Orap Forte

/ J-C Health Care Ltd

A single morning dose is recommended for all patients. Since individual response to anti-psychotic drugs is variable, dosage should be individually determined and is best initiated and titrated under close clinical supervision.
Adults: The initial recommended dose in patients with chronic schizophrenia 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 per day. The maximum daily dose is 20 mg. The patients should be reviewed regularly to ensure the minimum effective dose is being used.
Elderly patients: The maintenance dose is the same as in adults but it is recommended to startwith half of the adult starting dose.
Children: The recommended dose is half that of the adult dose. Experience in children below the age of 12 years is very limited.

Orap is mainly indicated in chronic psychoses, responsive to the specific antipsychotic effects of neuroleptics and as basic medication for long-term antipsychotic maintenance therapy aimed at promoting, restoring, or maintaining optimum social integration. Orap is also indicated as an initial therapy in outpatients and in newly or readmitted patients, provided psychomotor agitation, aggressiveness, or severe anxiety do not constitute the predominant symptoms. Orap is, moreover, indicated in patients with borderline psychosis, causing unadapted social behavior and requiring improvement or stabilization of their social integration.

Orap is contraindicated in central nervous system depression, comatose states, and in individuals who have previously displayed hypersensitivity to the drug. It should not be used in depressive disorders or Parkinson’s syndrome. Orap is contraindicated in patients with congenitally long QT syndrome or with a family history of this syndrome, and in patients with a history of cardiac arrhythmias or Torsade de Pointes. A pre-treatment ECG is thus recommended to exclude these conditions. Orap should not be used in cases of acquired long QT interval, such as associated with concomitant use of drugs known to prolong the QT interval known hypokalaemia or hypomagnesaemia,or clinically significant bradycardia. The concomitant use of CYP 3A4 inhibiting drugs such as azole antimycotics, antiviral protease inhibitors, macrolide antibiotics and nefazodone is contraindicated. The concomitant use of CYP 2D6 inhibiting drugs such as quinidine is also contraindicated. The inhibition of either or both of these cytochrome P450 systems, may result in the elevation of pimozide blood concentration and increase the possibility of QT-prolongation. Orap is contraindicated with concomitant use of serotonin reuptake inhibitors, such as, sertraline, paroxetine, citalopram and escitalopram.

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. Analyses of seventeen placebocontrolled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drugtreated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
Cardiac monitoring: There have been very rare reports of QT prolongation, ventricular arrhythmias, and Torsade de Pointes in patients without risk factors for QT prolongation administered therapeutic doses of pimozide, and in the setting of overdose. Ventricular tachycardia and ventricular fibrillation (in some cases with fatal outcomes) have also been reported, in addition to very rare reports of sudden death and cardiac arrest. As with other neuroleptics, cases of sudden unexpected death have been reported with pimozide at recommended doses and in the setting of overdose. An ECG should be performed prior to initiation of treatment with pimozide, as well as periodically during treatment. If repolarization changes (prolongation of QT interval, T-wave changes or U-wave development) appear or arrhythmias develop, the need for treatment with pimozide in these patients should be reviewed. They should be closely monitored and their dose of pimozide should be reduced or the drug discontinued. If QT or QTc exceeds 500 msec, pimozide should be discontinued.
Neuroleptic malignant syndrome: In common with other antipsychotic drugs, ORAP has been associated with neuroleptic malignant syndrome: an idiosyncratic response characterized by hyperthermia, generalised muscle rigidity, autonomic instability, 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.
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.
Seizures: As with other antipsychotic drugs, ORAP should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. In addition, grand mal convulsions have been reported in association with ORAP.
Extrapyramidal symptoms: In common with all neuroleptics, extrapyramidal symptoms may occur. Antiparkinson drugs of the anticholinergic type may be prescribed as required, but should not be prescribed routinely as a preventive measure.
Liver: Caution is advised in patients with liver disease because pimozide is metabolized in the liver.
Kinetics of response/withdrawal: 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. There is limited information available on the use of ORAP in children under 12 years of age.
Body Temperature Regulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing pimozide to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity or being subject to dehydration.Increased psychomotor activity Clinical trials with pimozide indicate that it is not or only poorly effective in the management of agitation, excitement and severe anxiey.
Endocrine Effects: Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia, oligomenorrhoea or amenorrhoea, and erectile dysfunction. Pimozide should only be used with great caution in patients with thyrotoxicosis.
Other: Caution is also advised in patients with renal failure, Parkinson’s disease and phaeochromocytoma. Concomitant use of pimozide with other neuroleptics should be avoided.
For full details see prescribing information.

Clinical Trial Data: Placebo-Controlled Double-Blind Data – Adverse Drug Reactions Reported at ≥2% Incidence The safety of Orap was evaluated in 299 subjects who participated in 7 placebo-controlled, double-blind clinical trials. The information presented in this section was derived from pooled data. The specific patient population in the different trials consisted of patients with schizophrenia, patients with borderline psychosis or with behavioural disorders.
For full details see prescribing information.

Pimozide is metabolised mainly via the cytochrome P450 subtype 3A4 (CYP3A4) 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, macrolide antibiotics and nefazodone will inhibit the metabolism of pimozide, resulting in markedly elevated plasma levels of pimozide. In-vitro data also indicated that quinidine diminishes the CYP 2D6 dependent metabolism of pimozide. Elevated pimozide levels may enhance the risk of QT-prolongation. Concomitant use of pimozide with drugs known to be inhibitors of cytochrome P450 CYP 3A4 or CYP 2D6 is contraindicated. Concomitant use of pimozide with drugs known to prolong the QT interval is contraindicated. Examples include certain antiarrhythmics, such as those of Class IA (such as quinidine, disopyramide and procainamide) and Class III (such as amiodarone and sotalol), tricyclic antidepressants (such as amitriptyline), certain tetracyclic antidepressants (such as maprotiline), certain other antipsychotic medications (such as phenothiazines, and sertindole), certain antihistamines (such as astemizole and terfenadine), cisapride, bepridil, halofantrine and sparfloxacin. This list is only indicative and not exhaustive. Do not administer in combination with drugs causing electrolyte alteration. Concomitant use with diuretics should be avoided, in particular those causing hypokalemia. As grapefruit juice is known to inhibit the metabolism of CYP3A4 metabolised drugs, concomitant use of grapefruit juice with Orap should be avoided.
An in vivo study of pimozide added to steady state sertraline revealed a 40% increase in the pimozide AUC and Cmax. An in vivo study of co-administered pimozide and citalopram resulted in a mean increase of QTc values of approximately 10 milliseconds. Citalopram did not alter the AUC and Cmax of pimozide. An in vivo study of co-administered pimozide (a single 2 mg dose) and paroxetine (60 mg daily) was associated with mean increases of 151% in pimozide AUC and 62% in pimozide Cmax. As CYP1A2 may also contribute to the metabolism of Orap, prescribers should be aware of the theoretical potential for drug interactions with inhibitors of this enzymatic system. Orap may in a dose-related way impair the antiparkinson effect of levodopa.
For full details see prescribing information.

The safety of the use of pimozide in pregnancy has not been established. Therefore, it should not be administered to women of child-bearing 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.
Orap may be excreted in breast milk. If the use of Orap is considered essential, breast-feeding should be discontinued. Animal data has shown some embryo-toxicity at dose levels similar to the maximum human use level (MHUL). Fetal growth retardation and fetal-toxicity was observed at dose levels of approximately 6 times the MHUL on an mg/kg basis. Teratogenic effects have not been observed. Neonates exposed to antipsychotic drugs (including pimozide) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms that may vary in severity following delivery. These symptoms in the neonates may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder.

Symptoms: In general, the signs and symptoms of overdose with Orap would be an exaggeration of known pharmacological effects, the most prominent of which would be extrapyramidal symptoms. The risk of cardiac arrhythmias, possibly associated with QT-prolongation and ventricular arrhythmias including Torsade de Pointes 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. Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration are advised. Continous Electrocardiographic monitoring should be performed due to the risk of QT interval prolongation and ventricular arrhythmias including Torsade de Pointes and continue until the ECG returns to normal. Severe arrhythmias should be treated with appropriate antiarrhythmic treatment. Associated hypotension and circulatory collapse can be counteracted by supportive measures such as intravenous fluids, plasma or concentrated albumin, and vasopressors such as dopamine or dobutamine. In cases of severe extrapyramidal symptoms, antiparkinsonian medication should be administered. Because of the long half-life of pimozide, patients who have taken an overdose should be observed for at least 4 days.