INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ORAP® 1 mg tablets
ORAP® 4 mg tablets

SCHEDULING STATUS:
Schedule 5

PROPRIETARY NAME
(and dosage form):

ORAP® 1 mg tablets
ORAP
® 4 mg tablets

COMPOSITION
Each tablet contains 1 mg of the active ingredient,
pimozide.
Each tablet contains 4 mg of the active ingredient, pimozide.

PHARMACOLOGICAL CLASSIFICATION
A.2.6.5 Central nervous system depressants. Tranquillisers. Miscellaneous structures.

PHARMACOLOGICAL ACTION
Pimozide is a neuroleptic of the diphenylbutylpiperidine series. It is a potent long-acting anti-psychotic. Pimozide selectively blocks the central dopaminergic receptors but has minimal effect on the noradrenergic receptors. Extrapyramidal effects are encountered.
Endocrine effects and ECG changes have also been reported with pimozide.
The clinical effects of this pharmacological action are to control effectively hallucinations and delusions and to normalize incoherent thought processes and bizarre behaviour patterns. Pimozide rarely produces significant hypnosedation or hypnokinesis and does not impair motor ability.
More than 50% of a dose of pimozide is absorbed after oral administration. Peak serum levels occur generally 6 –8 hours (range: 4 –12 hours) after dosing. Pimozide appears to undergo significant first pass metabolism. Pimozide is extensively metabolised, primarily by N-dealkylation in the liver. The two major metabolites have been identified: 1-(4-piperidyl)-2-benzimidazolinone and 4,4-bis-(4-fluorphenyl) butyric acid. These metabolites have no anti-psychotic activity. Only a very small fraction of pimozide is excreted unchanged in the urine. The major route of elimination of the metabolites is via the kidney.
The mean elimination half-life of pimozide in schizophrenic patients is approximately 55 hours.
There is more than a 10-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.

INDICATIONS
ORAP tablets are indicated for the maintenance treatment of chronic schizophrenics who respond to the anti-hallucinatory and anti-delusional effects of classical neuroleptics but who do not need, or are handicapped by, the hypnosedative action of such neuroleptics.
ORAP tablets are suitable for the long-term anti-psychotic maintenance therapy of psychically compensated schizophrenic out-patients.
ORAP tablets are indicated for initial and maintenance therapy in out-patients and in newly or re-admitted patients in whom psychomotor agitation, aggressiveness and severe anxiety are not the predominant symptoms.

CONTRA-INDICATIONS
Sensitivity to pimozide or other neuroleptics.
ORAP is contra-indicated in central nervous system depression and comatose states.
It should not be used in depressive disorders or Parkinson's syndrome. ORAP is contra-indicated in epilepsy.
ORAP is contra-indicated in patients congenitally long QT-syndrome, and in patients with a history of cardiac arrhythmias. A pre-treatment ECG is thus recommended to exclude these conditions.
The concomitant use of CYP 3A4 inhibiting agents such as azole antimycotics, antiviral protease inhibitors and macrolide antibiotics is contraindicated. The concomitant use of CYP 2D6 inhibiting agents 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.
Safety in pregnancy, lactation and children under the age of 12 years has not been established.

WARNINGS
Caution should be observed in cases of Parkinson's syndrome and epilepsy.
Caution should be exercised when pimozide, which may cause drowsiness and sedation, is taken with other central nervous system depressants.

DOSAGE AND DIRECTIONS FOR USE
A single morning dose is recommended for all patients.
Since individual response to ORAP is variable, dosage should be individually determined and is best initiated and titrated under close clinical supervision.
When patients are transferred from other neuroleptic medication to ORAP tablets, the former medication should be decreased gradually. This is particularly important for patients with signs of psychomotor agitation.
The combination of maintenance therapy with ORAP tablets and an additional psychotropic medicine (such as neuroleptic, tranquillizer or sedative antidepressant) may sometimes prove advantageous.
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 in adults but is recommended to start with half of the adult starting dose.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Extrapyramidal symptoms may occur, e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia and 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:
Tardive dyskinesia may appear in some patients on long-term therapy or after drug discontinuation.
The syndrome is mainly characterised 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 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:
ORAP has been associated with neuroleptic malignant syndrome: an idiosyncratic response characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness.
Hyperthermia is often an early sign of this syndrome. Anti-psychotic treatment should be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.
Other central nervous system effects:
These are occasionally reported and include drowsiness, insomnia, anxiety, headache and EEG changes and, in association with other anti-psychotic agents, grandmal convulsions.
Endocrine effects:
Hormonal effects of antipsychotic neuroleptic medicines include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia, oligo- or amenorrhoea and impotence. Very rare cases of hyponatraemia due to either Syndrome of Inappropriate ADH Secretion (SIADH) or psychogenic polydipsia, have been reported.
Cardiovascular effects:
Hypotension may very rarely occur. QT-interval prolongation and/or ventricular arrhythmias have rarely been reported, and predominantly with high doses and in predisposed patients.
Hypersensitivity reactions such as skin rash are exceptional. Other reported side-effects are: dizziness or vertigo, weakness, dry mouth, excessive sweating, body temperature disregulation and gastro-intestinal symptoms such as nausea and constipation.
Increased serum-cholesterol may occur. Glucosuria and blurred vision or other visual disturbances have been reported.
Cases of agranulocytosis have been reported but are extremely rare. Symptoms of sore throat and fever should be reported immediately and white cell count monitored.
Jaundice may rarely occur.
Precautions
Increased psychomotor activity:

Clinical trials with pimozide indicate that it is not or only poorly effective in the management of agitation, excitement and severe anxiety.
Liver disease:
Caution is advised in patients with liver disease because pimozide is metabolised in the liver.
Cardiac monitoring:
Cases of sudden unexpected death have been reported with pimozide, generally in doses in excess of the recommended maximum of 20 mg per day. Periodic assessment of cardiac function should be undertaken in those patients receiving pimozide in excess of 16 mg daily. If repolarisation 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 preferably be reduced.
Kinetics of response/withdrawal:
In schizophrenia, the response to anti-psychotic drug treatment may be delayed. If medication is 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 been described after abrupt cessation of high doses of anti-psychotic medicines. Gradual withdrawal is advisable.
Effects on driving ability and use of machinery:
ORAP 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.
Interactions
ORAP may, in a dose-related way, impair the anti-parkinsonian effect of levodopa.
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 antibotics, will inhibit the metabolizm of pimozide, resulting in markedly elevated plasma levels of pimozide. In-vitro data also indicated that quinidine diminishes the CYP 2D6 dependant metabolism of pimozide. Elevated pimozide levels may enhance the risk of QT-prolongation.
The possible additive effects of concomitant use of other medicines known to prolong the QT-interval (e.g. other anti-psychotic medicines, certain anti-arrhythmic medicines) should be considered in patients receiving long term pimozide treatment.
Electrolyte disturbances, notably hypokalaemia should be considered a risk factor.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Manifestations:
In general, the signs and symptoms of overdosage of 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 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 and treatment is primarily supportive. 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 returns to normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic treatment.
Associated hypotension and circulatory collapse can be counteracted by supportive measures such as intravenous fluids, plasma or concentrated albumin and vasopressors.
In cases of severe extrapyramidal symptoms, anti-parkinsonian 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.

IDENTIFICATION
An apricot coloured, biconvex tablet embossed with "0" above "1" on one side and “Janssen”on the other.
An green, circular, biconvex tablet with "Janssen" on the one side and "0" above "4" (local) or cross-scored (imported) on the other side.

PRESENTATION
Cartons containing one or more blister packs of 20 or 25 tablets each.

STORAGE INSTRUCTIONS
Store below 25°C. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
ORAP 1 mg –B/2.6.5/1017
ORAP 4 mg –K/2.6.5/137

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN-CILAG
JANSSEN PHARMACEUTICA (PTY) LTD.
(Reg No. 80/11122/07)
15th Road, HALFWAY HOUSE 1685.

DATE OF PUBLICATION OF THIS PACKAGE INSERT
11 June 1979.

                                Code: 023512
                                                        99E
B
® = TRADEMARK

Britepak
Updated on this site: October 1999

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