Active ingredients: Pimozide
ORAP 4 mg tablets
Why is Orap used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antipsychotics derived from diphenylbutylpiperidine
THERAPEUTIC INDICATIONS
ORAP is particularly indicated as a basic drug during long-term maintenance antipsychotic therapy in chronic and acute psychotic patients, sensitive to the specific antipsychotic effects of neuroleptics. ORAP is also indicated as attack therapy in outpatient or hospitalized patients recently or readmitted to the clinic provided that psychomotor agitation, aggression or particularly severe anxiety states are not the dominant symptoms of the clinical picture. ORAP is indicated, finally, in the borderline cases between schizophrenic and neurotic forms (eg paranoid and schizoid states) which involve difficulties in social relations.
The use of the product in high doses must be limited to hospitals and nursing homes with the indications reduced to the treatment of resistant cases.
Contraindications When Orap should not be used
Hypersensitivity to the active substance or to any of the excipients Comatose states of any origin. Endogenous depression and Parkinson's disease. Pregnancy (see also "Special warnings").
Clinically significant heart disease (e.g. recent acute myocardial infarction, decompensated heart failure, arrhythmias treated with class Ia and III antiarrhythmic drugs).
QTc interval prolongation.
Subjects with a family history of arrhythmia or torsades de pointes.
Uncorrected hypokalemia.
Concomitant use of QTc prolonging drugs, such as the following:
- azole derivatives used for systemic antifungal therapies (eg: ketoconazole, itraconazole, miconazole and fluconazole); however, ORAP can be used in combination with the local use formulations of these drugs (eg creams, lotions, vaginal pessaries);
- macrolide-type antibiotics (eg: erythromycin, clarithromycin or troleandomycin);
- some anti-AIDS drugs (protease inhibitors);
- some antidepressants, such as nefazodone, amitriptyline, maprotiline, sertraline, paroxetine, citalopram and escitalopram;
- some other antipsychotics, such as chlorpromazine and sertindole;
- some heart-active drugs, such as quinidine, disopyramide, procainamide, amiodarone, sotalol and bepridil;
- some antihistamines, such as astemizole and terfenadine;
- cisapride, a drug used for some digestive problems;
- halofantrine, antimalarial drug;
- sparfloxacin, antibiotic drug.
If you are taking these or other medicines, inform your doctor, who will evaluate which medicines can be used at the same time as ORAP (see also the section "Interactions").
ORAP is not indicated in states of aggression and psychomotor agitation (see also "Special warnings").
The product in high doses should not be used in asthenia and neurosis.
Precautions for use What you need to know before taking Orap
Use with caution in patients with cardiovascular disease or a family history of QT prolongation.
Carry out a basic ECG before starting treatment (see paragraph "Contraindications").
Monitor the ECG during therapy based on the patient's clinical condition.
During therapy, reduce dosage if QT prolongation is observed and discontinue if QTc is> 500ms.
Periodic checking of electrolytes is recommended.
Avoid concomitant therapy with other neuroleptics.Use with caution if the patient or someone else in their family has a history of blood clots (thrombi), as medicines like these have been associated with the formation of blood clots.
Particular caution will be adopted in epileptic patients, who will be carefully monitored.
With equal caution, therapy with ORAP should be undertaken in elderly patients, due to the greater sensitivity to the drug and in those with hepatic and / or renal insufficiency due to the risk of accumulation, and in individuals whose conditions may be aggravated by the anticholinergic action of pimozide.
An approximately three-fold increase in the risk of cerebrovascular events was observed in randomized clinical trials versus placebo in a population of patients with dementia treated with some atypical antipsychotics. The mechanism of this increased risk is unknown. An increased risk for other antipsychotics or other patient populations cannot be excluded. ORAP should be used with caution in patients with stroke risk factors.
Caution must also be exercised in the case of strenuous exercise, if you go to very hot places or if you don't drink enough. ORAP enhances the effects of alcohol. Therefore, alcohol should be avoided during therapy.
Very rarely, hypotension may occur.
ORAP is metabolized in the liver by certain enzymes. Some people have a variation of one of these enzymes. Dose adjustments are required in subjects metabolising ORAP slowly.
Interactions Which drugs or foods can change the effect of Orap
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
ORAP can potentiate the effects of alcohol, the action of hypotensive and antihypertensive drugs and drugs that depress the central nervous system.
ORAP can alter the effect of antiparkinsonian drugs.
Do not administer concomitantly with QT prolonging drugs such as some class Ia antiarrhythmics (e.g. quinidine, disopyramide and procainamide) and class III (e.g. amiodarone, sotalol), some antihistamines, other antipsychotics and some antimalarials (e.g. quinine and mefloquine) and also moxifloxacin. This list is to be considered only indicative and not exhaustive.
Do not administer concomitantly with drugs that cause electrolyte disturbances.
Concomitant use of diuretics, particularly those that can cause hypokalaemia, should be avoided.
Do not take grapefruit juice while taking ORAP.
Warnings It is important to know that:
Increased psychomotor activity
Clinical studies indicate that ORAP is ineffective, or only poorly, in the treatment of agitation, arousal and severe anxiety.
Liver disease
Patients with liver disease should inform their physician, who may find it advisable to have regular checks during ORAP therapy.
Extrapyramidal symptoms
As with all other neuroleptics, extrapyramidal symptoms may occur (see section "Undesirable effects"). Symptoms include slow, stiff, or jerking limb movements; unusual involuntary posture of the neck, face, eyes or mouth and tongue or facial expressions. It may be necessary to start therapy for these effects to stop. Anticholinergic antiparkinsonian drugs can be prescribed as needed, but these cannot be routinely prescribed as a preventive measure.
Tardive dyskinesia
As with all antipsychotics, tardive dyskinesia may occur in some patients on long-term therapy or after drug discontinuation. The syndrome is predominantly characterized by involuntary rhythmic movements of the tongue, face, mouth or jaw. Manifestations may be permanent in some patients. The syndrome may be masked when treatment is resumed, when the dosage is increased, or when a different antipsychotic is switched. Treatment should be stopped as soon as possible.
Neuroleptic Malignant Syndrome
A potentially fatal symptom complex called Neuroleptic Malignant Syndrome has been reported during treatment with antipsychotic drugs. Clinical manifestations of this syndrome are: hyperpyrexia, muscle stiffness, akinesia, vegetative disorders (irregularities in the pulse and blood pressure, sweating, tachycardia, arrhythmias); changes in consciousness which can progress to stupor and coma. The treatment of the S.N.M. it consists in immediately suspending the administration of antipsychotic drugs and other non-essential drugs and in instituting intensive symptomatic therapy (particular care must be taken to reduce hyperthermia and correct dehydration). If the resumption of antipsychotic treatment is deemed essential, the patient should be carefully monitored.
Seizures
Like other antipsychotics, ORAP should be used with caution in patients with a history of seizures or other conditions that have the potential to lower the seizure threshold. In addition, grand mal seizures have been reported in association with ORAP.
Body temperature regulation
Antipsychotic agents have been attributed with nullifying the body's ability to reduce body temperature. Care should be taken in cases where pimozide is prescribed to patients who may be subjected to conditions that contribute to elevated body temperature, such as strenuous training, exposure to high heat, concomitant administration of anticholinergic drugs, or a tendency to dehydration .
Endocrine effects
The hormonal effects of neuroleptic antipsychotic drugs include: hyperprolactinemia, which can cause galactorrhea, gynaecomastia, oligomenorrhea or amenorrhea, breast swelling, and erectile dysfunction.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
The following symptoms have been observed in newborn babies of mothers who have taken conventional or atypical antipsychotics, including ORAP, during the last trimester (last three months of pregnancy): shaking, muscle stiffness and / or weakness, sleepiness, agitation, breathing problems and difficulty in food intake. If your child shows any of these symptoms, contact your doctor.
Not to be taken in case of confirmed or presumed pregnancy. If in doubt, contact your doctor.
Small amounts of ORAP can be excreted with breast milk. Therefore, do not breastfeed if you are on ORAP therapy. If in doubt, contact your doctor about this.
Effects on ability to drive and use machines
The product, similar to what happens with drugs of the same type, could cause sedation and drowsiness. The subjects under treatment must be warned of this so that they avoid driving vehicles and attending to operations requiring integrity of the degree of supervision.
Dosage and method of use How to use Orap: Dosage
Since the individual response to antipsychotic drugs is variable, the dosage of pimozide should be established on a case-by-case basis, under close medical supervision.
The starting dose for an adult is 1-2 mg per day (depending on body weight and severity of symptoms); it must be adjusted individually until the optimal daily dose is reached. The daily dose should be increased by 2-4 mg at intervals of not less than one week. This optimal maintenance dose usually ranges from 1 to 8 mg per day.
If necessary, it can be progressively increased up to a maximum dose of 20 mg per day.
The patient should be monitored regularly to verify that he is being treated with the lowest effective dose. The daily dose should be taken in the morning in a single dose.
Do not take grapefruit juice while taking ORAP.
When a previous neuroleptic therapy in progress is passed to the administration of ORAP, it is advisable to gradually reduce the doses of the drug previously used, rather than abruptly interrupting it.
After the start of therapy, some time may pass before the symptoms disappear and the drug takes effect. After prolonged administration of ORAP it is advisable to gradually discontinue it due to the possible appearance of transient dyskinesia symptoms.
It is only possible to discontinue therapy with ORAP if directed by the physician. In case of discontinuation of therapy, under medical advice, a gradual withdrawal is recommended, especially if a high dose of the medicine is taken.
With a sudden discontinuation of ORAP the following symptoms may occur: stomach pain, vomiting, temporary muscle spasms and insomnia.
It is therefore recommended that you stay in contact with your doctor if therapy is interrupted.
In the treatment of elderly patients, the posology must be carefully established by the doctor who will have to evaluate a possible reduction of the dosages indicated above.
In poor metabolisers it is recommended that the dose does not exceed 4 mg per day and that doses are not increased earlier than every 14 days.
Overdose What to do if you have taken too much Orap
Possible signs of an overdose are: unusual muscle stiffness, inability to move or stay still and irregular heartbeats.
In case of overdose, given the risk of cardiac arrhythmias, possibly associated with a prolongation of the QT interval and ventricular arrhythmias, including torsades de pointes, it is advisable to monitor the ECG tracing until a normal trace is restored.
In case of accidental ingestion / intake of an excessive dose of ORAP, notify your doctor immediately or go to the nearest hospital.
IF IN ANY DOUBT ABOUT USING ORAP, CONTACT YOUR DOCTOR OR PHARMACIST.
Side Effects What are the side effects of Orap
Like all medicines, ORAP can cause side effects, although not everybody gets them.
- Metabolism and nutrition disorders: anorexia; hyponatremia, weight gain
- Psychiatric Disorders: insomnia, depression, agitation, restlessness, decreased libido
- Nervous system disorders: Dizziness, somnolence, headache, tremor, lethargy, extrapyramidal disorder, akathisia bradykinesia, jerky rigidity, dyskinesia, dystonia, dysarthria, neuroleptic malignant syndrome, grand mal seizures, tardive dyskinesia
- Eye disorders: blurred vision, oculorotation
- Gastrointestinal disorders: constipation, dry mouth, vomiting, salivary hypersecretion
- Skin and subcutaneous tissue disorders: hyperhidrosis, hyperactivity of the sebaceous glands, urticaria, pruritus, rash
- Renal and urinary disorders: nocturia, pollakiuria, glycosuria
- Reproductive system and breast disorders: impotence or erectile dysfunction, amenorrhea, galactorrhea, gynecomastia,
- General disorders and administration site conditions: prostration, facial edema, hypothermia, extreme fatigue
- Musculoskeletal and connective tissue disorders: muscle stiffness, muscle spasms, neck stiffness
- Diagnostic tests: prolongation of the "QT interval on" electrocardiogram, abnormal electroencephalogram; hyperglycemia, hyperprolactinaemia, brain electrical activity abnormalities (EEG)
- Cardiac disorders: torsades de pointes, ventricular fibrillation, ventricular tachycardia
- Blood clots (thrombi) in the veins particularly in the legs (symptoms include swelling, pain and redness in the legs), which can travel through blood vessels in the lungs causing chest pain and difficulty breathing. If you notice any of these symptoms, please contact your doctor immediately.
In older people with dementia, a small increase in the number of deaths has been reported for those patients taking antipsychotics compared to those not taking them.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at “www.agenziafarmaco.gov.it/it/responsabili.” By reporting side effects you can help provide more information on the safety of this medicine. "
Expiry and Retention
Expiry: see the expiry date indicated on the package.
WARNING: Do not use the medicine after the expiry date indicated on the package.
The expiry date refers to the product in intact packaging, correctly stored.
Store at a temperature not exceeding 30 ° C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
KEEP THIS MEDICINAL PRODUCT OUT OF THE SIGHT AND REACH OF CHILDREN.
Deadline "> Other information
COMPOSITION
One tablet contains:
Active ingredient: Pimozide 4 mg.
Excipients: dibasic calcium phosphate dihydrate, corn starch, microcrystalline cellulose, povidone K30, talc, hydrogenated vegetable oil, yellow iron oxide, sodium indigotindisulfonate, aluminum lake.
PHARMACEUTICAL FORM AND CONTENT
20 tablets for oral use.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
ORAP 4 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
One tablet contains:
Active ingredient: pimozide 4 mg.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Tablets
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
ORAP is particularly indicated as a basic drug during long-term maintenance antipsychotic therapy in chronic and acute psychotic patients, sensitive to the specific antipsychotic effects of neuroleptics.
ORAP is also indicated as attack therapy in outpatients or patients recently hospitalized or readmitted to the clinic as long as psychomotor agitation, aggression, or particularly severe anxiety states are not the dominant symptoms of the clinical picture.
Finally, ORAP is indicated in borderline cases between schizophrenic and neurotic forms (eg paranoid and schizoid states) which involve difficulties in social relations.
The use of the product in high doses must be limited to hospitals and nursing homes with the indications reduced to the treatment of resistant cases.
04.2 Posology and method of administration -
Since the individual response to antipsychotic drugs is variable, the dosage of pimozide should be established on a case-by-case basis under close medical supervision.
The starting dose for an adult is 1-2 mg per day (depending on body weight and severity of symptoms). It must be adjusted individually until the optimal daily dose is reached. The daily dose should be increased by 2-4 mg at intervals of not less than one week. This optimal maintenance dose usually varies between 1 and 8 mg per day.
If necessary, it can be progressively increased up to a maximum dose of 20 mg per day.
The patient should be monitored regularly to verify that he is being treated with the lowest effective dose.
The daily dose should be taken in the morning in a single dose.
Do not take grapefruit juice while taking ORAP.
When passing from a previous neuroleptic therapy in progress to the administration of Pimozide, it is advisable to gradually reduce the doses of the drug previously used, rather than abruptly interrupting it.
In the treatment of elderly patients, the posology must be carefully established by the doctor who will have to evaluate a possible reduction of the dosages indicated above.
04.3 Contraindications -
Hypersensitivity to the active substance or to any of the excipients
Comatose states of any origin. Endogenous depression and Parkinson's disease. Pregnancy (see section 4.6).
Clinically significant heart disease (e.g. recent acute myocardial infarction, decompensated heart failure, arrhythmias treated with class Ia and III antiarrhythmic drugs).
QTc interval prolongation.
Subjects with a family history of arrhythmia or torsades de pointes.
Uncorrected hypokalaemia.
Concomitant use of QTc prolonging drugs.
The concomitant use of drugs that inhibit the CYP 3A4 enzyme system such as azole derivatives antifungals, antivirals belonging to protease inhibitors, macrolide-type antibiotics and nefazodone and that of inhibitors of the CYP 2D6 system such as quinidine is contraindicated.
Inhibition of one or both of the above cytochrome P450 systems may cause an increase in plasma pimozide levels and increase the possibility of QT prolongation.
ORAP is contraindicated in case of concomitant use of serotonin reuptake inhibitors, such as sertraline, paroxetine, citalopram and escitalopram (see section 4.5).
Pimozide is not indicated in states of aggression and psychomotor agitation (see section 4.4).
The product in high doses should not be used in asthenia and neurosis.
04.4 Special warnings and appropriate precautions for use -
Increased psychomotor activity
Clinical studies indicate that pimozide is not, or only poorly, effective in the treatment of agitation, arousal and severe anxiety.
Liver disease
Caution is advised in patients with liver disease, as pimozide is metabolised in the liver.
Cardiac monitoring (See also section 4.3 Contraindications)
Use with caution in patients with cardiovascular disease or a family history of QT prolongation.
Carry out a basic ECG before starting treatment (see section 4.3).
Monitor the ECG during therapy based on the patient's clinical condition.
During therapy, reduce dosage if QT prolongation is observed and discontinue if QTc is> 500ms.
Periodic checking of electrolytes is recommended.
Avoid concomitant therapy with other neuroleptics.
Response / suspension kinetics
In schizophrenia, the response to antipsychotic drug treatments may be delayed. If drug therapy is stopped, symptoms of schizophrenia may not reappear for several weeks or months. Acute withdrawal symptoms such as nausea, vomiting, transient signs of dyskinesia and insomnia have been reported very rarely after abrupt cessation of high dose antipsychotic drugs. A gradual suspension of therapy is therefore recommended.
Extrapyramidal symptoms
As with all other neuroleptics, extrapyramidal symptoms may occur (see section 4.8). Anticholinergic antiparkinsonian drugs can be prescribed as needed, but these cannot be routinely prescribed as a preventive measure.
Tardive dyskinesia
As with all antipsychotics, tardive dyskinesia may occur in some patients on long-term therapy or after drug discontinuation. The syndrome is predominantly characterized by involuntary rhythmic movements of the tongue, face, mouth or jaw. Manifestations may be permanent in some patients. The syndrome may be masked when treatment is resumed, when the dosage is increased, or when a different antipsychotic is switched. Treatment should be stopped as soon as possible.
Neuroleptic Malignant Syndrome
As with other antipsychotic drugs, ORAP has been associated with a potentially fatal symptom complex called Neuroleptic Malignant Syndrome. Clinical manifestations of this syndrome are: hyperpyrexia, muscle stiffness, akinesia, vegetative disorders (irregularities in the pulse and blood pressure, sweating, tachycardia, arrhythmias); changes in consciousness which can progress to stupor and coma. Hyperthermia is often an early sign of this syndrome. The treatment of NMS consists in immediately stopping the administration of antipsychotic and other non-essential drugs and in instituting intensive symptomatic therapy (particular care must be taken to reduce hyperthermia. and in correcting dehydration.) If resumption of antipsychotic treatment is deemed essential, the patient should be carefully monitored.
Seizures
Like other antipsychotics, ORAP should be used with caution in patients with a history of seizures or other conditions that have the potential to lower the seizure threshold. In addition, grand mal seizures have been reported in association with ORAP.
Body temperature regulation
Antipsychotic agents have been attributed with nullifying the body's ability to reduce body temperature. Care should be taken in cases where pimozide is prescribed to patients who may be subjected to conditions that contribute to elevated body temperature, such as strenuous training, exposure to high heat, concomitant administration of anticholinergic drugs, or a tendency to dehydration .
Endocrine effects
The hormonal effects of neuroleptic antipsychotic drugs include: hyperprolactinaemia, which can cause galactorrhea, gynaecomastia, oligomenorrhea or amenorrhea, and erectile dysfunction.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Patients treated with antipsychotic drugs often have acquired risk factors for VTE; therefore all possible risk factors for VTE must be identified before and during therapy with ORAP and preventive measures undertaken.
An approximately three-fold increase in the risk of cerebrovascular events was observed in randomized clinical trials versus placebo in a population of patients with dementia treated with some atypical antipsychotics. The mechanism of this increased risk is unknown. An increased risk for other antipsychotics or other patient populations cannot be excluded. ORAP should be used with caution in patients with stroke risk factors.
With equal caution, therapy with ORAP should be undertaken in elderly patients, due to the greater sensitivity to the drug and in those with hepatic and / or renal insufficiency due to the risk of accumulation, and in individuals whose conditions may be aggravated by the anticholinergic action of pimozide.
Increased mortality in older people with dementia
In elderly patients with dementia-related psychosis treated with antipsychotics the risk of death is increased. From the analysis of seventeen placebo-controlled studies (modal duration of 10 weeks), patients treated with atypical antipsychotics showed a 1.6- to 1.7-fold increase in mortality compared to patients treated with placebo. by 10 weeks, an incidence of mortality of approximately 4.5% was observed in patients treated with the drug compared to the rate of approximately 2.6% in the placebo group. Although the causes of death were varied, most of these were cardiovascular (eg heart failure, sudden death) or infectious (eg pneumonia) states. Observational studies have shown that, similar to atypical antipsychotics, treatment with conventional antipsychotics may increase the risk of death. it is clear to what extent the increase in mortality found in observational studies can be attributed to the antipsychotic drug piuttos that to some characteristics of the patients.
ORAP is not licensed for the treatment of dementia-related behavior disorders.
04.5 Interactions with other medicinal products and other forms of interaction -
Do not administer concomitantly with QT prolonging drugs such as some class Ia antiarrhythmics (e.g. quinidine, disopyramide and procainamide) and class III (e.g. amiodarone, sotalol), some antihistamines, other antipsychotics and some antimalarials (e.g. quinine and mefloquine) and also moxifloxacin.
This list is to be considered only indicative and not exhaustive.
Do not administer concomitantly with drugs that cause electrolyte disturbances.
Concomitant use of diuretics, particularly those that can cause hypokalaemia, should be avoided.
Pimozide is metabolised primarily by the cytochrome P450 subtype 3A4 (CYP 3A4) enzyme system and to a lesser extent via the CYP 2D6 subtype. Data in vitro show that highly potent inhibitors of the CYP 3A4 enzyme system, such as azole-structured antifungals, protease inhibitor-type antivirals, macrolide antibiotics and nefazodone inhibit the metabolism of pimozide, significantly increasing its plasma levels.
The data in vitro also indicate that quinidine decreases the metabolism of pimozide via CYP 2D6. Elevated pimozide levels may increase the risk of QT interval prolongation.
The use of pimozide with other inhibitors of cytochrome P450 CYP 3A4 or CYP 2D6 is contraindicated (see section 4.3).
ORAP can enhance the effect of alcohol, the action of hypotensives, antihypertensives and depressants of the S.N.C.
Co-administration of ORAP with grapefruit juice should be avoided as grapefruit juice inhibits the metabolism of drugs metabolised via CYP3A4.
An in vivo study, adding pimozide to sertraline at steady state, revealed a 40% increase in pimozide AUC and Cmax (see section 4.3.)
An in vivo study of concomitant administration of pimozide and citalopram reported an average increase of approximately 10 milliseconds in QTc values.
Citalopram did not alter pimozide AUC and Cmax values (see section 4.3).
A study in vivo in which pimozide (single dose 2 mg) and paroxetine (60 mg daily) were co-administered was associated with mean increases of 151% in pimozide AUC and 62% in Cmax (see section 4.3).
Since CYP1A2 may also contribute to the metabolism of ORAP, it is important, when prescribing the drug, to consider the theoretical possibility of interaction with inhibitors of this enzyme system.
ORAP may reduce the antiparkinsonian effect of levodopa in a dose-dependent manner.
04.6 Pregnancy and breastfeeding -
The safety on the use of pimozide during pregnancy has not been established. Therefore, the drug should not be administered in the case of an established or suspected pregnancy and in particular during the first trimester of pregnancy, unless, in the opinion of the physician, the expected benefit to the mother outweighs the potential risk to the fetus.
Infants exposed to conventional or atypical antipsychotics including ORAP during the third trimester of pregnancy are at risk for side effects including extrapyramidal or withdrawal symptoms which may vary in severity and duration after birth. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, food intake disturbances. Infants should therefore be closely monitored.
ORAP can be excreted with breast milk. Therefore, in cases where drug treatment is considered essential, breastfeeding should be discontinued.
04.7 Effects on ability to drive and use machines -
ORAP can affect alertness, especially at the start of therapy. These effects can be enhanced by alcohol. Patients should be informed of the risks of sedation and advised not to drive or operate machinery during treatment until individual sensitivity to this effect is known.
04.8 Undesirable effects -
Data deriving from Clinical Studies
Double-Blind Placebo-Controlled Studies - Adverse Drug Reactions Reported with an Incidence ≥ 2%
The safety of ORAP was evaluated in 299 subjects participating in 7 double-blind placebo-controlled clinical trials. The information presented in this section is derived from aggregated data. The specific patient population in the different studies consisted of patients with schizophrenia, patients with borderline psychosis or with behavioral disorders.
Adverse Drug Reactions (ADRs) reported at ≥ 2% incidence of subjects treated with ORAP in these studies are shown in Table 1.
Data obtained in controlled comparator studies - Adverse Drug Reactions reported at ≥ 2% incidence
The safety of ORAP was evaluated in 303 patients participating in 11 double-blind comparator studies. The information reported in this section was obtained from the aggregated data. The specific patient population in the different studies consisted of (chronic) patients with schizophrenia or patients with other psychoses.
Adverse Drug Reactions (ADRs) reported at ≥ 2% incidence of subjects treated with ORAP in these studies and not listed in Table 1 are shown in Table 2.
Data obtained from placebo- and comparator-controlled studies
Adverse Drug Reactions reported with incidence
Additional ADRs occurring in less than 2% of subjects treated with ORAP in both of the aforementioned data groups are listed in Table 3 below.
Post-marketing data
Adverse events initially identified as ADRs during post-marketing experience with ORAP are included in Table 4, sorted by frequency category with which they were spontaneously reported.
The frequency is expressed according to the following convention:
very common ≥1 / 10;
common ≥1 / 100 e
uncommon ≥1 / 1000 e
rare ≥1 / 10,000 e
very rare
Very rare Weight gain
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic drugs - Frequency not known.
04.9 Overdose -
Symptoms :
in general, the signs and symptoms of an overdose with ORAP consist of an amplification of the known pharmacological effects, the most important of which are the extrapyramidal symptoms. The risk of cardiac arrhythmias, possibly associated with QT interval prolongation and ventricular arrhythmias, including torsades de pointes, should be considered. In the case of severe arrhythmias, hypotension and cardiovascular collapse may occur in association.
Treatment :
there is no specific antidote to pimozide.In the event of an overdose, gastric lavage, intubation or tracheostomy and, if necessary, artificial or mechanical respiration are recommended. Continuous ECG monitoring should be performed because of the risk of developing QT interval prolongation and ventricular arrhythmias, including torsades de pointes, until a normal ECG is restored.
Severe arrhythmias should be treated with appropriate antiarrhythmic therapies.
Hypotension and associated cardiovascular collapse can be counteracted with supportive measures such as: venous infusion of liquids, plasma or concentrated albumin, and hypertensives such as dopamine or dobutamine.
In the case of severe extrapyramidal symptoms, antiparkinsonian drugs should be administered.
Due to the long half-life of pimozide, patients who have taken an excessive dose should be monitored for at least 4 days.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: antipsychotics, diphenylbutylpiperidine derivatives.
ATC code: N05AG02.
Pimozide is a derivative of diphenylbutylpiperidine, which significantly affects:
- the spontaneous behavior of psycho-stressed animals
- conditioned behavior
- spontaneous or provoked aggression
- the somatization of psychostressant factors
- the hypnonarcotic activity of nonspecific psycho-depressing drugs.
Therefore, pimozide is endowed with psychotropic, psychosomatotropic and psycholeptic activity: its action is mainly expressed by a dopaminergic receptor block at the level of the S.N.C.
The drug:
- improves disturbances of perception and ideation
- favors interest, initiative and self-criticism
- it has little sedative effects so it does not normally affect intellectual and physical abilities and performance
- it is active orally and, given its long duration of action, is administered in a single daily intake.
Pimozide is therefore indicated for reintegration into the psychotic patient's environment.
Researches carried out on emotionally unstable subjects have shown that pimozide determines a psychic stabilization and an improvement of motivations, activities and subjective sensations even under stress.
05.2 "Pharmacokinetic properties -
More than 50% of the pimozide dose is absorbed following oral administration.
Its distribution is not affected by the route of administration: 10% liver; 0.7% blood; 0.1% brain.
The drug is localized in the pituitary and therefore in the n. Caudatus.
Generally, the serum peak occurs between 6 and 8 hours (in a range of 4-12 hours) after intake. Pimozide appears to undergo significant first pass metabolism. It is extensively metabolised in the liver, mainly by N -dealkylation. Two major metabolites have been identified: 1- (4-piperidyl) -2-benzimidazolinone and 4,4-bis (4-fluorophenyl) butyric acid. These two metabolites have no antipsychotic activity. Only a very large fraction. small amount of pimozide is excreted unchanged in the urine.The major route of elimination of the metabolites is via the kidney.
The mean serum half-life of pimozide in schizophrenic patients is approximately 55 hours.
C "is an interindividual difference in area under the curve, serum concentration-time, of 13 times and an equivalent degree of variation in peak serum levels among the patients studied. The significance of this is unclear as there is little correlation between plasma levels and clinical data.
05.3 Preclinical safety data -
Animal data showed some degree of embryotoxicity at doses similar to the maximum human level (MHUL). At doses approximately 6 times the MHUL based on the mg / kg ratio, fetal growth retardation and toxicity were observed. fetal No teratogenic effects were observed.
The results of mutagenicity studies do not indicate genotoxicity.
Carcinogenicity studies did not detect treatment-related tumors in male rats or mice, but an "increased incidence of pituitary adenomas and mammary gland adenocarcinomas in female mice. These histopathological changes in the mammary and pituitary glands are thought to be mediated by prolactin. and have been found in rodents following hyperprolactinaemia induced by a wide variety of neuroleptic drugs, although the relevance of these findings to humans is questionable.
In in vitro studies, pimozide has been shown to block cardiac hERG channels and prolong the duration of action potential in isolated and perfused heart. This effect on hERG channels can be attenuated by blocking the effect of pimozide on cardiac calcium-type channels. L. In in vivo animal studies, intravenous or oral administration of pimozide has been shown to cause significant prolongation of the QTc interval. Doses that prolonged the QTc interval did not cause arrhythmia.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Calcium dibasic phosphate dihydrate, corn starch, microcrystalline cellulose, povidone K30, talc, hydrogenated vegetable oil, yellow iron oxide, sodium indigotindisulfonate aluminum lake.
06.2 Incompatibility "-
Not relevant
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
Storage at a temperature not exceeding 30 ° C
06.5 Nature of the immediate packaging and contents of the package -
Box of 20 tablets of 4 mg in blister
06.6 Instructions for use and handling -
No special instructions
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Janssen-Cilag SpA
Via M.Buonarroti, 23
20093 COLOGNO MONZESE (Milan)
08.0 MARKETING AUTHORIZATION NUMBER -
20 tablets 4 mg AIC n. 022907036
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
May 1995 / June2005
10.0 DATE OF REVISION OF THE TEXT -
Determination of October 14, 2011
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