Klozapol

Package Leaflet: Information for the User

Clozapine, 25 mg, Tablets

Clozapine, 100 mg, Tablets

Clozapine

Read the package leaflet carefully before taking the medicine, as it contains important information for you.

• You should keep this leaflet, as you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of the Package Leaflet:

• 1. What Clozapine is and what it is used for
• 2. Important information before taking Clozapine
• 3. How to take Clozapine
• 4. Possible side effects
• 5. How to store Clozapine
• 6. Contents of the pack and other information

1. What Clozapine is and what it is used for

The active substance of Clozapine is clozapine, which belongs to a group of medicines called antipsychotics (medicines used to treat certain mental disorders, such as psychoses).
Clozapine is used to treat patients with schizophrenia who do not respond to treatment with other medicines.
Schizophrenia is a mental disorder that causes disturbances in thought, emotion, and behavior.
Clozapine should only be used to treat patients who have already taken at least two different antipsychotic medicines, including one of the new atypical antipsychotics indicated for the treatment of schizophrenia, and have not responded to these medicines or have experienced severe side effects that could not be controlled.
Clozapine is also used to treat severe disturbances in thought, emotion, and behavior in patients with Parkinson's disease who do not respond to treatment with other medicines.

2. Important information before taking Clozapine

When not to take Clozapine

• if you have ever had an allergic reaction (hypersensitivity) to clozapine or any of the other ingredients of Clozapine (listed in section 6);
• if you do not have the possibility of regular blood tests;
• if you have ever had a low white blood cell count in your blood (e.g., leukopenia or agranulocytosis), especially if it was caused by taking medicines, except for cases of low white blood cell count in your blood related to previous chemotherapy;
• if you have previously stopped taking Clozapine due to severe side effects (e.g., agranulocytosis or heart problems);
• if you are or have been treated with depot antipsychotic injections;
• if you have bone marrow depression;
• if you have uncontrolled epilepsy (seizures or other types of epilepsy);
• if you have acute mental disorders caused by alcohol or drugs (e.g., narcotics);
• if you have reduced consciousness and increased drowsiness;
• if you have circulatory collapse, which may be a consequence of severe shock;
• if you have severe kidney problems;
• if you have myocarditis;
• if you have other severe heart diseases;
• if you have symptoms of active liver disease, such as jaundice (yellowing of the skin and eyes, nausea, loss of appetite);
• if you have other severe liver function disorders;
• if you have paralytic ileus (your intestine does not work properly and you have severe constipation);
• if you are taking any medicines that suppress normal bone marrow function;
• if you are taking any medicines that decrease the number of white blood cells in your blood.

If any of the above points apply to you, tell your doctor and do not take Clozapine.
Clozapine must not be taken by patients who are unconscious or in a coma.

Warnings and precautions

Before starting treatment with Clozapine, discuss it with your doctor or pharmacist.

The safety issues mentioned in this section are very important. You must pay special attention to them to minimize the risk of severe side effects that can be life-threatening.

Before you start taking Clozapine, tell your doctor if you have or have had:

• blood clots, as medicines like this one have been associated with the formation of blood clots;
• glaucoma (increased pressure in the eye);
• diabetes (high blood sugar levels, which can occur in people with or without a history of diabetes) (see section 4);
• prostate problems or difficulty urinating;
• heart, kidney, or liver disease;
• chronic constipation or taking medicines that cause constipation (such as anticholinergic medicines);
• lactose intolerance, lactase deficiency, or glucose-galactose malabsorption;
• controlled epilepsy;
• gastrointestinal disease;
• previous abdominal surgery;
• a history of heart problems or abnormal heart rhythm, known as "QT prolongation";
• stroke risk, e.g., if you have high blood pressure, heart problems, or problems with blood vessels in the brain.

Tell your doctor immediately before taking the next Clozapine tablet:

• If you experience symptoms of a cold, flu, fever, sore throat, or any infection. Your doctor may order a blood test to see if the symptoms are related to the medicine.
• If you experience a sudden increase in temperature, muscle stiffness that can lead to loss of consciousness (neuroleptic malignant syndrome), which can be a severe side effect requiring immediate treatment.
• If you experience rapid or irregular heartbeat, even at rest, palpitations, difficulty breathing, chest pain, or unexplained fatigue. Your doctor will check your heart function and, if necessary, refer you to a cardiologist immediately.
• If you experience nausea, vomiting, and (or) loss of appetite. Your doctor will check your liver function.
• If you experience constipation, abdominal pain, abdominal tenderness, fever, bloating, and (or) bloody diarrhea. You should consult your doctor.

Medical check-ups and blood tests

Before starting treatment with Clozapine, your doctor will take your medical history and order blood tests to confirm that you have a normal white blood cell count. This is important because your body needs white blood cells to fight infections.

Regular blood tests must be performed before starting treatment, during treatment, and after stopping Clozapine.

• Your doctor will inform you exactly when and where to have the blood tests done. Clozapine can only be taken if you have a normal white blood cell count.
• Clozapine can cause a significant decrease in the number of white blood cells in your blood (agranulocytosis). Only regular blood tests can detect whether you are at risk of developing agranulocytosis.
• Blood tests should be performed once a week for the first 18 weeks of treatment. Then, blood tests should be performed at least once a month.
• If your white blood cell count decreases, you must stop taking Clozapine immediately. Your white blood cell count should return to normal.
• Blood tests should be performed for 4 weeks after stopping Clozapine.

Your doctor will also perform a physical examination before starting treatment with Clozapine.
Your doctor may order an electrocardiogram (ECG) to check your heart function if it is necessary for you or if you have specific concerns.
If you have liver function disorders, regular liver function tests will be performed throughout Clozapine treatment.
If you have high blood sugar levels (diabetes), your doctor may order regular blood sugar tests.
Clozapine may affect your lipid levels. Clozapine may cause weight gain. Your doctor may monitor your weight and lipid levels.
If you experience dizziness, lightheadedness, or fainting, you should change positions slowly when sitting or lying down, as you may be at risk of falls.
If you need to undergo surgery or be immobilized for a long time, you should discuss Clozapine treatment with your doctor. There is a risk of thrombosis (blood clotting in the veins).

Children and adolescents under 16 years

Patients under 16 years should not take Clozapine, as there is limited data on the use of the medicine in this age group.

Elderly patients (65 years and older)

In elderly patients (65 years and older), the following side effects may occur more frequently during Clozapine treatment: fainting or dizziness when changing positions, dizziness, rapid heartbeat, difficulty urinating, and constipation.
Tell your doctor if you have a condition called dementia.

Clozapine and other medicines

Tell your doctor or pharmacist about all medicines you are taking now or have taken recently, as well as any medicines you plan to take (including those available without a prescription and herbal medicines). You may need to take different doses or other medicines.

Do not take Clozapine with medicines that suppress normal bone marrow function and (or) decrease the number of white blood cells produced by your body, such as:

• carbamazepine, a medicine used to treat epilepsy;
• certain antibiotics: chloramphenicol, sulfonamides, such as cotrimoxazole;
• certain painkillers: pyrazolone derivatives, such as phenylbutazone or metamizole;
• penicillamine, a medicine used to treat rheumatoid arthritis;
• cytotoxic agents, medicines used in chemotherapy;
• depot antipsychotic injections.

These medicines increase the risk of developing agranulocytosis (lack of white blood cells).

Taking Clozapine with other medicines may affect the action of Clozapine and (or) other medicines. Tell your doctor if you plan to take, are taking, or have recently stopped taking the following medicines:

Medicines used to treat depression, such as lithium, fluvoxamine, tricyclic antidepressants, MAO inhibitors, citalopram, paroxetine, fluoxetine, and sertraline;

• other antipsychotic medicines used to treat mental illnesses, such as perazine;
• benzodiazepines and other medicines used to treat anxiety and sleep disorders;
• narcotics and other medicines that may affect breathing;
• medicines used to treat epilepsy, such as phenytoin and valproic acid;
• medicines used to treat high and low blood pressure, such as adrenaline and noradrenaline;
• warfarin, a medicine used to prevent blood clots;
• antihistamines, medicines used to treat colds or allergies, such as hay fever;
• anticholinergic medicines, used to relieve stomach cramps and motion sickness;
• medicines used to treat Parkinson's disease;
• digoxin, a medicine used to treat heart conditions;
• medicines used to treat rapid or irregular heartbeat;
• certain medicines used to treat stomach ulcers, such as omeprazole or cimetidine;
• certain antibiotics, such as erythromycin and rifampicin;
• certain medicines used to treat fungal or viral infections (such as ketoconazole or HIV protease inhibitors);
• atropine, a medicine that may be a component of certain eye drops, cold medicines, and cough medicines;
• adrenaline, a medicine used in emergency situations;
• hormonal contraceptives.

This list is not exhaustive. Your doctor or pharmacist has more information about medicines that should be used with caution with Clozapine or should be avoided during Clozapine treatment, as well as which medicines belong to the mentioned groups. You should ask them about it.

Clozapine with food and drink

Do not drink alcohol while taking Clozapine.
Tell your doctor if you smoke and how often you drink caffeinated beverages (coffee, tea, cola). Sudden changes in smoking or caffeine consumption habits may also change the effects of Clozapine.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a baby, ask your doctor for advice before taking this medicine.
Your doctor will discuss the benefits and possible risks of taking Clozapine during pregnancy.
Tell your doctor immediately if you become pregnant while taking Clozapine.
In newborns whose mothers took antipsychotic medicines (e.g., Clozapine) during the last trimester (last 3 months of pregnancy), the following symptoms may occur: trembling, muscle stiffness, and (or) weakness, drowsiness, agitation, difficulty breathing, and feeding problems. If your child develops these symptoms, contact your doctor.
Some women taking medicines for mental illnesses have irregular periods or do not have them at all. When switching from another medicine to Clozapine, normal menstruation may return. Therefore, women of childbearing age should use effective contraception.
Do not breastfeed while taking Clozapine. Clozapine, the active substance of Clozapine, may pass into breast milk and affect your baby.

Driving and using machines

Clozapine may cause drowsiness, dizziness, and seizures, especially during the initial treatment period. Do not drive vehicles or operate machinery if you experience these symptoms.

Clozapine contains lactose and sodium

One tablet contains 18 mg of lactose. If you have been diagnosed with an intolerance to some sugars, contact your doctor before taking this medicine.
The medicine contains less than 1 mmol (23 mg) of sodium per dose, which means it is essentially "sodium-free".

3. How to take Clozapine

Take this medicine always as directed by your doctor. If you are not sure, ask your doctor or pharmacist.

To minimize the risk of low blood pressure, seizures, and drowsiness, your doctor will gradually increase the dose of Clozapine.
It is very important not to change the dose or stop taking Clozapine without consulting your doctor first. Continue treatment for as long as your doctor recommends.
In patients over 60 years old, the doctor may start treatment with a lower dose and gradually increase it, as they are more likely to experience certain side effects (see section 2 "Important information before taking Clozapine").
If the prescribed dose cannot be achieved with this strength of the medicine, another strength of the medicine is available on the market that will allow the required dose to be achieved.

Treatment of schizophrenia

The recommended initial dose is 12.5 mg (half of a 25 mg tablet) once or twice a day on the first day, and then 25 mg once or twice a day on the second day.
Swallow the tablet with water.
If the treatment is well tolerated, the daily dose can then be gradually increased by 25 mg to 50 mg over 2-3 weeks to achieve a target dose of 300 mg per day.
Then, if necessary, the daily dose can be further increased by 50 mg to 100 mg at intervals of 3 to 4 days or, preferably, once a week.
The effective daily dose is usually 200 mg or 450 mg, divided into several single doses. Some patients may need higher doses. The maximum daily dose is 900 mg. At doses above 450 mg per day, some side effects may be more pronounced (especially seizures). You should always take the smallest effective dose for you. Most patients take part of the dose in the morning and part in the evening. Your doctor will explain how to divide the daily dose. If the dose is 200 mg, you can take it as a single dose in the evening. If you have been taking Clozapine for some time with good results, your doctor may try to reduce the dose. You should take Clozapine for at least 6 months.

Treatment of severe disturbances in thought, emotion, and behavior in patients with Parkinson's disease

The recommended initial dose is 12.5 mg (half of a 25 mg tablet) in the evening.
Swallow the tablet with water. Then, your doctor will gradually increase the dose by 12.5 mg, no faster than twice a week, to achieve a maximum dose of 50 mg per day by the end of the second week. If you experience fainting, dizziness, or confusion, the dose increase should be delayed or stopped. To avoid these symptoms, your doctor should check your blood pressure in the first weeks of treatment.
The effective daily dose is usually 25 mg to 37.5 mg, taken as a single dose in the evening. Doses above 50 mg per day should only be used in exceptional cases. The maximum daily dose is 100 mg.
You should always take the smallest effective dose of the medicine.
Clozapine 25 mg tablets can be divided into equal doses.

Overdose of Clozapine

If you have taken more than the prescribed dose of Clozapine or if someone else has taken your medicine, contact your doctor or go to the hospital immediately.
Overdose symptoms: drowsiness, fatigue, lack of energy, loss of consciousness, coma, confusion (disorientation), hallucinations, agitation, delirium, muscle stiffness, tremors, seizures (convulsions), excessive salivation, dilated pupils, blurred vision, low blood pressure, shock, rapid or irregular heartbeat, shallow breathing or difficulty breathing.

Missed dose of Clozapine

If you miss a dose, take it as soon as possible. However, do not take the medicine if it is almost time for your next dose. In this case, take the next dose at the usual time.
Do not take a double dose to make up for the missed dose.
If you have forgotten to take Clozapine for 48 hours or more, contact your doctor immediately.

Stopping Clozapine treatment

Do not stop taking Clozapine without consulting your doctor first, as withdrawal reactions may occur. These include sweating, headache, nausea, vomiting, and diarrhea. If you experience any of these symptoms, tell your doctor immediately.
More severe side effects may occur after these symptoms if you do not receive immediate treatment.Your symptoms may return. It is recommended to gradually reduce the dose by 12.5 mg over 1 to 2 weeks. If it is necessary to stop Clozapine treatment immediately, consult your doctor. If your doctor decides to restart Clozapine treatment and you have taken the last dose of Clozapine more than 2 days ago, the initial dose will be 12.5 mg.
If you have any further questions about taking Clozapine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, Clozapine can cause side effects, although not everybody gets them.

Some side effects may be severe and require medical attention. Tell your doctor immediately before taking the next Clozapine tablet if you experience any of the following symptoms:

Very common (may affect more than 1 in 10 people):

• severe constipation. Your doctor will provide treatment to prevent further complications.
• rapid heartbeat.

Common (may affect up to 1 in 10 people):

• symptoms of a cold, fever, flu-like symptoms, sore throat, or other infections. It is essential to perform a blood test to check if the symptoms are related to the medicine.
• seizures.
• sudden fainting or loss of consciousness with muscle weakness (syncope).

Uncommon (may affect up to 1 in 100 people):

• sudden increase in body temperature, muscle stiffness, which can lead to loss of consciousness (neuroleptic malignant syndrome); these can be severe side effects requiring immediate treatment.

Rare (may affect up to 1 in 1,000 people):

• infection symptomsof the respiratory system orpneumonia, such asfever, cough, difficulty breathing, wheezing.
• severe burning pain in the upper abdomen that radiates to the back, with nausea and vomiting, caused by pancreatitis.
• fainting and muscle weakness due to severely low blood pressure (circulatory collapse).
• difficulty swallowing (which can cause food to be inhaled).
• nausea, vomiting, and (or) loss of appetite. Your doctor will check your liver function.
• weight gain.
• sleep apnea with snoring or without snoring.

Rare (may affect up to 1 in 1,000 people) orvery rare (may affect up to 1 in 10,000 people):

• rapid and irregular heartbeat, even at rest, palpitations, difficulty breathing, chest pain, or unexplained fatigue. Your doctor will check your heart function and, if necessary, refer you to a cardiologist immediately.

Very rare (may affect up to 1 in 10,000 people):

• prolonged and painful erection of the penis (priapism) in men. If the erection lasts more than 4 hours, immediate treatment may be necessary to prevent complications.
• sudden bleeding or bruising, which can be symptoms of a low platelet count.
• symptoms of uncontrolled blood sugar levels (such as nausea or vomiting, abdominal pain, excessive thirst, excessive urination, confusion, or disorientation).
• abdominal pain, cramps, bloating, vomiting, constipation, and difficulty passing gas, which can be symptoms of intestinal obstruction.
• loss of appetite, bloating, abdominal pain, yellowing of the skin, severe weakness, and general feeling of being unwell. These symptoms may indicate liver failure, which can lead to rapid liver death.
• nausea, vomiting, fatigue, weight loss, which can be symptoms of kidney inflammation.

Frequency not known (frequency cannot be estimated from the available data):

• chest pain, feeling of tightness in the chest, pressure, or burning sensation in the chest, which may radiate to the left arm, jaw, neck, and upper abdomen, shortness of breath, sweating, weakness, dizziness, nausea, vomiting, and palpitations (symptoms of a heart attack). In these cases, you should see a doctor immediately.
• pressure in the chest, feeling of heaviness, pressure, or severe pain, which can be symptoms of inadequate blood flow and oxygen supply to the heart muscle. Your doctor will check your heart function.
• feeling of irregular heartbeat: "thumping", "pounding", or "fluttering" in the chest (palpitations).
• rapid and irregular heartbeat (atrial fibrillation). You may experience palpitations, fainting, shortness of breath, or chest discomfort. You should consult your doctor.
• symptoms of low blood pressure, such as dizziness, lightheadedness, fainting, blurred vision, excessive fatigue, cold and clammy skin, or nausea.
• swelling, pain, and redness of the leg - symptoms of blood clots in the veins, especially in the legs. Blood clots can travel through the bloodstream to the lungs, causing chest pain and difficulty breathing.
• confirmed or suspected infection with fever or low body temperature, rapid breathing, rapid heartbeat, changes in reaction speed and consciousness, low blood pressure (sepsis).
• excessive sweating, headache, nausea, vomiting, and diarrhea (symptoms of cholinergic syndrome).
• significant decrease in urine output (symptom of kidney failure).
• swelling, especially of the face, lips, and throat, as well as the tongue, which can cause itching and be painful (allergic reaction).
• loss of appetite, bloating, abdominal pain, yellowing of the skin, severe weakness, and general feeling of being unwell. These symptoms may indicate liver failure, which can be life-threatening.
• constipation, abdominal pain, abdominal tenderness, fever, bloating, and (or) bloody diarrhea. These symptoms may indicate acute colon dilation (acute intestinal dilation) or intestinal infarction (intestinal necrosis). You should consult your doctor.
• dull chest pain or abdominal pain with shortness of breath, with or without cough or fever, due to inflammation of multiple serous membranes, such as the pleura, pericardium, and peritoneum, at the same time (polyserositis).

Other side effects:
Very common (may affect more than 1 in 10 people):

• drowsiness, dizziness,
• excessive salivation.

Common (may affect up to 1 in 10 people):

• high white blood cell count (leukocytosis), high count of a certain type of white blood cell (eosinophilia),
• weight gain,
• blurred vision,
• headache, tremors, stiffness, restlessness,
• seizures, muscle jerks (myoclonus), involuntary movements, inability to move, inability to stay still,
• changes in ECG,
• high blood pressure, fainting or dizziness when changing positions,
• nausea, vomiting, loss of appetite, dry mouth,
• abnormal liver function tests,
• urinary incontinence, urinary retention, difficulty urinating,
• fatigue, fever, increased sweating,
• speech disorders (e.g., unclear speech).

Uncommon (may affect up to 1 in 100 people):

• low white blood cell count (agranulocytosis),
• speech disorders (e.g., stuttering).

Rare (may affect up to 1 in 1,000 people):

• low red blood cell count (anemia),
• restlessness, agitation, confusion, delirium,
• arrhythmia, myocarditis, or pericarditis, pericardial effusion,
• high blood sugar levels, diabetes,
• pulmonary embolism (blood clot in the lungs),
• hepatitis, liver disease causing yellowing of the skin, dark urine, itching (jaundice),
• increased levels of the enzyme creatine phosphokinase in the blood.

Very rare (may affect up to 1 in 10,000 people):

• increased platelet count with possible blood clotting in the blood vessels,
• uncontrolled movements of the mouth, tongue, and limbs, obsessive thoughts and compulsive actions (obsessive-compulsive symptoms),
• skin reactions, swelling of the parotid gland (enlargement of the salivary glands),
• breathing difficulties,
• very high levels of triglycerides or cholesterol in the blood,
• heart muscle disease (cardiomyopathy), cardiac arrest, sudden unexplained death.

Frequency not known (frequency cannot be estimated from the available data):

• changes in brain wave recordings (electroencephalogram - EEG),
• diarrhea, stomach discomfort, heartburn, discomfort in the stomach after eating,
• feeling of weakness, muscle cramps, muscle pain,
• stuffy nose,
• bedwetting,
• sudden, uncontrolled increase in blood pressure (pseudo-phaeochromocytoma syndrome),
• uncontrolled bending of the torso to one side (pleurothotonus),
• disorders of ejaculation in men, during which semen enters the bladder instead of exiting the penis (dry orgasm or retrograde ejaculation),
• rash, purple spots (bleeding into the skin), fever, or itching due to blood vessel inflammation,
• colon inflammation causing diarrhea, abdominal pain,
• fever, change in skin color, butterfly-shaped rash on the face, joint pain, muscle pain, fatigue with fever (lupus erythematosus),
• restless legs syndrome (irresistible urge to move the legs or arms, usually accompanied by an unpleasant feeling, especially in the evening or at night, temporarily relieved by movement),
• acute chest pain or abdominal pain with shortness of breath, with or without cough or fever, due to inflammation of multiple serous membranes, such as the pleura, pericardium, and peritoneum, at the same time (polyserositis).

In elderly patients with dementia, treated with antipsychotic medicines, a small increased risk of death has been reported compared to those not treated with these medicines.

Reporting side effects

If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. Side effects can be reported directly to the Department of Drug Safety, Ministry of Health, via the online reporting system at https://smz.ezdrowie.gov.pl or by phone: +48 22 49 21 301, fax: +48 22 49 21 309. Side effects can also be reported to the marketing authorization holder. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Clozapine

Store in a temperature below 25°C.
Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date (EXP) stated on the packaging.
The expiry date refers to the last day of the month shown.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What Clozapine contains

• The active substance of Clozapine is clozapine. One tablet contains 25 mg or 100 mg of clozapine.
• The other ingredients are: potato starch, lactose monohydrate (18 mg), microcrystalline cellulose, magnesium stearate, hydroxypropyl cellulose, sodium lauryl sulfate, colloidal anhydrous silica.

What Clozapine looks like and contents of the pack

Clozapine 25 mg tablets - oblong, biconvex, scored on one side, yellowish-beige in color.
Clozapine 100 mg tablets - round, biconvex, yellowish-beige in color.
Clozapine 25 mg tablets are available in packs containing 50 tablets in aluminum/PVC blisters (2 blisters of 25 tablets) in a cardboard box.
Clozapine 100 mg tablets are available in packs containing 50 tablets in aluminum/PVC blisters (2 blisters of 25 tablets) in a cardboard box.

Marketing authorization holder

Egis Pharmaceuticals PLC
1106 Budapest, Keresztúri út 30-38
Hungary

Manufacturer

Egis Pharmaceuticals PLC
9900 Körmend, Mátyás király u. 65
Hungary
To obtain more detailed information, contact the representative of the marketing authorization holder:
EGIS Polska Sp. z o.o.
ul. Komitetu Obrony Robotników 45D
02-146 Warszawa
Phone: +48 22 417 92 00
Date of last revision of the leaflet:14.10.2022