported with pimozide.

Pharmacokinetics: The peak plasma level of pimozide in man occurs between 3 and 8 hours after administration and plasma levels decrease slowly to about 50% of the peak level at 48 to 72 hours after dosing. In a single dose study involving healthy volunteers, the mean plasma half-life of tritiated pimozide (total radioactivity) was found to be 29±10 (S.D.) hours. In a repeat dose study of short duration involving chronic schizophrenics, the mean plasma half-life was 55±20 (S.D.) hours. There was a 13-fold interindividual difference in the area under the serum pimozide concentration-time curve and an equivalent degree of variation in peak serum levels among patients studied. The significance of this is unclear since there are few correlations between plasma levels and clinical findings. In the single dose study, 19% (range 8 to 32%) of the radioactivity was excreted in urine in 24 hours. Approximately 40 to 50% was excreted in urine and 20% in feces within a week. Negligible amounts were excreted after the 7th day, although labelled material was detected up to 14 days after administration. The main metabolite in both urine and feces is 4-bis (p-fluorophenyl) butyric acid. Unchanged pimozide constitutes at least 50% of the fecal radioactivity but only a very small fraction of the plasma and urinary radioactivity.

Indications And Clinical Uses: The management of the manifestations of chronic schizophrenia in which the main manifestations do not include excitement, agitation or hyperactivity. Pimozide has relatively little sedative action and can be used as a once daily medication.

Pimozide is not indicated in the management of patients with mania or acute schizophrenia.

Contra-Indications: In CNS depression, comatose states, liver disorders, renal insufficiency, and blood dyscrasias, and in individuals who have previously displayed hypersensitivity to the drug. It should not be used in depressive disorders or Parkinson’s syndrome.

Pimozide is contraindicated in patients with congenital long QT syndrome, patients with a history of cardiac arrhythmias, or patients taking other drugs which prolong the QT interval of the ECG (see Precautions, Drug Interactions). A pretreatment ECG is thus recommended to exclude these conditions.

The concomitant use of CYP 3A4-inhibiting drugs such as azole antimycotics, antiviral protease inhibitors and macrolide antibiotics is contraindicated. The concomitant use of CYP 2D6-inhibiting drugs such as quinidine is also contraindicated. The inhibition of either or both cytochrome P450 systems may result in the elevation of pimozide blood concentration and increase the possibility of QT-prolongation.

Manufacturers’ Warnings In Clinical States: Increased Psychomotor Activity: Clinical trials with pimozide indicate that it is not effective in, and therefore should not be used in, the management of manifestations of chronic schizophrenia in which the main symptoms include agitation, excitement and anxiety.

Cardiac Monitoring: As with other neuroleptics, cases of sudden, unexpected deaths have occurred with pimozide, mainly at doses above 20 mg/day. ECG changes have been reported in association with the use of pimozide (see Adverse Effects), and one possible mechanism for the deaths is prolongation of the QT interval, predisposing patients to ventricular arrhythmia. Periodic assessment of cardiac function, primarily ECG, should be undertaken in those patients receiving pimozide in excess of 16 mg daily. Any indication of repolarization changes, such as prolongation of QT intervals beyond 0.52 seconds in adults, or more than 25% above the patient’s original baseline, or T-wave or U-wave changes, should be considered a basis for stopping further increases, possibly lowering the dose, and reviewing the need for pimozide. Caution should be exercised if it is necessary to use pimozide in patients with cardiovascular disorders. Electrolyte imbalance, particularly hypokalemia, should be considered a risk factor.

Liver Disease: Caution is advised in patients with liver disease because pimozide is metabolized in the liver.

Tardive Dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or after drug discontinuation. The syndrome is mainly characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dosage is increased or when a switch is made to a different antipsychotic drug. Treatment should be discontinued as soon as possible.

Neuroleptic Malignant Syndrome: In common with other antipsychotic drugs, pimozide has been associated with neuroleptic malignant syndrome: an idiosyncratic response characterized by hyperthermia, generalized muscle rigidity, autonomic instability and altered consciousness. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment should be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.

Hyperpyrexia, not associated with the above symptom complex, has been reported with other antipsychotic drugs.

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 above 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 antipsychotic drugs.

In schizophrenia, the response to antipsychotic drug treatment may be delayed. If drugs are withdrawn, recurrence of symptoms may not become apparent for several weeks or months. Acute withdrawal symptoms, including nausea, vomiting, transient dyskinetic signs, and insomnia, have very rarely been described after abrupt cessation of high doses of antipsychotic drugs. Gradual withdrawal is advisable.

Potential for Hypotension: Patients receiving pimozide should be observed for evidence of hypotension. Some individuals, especially the elderly or debilitated, have demonstrated transient hypotension for several hours following drug administration.

Precautions: Blood dyscrasia: Leukopenia, granulocytopenia, agranulocytosis and anemia have been reported occasionally following antipsychotic therapy, notably with phenothiazines. Therefore, the possibility of blood dyscrasias cannot be ruled out in patients receiving treatment with pimozide, and they should be observed for any signs or symptoms of blood dyscrasia.

Anticonvulsants: Since pimozide may lower the convulsive threshold, it should be used with caution in epileptic patients and adequate anticonvulsive medication should be maintained.

Antiemetic Effects: As with other antipsychotics, pimozide has a substantial antiemetic effect. Thus, caution should be exercised in cases where the suppression of nausea and vomiting might hinder the diagnosis of an underlying physical disorder.

Pregnancy: The safety of use of pimozide in pregnancy has not been established. Therefore, it should not be administered to women of childbearing potential, particularly during the first trimester of pregnancy, unless, in the opinion of the physician, the expected benefits of the drug to the patient outweigh the potential risk to the fetus or child.

Lactation: Pimozide may be excreted in breast milk. If the use of pimozide is considered essential, breast-feeding should be discontinued.

Children: Safety and effectiveness in children have not been established; therefore, this drug is not recommended for use in the pediatric age group.

Geriatrics: For recommendations for use in elderly see Dosage.

Occupational Hazards: Pimozide may impair alertness, especially at the start of treatment. These effects may be potentiated by alcohol. Patients should be warned of the risks of sedation and advised not to drive or operate machinery during treatment until their susceptibility is known.

Drug Interactions: CNS: Potentiation of the effects of drugs acting on the CNS (anesthetics, opiates, alcohol, etc.) as well as atropine and organophosphorous insecticides may occur with the use of pimozide. Both animal and human data indicate that pimozide may block the action of amphetamines. Therefore, concomitant use of the two medications is not recommended.

Levodopa: Pimozide may in a dose-related way impair the antiparkinson effect of levodopa.

Antihypertensives: Concomitant administration of antihypertensive agents should be undertaken with caution in view of the fact that other antipsychotics, notably the phenothiazines, have blocked the action of these agents.

Drugs that Inhibit Cytochrome P450: Pimozide is metabolized mainly via the cytochrome P450 subtype 3A4 (CYP 3A4) enzyme system and more discreetly via the CYP 2D6 subtype. In vitro data indicate that especially potent inhibitors of CYP 3A4 enzyme system, such as azole antimycotics, antiviral protease inhibitors and macrolide antibiotics will inhibit the metabolism of pimozide, resulting in markedly elevated plasma levels of pimozide. In vitro data also indicate that quinidine diminishes the CYP 2D6-dependent metablism of pimozide. Elevated pimozide levels may enhance the risk of QT prolongation.

Drugs that Prolong QT Interval: Because pimozide prolongs the QT interval of the ECG, an additive effect on QT interval would be anticipated if administered with other drugs, such as phenothiazines (antipsychotics), tricyclic antidepressants or antiarrhythmic agents, which prolong the QT interval. Such concomitant administration should not be undertaken (see Contraindications). Particular care should be taken to avoid toxic plasma levels of lithium when this agent is administered together with pimozide, since such toxic levels have also been associated with QT prolongation.

Adverse Reactions: The following adverse reactions have been reported with pimozide or with other antipsychotic agents:

Extrapyramidal symptoms: In common with all neuroleptics, extrapyramidal symptoms may occur, e.g., tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia. Antiparkinson drugs of the anticholinergic type may be prescribed as required, but should not be prescribed routinely as a preventive measure.

Tardive Dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or may appear after drug therapy has been discontinued (see Warnings).

Neuroleptic Malignant Syndrome: In common with other antipsychotic drugs, pimozide has been associated with neuroleptic malignant syndrome (see Warnings).

Other CNS Effects: These are occasionally reported and include: insomnia, restlessness, agitation, drowsiness, decreased attention, fatigue and depression have been most commonly observed with pimozide. Irritability, tension, jitteriness, excitement, aggressiveness, anxiety, confusion, nightmares and hallucinations have also been recorded. In some instances, aggravation of the patient’s psychotic symptoms has occurred. Toxic confusional states and euphoria have been reported with other antipsychotic therapy.

The most commonly reported neurological adverse reactions are extrapyramidal, including parkinsonism. As with most neuroleptics, reports of parkinsonian side effects, such as tremor, rigidity and sialorrhea, are not uncommon. Akathisia occurs relatively frequently, but can usually be managed by reducing the dosage of pimozide or by the concomitant administration of an antiparkinsonian agent.

Dystonic reactions have been reported, the most common being torticollis, which is generally accompanied by oro-facial symptoms and, in some instances, oculogyric crises, as well as spasms of the face, tongue and jaw. Mouth and throat area dyskinesias, trismus, dysarthria, muscle cramps and athetoid movements have also been observed occasionally. In addition, dizziness or vertigo, weakness, excessive sweating, body temperature disregulation, headache, EEG changes, and an increased incidence of epileptic seizures have been reported, and, in association with other antipsychotics, opisthotonus, hyperreflexia and grand mal convulsions.

Autonomic: Autonomic adverse reactions that have occurred with pimozide are dry mouth, blurred vision, difficulty with accommodation, urinary retention, and urinary and fecal incontinence. Nasal congestion, paralytic ileus and reversed epinephrine effect have been reported with the use of other antipsychotics.

Cardiovascular: Hypotension, tachycardia and fluctuations in blood pressure have been noted with pimozide. Hypertension has occasionally occurred. QT-interval prolongation and/or ventricular arrhythmias have very rarely been reported, and predominantly with high doses and in predisposed patients.

Gastrointestinal: Anorexia, nausea and/or vomiting, constipation, diarrhea, and abdominal cramps or pain have been observed in some patients receiving pimozide.

Endocrine: Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinemia, which may cause galactorrhea, gynecomastia, oligo- or amenorrhea and impotence. Very rarely, cases of hyponatremia due to either Syndrome of Inappropriate ADH Secretion (SIADH) or psychogenic polydipsia, have been reported.

Miscellaneous: Cases of urticaria and erythematous rash have been reported with pimozide, as well as instances of severe edema, generally limited to the facial area.

Fever, laryngeal edema, angioneurotic edema, asthma, anaphylactoid reactions, hyperpyrexia, obstructive jaundice, biliary stasis, photosensitivity, eczema, exfoliative dermatitis, maculopapular and acneiform reactions, and alopecia have been reported in association with the use of other antipsychotics. Blood dyscrasias (agranulocytosis, leukopenia, granulocytopenia, pancytopenia, thrombocytopenic purpura, eosinophilia, anemia, aplastic anemia) have also occurred.

Cerebral edema, peripheral edema and altered cerebrospinal fluid proteins have been observed with other antipsychotic agents.

Since a peculiar skin-eye syndrome has been recognized as a side effect following long-term treatment with certain phenothiazines, the possibility of this side effect occurring with pimozide cannot be excluded. This reaction is marked by progressive pigmentation of areas of skin or conjunctivae and may be accompanied by discoloration of the exposed sclera and cornea. Opacities of the anterior lens and cornea described as irregular or stellate in shape have also been reported.

Hyperpyrexia: Hyperpyrexia has been reported with other antipsychotic drugs.

Symptoms And Treatment Of Overdose: Symptoms: In general, the signs and symptoms of overdosage with pimozide would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be extrapyramidal symptoms. The risk of cardiac arrhythmias, possibly associated with QT-prolongation should be considered. If these arrhythmias are severe, they can be associated with hypotension and circulatory collapse.

Treatment: There is no specific antidote to pimozide. In the event of overdosage, gastric lavage, establishment of a patent airway and, if necessary, mechanically-assisted respiration are advised. Electrocardiographic monitoring should commence immediately and continue until the ECG parameters are within the normal range. Hypotension and circulatory collapse may be counteracted by use of i.v. 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. Because of the long half-life of pimozide, patients who take an overdose should be observed for at least 4 days. As with all drugs, the physician should consider contacting a Poison Control Centre for additional information on the treatment of overdose.

Dosage And Administration: Adults: The initial recommended dose in patients with chronic schizophrenia for whom pimozide might be indicated is 2 to 4 mg once daily, with weekly increments of 2 to 4 mg until a satisfactory level of therapeutic effect is attained or excessive adverse effects occur. The average maintenance dose is 6 mg daily with the usual range of 2 to 12 mg/day. Daily doses above 20 mg are not recommended.

Geriatrics: The maintenance dose is the same as in adults but it is recommended to start with one half of the adult initial dose.

A single morning dose is recommended for all patients.

Availability And Storage: 2 mg: Each white, uncoated tablet, scored on one side and embossed with McNEIL on the other side, contains: pimozide 2 mg. Nonmedicinal ingredients: calcium stearate, cornstarch, lactose and microcrystalline cellulose. Energy: 1.784 kJ (0.424 kcal). Sodium:

4 mg: Each green, uncoated tablet, scored on one side and embossed with McNEIL on the other side, contains: pimozide 4 mg. Nonmedicinal ingredients: calcium stearate, FD&C Blue No. 1, FD&C Yellow No. 5, lactose, microcrystalline cellulose, starch (corn) and tartrazine. Energy: 1.750 kJ (0.415 kcal). Sodium:

Store at controlled room temperature (15 to 30°C) in well-closed containers.

ORAP® Janssen-Ortho Pimozide Antipsychotic

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General Illness Information Medical Term: Schizophrenia Common Name: Schizophrenia Description: Schizophrenia is a mental disorder that affects a person’s ability to think, feel, and behave….