Active ingredients: Clozapine
Leponex 25 mg tablets
Leponex package inserts are available for pack sizes:- Leponex 25 mg tablets
- Leponex 100 mg tablets
Why is Leponex used? What is it for?
The active substance in Leponex is clozapine which belongs to a group of medicines called antipsychotics (medicines which are used to treat specific mental disorders such as psychosis).
Leponex is used to treat people with schizophrenia who have not benefited from other medicines. Schizophrenia is a mental illness that affects the way you think, how you feel and how you behave. You should use this medicine only after you have tried at least two other antipsychotics for the treatment of schizophrenia, including one of the newer atypical antipsychotics, and only if these medicines have not worked or have caused serious side effects that cannot be treated.
Leponex is also used to treat severe thought, emotional and behavioral disorders in people with Parkinson's disease who have not benefited from other medicines.
Contraindications When Leponex should not be used
Do not take Leponex
- if you are allergic (hypersensitive) to clozapine or any of the other ingredients of Leponex
- if you are unable to have regular blood tests.
- if you have had a low white blood cell count (for example leukopenia or agranulocytosis) in the past, especially if caused by medicines. This does not apply to you if the low white blood cell count was caused by previous chemotherapy treatment.
- if you have or have suffered from bone marrow disease.
- if you use any medicines that prevent the bone marrow from working properly.
- if you use any medicine that reduces the number of white blood cells in the blood.
- if you have had to stop taking Leponex in the past due to serious side effects (eg agranulocytosis or heart problems).
- if you suffer from uncontrolled epilepsy (seizures or convulsions).
- if you have an acute mental illness caused by alcohol or drugs (e.g. narcotics).
- if you suffer from myocarditis (an "inflammation of the heart muscle).
- if you suffer from any other serious heart disease.
- if you have any severe kidney disease.
- if you have symptoms of acute liver disease such as jaundice (yellowing of the skin and eyes, nausea and loss of appetite).
- if you have any other severe liver disease.
- if you suffer from decreased consciousness and severe sleepiness.
- if you suffer from circulatory collapse which can occur following a severe shock.
- if you suffer from paralytic ileus (your bowel does not work properly causing severe constipation).
- if you are or have been being treated with long-acting depot injections of antipsychotics.
If any of the above apply to you, tell your doctor and do not take Leponex.
Leponex must not be given to people who are unconscious or in a coma.
Precautions for use What you need to know before taking Leponex
The precautionary measures described in this section are very important and must be observed to minimize the risk of serious side effects which could be life threatening.
Before treatment with Leponex, tell your doctor if you have or have suffered from:
- blood clot formation or family history of blood clot formation, as medicines like these have been associated with blood clot formation.
- glaucoma (increased pressure in the eye).
- diabetes. Elevated (sometimes even significantly) blood sugar levels have been reported in patients with or without a history of diabetes mellitus.
- prostate problems or difficulty urinating.
- any heart, kidney or liver problems.
- chronic constipation or if you are taking medicines that cause constipation (such as anticholinergics).
- galactose intolerance, lactase deficiency or glucose / galactose malabsorption syndrome.
- controlled epilepsy
- large intestine disorders.
- tell your doctor if you have had any surgery on the abdomen in the past.
- if you have had a heart disorder or a family history of cardiac conduction abnormality known as 'QT interval prolongation'.
- if you are at risk of having a stroke, for example if you have high blood pressure, cardiovascular disease or if you have problems with the blood vessels in your brain.
Tell your doctor immediately before taking your next Leponex tablet:
- if you experience signs of a cold, fever, flu-like symptoms, sore throat or infections of any kind. You will need to have a blood test urgently to see if your symptoms are related to the medicine.
- if you experience a sudden and rapid rise in body temperature, muscle stiffness which can lead to loss of consciousness (neuroleptic malignant syndrome): in this case there is a possibility that a serious side effect is occurring which requires immediate treatment.
- if you have a fast and irregular heartbeat even at rest, palpitations, difficulty breathing, chest pain or unexplained tiredness. Your doctor will need to have your heart checked and, if necessary, will refer you to a cardiologist immediately.
- if you feel nausea, vomiting and / or loss of appetite. Your doctor will need to check your liver.
- if you experience severe constipation. Your doctor will need to treat this to avoid further complications.
Clinical checks and haematological tests
Before starting treatment with Leponex, your doctor will ask about your medical history and carry out a blood test to make sure your white blood cell count is normal. This is important to know, because the body needs white blood cells to fight infections.
Make sure you have a regular blood test before starting treatment, during treatment and after stopping Leponex treatment.
- Your doctor will tell you exactly when and where to have the tests. Leponex can only be taken if the number of blood cells is normal.
- Leponex can cause a severe decrease in the number of white blood cells in the blood (agranulocytosis). Only regular blood tests can tell your doctor if you are at risk of developing agranulocytosis.
- During the first 18 weeks of treatment, blood tests are required once a week. Thereafter, blood tests must be done at least once a month.
- If there is a decrease in the number of white blood cells, you will have to stop treatment with Leponex immediately. Your white blood cell count should then return to normal.
- After stopping Leponex treatment, you will need to have blood tests for another 4 weeks.
Your doctor will also do a general examination before starting treatment. Your doctor may also do an electrocardiogram (ECG) to check your heart, but only if necessary or if you have any particular concerns.
If you suffer from liver problems, you will need to have liver function tests regularly as long as you are being treated with Leponex.
If you have high blood sugar levels (diabetes), your doctor may need to check your blood sugar levels regularly. Leponex can cause changes in blood fats.
Leponex can cause weight gain. Your doctor may need to check your weight and blood fat levels.
If Leponex causes you to feel light-headed, staggered or faint, take care when standing up when sitting or lying down.
If you need to have surgery or if for some reason you are unable to walk for a long time, tell your doctor that you are taking Leponex. In these cases, you may be at risk for thrombosis (formation of blood clots in the veins).
Children and adolescents under the age of 16
If you are under 16 you should not take Leponex as there is not enough information on its use in this age group.
- Elderly (aged 60 years or older)
Elderly patients (aged 60 years and over) may be more likely to experience the following side effects during treatment with Leponex: weakness or light-headedness after changing position, dizziness, rapid heartbeat, difficulty urinating and constipation.
Tell your doctor or pharmacist if you have a condition called dementia.
Interactions Which drugs or foods may change the effect of Leponex
Before starting treatment with Leponex, tell your doctor if you are taking or have recently taken any other medicines, including those without a prescription or herbal preparations. You may need to change the dose of these medicines or take different medicines.
Do not take Leponex together with medicines that stop the bone marrow from working properly and / or decrease the number of blood cells produced by the body, such as:
- carbamazepine, a medicine used for epilepsy.
- some antibiotics: chloramphenicol, sulfonamides, such as co-trimoxazole.
- some pain relievers: pyrazolone analgesics, such as phenylbutazone.
- penicillamine, a medicine used to treat rheumatic inflammation of the joints.
- cytotoxic drugs, medicines used for chemotherapy.
- long-acting depot antipsychotic injections. These medicines increase the risk of developing agranulocytosis (deficiency of white blood cells).
Taking Leponex could affect the effect of other medicines, or the medicines you are taking could influence the effect of Leponex. Tell your doctor if you are taking any of the following medicines:
- medicines to treat depression, such as lithium, fluvoxamine, tricyclic antidepressants, MAO inhibitors, citalopram, paroxetine, fluoxetine and sertraline.
- other antipsychotics used to treat mental disorders.
- benzodiazepines and other medicines used to treat anxiety or sleep disorders.
- narcotics and other medicines which can affect your breathing.
- medicines used to control epilepsy, such as phenytoin and valproic acid.
- medicines used to treat high or low blood pressure, such as adrenaline and noradrenaline.
- warfarin, a medicine used to prevent blood clots.
- antihistamines, medicines used for colds or allergies such as hay fever.
- anticholinergic medicines, which are used to relieve stomach cramps, spasms and travel sickness.
- medicines used to treat Parkinson's disease.
- digoxin, a medicine used to treat heart problems.
- medicines used to treat a fast or irregular heartbeat.
- some medicines used to treat stomach ulcers, such as omeprazole or cimetidine.
- some antibiotics, such as erythromycin and rifampicin.
- some medicines used to treat fungal infections (such as ketoconazole) or viral infections (such as protease inhibitors, used to treat HIV infections).
- atropine, a medicine that may be present in some eye drops or cough and cold preparations.
- adrenaline, a medicine used in emergency situations.
The list is not exhaustive. Your doctor and pharmacist have more information on medicines to take carefully or to avoid while taking Leponex, and they also know if the medicine you are taking belongs to those listed. Please discuss this with them.
Taking Leponex with food and drink
Do not drink alcohol while taking Leponex.
Tell your doctor if you smoke and how often you take caffeinated drinks (coffee, tea, Coca-Cola). Sudden changes in smoking and caffeine habits could also change the effects of Leponex.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or planning to become pregnant, please inform your doctor before starting treatment with Leponex. Your doctor will discuss with you the benefits and potential risks of taking this medicine during pregnancy. Tell your doctor promptly if you become pregnant while taking Leponex.
The following symptoms have been observed in newborn babies of mothers who have taken Leponex during the last trimester (the last three months of their pregnancy): shaking, muscle stiffness and / or weakness, sleepiness, agitation, breathing problems and difficulty in eating. . If your child shows any of these symptoms, contact your doctor.
Some women who are taking certain medicines for mental disorders do not have periods or have irregular periods. If this is the case, your period may come back when you switch from the medicine you are taking to treatment with Leponex. This means that you must take adequate contraceptive measures.
Do not breast-feed if you are taking Leponex. Clozapine, the active substance in Leponex, could pass into breast milk and affect the baby.
Driving and using machines
Leponex may cause tiredness, sleepiness and seizures, especially at the start of treatment. You should not drive or operate machinery when you experience these symptoms.
Important information about some of the ingredients of Leponex
Leponex contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor before taking Leponex.
Dosage and method of use How to use Leponex: Dosage
To minimize the risk of low blood pressure, seizures and sleepiness, your doctor will need to increase the dose gradually. Always take Leponex exactly as your doctor has told you. If in doubt, you should consult your doctor or pharmacist.
It is important that you do not change your dose or stop taking Leponex without first consulting your doctor. Continue to take the tablets until otherwise directed by your doctor. If you are 60 or over 60, your doctor may have you start treatment with a lower dose and gradually increase it, as some side effects may be more likely to occur (see section "Before taking Leponex").
If the dose you have been prescribed cannot be obtained with this tablet, other doses of this medicine are available.
Treatment of schizophrenia
The starting dose is usually 12.5 mg (half a 25 mg tablet) once or twice a day on the first day, followed by 25 mg once or twice a day on the second day. Swallow the tablet with water. If well tolerated, your doctor will gradually increase the dose by 25-50 mg over the next 2-3 weeks until a dose of 300 mg per day is reached. Thereafter, if necessary, the daily dose can be increased by 50-100 mg every 3-4 days or, preferably, at weekly intervals.
The effective daily dose is usually between 200 and 450 mg, divided into several single doses per day. Some people may need a higher dose. A daily dose of up to 900 mg is permitted. More undesirable effects (particularly seizures) are possible with daily doses above 450 mg. Always take the lowest effective dose for you. Most people take one portion of their dose in the morning and one portion in the evening. Your doctor will tell you exactly how to divide the daily dose. If the daily dose is only 200 mg then you can take this as a single dose in the evening. After taking Leponex for some time with good results, your doctor may try to lower your dose. You will need to take Leponex for at least 6 months.
Treatment of severe thought disorders in patients with Parkinson's disease
The starting dose is usually 12.5 mg (half a 25 mg tablet) in the evening. Swallow the tablet with water.Your doctor will gradually increase the dose by 12.5 mg at a time, with a maximum of 2 increments per week, up to the maximum dose of 50 mg at the end of the second week. Dose increases should be stopped or postponed if you feel faint, confused or light-headed. To avoid these symptoms, you must measure your blood pressure during the first few weeks of treatment.
The effective daily dose is usually between 25 and 37.5 mg taken as a single dose in the evening. Only in exceptional cases should the dose of 50 mg per day be exceeded. The maximum daily dose is 100 mg. Always take the lowest effective dose for you.
Overdose What to do if you have taken too much Leponex
If you take more Leponex than you should
Contact your doctor immediately or call for urgent medical help if you think you have taken too many tablets, or if someone else has taken some of your tablets. Symptoms of overdose are: Somnolence, fatigue, lack of energy, loss of consciousness, coma, confusion, hallucinations, agitation, slurred speech, joint stiffness, hand tremor, seizures (convulsions), increased saliva production, enlarged black part of the eye, visual disturbances, low blood pressure, collapse, rapid or irregular heartbeat, difficult or shallow breathing.
If you forget to take Leponex
If you have forgotten to take a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take your next dose at the correct time. Do not take a double dose to make up for a forgotten dose. Contact your doctor as soon as possible if you have not taken Leponex for more than 48 hours.
If you stop taking Leponex
Do not stop taking Leponex without consulting your doctor, as you may have withdrawal reactions. These reactions include sweating, headache, nausea, vomiting and diarrhea. If any of these signs occur, contact your doctor immediately. These signs could be followed by more serious side effects if you do not receive adequate treatment immediately. The original symptoms may reappear. If you have to stop treatment, a gradual decrease of the dose in fractions of 12.5 mg over one to two weeks is recommended. Your doctor will advise you on how to reduce the daily dose. check with your doctor. If your doctor decides to restart treatment with Leponex and it has been more than two days since the last administration of Leponex, you will need to start again with a dose of 12.5 mg.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Leponex
Like all medicines, Leponex can cause side effects, although not everybody gets them.
Some side effects can be serious and need immediate medical attention. Consult your doctor immediately before taking your next Leponex tablet:
- if you experience signs of a cold, fever, flu-like symptoms, sore throat or infections of any kind. You will need to have a blood test urgently to check that your symptoms are related to the medicine.
- if you experience a sudden and rapid rise in body temperature, muscle stiffness which can lead to loss of consciousness (neuroleptic malignant syndrome): in this case there is a possibility that a serious side effect is occurring which requires immediate treatment.
- if you experience unbearable chest pain, a feeling of tightness, pressure or constriction in the chest (chest pain may radiate to the left arm, jaw, neck and upper abdomen), shortness of breath, sweating, weakness, feeling of light-headedness, nausea, vomiting and palpitations (symptoms of a heart attack): in this case, call for urgent medical assistance.
- if you have a fast and irregular heartbeat even at rest, palpitations, difficulty breathing, chest pain or unexplained tiredness. Your doctor will need to have your heart checked and, if necessary, will refer you to a cardiologist immediately.
- if you feel chest pressure, heaviness, tightness, tightness, burning or choking sensation (signs of insufficient blood and oxygen supply to the heart muscle): in this case your doctor will need to check your heart.
- if you feel nausea, vomiting and / or loss of appetite. Your doctor will need to check your liver.
- if you experience severe constipation. Your doctor will need to treat this to avoid further complications.
- if you experience signs of a respiratory infection or pneumonia such as fever, cough, difficulty in breathing, wheezing.
- if you experience signs of blood clotting in the veins, especially in the legs (symptoms include swelling, pain and redness in the legs): the clots can travel through blood vessels to the lungs and cause chest pain and difficulty in breathing.
- if you experience profuse sweating, headache, nausea, vomiting and diarrhea (symptoms of cholinergic syndrome).
- if you experience a severe decrease in the amount of urine (sign of kidney failure).
- if seizures occur.
- if you are a man and have episodes of painful and persistent penile erection: this is a condition known as priapism. If you experience an erection that persists for more than 4 hours you may need immediate medical treatment to avoid further complications.
All possible side effects are listed in order of decreasing frequency:
Very common (occurs in more than 1 in 10 patients):
Somnolence, dizziness, rapid heartbeat, constipation, increased saliv production
Common (affects up to 1 in 10 patients):
Low levels of white blood cells in the blood (leukopenia), high levels of white blood cells in the blood (leukocytosis), high levels of particular types of white blood cells (eosinophilia), weight gain, blurred vision, headache, tremor, stiffness, restlessness, seizures seizures, seizures, spasms, abnormal movements, inability to start movements, inability to stay still, high blood pressure, weakness or light-headedness after changing position, sudden loss of consciousness, nausea (feeling sick), vomiting , loss of appetite, dry mouth, slightly altered liver function test values, loss of bladder control, difficulty urinating, fatigue, fever, increased sweating, increased body temperature, speech disturbances (eg slurred speech Uncommon (affects up to 1 in 100 patients): Lack of white blood cells (agranulocytosis), neurolet syndrome malignant disease (disease characterized by high fever, impaired consciousness and muscle stiffness), speech disorders (eg. stuttering).
Rare (affects up to 1 in 1000 patients):
Low levels of red blood cells (anemia), inability to rest, agitation, confusion, delirium, circulatory collapse, irregular heartbeat, inflammation of the heart muscle (myocarditis) or the membrane surrounding the heart muscle (pericarditis), stagnation of fluid around the heart (pericardial effusion), difficulty swallowing (for example food goes down the wrong way), respiratory tract infection and pneumonia, high blood sugar levels, diabetes mellitus, blood clots in the lungs (thromboembolism), inflammation liver disease (hepatitis), liver disease causing yellow skin / dark urine / itching, inflammation of the pancreas causing severe upper stomach pain, increased levels of an enzyme called creatine kinase in the blood.
Very rare (affects up to 1 in 10,000 patients):
Increase in the number of platelets in the blood with possible formation of clots in the blood vessels, decrease in the number of platelets in the blood, uncontrolled movements of the mouth, tongue and lips, obsessive thoughts and repetitive compulsive behaviors (obsessive / compulsive symptoms), skin reactions , swelling of the front of the ears (swollen salivary glands), difficulty in breathing, complications due to uncontrolled blood sugar levels (for example coma or ketoacidosis), very high levels of cholesterol and triglycerides in the blood, heart muscle disease ( cardiomyopathy), heartbeat arrest (cardiac arrest), severe constipation with abdominal pain and stomach cramps caused by bowel obstruction (paralytic ileus), swollen abdomen, abdominal pain, severe liver damage (fulminant hepatic necrosis), inflammation of the kidneys , persistent and painful erection of the penis (priapism), improvised death isa inexplicable. Not known (frequency cannot be estimated from the available data) Blood clots in the veins, profuse sweating, headache, nausea, vomiting and diarrhea (symptoms of cholinergic syndrome), unbearable chest pain, shortness of breath (heart attack symptoms) , chest pressure or heaviness (signs of insufficient blood and oxygen supply to the heart muscle), severe decrease in urine output (sign of kidney failure), liver disorders including: fatty liver disease, death of liver cells, liver toxicity / damage, liver disorders resulting in the replacement of normal liver tissue with scar tissue resulting in loss of function: these include liver events that can lead to life-threatening consequences such as liver failure (which can be fatal), liver damage liver (damage to liver cells, the bile duct in the liver, or both) and liver transplantation, changes in blood ontrate EEG, diarrhea, stomach discomfort, heartburn, stomach discomfort after eating, muscle weakness, muscle spasms, muscle pain, stuffy nose, bed-wetting at night, sudden and uncontrollable increase in blood pressure (pseudopheochromocytoma ).
In older people with dementia, a small increase in the number of deaths has been reported among patients taking antipsychotics compared with those not taking them.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not use Leponex after the expiry date which is stated on the bottle or blister and carton. The expiry date refers to the last day of the month.
- This medicine does not require any special storage conditions.
- Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Leponex contains
- The active ingredient of Leponex is clozapine. Each tablet contains 25 mg of clozapine.
- The other ingredients are magnesium stearate, anhydrous colloidal silica, povidone (K 30), talc, maize starch, lactose monohydrate.
What Leponex looks like and contents of the pack
Leponex tablets are available in PVC / PVDC / aluminum or PVC / PE / PVDC / aluminum blisters containing 7, 14, 20, 28, 30, 40, 50, 60, 84, 98, 100, 500 (10x50) o 5000 (100x50) and in amber glass bottles (class III) containing 100 or 500 tablets.
Not all pack sizes may be marketed.
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
LEPONEX 25 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 25 mg of clozapine.
Excipients: Each tablet also contains 48.0 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
Yellow, round, flat tablet with beveled edges. Letters "L / O" separated by an angular fracture line on one side and letter "S" inside a triangle on the opposite side.
The tablet can be divided into equal halves.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment-resistant schizophrenia
Treatment with Leponex is indicated for treatment-resistant schizophrenic patients and for schizophrenic patients who have severe neurological adverse reactions that cannot be treated with other antipsychotic drugs, including atypical antipsychotics.
Resistance to treatment is defined as lack of satisfactory clinical improvement despite the use of appropriate doses of at least two different antipsychotic drugs, including one atypical, prescribed for an adequate period of time.
Psychosis in Parkinson's disease
Treatment with Leponex is also indicated in psychotic disorders in the course of Parkinson's disease, after the failure of classical therapeutic management.
04.2 Posology and method of administration
Dosage information
Dosage must be determined individually. The lowest effective dose should be used for each patient.
For doses not achievable with this strength, other strengths of this medicine are also available.
Careful titration and dose fractionation are necessary to minimize the risks of hypotension, seizures and sedation.
Initiation of Leponex treatment should be limited to patients with white blood cell count ≥3500 / mm3 (3.5x109 / l) and absolute neutrophil granulocytes ≥ 2000 / mm3 (2.0x109 / l) of the normal range.
The dose should be adjusted in patients taking concomitantly pharmacodynamic and pharmacokinetic interacting drugs with Leponex, such as benzodiazepines or selective serotonin reuptake inhibitors (see section 4.5).
Method of administration
Leponex is administered orally.
Switching from previous antipsychotic therapy to Leponex
In general, it is recommended not to administer Leponex in combination with other antipsychotics.
If it is necessary to initiate therapy with Leponex in a patient already being treated with an oral antipsychotic, it is recommended that the latter be stopped first by gradually reducing the dose.
The following doses are recommended:
Treatment-resistant schizophrenic patients
Initial dose
On the first day a dose of 12.5 mg once or twice a day, on the second day 25 mg once or twice a day. If well tolerated, the daily dose can be gradually increased by 25-50 mg to reach a level of 300 mg / day within 2-3 weeks. Subsequently, if necessary, the daily dose can be further increased by 50-100 mg every 3-4 days or, preferably, at weekly intervals.
Therapeutic range
In most patients, the antipsychotic effect should be achieved with 200-450 mg / day in divided doses. The overall daily dose can be divided irregularly, with the higher dose given in the evening.
Maximum dose
To obtain maximum therapeutic benefit, some patients may require higher doses; in this case, cautious increases (not more than 100 mg) are allowed up to a maximum dose of 900 mg / day.
However, it must be taken into account that the possibility of undesirable effects (particularly convulsions) increases at doses above 450 mg / day.
Maintenance dose
After reaching the maximum therapeutic benefit, many patients can be effectively controlled with lower doses. A cautious dose reduction to the lowest effective dose is therefore recommended. Treatment should continue for at least 6 months. If the daily dose does not exceed 200 mg, a single evening administration can be used.
Discontinuation of therapy
In case of planned discontinuation of Leponex therapy, it is recommended to gradually reduce the dose over 1-2 weeks.If it is necessary to abruptly discontinue treatment, the patient should be monitored carefully due to the risk of reactions due to discontinuation of therapy (see section 4.4).
Resumption of therapy
If therapy is interrupted for more than 2 days, treatment should be resumed by administering 12.5 mg once or twice daily on the first day. If this dose is well tolerated, it is possible to reach the optimal posology in a shorter time than the first treatment. However, in those patients who have had previous episodes of cardiac or respiratory arrest with the starting dose (see section 4.4) but who were subsequently able to successfully achieve the optimal posology, the re-titration should be performed with extreme caution.
Psychotic disorders in Parkinson's disease, after the failure of classical therapy
Initial dose
The starting dose should not exceed 12.5 mg / day, administered in the evening. The dose may then be increased in 12.5 mg increments, with a maximum of 2 increments per week up to the maximum dose of 50 mg, which cannot be reached before the end of the second week of treatment. & EGRAVE; It is preferable to administer the total daily dose as a single evening dose.
Therapeutic range
The mean effective dose is generally between 25 and 37.5 mg / day. If the 50 mg dose administered for at least one week does not provide a satisfactory therapeutic result, a cautious dose increase in weekly increments of 12.5 mg may be attempted.
Maximum dose
The dose of 50 mg / day can only be exceeded in exceptional cases, without however ever exceeding 100 mg / day.
Dose escalation should be limited or postponed if orthostatic hypotension, excessive sedative effect or mental confusion occurs. Blood pressure should be monitored during the first few weeks of treatment.
Maintenance dose
After complete remission of psychotic symptoms has been achieved and maintained for at least 2 weeks, the administration of anti-Parkinson drugs can be increased if the motor conditions require it. If this causes the psychotic symptoms to come back, a further dose increase of Leponex may be attempted in increments of 12.5 mg per week up to a maximum of 100 mg / day given in one or two doses per day (see above).
Discontinuation of therapy
A gradual reduction of the dose by 12.5 mg at a time is recommended over a period of at least one week (preferably two).
Treatment should be stopped immediately in case of neutropenia or agranulocytosis (see section 4.4). In this case, careful psychiatric monitoring of the patient is essential, due to the risk of sudden reappearance of psychotic symptoms.
Special populations
Impaired liver function
Patients with hepatic impairment should take Leponex with caution and should be accompanied by regular monitoring of liver function values (see section 4.4).
Pediatric population
Pediatric studies have not been conducted. The safety and efficacy of Leponex in children or adolescents under the age of 16 have not yet been established. The drug should therefore not be used in this patient population until new data become available.
Patients aged 60 years or older
It is recommended to start treatment at the minimum recommended dose (12.5 mg once daily on the first day), and to limit subsequent increases to 25 mg / day.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients.
• Patients who cannot have regular blood tests.
• Previous toxic or idiosyncratic granulocytopenia / agranulocytosis (except granulocytopenia / agranulocytosis from previous chemotherapy).
• Previous agranulocytosis induced by Leponex treatment.
• Alteration of bone marrow function.
• Uncontrolled epilepsy.
• Alcoholic psychosis and other toxic psychoses, drug intoxication, comatose conditions.
• Circulatory collapse and / or CNS depression of any cause.
• Severe kidney or heart disease (eg myocarditis).
• Ongoing liver disease associated with nausea, anorexia or jaundice; progressive liver disease; liver failure.
• Paralytic ileus.
• Leponex must not be administered at the same time as other substances known to have the potential to cause agranulocytosis; concomitant use of depot antipsychotics should be avoided.
04.4 Special warnings and appropriate precautions for use
Leponex can cause agranulocytosis. Therefore it is only indicated for patients:
• suffering from schizophrenia who do not respond or tolerate antipsychotic drugs, or who have psychotic disorders during Parkinson's disease, after the failure of other therapeutic strategies (see section 4.1)
• with an initially normal white blood cell picture (white blood cell count ≥ 3500 / mm3 (3.5x109 / l), and absolute value of neutrophil granulocytes ≥ 2000 / mm3 (2.0x109 / l)), and
• in which leukocyte and neutrophil granulocyte counts can be performed regularly as follows: weekly during the first 18 weeks of treatment, and thereafter at least every 4 weeks throughout treatment. Monitoring should continue throughout treatment and for 4 weeks after permanently discontinuing Leponex treatment (see section 4.4).
The doctor who prescribes the drug is required to fully comply with the prescribed precautions. At each visit, the patient treated with Leponex should be reminded to contact the treating physician immediately if any type of infection develops. Particular attention should be paid to flu-like symptoms, such as fever or sore throat, as well as other symptoms of infection, as they may indicate neutropenia (see section 4.4).
Leponex should be administered under close medical supervision according to official recommendations (see section 4.4).
Myocarditis
Clozapine is associated with an increased risk of developing myocarditis which, in rare cases, has been fatal. The risk of myocarditis occurring is more frequent in the first 2 months of treatment. In addition, rare fatal cases of cardiomyopathy have been reported (see section 4.4). Suspicion of myocarditis or cardiomyopathy should be considered in patients who present with persistent tachycardia at rest, particularly in the first 2 months of treatment, and / or palpitations, arrhythmias, chest pains, and other signs and symptoms of heart failure (e.g. unexplained feeling of fatigue, dyspnoea, tachypnea), or symptoms similar to those of myocardial infarction (see section 4.4).
If myocarditis or cardiomyopathy is suspected, treatment with Leponex should be stopped immediately and the patient immediately referred to a cardiologist (see section 4.4).
Patients presenting with clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to clozapine treatment (see sections 4.3 and 4.4).
Agranulocytosis
Leponex can cause agranulocytosis. The incidence of agranulocytosis and the mortality rate among patients who develop agranulocytosis declined markedly after the introduction of white blood cell count (WBC) and neutrophil granulocyte (ANC) monitoring. The precautionary measures listed below are therefore mandatory and should be carried out according to official recommendations.
Due to the risks associated with treatment with Leponex, use should be limited to patients in whom therapy is indicated as described in section 4.1 and:
• to patients with a normal leukocyte picture (white blood cell count ≥ 3500 / mm3 (3.5x109 / l) and absolute value of neutrophil granulocytes ≥ 2000 / mm3 (2.0x109 / l), and
• to patients in whom the white blood cell count and neutrophil granulocyte counts can be done regularly every week during the first 18 weeks of treatment and at intervals of at least 4 weeks thereafter. Monitoring should continue throughout treatment and for 4 weeks after stopping Leponex administration.
Patients should undergo a haematological examination (see "agranulocytosis") and a medical examination with a medical history prior to initiating therapy with Leponex. Patients who have had previous cardiac disorders or who have cardiac abnormalities during the visit should be referred to a specialist for further investigations which may include performing an electrocardiogram (ECG). These patients should only undergo treatment if the expected benefits outweigh the risks (see section 4.3). The physician treating the patient should consider performing an ECG before starting treatment.
The doctor who prescribes the drug is required to fully comply with the prescribed precautions.
Before the start of treatment, the physician must ensure, to the best of his knowledge, that the patient has not previously developed any adverse haematological reactions to clozapine that would require discontinuation of treatment. Prescriptions should not cover periods longer than the interval between two white blood cell counts.
In case of white blood cell count below 3000 / mm3 (3.0x109 / l) or absolute value of neutrophil granulocytes below 1500 / mm3 (1.5x109 / l) found at any time during therapy with Leponex, immediate treatment is mandatory. Discontinuation of treatment Patients in whom Leponex treatment has been interrupted due to a decrease in white blood cell count or neutrophil granulocytes should not be re-treated.
At each visit, the patient undergoing treatment with Leponex should be reminded to contact the treating physician immediately if any type of infection develops.
Particular attention should be paid to flu-like symptoms, such as fever or sore throat, as well as other symptoms of infection, as they may indicate neutropenia. Patients and their "caregivers" (those who routinely care for the patient) should be aware that in the event of any of these symptoms, a white blood cell count should be performed immediately. Doctors are advised to keep a record of the results of the blood tests performed by their patients and to take the necessary measures to prevent these patients from being accidentally re-exposed to the drug in the future.
Patients with history of bone marrow dysfunction can only be treated if the benefit outweighs the risk. Before starting therapy with Leponex they must undergo a thorough examination by a haematologist.
Particular attention should be paid to patients with low white blood cell counts due to benign ethnic neutropenia, who can only be treated with Leponex with the consent of the haematologist.
White blood cell count (WBC) and neutrophil granulocyte (ANC) monitoring
The white blood cell count and the white blood cell count should be performed within 10 days prior to initiation of Leponex treatment to ensure that only patients with normal white blood cell and neutrophil granulocyte counts (white blood cell count ≥ 3500 / mm3 (3.5x109 / l) and neutrophil granulocytes ≥ 2000 / mm3 (2.0x109 / l)) receive Leponex. After initiation of treatment with Leponex, regular white blood cell and neutrophil granulocyte counts should be made and monitored weekly during the first 18 weeks, and thereafter at intervals of at least 4 weeks.
Monitoring should continue for the duration of treatment with Leponex and for 4 weeks after discontinuation of treatment or until complete haematological recovery (see under "Low white blood cell and neutrophil count"). At each visit, the patient should be reminded patient undergoing treatment with Leponex to contact the treating physician immediately if any type of infection develops, fever, sore throat or other flu-like symptoms. If any of these signs or symptoms develop, a white blood cell count and a white blood cell formula test should be performed immediately.
Low white blood cell and neutrophil granulocyte counts
If, during treatment with Leponex, the leukocyte count falls to values between 3500 / mm3 (3.5x109 / l) and 3000 / mm3 (3.0x109 / l) or the absolute value of neutrophils between 2000 / mm3 ( 2.0x109 / l) and 1500 / mm3 (1.5x109 / l), haematological checks should be performed at least twice a week until the leukocyte count and the absolute value of neutrophil granulocytes stabilize respectively between 3000-3500 / mm3 (3.0-3.5x109 / l) and 1500-2000 / mm3 (1.5-2.0x109 / l) or do not reach higher values.
In the event of a white blood cell count below 3000 / mm3 (3.0x109 / l) or absolute value of neutrophil granulocytes below 1500 / mm3 (1.5x109 / l), Leponex treatment should be stopped immediately. WBC counts and WBC testing should therefore be performed daily and the onset of flu-like symptoms or other symptoms that may suggest infection should be carefully monitored. It is recommended that haematological findings be confirmed by two consecutive counts in the blood. two subsequent days; treatment with Leponex must in any case be stopped after the first checkup.
After discontinuation of Leponex therapy, haematological evaluation is required until complete haematological recovery.
Table 1
If, after discontinuation of treatment with Leponex, the leukocyte count falls below 2000 / mm3 (2.0x109 / l) or the absolute value of neutrophil granulocytes below 1000 / mm3 (1.0x109 / l), it is necessary to send the patient immediately to a haematologist specialist.
Discontinuation of therapy for haematological reasons
Patients in whom Leponex treatment has been stopped due to a decrease in white blood cell count or neutrophil granulocytes should no longer take Leponex (see above).
It is recommended that physicians keep all blood test results of their patients and take the necessary measures so that the patient is not accidentally re-exposed to clozapine treatment in the future.
Discontinuation of therapy for other reasons
In patients treated with Leponex for over 18 weeks and in whom therapy has been suspended for more than 3 days but less than 4 weeks, it is recommended that the leukocyte and neutrophil granulocyte counts be monitored weekly for a further 6 weeks. If no haematological abnormalities are found, the checks can be re-performed at intervals not exceeding 4 weeks. If treatment has been interrupted for 4 weeks or more, weekly monitoring is required for the next 18 weeks of therapy, as well as a new dose titration (see section 4.2).
Other precautions
This medicinal product contains lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose / galactose malabsorption should not take this medicine.
Eosinophilia
In the event of eosinophilia, it is recommended to discontinue Leponex treatment if the eosinophil count exceeds 3000 / mm3 (3.0x109 / l) and to resume therapy only after the eosinophil count has dropped below 1000. / mm3 (1.0x109 / l).
Thrombocytopenia
In the event of thrombocytopenia, it is recommended to discontinue treatment with Leponex if the platelet count falls below 50,000 / mm3 (50x109 / l).
Cardiovascular Disorders
Orthostatic hypotension, with or without syncope, may occur during treatment with Leponex. Rarely, severe collapse may occur with or without cardiac and / or respiratory arrest. These events tend to occur mainly with the concomitant use of a benzodiazepine or any other psychotropic agent (see section 4.5) and during the initial phase of treatment in association with a too rapid dose increase; very rarely these events may also occur after the first dose. Therefore, patients starting treatment with Leponex require close medical supervision. In patients with Parkinson's disease, monitoring of supine and standing blood pressure is required during the first weeks of therapy.
Analysis of the available safety data suggests that the use of Leponex is associated with an increased risk of myocarditis, particularly (but not limited to) during the first two months of treatment, in some cases with fatal outcomes. Cases of pericarditis / pericardial effusion and cardiomyopathy, some with fatal outcome, have also been reported in association with the use of Leponex. Suspicion of myocarditis or cardiomyopathy should be considered in patients with persistent tachycardia at rest, particularly in the first two. months of treatment, and / or palpitations, arrhythmias, chest pains, and other signs and symptoms of heart failure (e.g. unexplained feeling of fatigue, dyspnoea, tachypnea), or symptoms similar to those of myocardial infarction. Other symptoms which may be present are flu-like ones.If myocarditis or cardiomyopathy is suspected, treatment with Leponex should be stopped immediately and the patient immediately referred to a cardiologist.
Patients with clozapine induced myocarditis or cardiomyopathy should no longer receive Leponex.
Myocardial infarction
There have also been some reports of myocardial infarction post-marketing, in some cases with fatal outcomes. Assessment of causality was difficult in most cases due to pre-existing severe heart disease and likely alternative causes.
Prolongation of the QT interval
As with other antipsychotics, special care is advised in patients with known cardiovascular disease or family history of QT interval prolongation.
As with other antipsychotics, special care should be taken when prescribing clozapine with medicinal products known to increase the QTc interval.
Cerebrovascular adverse events
An approximately 3-fold increased risk of cerebrovascular adverse events was observed in randomized placebo-controlled clinical trials with some atypical antipsychotics in patients with dementia. The mechanism behind this increased risk is not known. It cannot be excluded that the risk also increases with other antipsychotics or other patient populations. Clozapine should be used with caution in patients with stroke risk factors.
Risk of thromboembolism
Since Leponex may be associated with thromboembolism, immobilization of patients should be avoided. Cases of venous thromboembolism (VTE) have been reported in association with antipsychotic drugs. As patients treated with antipsychotics often have acquired risk factors for VTE, they must identify all possible risk factors for VTE before and during treatment with Leponex and take preventive measures.
Seizures
Patients with a history of epilepsy should be closely monitored during therapy with Leponex, as dose-related seizures have been detected. In this case, the dose should be reduced (see section 4.2) and, if necessary, treatment with an anticonvulsant drug should be started.
Anticholinergic effects
Leponex has anticholinergic activity, which can cause the onset of undesirable effects affecting the whole organism. In the presence of prostatic hypertrophy and closed-angle glaucoma, careful monitoring is necessary. Probably due to its anticholinergic properties, Leponex has been associated with the occurrence of changes in intestinal peristalsis of varying intensity, ranging from constipation to intestinal obstruction, fecal impaction and paralytic ileus (see section 4.8). In rare cases, these episodes have been fatal. Particular attention should be paid to those patients receiving concomitant treatments that are known to cause constipation (especially drugs with anticholinergic properties, such as some antipsychotics, antidepressants and antiparkinsonian drugs), as well as those patients who have suffered from colon disease in the past and have undergone surgery of the lower abdomen, as in such cases an exacerbation of the situation may occur. It is important that constipation is correctly diagnosed and adequately treated.
Fever
Transient temperature rises above 38 ° C may occur during treatment with Leponex, with a peak in incidence within the first 3 weeks of treatment. This fever is usually benign. Sometimes it can be associated with an increase or decrease in the white blood cell count. Patients with fever should be carefully examined for the possibility of a concomitant infection or developing agranulocytosis. In the presence of high fever, the possibility of neuroleptic malignant syndrome (NMS) should be considered. If the diagnosis of NMS is confirmed, Leponex therapy should be discontinued immediately and appropriate medical treatment initiated.
Metabolic alterations
Atypical antipsychotic drugs, including Leponex, have been associated with metabolic alterations that may increase cardiovascular / cerebrovascular risk. These metabolic changes can include hyperglycemia, dyslipidemia and weight gain. Since atypical antipsychotic drugs can produce metabolic alterations, each drug in the class has its own specific profile.
Hyperglycemia
Rarely, impaired glucose tolerance and / or development or exacerbation of diabetes mellitus have been reported during treatment with clozapine. The mechanism to explain this possible correlation has not yet been identified. Very rarely, severe hyperglycaemia with ketoacidosis or hyperosmolar coma, in some cases with fatal outcome, has been reported in patients with no previous episode of hyperglycaemia. When data were available from follow up, it was observed that discontinuation of clozapine treatment generally resolved the impairments related to glucose tolerance, and resumption of clozapine treatment resulted in the problem returning. Patients with a certain diagnosis of diabetes mellitus who are started treatment with atypical antipsychotics, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are about to start treatment with atypical antipsychotics should be tested fasting blood glucose levels at the start of treatment and regularly during treatment. Patients who present with symptoms of hyperglycaemia during treatment with atypical antipsychotics should have a fasting blood glucose test. In some cases the hyperglycaemia resolved when treatment with atypical antipsychotics was stopped; however, in some patients it was necessary to continue treatment with antidiabetics despite discontinuation of the suspect drug. In patients whose active management of hyperglycaemia has not yielded positive results, discontinuation of clozapine should be considered.
Dyslipidemia
Undesirable changes in lipid levels have been observed in patients treated with atypical antipsychotics, including Leponex. Clinical monitoring is recommended in patients receiving clozapine, which should include lipid assessments at baseline and regularly in the follow-up.
Weight gain
Weight gain has been observed in patients treated with atypical antipsychotics, including Leponex. Clinical weight monitoring is recommended.
Rebound effects from discontinuation of therapy
Acute reactions have been reported following abrupt discontinuation of clozapine administration: therefore a gradual discontinuation of therapy is recommended. If it is necessary to abruptly discontinue treatment (e.g. in the presence of leukopenia), the patient should be monitored carefully due to the risk of recurrence of psychotic symptoms and symptoms related to the cholinergic rebound effects, such as intense sweating, headache, nausea, vomiting and diarrhea.
Special populations
Impaired liver function
In patients with pre-existing stable liver disease, Leponex can be administered, but regular monitoring of liver function is required. In patients who experience symptoms of possible liver dysfunction such as nausea, vomiting and / or anorexia during treatment with Leponex, liver function tests should be performed. If the rise in values is clinically significant (more than three times the normal range) or if symptoms of jaundice occur, treatment with Leponex should be discontinued. Treatment can be resumed (see "Resumption of therapy" in section 4.2. ) only when liver function parameters have returned to normal In these cases, liver function should be monitored very closely after resuming Leponex treatment.
Patients aged 60 years or older
In patients 60 years of age and older it is recommended to start treatment at the lowest recommended dose (see section 4.2).
Orthostatic hypotension may occur during therapy with Leponex; tachycardia, even prolonged, has also been reported. Patients 60 years of age or older, particularly those with impaired cardiovascular function, may be more sensitive to these effects.
Patients 60 years of age and older may also be particularly sensitive to the anticholinergic effects of Leponex, such as urinary retention and constipation.
Increased mortality in older people with dementia
Data from two large observational studies showed that older people with dementia treated with antipsychotics have a small increased risk of death compared to those not treated. The available data are insufficient to provide an accurate risk estimate and the cause of this increased risk is unknown.
Leponex is not approved for the treatment of dementia-related behavioral disorders.
04.5 Interactions with other medicinal products and other forms of interaction
Contraindications for the concomitant use of Leponex with other drugs
Substances known to have the potential to reduce bone marrow function should not be used concomitantly with Leponex (see section 4.3).
Leponex should not be administered concomitantly with long-acting depot antipsychotic drugs (which have a potential myelosuppressive effect), as they cannot be rapidly removed from the body if necessary, for example in case of neutropenia (see section 4.3). .
It is recommended not to consume alcohol concomitantly with Leponex, as it could enhance the sedative effect.
Precautions (including dose adjustments)
Leponex may enhance the central effects of CNS depressant drugs such as narcotics, antihistamines and benzodiazepines. Particular care should be taken when initiating therapy with Leponex in patients already being treated with benzodiazepines or other psychotropic substances, as they may have an increased risk of circulatory collapse which, in rare cases, can be severe and lead to cardiac arrest and / or respiratory. It is unclear whether circulatory or respiratory collapse can be prevented with dose adjustment.
Due to the possibility of additive effects, caution should be exercised in concomitant administration of substances with anticholinergic, hypotensive or breath-depressing effects.
Due to its anti-alpha-adrenergic properties, Leponex may reduce the blood pressure-increasing effect of norepinephrine or other agents with predominantly alpha-adrenergic activity, and reverse (paradoxical effect) the pressure effect of epinephrine.
Concomitant administration of substances that inhibit the activity of some cytochrome P450 isoenzymes may increase clozapine levels; doses of clozapine may need to be reduced to avoid any unwanted effects. This is more important for CYP 1A2 inhibitors such as caffeine. (see below) and the selective serotonin reuptake inhibitor, fluvoxamine.
Other serotonin reuptake inhibitors, such as fluoxetine, paroxetine and to a lesser extent sertraline, inhibit CYP 2D6 and consequently major pharmacokinetic interactions with clozapine are less likely. Similarly, pharmacokinetic interactions with CYP 3A4 inhibitors, such as azole antifungals, cimetidine, erythromycin and protease inhibitors, are less likely, although some reports have been received. As plasma concentrations of clozapine are increased by taking caffeine and decrease by almost 50% after a period of 5 days without caffeine intake, if there is a change in the intake habits of this substance it is necessary to change the dose of clozapine. If nicotine is stopped suddenly, the plasma concentrations of clozapine may increase, leading to an increased risk of side effects.
There have been reports of interactions between citalopram and clozapine, which may lead to an increased risk of adverse events associated with clozapine. The nature of this interaction has not been fully understood.
Concomitant administration of substances that induce cytochrome P450 enzymes may lead to decreased plasma levels of clozapine, resulting in reduced efficacy.
Substances inducing the activity of cytochrome P450 enzymes and for which interactions with clozapine have been reported include, for example, carbamazepine (not to be used concomitantly with clozapine, due to the potential myelosuppressive effect), phenytoin and rifampicin Known inducers of CYP 1A2, such as omeprazole, can lead to decreased clozapine levels. The possible decrease in efficacy of clozapine should be taken into account when used in combination with such substances.
Other interactions
Concomitant administration of lithium or other CNS active substances may increase the risk of developing neuroleptic malignant syndrome (NMS).
There have been rare but serious reports of seizures, including in non-epileptic patients, and isolated cases of delirium, in patients treated concomitantly with Leponex and valproic acid. These effects are likely due to pharmacodynamic interactions, the mechanism of which has not yet been determined.
Particular attention should also be paid to patients treated concomitantly with other substances capable of inhibiting or inducing cytochrome P450 isoenzymes. Regarding tricyclic antidepressants, phenothiazines and type 1C antiarrhythmic drugs known to bind to cytochrome P450 2D6, no clinically significant interactions have been observed to date. As with other antipsychotics, special care should be taken when clozapine is prescribed with medicinal products known to increase the QTc interval or to cause electrolyte imbalance. A list of the most important interactions between Leponex and other medicinal products is presented in Table 2. The list it is not exhaustive.
Table 2: Most frequent interactions between Leponex and other medicinal products
04.6 Pregnancy and lactation
Pregnancy
There are only limited clinical data in pregnant women exposed to clozapine treatment. Animal studies do not indicate direct or indirect harmful effects with respect to the course of pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3). Caution is advised when administering the drug during pregnancy.
Infants exposed to antipsychotics (including Leponex) during the third trimester of pregnancy are at risk of 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.
Feeding time
Animal studies indicate that clozapine is excreted in breast milk and has an effect on infants; mothers treated with Leponex should therefore not breastfeed.
Women of childbearing age
Switching from other antipsychotics to Leponex may result in a resumption of a normal menstrual cycle. The use of adequate contraceptive measures is therefore recommended for all women of childbearing age.
04.7 Effects on ability to drive and use machines
Given the ability of Leponex to cause sedation and lower the seizure threshold, it is recommended to avoid activities such as driving or using machines, particularly during the first few weeks of treatment.
04.8 Undesirable effects
Summary of the safety profile
The undesirable effect profile of clozapine can be largely inferred from its pharmacological properties. An important exception is the propensity to cause agranulocytosis (see section 4.4), due to which the use of the drug is limited to treatment-resistant schizophrenia and psychosis in Parkinson's disease, after the failure of classical therapeutic management. . Although haematological monitoring is essential in the care of patients treated with clozapine, the physician will need to be aware of other rare but serious adverse reactions that can only be diagnosed at an early stage through "careful observation and history of the patient in order to to prevent pathological states and fatal outcomes.
The most serious adverse reactions reported with clozapine are agranulocytosis, seizures, cardiovascular effects and fever (see section 4.4). The most common side effects are somnolence / sedation, dizziness, tachycardia, constipation and hypersalivation.
Clinical trial results show that a variable proportion of clozapine-treated patients (7.1 to 15.6%) discontinued treatment due to an adverse event, including only those that can reasonably be attributed to clozapine. The most common events considered responsible for the discontinuation were leukopenia, somnolence, dizziness (excluding vertigo) and psychotic disturbances.
Disorders of the blood and lymphatic system:
The appearance of granulocytopenia and agranulocytosis is a risk related to treatment with Leponex. Although these reactions are generally reversible upon discontinuation of the drug, agranulocytosis can in some cases lead to sepsis and be fatal. Since immediate discontinuation of treatment is required in order to prevent the development of a fatal agranulocytosis control of white blood cell count (see section 4.4). Table 3 shows the estimated incidence of agranulocytosis for each treatment period with Leponex.
Table 3: Estimated incidence of agranulocytosis 1
1 Data from the Clozaril Patient Monitoring Service, UK, 1989 to 2001 registers.
2 Person-time value is the sum of the individual units of time during which patients on the registry were exposed to Leponex before developing agranulocytosis. For example, 100,000 person-weeks can be observed in 1000 patients in the registry for 100 weeks (100 * 1000 = 100,000),
or in 200 patients in the registry for 500 weeks (200 * 500 = 100,000) before developing agranulocytosis.
The cumulative incidence of agranulocytosis obtained from the experience reported in the records of the Clozaril Patient Monitoring Service, United Kingdom (0 - 11.6 years in the period from 1989 to 2001) is equal to 0.78%. Most cases (about 70%) occur within the first 18 weeks of treatment.
Metabolism and nutrition disorders:
Rarely, impaired glucose tolerance and / or development or exacerbation of diabetes mellitus have been reported during treatment with clozapine. Cases of severe hyperglycaemia, sometimes leading to hyperosmolar ketoacidosis / coma, have been observed very rarely in patients with no history of hyperglycaemia treated with Leponex. After discontinuation of therapy, glucose levels normalized in almost all patients, and in some cases the hyperglycaemia returned when treatment was resumed. Although most patients had non-insulin risk factors for diabetes mellitus. -dependent, hyperglycaemia was also observed in subjects with no known risk factors (see section 4.4).
Nervous system disorders:
The most commonly observed adverse reactions are somnolence / sedation and dizziness.
Leponex can cause electroencephalographic changes, including the appearance of tip-wave complexes; it lowers the seizure threshold in a dose-dependent manner and can induce myoclonic spasms or generalized seizures. These symptoms usually occur when the dose is increased rapidly and in patients with pre-existing epilepsy. In this case, the dose should be reduced and, if necessary, anticonvulsant treatment initiated. The use of carbamazepine should be avoided due to its potential myelosuppressive effect, while the possibility of a pharmacokinetic interaction should be considered for other anticonvulsants. Rarely, delirium may occur in patients treated with Leponex.
Cases of tardive dyskinesia have been reported very rarely in patients receiving Leponex and receiving other antipsychotics. In patients who had experienced tardive dyskinesia with other antipsychotics, improvement was seen with Leponex.
Cardiac disorders:
Tachycardia and postural hypotension, with or without syncope, may occur, especially during the first few weeks of treatment. The prevalence and severity of hypotension depend on the speed and extent of the dose increase. Circulatory collapse has been reported following severe hypotension, particularly associated with aggressive titration, with possible serious consequences of cardiac or pulmonary arrest. .
ECG changes similar to those reported with other antipsychotics (including S-T segment depression and crushing or inversion of T waves) have been observed in a minority of patients treated with Leponex and have normalized after discontinuation of treatment. The clinical significance of these changes is unclear. However, these anomalies have been observed in patients with myocarditis, which must therefore be taken into consideration.
There have been isolated reports of cardiac arrhythmia, pericarditis / pericardial effusion and myocarditis, some with fatal outcomes. Most cases of myocarditis occurred within the first 2 months after initiation of Leponex therapy. Cardiomyopathies generally occurred with advanced treatment.
In some cases, myocarditis (approximately 14%) and pericarditis / pericardial effusion were accompanied by eosinophilia; however, it is not known whether eosinophilia is a reliable predictor of carditis.
Signs and symptoms of myocarditis or cardiomyopathy include persistent resting tachycardia, palpitations, arrhythmias, chest pains and other signs and symptoms of heart failure (e.g. unexplained feeling of fatigue, dyspnoea, tachypnea) or myocardial infarction-like symptoms. Other symptoms that may be present are flu-like ones.
Sudden unexplained deaths can occur in psychiatric patients, whether on or not on antipsychotic drugs. Such deaths have been observed very rarely among patients treated with Leponex.
Vascular disorders:
Rare cases of thromboembolism have been reported.
Respiratory, thoracic and mediastinal disorders:
Cases of respiratory depression or arrest, with or without circulatory collapse, have been reported very rarely (see sections 4.4 and 4.5).
Gastrointestinal disorders:
Constipation and hypersalivation have been observed very frequently, nausea and vomiting frequently.
Paralytic ileus may occur very rarely (see section 4.4). Leponex has rarely been associated with dysphagia. Aspiration of ingested food may occur in patients with dysphagia or following acute overdose.
Hepatobiliary disorders:
Transient and asymptomatic elevations of liver enzymes and rarely hepatitis and cholestatic jaundice have been reported. Cases of fulminant hepatic necrosis have been reported very rarely. In the presence of jaundice, Leponex therapy should be discontinued (see section 4.4). Cases of acute pancreatitis have rarely occurred.
Renal and urinary disorders:
Isolated cases of acute interstitial nephritis have been observed in association with Leponex.
Reproductive system and breast disorders:
Cases of priapism have been reported very rarely.
General disorders and administration site conditions:
Cases of neuroleptic malignant syndrome (NMS) have been reported in patients treated with Leponex alone or in combination with lithium or other CNS active substances.
Acute reactions due to treatment discontinuation have been reported (see section 4.4).
List of adverse reactions
The table below (Table 4) summarizes the adverse reactions resulting from spontaneous reports and clinical studies.
Table 4: Estimated frequency of treatment-related adverse events from spontaneous reporting and clinical trials
Adverse reactions are categorized by frequency, using the following parameters: very common (≥1 / 10), common (≥1 / 100,
* Adverse reactions arising from post-marketing experience through spontaneous reports and published cases in the literature
Very rare cases of ventricular tachycardia and QT interval prolongation which may be associated with 'torsade de pointes' arrhythmia have been observed, although there is no sure causal relationship with the use of this medicine.
04.9 Overdose
Cases of acute overdose of Leponex, intentional or accidental, of which the outcome is known, resulted in a mortality of approximately 12%. Most fatalities were associated with heart failure or aspiration pneumonia and occurred at doses greater than 2,000 mg.
There have been reports of patients recovering from an overdose greater than 10,000 mg.
However, in some adults, especially in those not previously exposed to Leponex, the ingestion of low doses of 400 mg resulted in life-threatening comatose situations and, in one case, death. In young children, intake doses between 50 and 200 mg led to severe sedation or coma, without fatal outcomes.
Signs and symptoms
Somnolence, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extrapyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnoea, depression or respiratory failure.
Treatment
There are no specific antidotes for Leponex.
Gastric lavage and / or administration of activated charcoal within the first 6 hours of drug ingestion. Peritoneal dialysis and hemodialysis have not been shown to be effective. Symptomatic treatment with continuous monitoring of cardiac function, respiration, electrolytes and acid-base balance. The use of adrenaline should be avoided in the treatment of hypotension as there is the possibility of a paradoxical effect of adrenaline.
Close medical surveillance is required for at least 5 days, due to the possibility of delayed reactions.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antipsychotics; diazepines, oxazepines and thiazepines, ATC code: N05A H02
Leponex has been shown to be a different antipsychotic from classic antipsychotics.
In pharmacological experiments, the compound does not induce catalepsy or inhibit the stereotypical behavior induced by apomorphine or amphetamine. It has only weak dopaminergic receptor blocking activity D1, D2, D3 and D5, but shows high affinity for the D4 receptor, in addition to potent anti-α-adrenergic, anticholinergic, antihistamine and excitatory reaction inhibiting effects. The compound has also been shown to possess antiserotonergic properties.
Clinically Leponex produces a rapid and marked sedative effect and exerts antipsychotic effects in schizophrenic patients resistant to other pharmacological treatments. In these cases, Leponex has been shown to be effective in reducing both positive and negative symptoms of schizophrenic disease, mainly in short-term clinical trials. In an open-label clinical study in 319 treatment-resistant patients treated for 12 months, significant clinical improvement was observed in 37% of patients within the first week of treatment, and in an additional 44% by the end of 12 months. . Improvement was defined as approximately 20% reduction from baseline on the rating scale Brief Psychiatric Rating Scale Score. An improvement in some aspects of cognitive dysfunction was also described.
Compared to classic antipsychotics, Leponex produces fewer major extrapyramidal reactions such as acute dystonia, parkinsonian side effects and akathisia.Unlike classic antipsychotics, Leponex causes little or no increase in prolactin, thus avoiding adverse events such as gynecomastia, amenorrhea, galactorrhea and impotence.
A potentially serious adverse reaction caused by treatment with Leponex is the onset of granulocytopenia and agranulocytosis, the frequency of which is estimated at around 3% and 0.7%, respectively.
Therefore, the use of Leponex should be limited to treatment-resistant schizophrenic patients or to patients with psychotic disorders in Parkinson's disease, after failure of other therapeutic strategies (see section 4.1), and who may undergo regular haematological tests. (see sections 4.4 and 4.8).
05.2 Pharmacokinetic properties
Absorption
Absorption of orally administered Leponex is 90-95%; the rate and extent of absorption are not affected by food intake.
Leponex undergoes moderate first pass metabolism, resulting in an absolute bioavailability of 50-60%.
Distribution
At steady state, with two administrations / day, the blood peak occurs on average after 2.1 hours (range: 0.4-4.2 hours) and the volume of distribution is 1.6 l / kg. Leponex is approximately 95% bound to plasma proteins.
Biotransformation / Metabolism
Leponex is almost completely metabolised prior to excretion. Of its major metabolites, only one, the demethyl metabolite, has been shown to be active. Its pharmacological activity is similar to that of clozapine, but is considerably weaker and of shorter duration.
Elimination
Its elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6-26 hours). After a single dose of 75 mg the mean terminal half-life is 7.9 hours; it increases to 14.2 hours when steady state is reached through daily administration of 75 mg for at least 7 days. Only traces of unchanged drug are found in the urine and faeces, as approximately 50% of the administered dose is excreted as metabolites in the urine, and 30% in the faeces.
Linearity / Non-linearity
Increasing doses of 37.5, 75 and 150 mg in two daily administrations result in dose-dependent linear increases in area under the plasma concentration / time curve (AUC), peak and trough plasma concentrations at steady state.
05.3 Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential (for reproductive toxicity, see section 4.6).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Magnesium stearate
Anhydrous colloidal silica
Povidone (K 30)
Talc
Cornstarch
Lactose monohydrate
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
PVC / PVDC / aluminum blisters
Pack sizes: 7, 14, 20, 28, 30, 40, 50, 60, 84, 98, 100 tablets.
Hospital packs: 500 (10x50) and 5000 (100x50) tablets.
Amber glass bottles (class III) with tamper-proof polyethylene (PE) closure
Packaging: 100 tablets.
Hospital pack: 500 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Farma S.p.A.
Largo Umberto Boccioni, 1 - 21040 Origgio (VA)
08.0 MARKETING AUTHORIZATION NUMBER
Leponex 25 mg tablets 28 tablets of 25 mg A.I.C. n. 028824011
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 07.03.1995
Date of last renewal: 09.07.2008
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 02.05.2013
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