Pimozide

Orap is an antipsychotic of the diphenylbutyl-piperidine series and is indicated in: - Chronic schizophrenia, for the treatment of symptoms and prevention of relapse. - Other psychoses, especially paranoid and monosymptomatic hypochondriacal psychoses (eg delusional parasitosis).

Orap is indicated in adults and children over 12 years old.

Posology Orap is intended for once daily oral administration in adults and children over 12 years of age. Since individual response to antipsychotic drugs is variable, dosage should be individually determined and is best initiated and titrated under close clinical supervision.

In determining the initial dose, consideration should be given to the patient's age, severity of symptoms and previous response to other neuroleptic drugs. Dose increases should be made at weekly intervals or longer, and by increments of 2-4 mg in the daily dose.

The patient should be reviewed regularly to ensure the minimum effective dose is being used.

Chronic schizophrenia:

The dose ranges between 2 and 20 mg daily, with 2 mg as a starting dose. This may be increased according to response and tolerance to achieve an optimum response. Other psychoses, paranoid states and monosymptomatic hypochondriacal psychoses (MHP): An initial dose of 4 mg daily which may then be gradually increased, if necessary, according to response, to a maximum of 16 mg daily.

Use in elderly:

Elderly patients require half the normal starting dose of pimozide. Paediatric population (less than 12 years old) No data are available Method of Administration Oral use.

The safety of ORAP was evaluated in 165 pimozide-treated subjects who participated in seven placebo-controlled trials of patients with schizophrenia, or patients with anxiety or behavioural disorders, and in 303 pimozide-treated subjects who participated in eleven active-comparator controlled clinical trials in patients with schizophrenia (10 trials, including chronic schizophrenia) or psychic fatigability (1 trial).

Based on pooled safety data from these clinical trials, the most commonly reported (≥ 9% incidence) Adverse Drug Reactions (ADRs) were (with % incidence): Nervous System Disorders: Dizziness (11) and Somnolence (11), Extrapyramidal Disorder (9); Muscle Rigidity (9); Hyperhidrosis (13); Nocturia (12).

Including the above-mentioned ADRs, the following table (next page) displays ADRs that have been reported with the use of ORAP from either clinical-trial or post-marketing experiences.

The displayed frequency categories use the following convention:

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated form the available data) Adverse Drug Reactions Frequency Category System Organ Class Very Commo n (≥ 1/10) Common (≥ 1/100 to < 1/10 ) Uncommon (≥ 1/1,000 to < 1/100 ) Not Known Endocrine Disorders Hyperglycaemia (in patients with pre-existing diabetes); Blood Prolactin Increased Metabolism and Nutrition Disorders Anorexia Hyponatraemia Psychiatric Disorders Depression; Insomnia; Agitation; Restlessness Libido Decreased Nervous System Disorders Dizziness; Somnolence; Extrapyramidal Disorder; Akathisia; Headache; Tremor; Lethargy; Muscle Rigidity Bradykinesia; Cogwheel Rigidity; Dyskinesia; Dystonia; Dysarthria Neuroleptic Malignant Syndrome; Grand Mal Convulsion; Tardive Dyskinesia; Neck Rigidity Eye Disorders Vision Blurred Oculogyric crisis Cardiac Disorders Torsade de Pointes; Ventricular Tachycardia; Ventricular Fibrillation Gastrointestina l Disorders Constipation; Dry Mouth; Vomiting; Salivary Hypersecretion Skin and subcutaneous tissue disorders Hyperhidrosis Sebaceous Gland Overactivity Pruritus; Rash, Urticaria Musculoskeleta l and Connective Muscle Spasms Adverse Drug Reactions Frequency Category System Organ Class Very Commo n (≥ 1/10) Common (≥ 1/100 to < 1/10 ) Uncommon (≥ 1/1,000 to < 1/100 ) Not Known Tissue Disorders Renal and urinary disorders Nocturia Urinary frequency Glycosuria Pregnancy, puerperium and perinatal conditions.

6) Reproductive System and Breast Disorders Erectile Dysfunction Amenorrhoea Galactorrhoea; Gynaecomastia General Disorders and Administration Site Conditions Extreme exhaustion Face oedema Body Temperature Dysregulation; Hypothermia Investigations Weight increased Electrocardiogram QT Interval Prolonged; Electroencephalogra m Abnormal In addition to the above, cardiac arrest and sudden unexplained death have been reported with the use of pimozide.

These events should be considered ADRs associated with the class of medicinal products, the D2, dopamine-antagonist neuroleptics. Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs (frequency unknown).

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard

In common with several other neuroleptics, pimozide has been reported to prolong the QT interval. It is, therefore, contra-indicated in patients with a pre-existing congenital prolongation of QT, or with a history or family history of this syndrome, and in patients with a history of cardiac arrhythmias and a history of Torsades de pointes.

5), known uncorrected hypokalaemia or hypomagnesaemia, or clinically significant cardiac disorders (eg recent acute myocardial infarction, uncompensated heart failure, arrhythmias treated with class IA and III antiarrhythmic medicinal products) or clinically significant bradycardia.

1. It should not be used in patients with depression or Parkinson’s syndrome. The concomitant use of orally or parenterally administered cytochrome P450 CYP 3A4 inhibiting drugs such as azole antimycotics, antiviral protease inhibitors, macrolide antibiotics and nefazodone is contra-indicated.

The concomitant use of CYP 2D6 inhibiting drugs such as quinidine is also contra-indicated. 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.

5).

A single morning dose is recommended for all patients. 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 per day. Daily doses above 20 mg are not recommended. 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 start with half of the adult starting dose.

56 Melting Range: 214-218oC.

Description:

White to creamy-white crystalline powder. 18 Composition: pms-PIMOZIDE, 2 mg Tablets contain 2 mg Pimozide USP and following non-medicinal ingredients: Calcium Stearate, Lactose, Microcrystalling Cellulose, Starch (Corn). pms-PIMOZIDE, 4 mg Tablets contain 4 mg Pimozide USP and following non-medicinal ingredients: Calcium Stearate, Lactose, Microcrystalling Cellulose, Starch (Corn), FD&C Blue #1 Lake 13% and FD&C Yellow #5 Lake 15%.

pms-PIMOZIDE, 10 mg Tablets contain Pimozide Micronized and following non-medicinal ingredients: Colloidal Silicon Dioxide, Croscarmellose Sodium, FD&C Yellow #6, Lactose Hydrous Spray Dried, Magnesium Stearate and Microcrystalline Cellulose.

Stability and Storage Recommendations Store at controlled room temperature (15°C-30°C) in well-closed containers. 19 AVAILABILITY OF DOSAGE FORMS pms-PIMOZIDE (pimozide) is available as tablets of the following strengths: 2 mg pimozide as white, flat face bevelled edge, uncoated tablets, scored and engraved “PIM 2" on the same side; in HDPE bottles of 100.

4 mg pimozide as green, flat face bevelled edge, uncoated tablets, scored and engraved “PIM 4 “ on the same side; in HDPE bottles of 100. 10 mg pimozide as orange, round, flat face bevelled edge tablets, scored and engraved “PIM 10" on the same side: in HPDE bottles of 100.

PHARMACOLOGY The pharmacological profile of pimozide in laboratory animals resembles that of other antipsychotics. Its pharmacological properties are more similar to haloperidol than to chlorpromazine, but it has a slower onset and longer duration of action than either of these drugs.

As with other neuroleptics, pimozide reduces locomotor and exploratory behaviour at low doses, and induces catatonic immobility and palpebral ptosis in rats at higher doses. However, the muscle hypotonia seen regularly after administration of chlorpromazine is not observed with pimozide or haloperidol.

In inhibiting conditioned avoidance responding in rats and dogs and self-stimulation in rats, pimozide is less active than haloperidol but considerably more potent than chlorpromazine. 20 Pimozide is a potent antagonist to amphetamine- and apomorphine-induced stereotypy in most animal species tested.

It also blocks apomorphine-induced emesis. Stereotypic chewing in rats is inhibited more than agitation by both pimozide and haloperidol, whereas chlorpromazine is significantly more active against agitation. Pimozide has little activity in the norepinephrine test in rats.

It is 66 times less active than chlorpromazine and 13 times less active than haloperidol in this test. 5 mg/kg chlorpromazine subcutaneously. Obvious to severe extrapyramidal (dystonic) effects were observed at the same doses in 4 out of 8 pimozide-treated, 8 out of 8 haloperidol- treated and 1 out of 8 chlorpromazine-treated monkeys.

Pimozide causes no significant alterations in the hemodynamic parameters in cardiovascular experiments in rats, dogs, and dwarf pigs. It is a weak hypotensive agent and norepinephrine antagonist in rats and dogs, and exhibits very weak alpha-adrenergic blocking activity in dogs.

In other tests, it has been found to antagonize the action of angiotensin on rat colon and rabbit aorta. Bio- and histochemical studies in rats have indicated that, at the lower-dose levels, pimozide is a highly selective blocker of central dopamine receptors and increases turnover of dopamine in the central nervous system.

At higher doses, increased turnover of noradrenaline has also been observed. The following Table shows dosage details for some of the above-mentioned tests. C. O. C. O. C. O. 6 * Results from earlier pharmacological studies. ** The ED50's varied with time after administration; on the anti-apomorphine test the lower ED50 with PIM occurred at 4 hours, with HAL and CPZ at 1 hour; the respective peak values on the anti-amphetamine test occurred at 4, 1 and 2 hours and on the anti-norepinephrine test at 2, 1 and 1 hours.

Metabolism:

Pimozide is well absorbed after oral […]

Postmarketing Data Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience with pimozide that meet threshold criteria are included in the table below. The adverse drug reactions are ranked by frequency, using the following conversion: Very common $1/10 Common $ 1/100 and < 1/10 Uncommon $ 1/1,000 and < 1/100 Rare $ 1/1,000 and < 1/1,000 Very rare <1/10,000 including isolated repots The frequencies provided below reflect reporting rates for adverse drug reactions (ADR) from spontaneous reports and do not represent more precise estimates that might be obtained in clinical or epidemiological studies: Table: Adverse Drug Reactions in Postmarketing Reports Cardiac Disorders Very Rare torsade de pointes, ventricular tachycardia, ventricular fibrillation Endocrine Disorder Very rare hyperprolactinemia Eye Disorder Very Rare oculogyration Gastrointestinal Disorders Very Rare salivary hypersecretion, dry mouth, constipation General Disorder and Administration Site Conditions Very Rare hypothermia Investigations Very Rare electrocardiogram QT prolonged, electroencephalogram abnormal, blood prolaction increase 14 Musculoskeletal and Connective Tissue Disorders Very Rare muscle rigidity, nuchal rigidity Nervous System Disorders Very Rare extrapyramidal disorder, tardive dyskinesia, bradykinesia, akathisia, dystonia, tremor, cogwheel rigidity, somnolence, headache, neuroleptic malignant syndrome, grand mal convulsion, dizziness Psychiatric Disorder Very Rare insomnia Reproductive System and Breast Disorder Very Rare galactorrhoea, amenorrhoea, gynaecomastia, erectile dysfunction Skin and Subcutaneous Tissue Disorders Very Rare rash, urticaria, pruritus, hyperhidrosis Autonomic Effects blurred vision, difficulty with accommodation, urinary retention, and urinary and fecal incontinence.

Miscellaneous Blood Dyscrasias agranulocytosis, leukopenia, granulocytopenia, pancytopenia, thrombocytopenic purpura, eosinophilia, anemia, aplastic anemia 15 SYMPTOMS AND TREATMENT OF OVERDOSAGE Symptoms In general, the signs and symptoms of overdosage with pms-PIMOZIDE (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 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. In the event of overdosage, gastric lavage, establishment of a patent airway and, if necessary, mechanically-assisted respiration are advised. Continuous electrocardiographic monitoring should be performed due to risk of QT interval prolongation and ventricular arrhythmias including Torsade de Pointes and continued until the ECG parameters are within the normal range.

Severe arrhythmias should be treated with appropriate antiarrhythmic treatment. Associated hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as dopamine or dobutamine.

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. 16 DOSAGE AND ADMINISTRATION A single morning dose is recommended for all patients. 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 per day. Daily doses above 20 mg are not recommended. 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 start with half of the adult starting dose.

56 Melting Range: 214-218oC.

Description:

White to creamy-white crystalline powder. 18 Composition: pms-PIMOZIDE, 2 mg Tablets contain 2 mg Pimozide USP and following non-medicinal ingredients: Calcium Stearate, Lactose, Microcrystalling Cellulose, Starch (Corn). pms-PIMOZIDE, 4 mg Tablets contain 4 mg Pimozide USP and following non-medicinal ingredients: Calcium Stearate, Lactose, Microcrystalling Cellulose, Starch (Corn), FD&C Blue #1 Lake 13% and FD&C Yellow #5 Lake 15%.

pms-PIMOZIDE, 10 mg Tablets contain Pimozide Micronized and following non-medicinal ingredients: Colloidal Silicon Dioxide, Croscarmellose Sodium, FD&C Yellow #6, Lactose Hydrous Spray Dried, Magnesium Stearate and Microcrystalline Cellulose.

Stability and Storage Recommendations Store at controlled room temperature (15°C-30°C) in well-closed containers. 19 AVAILABILITY OF DOSAGE FORMS pms-PIMOZIDE (pimozide) is available as tablets of the following strengths: 2 mg pimozide as white, flat face bevelled edge, uncoated tablets, scored and engraved “PIM 2" on the same side; in HDPE bottles of 100.

4 mg pimozide as green, flat face bevelled edge, uncoated tablets, scored and engraved “PIM 4 “ on the same side; in HDPE bottles of 100. 10 mg pimozide as orange, round, flat face bevelled edge tablets, scored and engraved “PIM 10" on the same side: in HPDE bottles of 100.

PHARMACOLOGY The pharmacological profile of pimozide in laboratory animals […]