Consumer medicine information

Clozitor

Clozapine

BRAND INFORMATION

Brand name

Clozitor

Active ingredient

Clozapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Clozitor.

SUMMARY CMI

CLOZITOR

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. WHY AM I USING CLOZITOR?

CLOZITOR contains the active ingredient clozapine. CLOZITOR is used to treat schizophrenia, which is a mental illness with disturbances in thinking, feelings and behaviour. For more information, see Section 1. Why am I using CLOZITOR? in the full CMI.

2. WHAT SHOULD I KNOW BEFORE I USE CLOZITOR?

Do not use CLOZITOR if you have an allergy to reaction to any medicine containing clozapine or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use CLOZITOR? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CLOZITOR and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. HOW DO I USE CLOZITOR?

The usual starting dose is half of a 25 mg tablet once or twice on the first day, followed by one 25 mg tablet once or twice on the second day. If this dose is well tolerated, then the dose may be slowly increased. More instructions can be found in Section 4. How do I use CLOZITOR? in the full CMI.

5. What should I know while using CLOZITOR?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using CLOZITOR.
  • You must have strict and regular blood tests while taking CLOZITOR.
  • Contact your doctor immediately if you develop a fever, signs and symptoms of an infection, notice any changes to your bowel movements (poo) or become pregnant.
Things you should not do
  • Do not stop using this medicine suddenly or lower the dosage, even if you are feeling better, without checking with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how CLOZITOR affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • You should not drink alcohol while you are taking CLOZITOR.
Looking after your medicine
  • Store below 25°C in a cool dry place. Protect from light.

For more information, see Section 5. What should I know while using CLOZITOR? in the full CMI.

6. Are there any side effects?

Speak to your doctor if you have any of the following and they worry you:, nausea (feeling sick), vomiting, stomach discomfort especially after a meal, diarrhoea, dry mouth. Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of the following: constipation or fewer bowel movements than normal, abdominal pain or chest pain, a fast or irregular heartbeat and discomfort of the heart, fever, sore throat, mouth ulcers, "flu-like" symptoms, sudden signs of allergy, sudden increase in body temperature, muscle stiffness, stomach pain often accompanied by nausea, severe or prolonged constipation. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING: Gastrointestinal hypomotility with severe complications:
Clozapine may cause slowing down or blockage of intestine function, causing reactions such as constipation; nausea with or without vomiting; tenderness or swelling of the abdomen, or bloating; gas/wind; foul-smelling breath; stomach pains/spasms; leakage of diarrhoea or frequent and forceful bowel movements; bowel urges with no resulting movements; weight loss due to lack of appetite; lower back pain; pain or pressure in the rectum and bleeding from the rectum. These can lead to extremely severe outcomes. Your doctor must monitor intestine function before prescribing and during your therapy with CLOZITOR. It is extremely important to immediately advise your doctor, coordinator, pharmacist, or any other health professional, of any changes to your bowel movements.

Myocarditis/cardiomyopathy:
Cases of myocarditis (heart inflammation) and cardiomyopathy (disease of heart muscles) have been reported in patients on clozapine, some being very severe. Please advise your doctor if you have, or previously had, any heart problems. Your doctor will also monitor for this. If you feel any symptoms such as chest pain, please speak to your doctor immediately.



FULL CMI

CLOZITOR

Active ingredient(s): Clozapine

Consumer Medicine Information (CMI)

This leaflet provides important information about using CLOZITOR. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using CLOZITOR.

Where to find information in this leaflet:

1. Why am I using CLOZITOR?
2. What should I know before I use CLOZITOR?
3. What if I am taking other medicines?
4. How do I use CLOZITOR?
5. What should I know while using CLOZITOR?
6. Are there any side effects?
7. Product details

1. Why am I using CLOZITOR?

CLOZITOR contains the active ingredient clozapine. CLOZITOR belongs to a group of medicines called antipsychotics. It helps to correct the chemical imbalances in the brain which may cause mental illness.

CLOZITOR is used to treat schizophrenia, which is a mental illness with disturbances in thinking, feelings and behaviour.

CLOZITOR is only used to treat patients with schizophrenia when other antipsychotic medicines either have not worked or have caused severe side effects.

Ask your doctor if you have questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

There is no evidence that this medicine is addictive.

CLOZITOR is not recommended for use in children or adolescents under the age of 16 years, as there is not enough information on its use in that age group.

2. WHAT SHOULD I KNOW BEFORE I USE CLOZITOR?

Warnings

Do not use CLOZITOR:

  • if you are allergic to clozapine, or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin.
  • if you have a low white blood cell count or if you have previously had a low white blood cell count caused by a medicine (except if it was following a treatment for cancer).
    CLOZITOR can cause agranulocytosis/ severe neutropenia This is a condition where the number of white blood cells is reduced. These cells are needed to fight infections. If you have a low white blood cell count or have had one in the past, you must not take CLOZITOR.
  • if you are unable to have regular blood tests.
    Before starting this medicine and during your therapy, checks will be required to monitor the levels of various components in your blood. Your doctor will tell you when these tests are needed.

CLOZITOR must not be given to anyone who is unconscious or in a coma, or who has an acute mental illness caused by alcohol or drugs.

Do not use CLOZITOR if:

  • you have a problem with your intestines/bowel such as severe constipation, obstruction of the bowel, or any other condition which has affected your large bowel
  • you experience a medical condition known as paralytic ileus (your intestines do not work properly and you have severe constipation)
  • you have severe heart disease or myocarditis (an inflammation of the heart muscle) or any other heart problems. Symptoms may include chest pain, swelling of legs, ankles or feet, rapid or inconsistent heartbeat, or shortness of breath at rest.
  • you are unable to have a blood test
  • you have bone marrow disease
  • you have severe kidney disease
  • you have symptoms of active liver disease such as jaundice (yellowing of the skin and eyes, feeling sick, loss of appetite), liver failure or any other severe liver disease
  • you have any disease of the blood which causes a reduced number or red blood cells or platelets
  • you have problems with the circulatory (blood) or nervous system
  • you have uncontrolled epilepsy (i.e. you still have some seizures)
  • you have problems with alcohol or drug abuse.

Tell your doctor if you have or have had any of the following medical conditions:

  • any form of heart disease or a family history of heart disease, including blood clots.
  • stroke
  • chronic constipation or problems with your intestines/bowel which needs to be treated before you start taking CLOZITOR. Your doctor must also monitor bowel function while you are on CLOZITOR
  • inflammatory bowel disease (e.g. Crohn's disease)
  • neuroleptic malignant syndrome, a reaction to some medicines with a sudden increase in body temperature, sweating, fast heartbeat, muscle stiffness and fluctuating blood pressure, which may lead to coma
  • tardive dyskinesia, a reaction to some medicines with uncontrolled movements of the tongue, face, mouth or jaw (such as puffing of the cheeks, puckering of the mouth or chewing movements)
  • problems with your liver or kidneys
  • glaucoma (a condition in which there is usually a build up of fluid in the eye)
  • enlargement of the prostate or prostate problems, or difficulty passing urine or unable to pass urine epilepsy that is under control (i.e. you no longer have seizures)
  • diabetes or a family history of diabetes
  • dementia, a condition in which there is a decline in all areas of mental ability.

Check with your doctor if you:

  • take any medicines for any other condition
  • will be in a hot environment or you do a lot of vigorous exercise. CLOZITOR may make you sweat less, causing your body to overheat
  • smoke and drink coffee. Sudden changes in your usual smoking or coffee drinking habits can also change the effects of CLOZITOR.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you are pregnant or intend to become pregnant.

Experience with CLOZITOR in pregnancy is very limited. If you need to take this medicine during pregnancy, your doctor will discuss the risks and benefits of taking this medicine.

Tell your doctor if you are breastfeeding or intend to breastfeed.

You should not breastfeed during CLOZITOR treatment. This medicine may pass into breast milk and affect your baby.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with CLOZITOR and affect how it works. These include:

  • medicines that decrease the number of blood cells produced by your body
  • other antipsychotic medicines use to treat mental illnesses
  • medicines used to control mood swings or depression
  • benzodiazepines and other medicines used to treat anxiety or help you sleep
  • medicines used to control epilepsy such as phenytoin, carbamazepine and valproic acid
  • warfarin, a medicine used to prevent blood clots
  • strong pain killers such as morphine
  • St John's Wort (Hypericum perforatum)
  • antihistamines, medicines used to control and prevent symptoms of allergies such as hayfever
  • anticholinergic medicines, which are used to relieve stomach cramps, spasms and travel sickness
  • medicines used to treat Parkinson's disease
  • medicines used to treat high blood pressure
  • digoxin, a medicine used to treat heart problems
  • medicines used to treat a fast or irregular heart beat
  • medicines used to treat stomach ulcers such as cimetidine, pantoprazole, lansoprazole and omeprazole
  • atropine, a medicine which may be used in some eye drops or cough preparations
  • adrenaline, a drug used in emergency situations
  • medicines used to treat fungal and viral infections
  • birth control tablets, or hormone replacement therapy.

These medicines may be affected by CLOZITOR or may affect how well it works. You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while taking CLOZITOR.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect CLOZITOR.

4. HOW DO I USE CLOZITOR?

How much to use

  • The usual starting dose is half of a 25 mg tablet (12.5 mg) taken once or twice on the first day, followed by one 25 mg tablet, once or twice on the second day.
  • If this dose is well tolerated, then the dose may be slowly increased, usually to between 200 mg and 450 mg each day. Once the maximum benefit is reached, the dose can often be decreased to between 150 mg and 300 mg each day.
  • If you have heart, kidney or liver disease, epilepsy or you are elderly, your doctor may start you on a lower dose and gradually increase the dose to prevent unwanted side effects.
  • The dose may be altered by your doctor from time to time. Do not alter the dose yourself.
  • It is important to keep taking your medicine even if you feel well.
  • Your doctor will check your progress to make sure the medicine is working and will discuss with you how long your treatment should continue.

When to take CLOZITOR

  • CLOZITOR should be taken at the same time each day.
  • The total daily amount of CLOZITOR is usually divided into two doses. However, if your total dose is 200 mg or less, your doctor may allow you to take the whole amount in one dose, usually in the evening.
  • It does not matter if you take this medicine before or after food.

How to take CLOZITOR:

Swallow CLOZITOR tablets with water or other liquid.

If you forget to use CLOZITOR

If it is almost time for your next dose (within four hours), skip the dose you missed and take your next dose when you are meant to.

Otherwise take it as soon as you remember, and then go back to taking CLOZITOR as you would normally.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

If you have missed taking CLOZITOR for more than two days, do not start taking it again before you contact your doctor.

To prevent unwanted side effects, your doctor will probably restart you on CLOZITOR at a lower dose and increase it gradually back to your normal dose.

If you are not sure what to do, ask your doctor or pharmacist.

If you use too much CLOZITOR

If you think that you have used too much CLOPINE, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

The most common signs and symptoms of CLOZITOR overdose include drowsiness, confusion coma, light-headedness, shallow breathing or breathing more slowly, fast or irregular heart beat and dribbling. Occasionally, fits have also been reported.

5. WHAT SHOULD I KNOW WHILE USING CLOZITOR?

Things you should do

Continue taking CLOZITOR as long as your doctor tells you.

You must have strict and regular blood tests while taking CLOZITOR. Your doctor will tell you when and how often you need to have your blood tested. This medicine can cause agranulocytosis. This is a condition where the number of white blood cells may be reduced.

There is no way of knowing who is at risk of developing agranulocytosis.

Deaths have occurred in severe cases of agranulocytosis. However, with regular blood tests, agranulocytosis can be detected early, and if CLOZITOR is stopped as soon as possible, the white blood cell numbers should return to normal.

You must have a blood test at least once a week for the first 18 weeks after starting CLOZITOR.

This is the time when the risk of agranulocytosis is greatest. These tests can tell the doctor whether the white blood cell count is dropping.

After 18 weeks, you must have a blood test at least every 4 weeks for as long as you are taking CLOZITOR, and for a month after stopping the medicine.

There are some situations where you may need to have blood tests more often (e.g. twice a week). Your doctor will explain this to you.

If the number of your white blood cells falls below a critical level, CLOZITOR must be stopped immediately and you must never take any medicines containing clozapine again.

If you suffer from a high level of sugar in the blood (diabetes) your doctor may regularly check you level of sugar in the blood.

Watch for important side effects

If you develop symptoms such as severe constipation, obstruction of the intestine, or any changes to your intestine or poo habits, contact your doctor immediately as these may cause death.

If you develop a fast or irregular heartbeat that is present even when you are resting, accompanied by rapid breathing, shortness of breath, swelling of the feet or legs, dizziness or light headedness, or chest pain, contact your doctor immediately as these may cause death.

These symptoms could be signs of myocarditis, an inflammation of the heart muscle, or another heart condition. Your doctor may want to refer you to a cardiologist for further tests.

Make sure you use a contraceptive to prevent pregnancy during treatment with CLOZITOR.

Some women taking some antipsychotic medications have irregular or no periods. If you are female and you have been affected in this way, your periods may return when your medication is changed to CLOPINE.

Contact your doctor immediately if you:

  • develop a fever
    Some patients develop fever in the first few weeks of taking CLOZITOR. This is usually harmless. However, you must be checked carefully to make sure you do not have an infection, agranulocytosis, myocarditis or neuroleptic malignant syndrome, a reaction to some medicines which can cause a sudden increase in body temperature.
  • develop a sore throat, mouth ulcers, flu-like symptoms, or other signs of a cold or infection
    This is necessary, as these symptoms may be an early sign of agranulocytosis, a problem with the blood resulting in an increased risk of infections. Flu-like symptoms may also be a sign of myocarditis.
  • notice any uncontrolled movements of the tongue, face, mouth or jaw, such as puffing of the cheeks, puckering of the mouth or chewing movements
    These are symptoms of a condition called tardive dyskinesia which may develop in people taking antipsychotic medicines. This condition is more likely to happen during long term treatment, especially in older women. In very rare cases, it may be permanent. However, if detected early, these symptoms are usually reversible.
  • notice any changes to your gastrointestinal function such as stomach pain or difficulty having a bowel movement and they worry you. Clozapine may cause slowing down of bowel function, which may result in blockage, perforation, tissue damage and cause reactions such as constipation, nausea with or without vomiting, tenderness or swelling of the abdomen, or bloating, gas/wind, foul-smelling breath, severe dull to sharp stomach pains in the lower belly, leakage of diarrhoea or frequent and forceful bowel movements, bowel urges with no resulting movements, weight loss due to lack of appetite, lower back pain, pain or pressure in the rectum, and bleeding from the rectum. These can lead to extremely severe outcomes.
    Your doctor must monitor bowel function before prescribing and during your therapy with CLOZITOR. It is extremely important to immediately advise your doctor, coordinator, pharmacist, or any other health professional, of any changes to your bowel movements.

Remind any doctor or dentist you visit that you are using CLOPINE or if you are about to be started on any new medicines.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking CLOZITOR. It may affect other medicines used during surgery.

Be sure to keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you should not do

  • Do not stop taking CLOZITOR or lower the dosage, even if you are feeling better, without checking with your doctor.
    If you stop taking CLOZITOR suddenly, your condition may worsen or you may experience headache, nausea (feeling sick), vomiting or diarrhoea. Your doctor will gradually reduce the amount you take each day before stopping the medicine completely.
  • Do not take CLOZITOR to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else even if their condition seems similar to yours.
  • Do not let yourself run out of CLOZITOR over the weekend or on holidays.

Things to be careful of

  • Sudden unexplained death and heart attacks that may lead to death have been reported with CLOZITOR.
  • Be careful when taking antihistamines (medicines used for hayfever, allergies or colds), sleeping tablets or tablets to relieve pain while taking CLOZITOR.
    CLOZITOR can increase the drowsiness caused by medicines that affect your nervous system.
  • CLOZITOR may cause alteration in blood sugar and lipids. It may also cause weight gain. Your doctor may monitor your weight, blood sugar and lipid levels.
  • CLOZITOR can cause sleepiness, and remaining in bed for prolonged duration in combination with weight gain may lead to the formation of blood clots in some patients.
  • If CLOZITOR makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position.
  • Make sure you keep cool in hot weather and keep warm in cool weather. CLOZITOR may affect the way your body reacts to temperature changes. It may prevent sweating and you may feel dizzy or faint if you are too hot.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how CLOPINE affects you.

CLOZITOR may cause tiredness, drowsiness, light-headedness, dizziness, fainting or seizures (fits) in some people, especially at the start of treatment. Seizures, drowsiness, fainting, muscle weakness may lead to falls.

Drinking alcohol

Tell your doctor if you drink alcohol.

You should not drink alcohol while you are taking CLOZITOR. This medicine may enhance the effects of alcohol.

Looking after your medicine

  • Store CLOZITOR Tablets below 25°C. Protect from light.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Do not use this medicine after the expiry date.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Nervous system related:
  • dizziness, or light headedness when standing up
  • tiredness, drowsiness
  • headache
Gastrointestinal related:
  • nausea, vomiting
  • constipation or fewer bowel movements than normal (if it seems to be getting worse, check with your doctor immediately)
  • diarrhoea
  • dry mouth
  • stomach discomfort, especially after a meal
  • heartburn
Metabolism related:
  • weight gain
Urinary system related:
  • problems in passing or holding urine, dark urine, excessive urination, nocturnal bedwetting
Eye related:
  • blurred vision
Respiratory related:
  • stuffy nose
  • difficulty in swallowing
Skin related:
  • skin reactions or change in skin colour
Musculoskeletal related:
  • "butterfly" rash, joint pain, muscle pain, fever and fatigue
Other:
  • too much saliva
  • swelling of the glands in the cheeks
  • mild fever
  • agitation, confusion, disorientation, vivid dreams
  • changes in sexual function
  • painful menstrual periods
  • repetitive and ritualised behaviour (obsessive compulsive symptoms)
  • stuttering in speech
  • for males, dry orgasm (retrograde ejaculation) where very little or no semen is ejaculated as it enters the bladder instead. Urine will appear cloudy after an orgasm
  • increased or decreased sweating
  • uncontrolled bending of the body to one side
  • a strong urge to move the legs (restless legs syndrome) with an unpleasant feeling in the legs
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Respiratory related:
  • signs of an allergic reaction such as itching, skin rash, hives, swelling of the face, lips or tongue, difficulty in swallowing or breathing
  • fever, sore throat, mouth ulcers, "flu-like" symptoms (chills, aching joints, swollen glands, lack of energy) or any other signs of infection
  • chest pain, cough, hiccups, rapid breathing
  • signs of respiratory tract infection or pneumonia such as fever, coughing, difficulty breathing, wheezing
Gastrointestinal related:
  • severe or prolonged constipation, which may be accompanied by tenderness or swelling of the stomach, or bloating
  • varying degrees of pain in the chest and stomach
  • severe dull to sharp pain in the stomach, often accompanied by nausea with or without vomiting, leakage of diarrhoea or frequent and forceful bowel movements, bowel urges with no resulting movements, weight loss due to lack of appetite, lower back pain, pain or pressure in your bottom and bleeding from the bottom.
Musculoskeletal related
  • rigidity or stiffness in the arms and legs, shaking or tremor, feeling unable to sit still
  • muscle stiffness, muscle weakness, muscle spasms, or muscle pain
  • muscle spasms associated with fever, red-brown urine
Skin related
  • rash, purplish-red spots, usually associated with fever or itching
urinary system related
  • difficulty in passing urine (pee) or blood in the urine
  • loss of bladder control
Nervous system related
  • symptoms of neuroleptic malignant syndrome, with a sudden increase in body temperature, sweating, fast heartbeat, muscle stiffness and fluctuating blood pressure which may lead to coma
  • seizures or fits
  • fainting or loss of consciousness
  • falls due to seizure, drowsiness, fainting, muscle weakness
Heart related:
  • chest pain
  • a fast or irregular heartbeat that is present even when you are resting, accompanied by rapid breathing, shortness of breath, swelling of the feet or legs, dizziness or light headedness, or chest pain
Other:
  • signs that blood clots may have formed, such as sudden severe headache, sudden loss of coordination, blurred vision or sudden loss of vision, slurred speech, numbness in an arm or leg
  • symptoms of tardive dyskinesia (uncontrolled movements of the tongue, face, mouth or jaw such as puffing of the cheeks, puckering of the mouth, chewing movements, grimacing, lip smacking, rapid eye blinking)
  • abnormal movements, inability to initiate movement, inability to remain motionless, inner feeling of restlessness, stiff limbs, trembling hands
  • signs of sepsis such as shivering, fever, rapid breathing and heart rate, a change in your mental state such as confusion or disorientation
  • jaundice, yellowing of the skin and/or eyes
  • signs of loss of blood sugar control (diabetes) such as excessive thirst, drinking or eating large amounts, weakness, passing large amounts of urine, dry mouth and skin
  • persistent painful erection or prolonged erection
  • pauses in breathing or periods of shallow breathing during sleep.
  • spontaneous bleeding or bruising more easily than normal
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people. Some side effects can only be found when your doctor does tests to check your progress.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What CLOZITOR contains

Active ingredient
(main ingredient)		CLOZITOR 25 tablets contain 25 mg of clozapine.
CLOZITOR 50 tablets contain 50 mg of clozapine.
CLOZITOR 100 tablets contain 100 mg of clozapine.
CLOZITOR 200 tablets contain 200 mg of clozapine.
Other ingredients
(inactive ingredients)
  • Lactose Monohydrate
  • Microcrystalline Cellulose
  • Povidone
  • Sodium starch glycollate type A
  • Magnesium stearate.

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

Pack Sizes:

CLOZITOR 25, CLOZITOR 50, CLOZITOR 100 and CLOZITOR 200 comes in PVC/PVDC blister pack of 50 & 100 tablets and HDPE bottle of 50 & 100 tablets.

What CLOZITOR looks like

CLOZITOR 25 mg: CLOZITOR 25 are “Round yellow, flat, beveled edge tablets engraved with 25 over a pressure sensitive break line on one face, the other face plain.
Australian Register Number: Bottle: AUSTR 311146
Blister: AUSTR 311147

CLOZITOR 50 mg: CLOZITOR 50 are “Round, yellow, flat, beveled edge tablets engraved with 50 over a pressure sensitive break line on one face. The other face plain.
Australian Register Number: Bottle: AUSTR 311154
Blister: AUSTR 311155

CLOZITOR 100 mg: CLOZITOR 100 are “Round yellow, flat, beveled edge tablets engraved with 100 over a pressure sensitive break line on one face. The other face plain.
Australian Register Number: Bottle: AUSTR 311160
Blister: AUSTR 311161

CLOZITOR 200 mg: CLOZITOR 200 are “Oval shaped, yellow tablets with "200” on one side and break line on other side.
Australian Register Number: Bottle: AUSTR 311166
Blister: AUSTR 311167

Who distributes CLOZITOR

CLOZITOR is supplied in Australia by:

Pharmacor Pty Ltd.
CHATSWOOD, NSW, 2067
Australia
www.pharmacor.com.au

The quantity provided to you by the pharmacy will be determined by your doctor.

This leaflet was prepared in 10/2024

Published by MIMS December 2024

BRAND INFORMATION

Brand name

Clozitor

Active ingredient

Clozapine

Schedule

S4

 

1 Name of Medicine

Clozapine.

2 Qualitative and Quantitative Composition

Clozitor is available in 4 strength for oral administration containing 25 mg, 50 mg, 100 mg and 200 mg clozapine.
Clozitor 25 mg: Each tablet contains 25 mg clozapine.
Clozitor 50 mg: Each tablet contains 50 mg clozapine.
Clozitor 100 mg: Each tablet contains 100 mg clozapine.
Clozitor 200 mg: Each tablet contains 200 mg clozapine.

Excipients with known effect.

Tablets.

Contains sugars (as lactose monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets, uncoated.

Clozitor 25 mg.

Round yellow, flat, beveled edge tablets engraved with 25 over a pressure sensitive break line on one face, the other face plain.

Clozitor 50 mg.

Round, yellow, flat, beveled edge tablets engraved with 50 over a pressure sensitive break line on one face. The other face plain.

Clozitor 100 mg.

Round yellow, flat, beveled edge tablets engraved with 100 over a pressure sensitive break line on one face. The other face plain.

Clozitor 200 mg.

Oval shaped, yellow tablets with "200" on one side and break line on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment with Clozitor is indicated only in people with treatment-resistant schizophrenia, i.e. people with schizophrenia who are non-responsive to, or intolerant of other antipsychotic drugs.
Non-responsiveness is defined as lack of satisfactory clinical improvement despite the use of adequate doses of at least two classes of marketed antipsychotic drugs prescribed for reasonable durations.
Intolerance is defined as the impossibility to achieve adequate benefit with other antipsychotic drugs because of severe and untreatable neurological adverse effects (extrapyramidal side effects or tardive dyskinesia).

4.2 Dose and Method of Administration

(Also see Section 4.4 Special Warnings and Precautions for Use.)

Dosage.

The dosage must be adjusted individually. For each patient the lowest effective dose should be used. Appropriate resuscitative facilities should be available and the patient adequately supervised during initiation of therapy.

Method of administration.

Clozapine tablets are administered orally with water or other liquids. Clozapine tablets can be taken with or without food.
The recommended dosages which follow are for oral administration.

Starting therapy.

Prior to initiating treatment with Clozitor, a baseline absolute neutrophil count (ANC) must be obtained (also see Section 4.4 Special Warnings and Precautions for Use, Agranulocytosis/ severe neutropenia).
12.5 mg once or twice daily on the first day, followed by one or two doses of 25 mg on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25 to 50 mg in order to achieve a dose level of up to 300 mg/day within two to three weeks. Thereafter, if required, the daily dose may be further increased in increments of 50 to 100 mg at half-weekly or, preferably, weekly intervals.

Special patient populations.

For use in special populations, or patients aged 60 years and older, see Section 4.4 Special Warnings and Precautions for Use.

Therapeutic dose range.

In most patients, antipsychotic efficacy can be expected with 200 to 450 mg/day in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime.
Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided.

Maximum dose.

For most patients the recommended maximum dose is 600 mg/day. However, a few patients may require larger doses to obtain maximum therapeutic benefit, in which case judicious increments (i.e. not exceeding 100 mg) are permissible up to a maximum of 900 mg/day. The possibility of increased adverse effects occurring at doses over 450 mg/day must be borne in mind.

Maintenance dose.

After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses. Careful downward titration is recommended to the level of 150 to 300 mg/day given in divided doses. If the daily dose does not exceed 200 mg, a single administration in the evening may be appropriate.

Ending therapy.

In the event of planned termination of clozapine therapy, a gradual reduction in dose is recommended over a one to two week period. If abrupt discontinuation is necessary, the patient should be carefully monitored for the recurrence of psychotic symptoms and observed for symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting and diarrhoea. Additional ANC monitoring is required for any patient reporting onset of fever during the two weeks after discontinuation (see Section 4.4 Special Warnings and Precautions for Use).

Restarting therapy.

In patients in whom the interval since the last dose of clozapine exceeds two days, treatment should be reinstated with 12.5 mg (half a 25 mg tablet) given once or twice daily on the first day. If this dose is tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is recommended for initial treatment. However, in any patient who has previously experienced respiratory or cardiac arrest with initial dosing (see Section 4.4 Special Warnings and Precautions for Use) but was then able to be successfully titrated to a therapeutic dose, retitration should be done with extreme caution.

Switching from a previous antipsychotic to clozapine.

It is generally recommended that clozapine should not be used in combination with other antipsychotic drugs. When clozapine therapy is to be initiated in a patient undergoing oral antipsychotic therapy, the other antipsychotic drug should first be discontinued by tapering the dosage downward over a period of approximately one week. Once the other antipsychotic drug is completely discontinued for at least 24 hours, begin clozapine as described previously.
If, in a particular patient, discontinuation of the antipsychotic drug is not a realistic option prior to institution of clozapine, combination therapy can be cautiously undertaken in hospital during a transition period. Taper the dose of antipsychotic drug downward over a period of a week, while gradually adding clozapine in increasing doses.

Dosage adjustment.

It may be necessary to reduce the clozapine dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolisers (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacokinetic-related interactions).

4.3 Contraindications

Clozitor is contraindicated in patients with a history of drug induced granulocytopenia/agranulocytosis; bone marrow disorders.
Patients unable to undergo regular blood tests.
Circulatory collapse and/or CNS depression due to any cause.
Alcoholic and other toxic psychoses; drug intoxication; comatose conditions.
Severe renal or cardiac disease (e.g. myocarditis).
Severe hepatic disease including active hepatic disease associated with nausea, anorexia or jaundice; progressive hepatic disease; hepatic failure.
Uncontrolled epilepsy.
Paralytic ileus.
Clozitor is contraindicated in patients who have demonstrated hypersensitivity to clozapine or other components of the product.

4.4 Special Warnings and Precautions for Use

Special precautionary measures.

Gastrointestinal hypomotility with severe complications.

Severe gastrointestinal adverse reactions have occurred with the use of clozapine, primarily due to its potent anti-cholinergic effects and resulting in gastrointestinal hypomotility. In post-marketing experience, reported effects range from nausea, vomiting, overflow diarrhoea, constipation, to paralytic ileus, intestinal impaction and more severe complications. Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, resulting in faecal impaction, megacolon, paralytic ileus and intestinal obstruction, ischaemia, infarction, perforation, ulceration or necrosis (see Section 4.8 Adverse Effects (Undesirable Effects)). These reactions have resulted in hospitalisation, surgery and death. The risk of severe adverse reactions is further increased with anticholinergic medications (and other medications that decrease gastrointestinal peristalsis); therefore, concomitant use should be avoided when possible (see Section 4.4 Special Warnings and Precautions for Use, Other precautions, Anticholinergic effects; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Prior to initiating Clozitor, screen for constipation and treat as necessary. Early diagnosis and treatment of constipation at the start of clozapine therapy is important in preventing serious gastrointestinal-related complications (e.g. appendicitis). Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in clozapine-treated patients. Therefore, reassess bowel function frequently with careful attention to any changes in the frequency or character of bowel movements, as well as signs and symptoms of complications of hypomotility (e.g. nausea, vomiting, abdominal distension, abdominal pain, lack of urge to defecate, constipation, inability to defecate). If constipation or gastrointestinal hypomotility are identified, monitor closely and manage promptly, as per current clinical guidelines to prevent severe complications (see Boxed Warnings).
Appendicitis, including perforated appendicitis, have been reported in post-marketing cases in patients treated with clozapine of any duration, regardless of age or gender. Some of these cases have reported fatal outcomes. Appendicitis and perforated appendicitis require intervention with medicine and surgery.

Agranulocytosis/ severe neutropenia.

Clozapine can cause agranulocytosis and neutropenia (a low absolute neutrophil count (ANC)) which is below the normal pre-treatment levels of blood neutrophils.
The use of clozapine should be limited to patients diagnosed with schizophrenia who are non-responsive to, or intolerant of other antipsychotic drugs and:
who have initially normal leucocyte findings (white blood cell (WBC) count > 3.5 x 109/L, normal differential blood count), and
in whom regular WBC counts and ANC counts [tested weekly during the first 18 weeks, at least monthly thereafter, throughout treatment, and tested for 1 month after complete discontinuation of clozapine] can be performed.
Development of agranulocytosis/ severe neutropenia is a risk inherent to clozapine treatment. Severe neutropenia, ANC less than 0.5 x 109/L, is associated with an increase in the risk of serious and potentially fatal infections. Although generally reversible on withdrawal of the drug, agranulocytosis and neutropenia can prove fatal. The majority of cases occur within the first 18 weeks of treatment. Because immediate withdrawal of the drug is required to prevent the development of life-threatening agranulocytosis/ severe neutropenia, monitoring of the WBC and ANC counts is mandatory.
Prescribing physicians should fully comply with the instituted safety measures. Because of the association of clozapine with agranulocytosis/ severe neutropenia, the precautionary measures which follow are mandatory:
Patients with a history of bone marrow disorders may be treated only if the benefit outweighs the risk. They should be carefully reviewed by a haematologist prior to starting treatment with clozapine.
Drugs known to have a substantial potential to depress bone marrow function should not be used concurrently with clozapine. In addition, the concomitant use of long-acting depot antipsychotics should be avoided because of the inability of these medications, which may have the potential to be myelosuppressive, to be rapidly removed from the body in situations where this may be required, e.g. granulocytopenia.
Before starting clozapine treatment, a WBC count and a differential count must be performed within ten days prior to starting clozapine treatment to ensure that only patients with normal leucocyte findings (WBC count ≥ 3.5 x 109/L, normal differential blood count), and normal ANC will receive the drug. After the start of clozapine treatment, the WBC and ANC must be monitored weekly for 18 weeks. Thereafter the WBC and ANC must be performed at least monthly throughout treatment and for one month after complete discontinuation of clozapine. At each consultation the patient should be reminded to contact the treating doctor immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia (see Section 4.8 Adverse Effects (Undesirable Effects)). An immediate differential blood count must be performed if any symptoms or signs of infection occur.

In the event of interruption of therapy for non-haematological reasons.

Patients who have been on clozapine for more than 18 weeks and have had their treatment interrupted for more than three days but less than four weeks should have their WBC count and ANC monitored weekly for an additional six weeks. If no haematological abnormality occurs, monitoring at intervals not exceeding four weeks may be resumed. If clozapine treatment has been interrupted for four weeks or longer, weekly monitoring is required for the next 18 weeks of treatment.
If, during treatment with clozapine, an infection occurs and/or the WBC count has dropped below 3.5 x 109/L, or has dropped by a substantial amount from baseline (even if the count is above 3.5 x 109/L), a repeat WBC count and a differential count should be done. Should the results confirm a WBC count below 3.5 x 109/L and/or reveal an ANC of between 1.5 and 2.0 x 109/L, the leucocytes and the granulocytes must be checked at least twice weekly. If the WBC count falls below 3.0 x 109/L and/or the ANC drops below 1.5 x 109/L, clozapine therapy must be withdrawn at once and the patient should be closely monitored. WBC counts and differential blood counts should then be performed daily and patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection. Following discontinuation of clozapine, haematological evaluation must be continued until haematological recovery has occurred.
If clozapine therapy has been withdrawn and a further fall of WBC count below 2.0 x 109/L occurs and/or the ANC decrease below 1.0 x 109/L, the management of this condition must be guided by an experienced haematologist. If possible, the patient should be referred to a specialised haematological unit, where protective isolation may be indicated.
Patients in whom clozapine therapy has been discontinued as a result of white blood cell deficiencies (WBC count < 3.0 x 109/L and/or ANC < 1.5 x 109/L) must not be re-exposed to clozapine.

Other precautions.

Using clozapine with other drugs associated with neutropenia.

It is unclear if concurrent use of other drugs known to cause neutropenia increases the risk or severity of clozapine-induced neutropenia. Patients should be closely monitored if clozapine is used concurrently with an agent known to cause neutropenia (e.g. some chemotherapeutic agents). Consult with the treating oncologist in patients receiving concomitant chemotherapy.

Myocardial infarction.

There have been post-marketing reports of myocardial infarction, including fatal cases. Causality assessment was difficult in the majority of these cases because of serious pre-existing cardiac disease and plausible alternative causes.

Myocarditis/ cardiomyopathy.

Cases of myocarditis (with or without eosinophilia), some of which have been fatal, and cardiomyopathy have been reported in patients on clozapine. The incidence of myocarditis reported globally is rare (< 0.1%) during the first month of treatment and very rare (< 0.01%), thereafter. The reported incidence of myocarditis in Australia is slightly higher, being rated as uncommon (≥ 0.1% and < 1%). The reason for this discrepancy is unknown (see Boxed Warnings).
In patients who develop persistent tachycardia at rest accompanied by other signs and symptoms of heart failure (e.g. tachypnoea, shortness of breath, hypotension, raised jugular venous pressure) or arrhythmias, the possibility of myocarditis or cardiomyopathy must be considered. Other symptoms which may be present in addition to the above include fatigue, flu-like symptoms, chest pain or fever that is otherwise unexplained. The occurrence of these signs and symptoms necessitates an urgent diagnostic evaluation for myocarditis or cardiomyopathy by a cardiologist. If myocarditis or cardiomyopathy is suspected, clozapine treatment should be promptly stopped, and the patient immediately referred to a cardiologist. If myocarditis is confirmed, clozapine should be discontinued. If cardiomyopathy is diagnosed, clozapine should be discontinued unless the benefit clearly outweighs the risk to the patient. If patients are diagnosed with cardiomyopathy while on clozapine treatment, there is potential to develop mitral valve incompetence. Mitral valve incompetence has been reported in cases of cardiomyopathy related to clozapine treatment. These cases of mitral valve incompetence reported either mild or moderate mitral regurgitation on two-dimensional echocardiography (2D Echo) (see Section 4.8 Adverse Effects (Undesirable Effects)). Most reported cases of myocarditis have occurred in the first month of treatment. Therefore, patients commencing clozapine treatment require close medical supervision. Patients with a family history of heart failure should have a cardiac evaluation prior to commencing treatment (see Boxed Warnings; Section 4.8 Adverse Effects (Undesirable Effects)).
Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with clozapine. However, if the benefit of clozapine treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with clozapine in consultation with cardiologist, after a complete cardiac evaluation and under close monitoring.

QT interval prolongation.

As with other antipsychotics, caution is advised in patients with known cardiovascular disease or family history of QT prolongation.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase the QTc interval.

Eosinophilia.

Unexplained leucocytosis and/or eosinophilia may occur especially in the initial weeks of treatment. In the event of eosinophilia (see Section 4.8 Adverse Effects (Undesirable Effects)), it is recommended to discontinue clozapine if the eosinophil count rises above 3.0 x 109/L and to restart therapy only after the eosinophil count has fallen below 1.0 x 109/L.

Thrombocytopenia.

In the event of thrombocytopenia (see Section 4.8 Adverse Effects (Undesirable Effects)), it is recommended to discontinue clozapine if the platelet count falls below 50,000/mm3.

Orthostatic hypotension.

Tachycardia, bradycardia and postural hypotension with or without syncope may occur especially in the initial weeks of treatment and may represent a continuing risk in some patients. Rarely (about one case per 3,000 patients), collapse can be profound and accompanied by respiratory and/or cardiac arrest. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB). Such events are more likely to occur during initial dose titration in association with rapid dose escalation; on very rare occasions they occurred after the first dose (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). When restarting therapy in patients who have had even a brief interruption with clozapine treatment, the dosage must be reduced (also see Section 4.2 Dose and Method of Administration, Restarting therapy).

Acute withdrawal effects.

Acute withdrawal reactions have been reported following abrupt cessation of clozapine, therefore gradual withdrawal is recommended. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound (see Section 4.2 Dose and Method of Administration, Ending therapy).

Treatment initiation.

Patients commencing clozapine treatment need to be under close medical supervision.

Seizures.

Clozapine can cause EEG changes, including the occurrence of spike and wave complexes. Clozapine lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalized seizures. Caution should be used in administering clozapine to patients having a history of seizures or other predisposing factors. These symptoms are more likely to occur with rapid dose increase and in patients with pre-existing epilepsy. In this case the dose should be reduced and, if necessary, anticonvulsant treatment initiated. Carbamazepine should be avoided because of its potential to depress bone marrow function, and with other anticonvulsant drugs, the possibility of a pharmacokinetic interaction should be considered. (Also see Section 4.4 Special Warnings and Precautions for Use, Dosing in special populations).

Sleep apnoea.

Sleep apnoea and related disorders have been reported in patients treated with clozapine, with or without prior history of sleep apnoea, and with or without concomitant weight gain. In patients who have a history of or are at risk for sleep apnoea, or who are concomitantly using central nervous system depressants, clozapine should be used with caution.

Dosing in special populations.

In patients with a history of seizures, or suffering from cardiovascular, renal or hepatic disorders (note that severe hepatic, renal or cardiovascular disorders including active hepatic disease associated with nausea, anorexia or jaundice, progressive hepatic disease and hepatic failure, are contraindications), the initial dose should be 12.5 mg given once on the first day, and any dose increase should be slow and in small increments.

Fever.

Patients on clozapine can experience fever with temperature elevations above 38°C within the first month of treatment. The overall incidence is 5%; individual studies have reported up to 20%. This should be carefully evaluated to rule out the possibility of the development of agranulocytosis, neutropenia or myocarditis/ cardiomyopathy (see Boxed Warnings; Section 4.4 Special Warnings and Precautions for Use, Myocarditis/ cardiomyopathy; Section 4.4 Special Warnings and Precautions for Use, Agranulocytosis/ severe neutropenia). The possibility of an underlying infectious process should also be considered.

Falls.

Clozapine may cause seizures, somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long term antipsychotic therapy.

Neuroleptic malignant syndrome (NMS).

In the presence of high fever, the possibility of neuroleptic malignant syndrome (NMS) must be considered. There have been cases of NMS in patients receiving clozapine, either alone or in combination with lithium or other CNS-active agents (estimated incidence < 0.1%). If the diagnosis of NMS is confirmed, clozapine should be discontinued immediately and appropriate medical measures should be administered.

Anticholinergic effects.

Clozapine has potent anticholinergic effects. Treatment with Clozitor can result in CNS and peripheral anticholinergic toxicity, especially at higher dosages, or in overdose situations (see Section 4.9 Overdose). Use with caution and careful supervision is required in patients with a current diagnosis or prior history of constipation, urinary retention, prostatic enlargement, narrow angle glaucoma or other conditions in which anticholinergic effects can lead to significant adverse reactions. Where possible, avoid concomitant use, with other anticholinergic medications because the risk for anticholinergic toxicity or severe gastrointestinal adverse reactions is increased (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Metabolic changes.

Atypical antipsychotic drugs, including clozapine, have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes may include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile.

Risk of thromboembolism.

Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs including clozapine in case reports and/or observational studies. When prescribing clozapine, all possible risk factors for VTE should be identified before and during treatment. As clozapine may cause sedation and weight gain, thereby increasing the risk of thromboembolism, immobilisation of patients should be avoided.

Increased mortality in elderly patients with dementia-related psychosis.

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo based on a retrospective analysis conducted by the Food and Drug Administration of seventeen placebo-controlled trials with atypical antipsychotics. This analysis revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Data from clozapine was not included in this analysis.
Use of clozapine has not been studied in patients with dementia-related psychosis and is therefore not recommended in this patient population.

Cerebrovascular adverse events.

An increased risk of cerebrovascular adverse events has been seen in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Clozapine should be used with caution in patients with risk factors for stroke.

Extrapyramidal effects.

Extrapyramidal symptoms may occur but are milder and less frequent than those seen during treatment with "typical" antipsychotic drugs. Rigidity, tremor and akathisia have been reported but acute dystonia is not an established side effect of clozapine treatment. There have been no reports of tardive dyskinesia directly attributable to clozapine alone. However, the syndrome has been reported in a few patients who, prior to or concomitantly with clozapine therapy, have been treated with other antipsychotic agents, so that a causal relationship to clozapine can neither be established nor excluded.
The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot or both. Particular attention should be paid to the monitoring for such symptoms and signs, as left untreated, akathisia is associated with poor compliance and an increased risk of relapse.

Suicide.

The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany therapy.

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in people with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on 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 starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
In patients with significant treatment-emergent hyperglycaemia, discontinuation of clozapine should be considered.
There is a risk of altering the metabolic balance resulting in slight impairment of glucose homeostasis and a possibility of unmasking a pre-diabetic condition or aggravating pre-existing diabetes.

Dyslipidemia.

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine, is recommended.

Weight gain.

Weight gain has been observed with atypical antipsychotic use, including clozapine. Clinical monitoring of weight is recommended.

Use in hepatic impairment.

Patients with stable pre-existing hepatic disorders may receive clozapine but need regular liver function test monitoring. Patients who develop symptoms of possible hepatic dysfunction such as nausea, vomiting and/or anorexia during treatment with clozapine should have liver function tests performed immediately. If there is a clinically relevant elevation in liver function values or if symptoms of jaundice occur, treatment with clozapine must be discontinued. Treatment may be resumed only when liver function tests have returned to normal values. In such cases, liver function should be closely monitored after the reintroduction of the drug. (Also see Section 4.4 Special Warnings and Precautions for Use, Dosing in special populations).

Use in renal impairment.

See Section 4.4 Special Warnings and Precautions for Use, Dosing in special populations.

Use in the elderly.

It is recommended to initiate treatment at a particularly low dose (12.5 mg given once on the first day) and to restrict subsequent dose increments to 25 mg/day. Orthostatic hypotension can occur with clozapine treatment and there have been reports of tachycardia, which may be sustained, in patients taking clozapine. Elderly patients, particularly those with compromised cardiovascular function, may be more susceptible to these effects. Elderly patients may also be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation.

Elderly patients with dementia-related psychosis.

In patients aged 60 years and older with dementia-related psychosis, the efficacy and safety of clozapine has not been studied. Observational studies suggest that patients aged 60 years and older with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. In the published literature, risk factors that may predispose this patient population to increased risk of death when treated with antipsychotics include sedation, the presence of cardiac conditions (e.g. cardiac arrhythmias) or pulmonary conditions (e.g. pneumonia, with or without aspiration). Clozapine should be used with caution in patients aged 60 years and older with dementia.

Paediatric use.

No paediatric studies have been performed. Safety and effectiveness in children and adolescents less than 16 years of age have not been established. As with all medicines, clozapine must be kept out of reach of children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic-related interactions.

Drugs known to have a substantial potential to depress bone marrow should not be used concurrently with clozapine (also see Section 4.4 Special Warnings and Precautions for Use). Clozapine may enhance the central effects of alcohol, MAOIs and CNS depressants such as narcotics, antihistamines and benzodiazepines.
Particular caution is advised when clozapine therapy is initiated in patients who are receiving (or have recently received) a benzodiazepine or any other antipsychotic drug, as these patients may have an increased risk of circulatory collapse, which on rare occasions may be profound and may lead to cardiac and/or respiratory arrest.
Because of the possibility of additive effects, caution in the concomitant administration of drugs with anticholinergic, hypotensive or respiratory depressant effects is essential.
Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where clozapine was co-administered with valproic acid have been reported. These effects are possibly due to a pharmacodynamic interaction, the mechanism of which has not been determined.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase the QTc interval, or causing electrolyte imbalance.
Concomitant use of lithium or other CNS-active agents may increase the risk of development of neuroleptic malignant syndrome (NMS).
In clozapine-treated patients, the blood pressure increasing effect of adrenaline (epinephrine) and its derivatives may be reversed.

Pharmacokinetic-related interactions.

Competition for protein binding sites may lead to adverse effects as a result of changes in plasma levels of clozapine or other highly protein bound drugs such as warfarin and digoxin.
Clozapine is a substrate for many cytochrome P450 isoenzymes, in particular CYP 1A2, CYP 2D6 and CYP 3A4. Caution is called for in patients receiving concomitant treatment with other drugs which are inhibitors or induces of these enzymes.
Concomitant administration of cimetidine, erythromycin and ciprofloxacin, drugs known to inhibit the cytochrome P450 enzyme system, may increase the plasma levels of clozapine, possibly resulting in adverse effects.
In one study of seven patients, the plasma concentration of clozapine was increased by caffeine (an inhibitor of CYP 1A2) intake and decreased by 29 to 80% following a 5-day caffeine-free period.
Potent inhibitors of CYP 3A4, such as azole antimycotics and protease inhibitors, could potentially also increase clozapine plasma concentrations.
Concomitant administration of phenytoin, carbamazepine, rifampicin, St John's wort (Hypericum perforatum) [drugs known to induce the activity of CYP 3A4] and possibly other drugs known to induce the cytochrome P450 enzyme system, may reduce the plasma levels of clozapine and may be associated with the recurrence of psychotic symptoms.
Discontinuation of the concomitant administration of carbamazepine has resulted in an increase in clozapine plasma levels.
With other drugs known to bind to the CYP 2D6 isoenzyme, such as antidepressants, phenothiazines and type 1C antiarrhythmics, no clinically relevant interactions with clozapine have been observed so far. On theoretical grounds, however, it is possible that the plasma levels of such drugs are increased by clozapine, so it may be appropriate to use them at doses lower than are usually prescribed.
Elevated serum levels of clozapine have been reported in patients receiving the drug in combination with selective serotonin re-uptake inhibitors (SSRIs) such as fluoxetine, paroxetine, citalopram, sertraline (up to two fold), fluvoxamine (up to ten fold) and oral contraceptives (which inhibits 1A2, 3A4 and 2C19 isozymes). Fluvoxamine is known to inhibit the metabolism of clozapine by the isoenzyme CYP 1A2. Such patients should be monitored closely and dosage adjustments may be indicated.
Tobacco smoke, a known inducer of CYP 1A2, may decrease the plasma levels of clozapine. In such cases of sudden cessation of tobacco smoking, the plasma clozapine concentration may be increased, thus leading to an increase in adverse effects.
Omeprazole, another known inducer of CYP 1A2, could potentially also decrease the plasma levels of clozapine.
The concomitant administration of enzyme inhibitors such as clarithromycin or azithromycin with high doses of clozapine has been associated with increased plasma clozapine levels and the occurrence of adverse effects.
A significant increase in the levels of clozapine and n-desmethyl-clozapine was reported when concomitant treatment was given with 2 x 250 mg ciprofloxacin. There have also been reports of interactions with norfloxacin and enoxacin.
There have been isolated reports of interactions with proton pump inhibitors (elevated concentrations of clozapine when given with omeprazole and pantoprazole, or with combinations of lansoprazole and paroxetine).
Increased concentrations of clozapine have also been reported in patients who received clozapine in combination with venlafaxine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Clozapine did not affect fertility in rats at oral doses less than the maximum human dose (mg/m2 basis), but in long term dietary studies, dosing at less than the maximum human dose (mg/m2 basis) inhibited spermatogenesis in mice and produced testicular atrophy in rats.
(Category C)
Studies in animals are inadequate but available data in rats and rabbits with daily oral administration of clozapine during the period of organogenesis at doses less than the maximum human dose (mg/m2 basis) show no evidence of an increased occurrence of foetal damage. However, clozapine and/or its metabolites cross the placenta and enter the foetus in rabbits. The adverse pharmacological and toxicological effects of clozapine in adults may also occur in the foetus. Therefore, the drug should be used in pregnancy or in women likely to become pregnant, only if the expected benefit is considered to outweigh the potential risk. In women of child-bearing potential, adequate contraceptive measures must be ensured (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacokinetic-related interactions).

Non-teratogenic class effect.

Neonates exposed to antipsychotic drugs (including clozapine) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been post-market reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required additional medical treatment or monitoring.
Clozapine should be used during pregnancy or in women likely to become pregnant only if the anticipated benefit outweighs the risk, and the administered dose and duration of treatment should be as low and as short as possible. In women of child-bearing potential, adequate contraceptive measures must be ensured.
 Animal studies suggest that clozapine is excreted in milk. Oral administration of clozapine to rats during late gestation and throughout lactation at a dose less than the maximum human dose (mg/m2 basis) was associated with reduced offspring survival and offspring hyperactivity, but no lasting effect on pup development after weaning. Mothers receiving clozapine should not breast feed.

4.7 Effects on Ability to Drive and Use Machines

Owing to the ability of clozapine to cause sedation and lower the seizure threshold, patients should be advised not to engage in activities such as driving or operating machinery and other activities where sudden loss of consciousness could cause serious risk to the patient or others, especially during the initial weeks of treatment.

4.8 Adverse Effects (Undesirable Effects)

The adverse effects (AEs) of clozapine are most often predictable based on its pharmacological properties with the exception of agranulocytosis/ severe neutropenia (see Section 4.4 Special Warnings and Precautions for Use).
The most serious adverse reactions experienced with clozapine are agranulocytosis, seizure, cardiovascular effects, severe gastrointestinal effects (intestinal obstruction, severe constipation, gastrointestinal hypomotility) and fever (see Section 4.4 Special Warnings and Precautions for Use). The most common side effects are drowsiness/sedation, dizziness, tachycardia, constipation, and hypersalivation.
Data from the clinical trials experience showed that a varying proportion of clozapine-treated patients were discontinued due to an adverse event, including only those that could be reasonably attributed to clozapine. The more common events considered to be causes of discontinuation were leukopenia; somnolence; dizziness (excluding vertigo); and psychotic disorder.
The following section (Table 1) lists treatment-emergent adverse effects from spontaneous and clinical trial reports. Adverse effects are listed by MedDRA system organ class and ranked under the headings of frequency, using the following convention: very common (≥ 10%), common (≥ 1% to < 10%), uncommon (≥ 0.1% to < 1%), rare (≥ 0.01% to < 0.1%), very rare (< 0.01%) including isolated reports.

Note.

See Section 4.4 Special Warnings and Precautions for Use for further information on important adverse reactions.
Very rare events of ventricular tachycardia, cardiac arrest and QT prolongation which may be associated with Torsades De Pointes have been observed although there is no conclusive causal relationship to the use of this medicine.

Post marketing experience.

AEs from spontaneous reports and literature (frequency unknown).
The following post-marketing adverse effects were derived from experience with clozapine via spontaneous case reports and literature cases and have been categorized according to MedDRA system organ class (Table 2). Because these have been reported voluntarily from a population of uncertain size and are subject to confounding factors, these post-marketing AEs have been categorized with a frequency of "unknown" since it is not possible to reliably estimate their frequency. Adverse effects are listed according to system organ classes in MedDRA. Within each system organ class, AEs are presented in order of decreasing seriousness.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Human experience.

The most commonly reported signs and symptoms associated with clozapine overdose are altered states of consciousness, including drowsiness, delirium and coma; tachycardia; hypotension; respiratory depression; hypersalivation. Seizures have occurred in a minority of reported cases. Other reported symptoms include lethargy, areflexia, confusion, hallucinations, agitation, extrapyramidal symptoms, hyper-reflexia, mydriasis, blurred vision, thermolability, cardiac arrhythmias, aspiration pneumonia, dyspnoea and respiratory failure. Fatal overdoses have been reported with clozapine, generally at doses above 2,500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. However, in a few adults, primarily those not previously exposed to clozapine, the ingestion of doses as low as 400 mg led to life-threatening comatose conditions, and in one case, to death.

Treatment.

Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, should be considered in treating overdosage. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Additional surveillance should be continued for several days because of the risk of delayed effects. Avoid adrenaline (epinephrine) and derivatives when treating hypotension, and quinidine and procainamide when treating cardiac arrhythmia, because all of these drugs may exacerbate hypotension.
There are no specific antidotes for clozapine. Forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Clozapine has been shown to be an antipsychotic agent different from typical antipsychotic drugs.
In animal experiments, the compound does not induce catalepsy or inhibit apomorphine or amphetamine induced stereotyped behaviour. It has weak D2- and D1-receptor blocking activity, but potent noradrenolytic, anticholinergic, antihistaminic and arousal reaction inhibiting effects. It has also been shown to possess antiserotonergic properties.
Clinically, clozapine produces rapid and marked sedation, and exerts antipsychotic effects. In particular, the latter have been shown in people with schizophrenia that are resistant to other drug treatment. In such cases, clozapine has proven effective in relieving both positive and negative symptoms of schizophrenia, with about one-third of patients showing clinically relevant improvement. Clozapine is relatively free from extrapyramidal side effects, such as acute dystonia or a fully developed parkinsonian syndrome, when compared with typical antipsychotic agents. There have been no reports of tardive dyskinesia directly attributable to clozapine alone. However, the syndrome has been reported in a few patients who prior to or concomitantly with clozapine therapy have been treated with other antipsychotic agents, so that a causal relationship to clozapine can be neither established nor excluded. In contrast to typical antipsychotic drugs, clozapine therapy produces little or no prolactin elevation, sparing adverse effects such as gynaecomastia, amenorrhoea, galactorrhoea or impotence.
A serious adverse reaction which may occur with clozapine therapy is granulocytopenia/agranulocytosis. In view of this risk the use of clozapine should be limited to people who are treatment-resistant (see Section 4.1 Therapeutic Indications) and in whom regular haematological examination can be performed (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Clinical trials.

See Section 4.8 Adverse Effects (Undesirable Effects).

5.2 Pharmacokinetic Properties

Absorption.

The absorption of orally administered clozapine is 90 to 95%; the rate or extent of absorption is not influenced by food.
Clozapine, the active ingredient, is subject to a moderate first-pass metabolism, resulting in an absolute bioavailability of 50 to 60%.

Distribution.

In steady state conditions, when given twice daily, peak blood levels occur on an average at 2.1 hours (range 0.4 to 4.2 hours). Clozapine is 95% bound to plasma proteins.

Metabolism.

Clozapine is almost completely metabolised prior to excretion. Of the main metabolites, only one, the desmethyl metabolite, was found to be active. Its pharmacological actions resemble those of clozapine, but are considerably weaker and of shorter duration.

Excretion.

Its elimination is biphasic with a mean terminal half-life of approximately fourteen hours (range 7.9 - 29.1 hours).
Only trace amounts of unchanged drug are detected in the urine and faeces. Approximately 50% of the administered dose is excreted in the urine and 30% in the faeces.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of genotoxicity was observed in assays for gene mutations, chromosomal damage or DNA damage.

Carcinogenicity.

No evidence of carcinogenicity was observed following dietary administration of clozapine for at least 78 weeks to mice and for 108 weeks to rats, with the highest dose equivalent to less than the maximum human dose on a mg/m2 basis.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Clozitor tablets contains: lactose monohydrate, microcrystalline cellulose, povidone, sodium starch glycollate type A, magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C in a cool dry place. Protect from light.

6.5 Nature and Contents of Container

Clozitor 25 mg, 50 mg, 100 mg and 200 mg.

Tablets are supplied in PVC-PVDC blister packs in pack sizes of 50 and 100 tablets and HDPE Bottle pack in pack size of 50 and 100 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

This compound is practically insoluble in water.

Chemical structure.


Chemical name: 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4] diazepine.
Molecular formula: C18H19ClN4.
Molecular weight: 326.83.

CAS number.

5786-21-0.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes