Consumer medicine information

Clozaril

Clozapine

BRAND INFORMATION

Brand name

Clozaril

Active ingredient

Clozapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Clozaril.

SUMMARY CMI

CLOZARIL®

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 CLOZARIL?

CLOZARIL contains the active ingredient clozapine. CLOZARIL 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 CLOZARIL? in the full CMI.

2. What should I know before I use CLOZARIL?

Do not use if you have ever had an allergic reaction to 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 CLOZARIL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CLOZARIL 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 CLOZARIL?

  • The usual starting dose is half of a 25 mg tablet once or twice on the first day. The dose is usually increased to one 25 mg tablet once or twice on the second day. After that the dose can be slowly increased until the desired effect is achieved.

More instructions can be found in Section 4. How do I use CLOZARIL? in the full CMI.

5. What should I know while using CLOZARIL?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using CLOZARIL.
  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking CLOZARIL.
  • You must have strict and regular blood tests while taking CLOZARIL.
  • Call your doctor straightaway if you develop a fever, signs and symptoms of an infection, changes to your bowel movements 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 CLOZARIL affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • You should not drink alcohol while you are taking CLOZARIL.
Looking after your medicine
  • Keep your tablets in a cool dry place where the temperature stays below 30°C.
  • Keep it where children cannot reach it.

For more information, see Section 5. What should I know while using CLOZARIL? 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: constipation or fewer bowel movements than normal, abdominal pain, 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: fever, sore throat, mouth ulcers, "flu-like" symptoms, a fast or irregular heartbeat, 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 (reduced gastrointestinal movement) due to clozapine

Clozaril may cause slowing down or blockage of intestine function, resulting in reactions such as constipation; nausea with or without vomiting; tenderness or swelling of the abdomen, or bloating; stomach pains/spasms; leakage of diarrhoea or frequent and forceful bowel movements; bowel urges with no resulting movements; pain or pressure in the rectum and inflammation and bleeding of the bowels from the rectum. These can lead to severe outcomes. Your doctor must monitor bowel function before prescribing and during your therapy with Clozaril. It is extremely important to immediately advise your doctor, coordinator, pharmacist or any other healthcare professional, of any changes to your stool/bowel movements.

Myocarditis

CLOZARIL may cause myocarditis (inflammation of heart muscle), which may be fatal, or another heart condition. Your doctor will monitor you during treatment. If required, your doctor may want to refer you to a cardiologist for further tests.



FULL CMI

CLOZARIL®

Active ingredient(s): Clozapine

Consumer Medicine Information (CMI)

This leaflet provides important information about using CLOZARIL. 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 CLOZARIL.

Where to find information in this leaflet:

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

1. Why am I using CLOZARIL?

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

CLOZARIL is used to treat schizophrenia, which is a mental illness with disturb ances in thinking, feelings and behaviour.

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

Ask your doctor if you have any questions about why CLOZARIL has been prescribed for you.

Your doctor may have prescribed it for another reason.

CLOZARIL is available only with a doctor's prescription. There is no evidence that it is addictive.

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

2. What should I know before I use CLOZARIL?

Warnings

Do not use CLOZARIL 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, mouth and throat, as well as the tongue, which may be itchy or painful; or swelling of other parts of the body; rash, itching or hives on the skin.
  • If you think that you are allergic to CLOZARIL, ask your doctor for advice before taking this medicine."
  • Always check the ingredients to make sure you can use this medicine.
  • you have a low white blood cell count or have previously had a low white blood cell count caused by a medicine (except if it was following a treatment for cancer).
    CLOZARIL can cause agranulocytosis (a condition with a reduced number of white blood cells).
    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 CLOZARIL.
  • 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.
  • CLOZARIL 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 take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Do not take CLOZARIL if you have any of the following medical conditions:

  • any disease of the blood which causes a reduced number of red blood cells or platelets.
  • symptoms of active liver disease such as jaundice (yellow colour to the skin and eyes, feeling sick, loss of appetite) or any other severe liver disease.
  • severe kidney disease.
  • myocarditis (an inflammation of the heart muscle) or any other heart problems.
  • uncontrolled epilepsy (i.e. you still have some seizures).
  • paralytic ileus (your bowel does not work properly and you have severe constipation).
  • severe constipation, obstruction of the bowel, or any other condition which has affected your large bowel.
  • bone marrow disease.
  • problems with alcohol or drug abuse.

Check with your doctor if you:

  • take any medicines for any other condition.
  • smoke and how much coffee you drink. Sudden changes in your usual smoking or coffee drinking habits can also change the effects of CLOZARIL.
  • will be in a hot environment or you do a lot of vigorous exercise. CLOZARIL may make you sweat less, causing your body to overheat.
  • are lactose intolerant. This medicine contains lactose.
  • have allergies to other medicines or to any other substances such as foods, preservatives or dyes.

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

  • any form of heart disease or a family history of heart disease
  • family history of an abnormal conduction in the heart called "prolongation of the QT interval"
  • stroke
  • 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
  • epilepsy that is under control (i.e. you no longer have seizures)
  • diabetes or a family history of diabetes
  • chronic constipation, which needs to be treated before you start taking CLOZARIL. Your doctor must also monitor bowel function while you are on CLOZARIL.
  • dementia, a condition in which there is a decline in all areas of mental ability
  • any other serious medical condition.

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

Check with your doctor if you are pregnant or intend to become pregnant.

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

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

Newborn babies of mothers taking antipsychotic drugs during the third trimester of pregnancy may have increased risk of developing stiff limbs, trembling, agitation, muscle stiffness, muscle flaccidity, drowsiness, short and shallow breathing, and feeding disorders following delivery. In some cases these symptoms may be self-limiting, in other cases, babies may require intensive care unit support or hospitalization.

You should not breast feed during CLOZARIL treatment. This medicine may pass into breast milk and may 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 and CLOZARIL may interfere with each other. These include:

  • medicines that decrease the number of blood cells produced by your body
  • other antipsychotic medicines used to treat mental illnesses
  • medicines used to control depression or mood swings
  • benzodiazepines and other medicines used to treat anxiety or to help you sleep
  • medicines used to control epilepsy, including 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), an ingredient in many medicines that you can buy without a prescription from a pharmacy, health food shop or supermarket
  • antihistamines, medicines used for colds or allergies such as hay fever
  • anticholinergic medicines, which are used to relieve stomach cramps, spasms and travel sickness
  • medicines used to treat Parkinson's disease
  • medicines used to treat high blood pressure
  • digoxin, a medicine used to treat heart problems
  • medicines used to treat a fast or irregular heartbeat
  • some medicines used to treat stomach ulcers, including cimetidine, omeprazole, pantoprazole and lansoprazole
  • some antibiotic medicines, including erythromycin, clarithromycin, azithromycin, ciprofloxacin, norfloxacin and rifampicin
  • some medicines used to treat fungal or viral infections
  • nicotine in medicines used to help you quit smoking, such as nicotine patches or chewing gum
  • atropine, a medicine which may be used in some eye drops or cough and cold preparations
  • adrenaline, a drug used in emergency situations
  • birth-control tablets

These medicines may be affected by CLOZARIL or they may affect how well CLOZARIL works. You may need to take different amounts of your medicines or you may need to take different medicines.

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

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

4. How do I use CLOZARIL?

How much to take

  • The usual starting dose is half of a 25 mg tablet once or twice on the first day. The dose is usually increased to one 25 mg tablet once or twice on the second day. After that the dose can be slowly increased until the desired effect is achieved. Usually the total amount of CLOZARIL needed each day will be between 200 mg and 450 mg but some people will need higher doses. 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, are prone to seizures (fits) or are elderly, your doctor may start you on a lower dose and increase it more gradually to prevent unwanted side effects.
  • Follow all directions given to you by your doctor and pharmacist carefully. They may different from the information contained in the leaflet.
  • If you do not understand the instructions on the label, ask your doctor or pharmacist for help.
  • Follow the instructions provided and use CLOZARIL until your doctor tells you to stop.

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 CLOZARIL

  • Take your medicine at about the same time each day.
    Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
  • The total daily amount of CLOZARIL is usually divided into 2 doses (morning and bedtime). But, if your total dose is 200 mg or less, your doctor may allow you to take the whole amount at once, usually in the evening.

How to take CLOZARIL

  • Swallow the tablets with a full glass of water or other liquid.
  • Follow all directions given to you by your doctor or pharmacist carefully.
  • They may differ from the information contained in this leaflet.
  • If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

If you forget to take CLOZARIL

CLOZARIL should be taken regularly at the same time each day.

If you miss your dose and it is almost time for your next dose (within 4 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 it as you would normally.

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

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

If you have forgotten to take CLOZARIL for more than 2 days, do not start taking it again before you contact your doctor.

To prevent unwanted side effects, your doctor will probably want you to restart CLOZARIL at a low dose and increase it gradually back to the amount you were taking before.

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

If you have trouble remembering when to take your medicine, ask you pharmacist for some hints.

If you use too much CLOZARIL

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

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, 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 symptoms of an overdose include light headedness due to low blood pressure, too much saliva, difficulty breathing, fast or irregular heartbeat, drowsiness, confusion and unconsciousness.

5. What should I know while using CLOZARIL?

Things you should do

Continue taking CLOZARIL as long as your doctor tells you. If you have questions about how long to take CLOZARIL, talk to your doctor or pharmacist.

You must have strict and regular blood tests while taking CLOZARIL.

CLOZARIL can cause agranulocytosis. This is a condition where the number of white blood cells in your body is reduced. White blood cells are needed to fight infection.

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, the problem can be detected early. If CLOZARIL 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 CLOZARIL.

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 CLOZARIL 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 white blood cells falls below a critical level, CLOZARIL will be stopped immediately and you must never take CLOZARIL again.

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

Watch for important side effects. 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 CLOZARIL.

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 CLOZARIL.

Call your doctor straight away if you:

  • develop a fever.
    Some patients develop a fever in the first few weeks of taking CLOZARIL. You must be checked carefully to make sure that you do not have agranulocytosis, myocarditis or neuroleptic malignant syndrome, a reaction to some medicines with a sudden increase in body temperature.
  • develop a sour throat, mouth ulcers, flu-like symptoms or any other sign of a cold or infection.
    Your doctor will check your blood to decide if your symptoms are an early sign of agranulocytosis. 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 very rare 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 elderly women. In very rare cases, it may be permanent. However, if detected early, these symptoms are usually reversible.
  • Be mindful of any changes to your gastrointestinal (stomach/intestine) function. CLOZARIL may slow down or block intestinal function causing reactions such as constipation, nausea with or without vomiting, tenderness or swelling of the abdomen, leakage of diarrhoea or frequent and forceful bowel movements, bowel urges with no resulting movements, 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 CLOZARIL. If you develop any of these symptoms, you must tell your doctor, coordinator, pharmacist or any other healthcare professional of any changes to your bowel movements.
  • become pregnant while taking this medicine.
    Newborn babies of mothers taking antipsychotic drugs during the third trimester of pregnancy may have increased risk of developing stiff limbs, trembling, agitation, muscle stiffness, muscle flaccidity, drowsiness, short and shallow breathing, and feeding disorders following delivery. In some cases these symptoms may be self-limiting, in other cases, babies may require intensive care unit support or hospitalization.
    Your doctor can discuss with you the risks of taking it while you are pregnant.

Remind any doctor, dentist or pharmacist you visit that you are using CLOZARIL or if you are about to be started on any new medicine.

If you plan to have surgery, tell your doctor that you are taking CLOZARIL.

Things you should not do

  • Do not stop using this medicine or lower the dosage, even if you are feeling better, without checking with your doctor.
    If you stop taking CLOZARIL suddenly, your condition may worsen or you may have unwanted side effects such as excessive sweating, headache, nausea (feeling sick), vomiting and diarrhoea. If this medicine is stopped for any reason, your doctor will reduce the dose gradually, over a one-to-two-week period, to avoid side effects, before stopping the medicine completely.
  • Do not take CLOZARIL to treat any other complaints unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if their condition seems similar to yours.

Things to be careful of

  • Sudden unexplained death and heart attacks that may lead to death have been reported with CLOZARIL.
  • Be careful when taking pain relievers, sleeping tablets or antihistamines (medicines for colds or allergies such as hay fever) while you are taking CLOZARIL.
    CLOZARIL can increase the drowsiness caused by medicines that affect your nervous system.
  • CLOZARIL may cause alteration in blood lipids. It may also cause weight gain. Your doctor may monitor your weight and blood lipid levels.
  • CLOZARIL 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 CLOZARIL makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position.
    CLOZARIL may lower your blood pressure, especially at the start of treatment. These symptoms can usually be prevented by getting up slowly and flexing your leg muscles and toes to get the blood flowing. When getting out of bed, dangle your legs over the side for a minute or two before standing up.
  • Make sure you keep cool in hot weather and keep warm in cool weather.
    As with other antipsychotic medicines, CLOZARIL may affect the way your body reacts to temperature changes. It may prevent sweating, even during heatwaves. You may feel dizzy or faint if you are too hot.
    To stay cool in hot weather, try to do the following:
    - wear light clothing
    - spend time in air-conditioned environments (or keep windows open and use electric fans)
    - drink plenty of water
    - take cool baths or showers and avoid hot baths and saunas
    - try to restrict exercise or heavy work to cool parts of the day.
  • Inform your doctor if you stop smoking or change the number of caffeine-containing drinks that you have in one day. These changes can affect the levels of this medicine in your blood.

Driving or using machines

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

CLOZARIL may cause tiredness, drowsiness, dizziness, light-headedness, 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 CLOZARIL.

CLOZARIL may enhance the effects of alcohol.

Looking after your medicine

  • Keep your tablets in the pack until it is time to take them.
    If you take the tablets out of the pack they may not keep well.
  • Keep your tablets in a cool dry place where the temperature stays below 30°C.

Follow the instructions in the carton on how to take care of your medicine properly.

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.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

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.

Do not use this medicine after the expiry date.

Remember that you must still have your blood tested for a month after stopping this medicine.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking CLOZARIL, even if you do not think it is connected with the medicine.

All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical treatment if you get some of the side effects. Some of the side effects of CLOZARIL can be relieved by changing the dose.

If you are over 65 years old, you should be especially careful while taking this medicine. Report any side effects promptly to your doctor.

You may be more likely to get some of the side effects of CLOZARIL, such as rapid heartbeat, dizziness or light-headedness due to low blood pressure, constipation and difficulty urinating.

Do not be alarmed by this list of possible side effects.

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
  • constipation or fewer bowel movements than normal (if it seems to be getting worse, check with your doctor immediately)
  • abdominal pain
  • nausea (feeling sick), vomiting
  • stomach discomfort, especially after a meal
  • diarrhoea
  • dry mouth
  • too much saliva
  • difficulty in swallowing
  • heartburn
  • tiredness, drowsiness
  • dizziness or light headedness when standing up
  • headache
  • agitation, confusion, disorientation, vivid dreams
  • blurred vision, difficulty in reading
  • weight gain, especially excessive weight gain
  • changes in sexual function
  • painful menstrual periods
  • repetitive and ritualised behaviour (obsessive compulsive symptoms)
  • obsessive thoughts
  • stuttering in speech
  • problems in passing or holding urine
  • dark urine
  • excessive urination
  • 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
  • nocturnal bedwetting
  • increased or decreased sweating
  • skin reactions or change in skin colour
  • swelling of the glands in the cheeks
  • rash, purplish-red spots, fever or itching
  • "butterfly" rash, joint pain, muscle pain, fever and fatigue
  • stuffy nose
  • sudden, uncontrollable increase in blood pressure
  • 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
  • fainting or loss of consciousness
  • falls due to seizure, drowsiness, fainting, muscle weakness
  • crushing chest pain or chest pain
  • fever, sore throat, mouth ulcers, "flu-like" symptoms (chills, aching joints, swollen glands, lack of energy) or any other signs of infection
  • 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
  • sudden signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other parts of the body; wheezing or troubled breathing
  • 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 (fits)
  • 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.
  • severe or prolonged constipation, which may be accompanied by abdominal pain and bloating
  • 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, as CLOZARIL may cause or worsen diabetes
  • spontaneous bleeding or bruising more easily than normal
  • 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
  • yellowing of the skin and/or eyes, sometimes accompanied by feeling sick and loss of appetite
  • difficulty in passing urine (water) or blood in the urine
  • loss of bladder control
  • muscle stiffness, muscle weakness, muscle spasms, or muscle pain
  • muscle spasms, fever, red-brown urine
  • rigidity or stiffness in the arms and legs, shaking or tremor, feeling unable to sit still
  • abnormal movements, inability to initiate movement, inability to remain motionless, inner feeling restlessness, stiff limbs, trembling hands
  • symptoms of tardive dyskinesia (uncontrolled involuntary purposeful 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)
  • persistent painful erection or prolonged erection
  • signs of respiratory tract infection or pneumonia such as fever, coughing, difficulty breathing, wheezing
  • signs of sepsis such as shivering, fever, rapid breathing and heart rate, a change in your mental state such as confusion or disorientation
  • chest pain, cough, hiccups, rapid breathing
  • varying degrees of pain in the chest and abdomen
  • pauses in breathing or periods of shallow breathing during sleep.
The above are serious side effects that need medical attention.		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.

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 CLOZARIL contains

Active ingredientClozapine
Other ingredients
(inactive ingredients)
  • colloidal anhydrous silica
  • purified talc
  • magnesium stearate
  • lactose monohydrate
  • maize starch
  • povidone
Potential allergensSugars as lactose

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

What CLOZARIL looks like

CLOZARIL 25mg: circular, flat, yellow, bevelled edged tablets. Approximately 6.3 mm diameter, coded “CLOZ” on one side, and “L/O” and angle score on the reverse. Container of 100 tablets. (AUST R 50510)

CLOZARIL 100 mg: circular, flat, yellow, bevelled edged tablets. Approximately 10 mm diameter, coded “CLOZ” on one side, and “Z/A” and angle score on the reverse. Container of 100 tablets. (AUST R 50511)

The quantity of tablets provided to you will be determined by your doctor.

Who distributes CLOZARIL

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

For medical enquiries phone 1800 931 383

This leaflet was prepared in April 2023.

CLOZARIL® is a Viatris company trade mark.

CLOZARIL_cmi\Apr23/00

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Clozaril

Active ingredient

Clozapine

Schedule

S4

 

1 Name of Medicine

Clozapine.

2 Qualitative and Quantitative Composition

Each Clozaril tablet contains clozapine 25 mg or 100 mg of the active ingredient, clozapine.

Excipients with known effect.

Sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets, uncoated.
25 mg tablet: Circular, flat, yellow, bevelled edged tablets. Approximately 6.3 mm diameter, coded "CLOZ" on one side, and "L/O" and angle score on the reverse.
100 mg tablet: Circular, flat, yellow, bevelled edged tablets. Approximately 10 mm diameter, coded "CLOZ" on one side, and "Z/A" and angle score on the reverse.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment with Clozaril is indicated in treatment-resistant schizophrenic patients only, i.e. schizophrenic patients 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 reactions (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. The following dosages for oral administration are recommended.

Starting therapy.

12.5 mg (half a 25 mg tablet) once or twice daily on the first day, followed by one or two 25 mg tablets 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 2 to 3 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 patient populations, or patients aged 60 years and older, see Section 4.4 Special Warnings and Precautions for Use, Other precautions.

Therapeutic dose range.

In most patients, antipsychotic efficacy can be expected with 200-450 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 reactions 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 150-300 mg/day given in divided doses. With daily doses not exceeding 200 mg, a single administration in the evening may be appropriate.

Ending therapy.

In the event of planned termination of Clozaril therapy, a gradual reduction in dose is recommended over a 1 to 2 week period. If abrupt discontinuation is necessary the patient's mental state should be followed carefully. The patient should also be carefully observed for symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting and diarrhoea.

Re-starting therapy.

In patients in whom the interval since the last dose of Clozaril exceeds 2 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, Other precautions) but was then able to be successfully titrated to a therapeutic dose, retitration should be done with extreme caution.

Switching from a previous antipsychotic drug to Clozaril.

It is generally recommended that Clozaril should not be used in combination with other antipsychotic drugs. When Clozaril 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 Clozaril as described above.
If, in a particular patient, discontinuation of the antipsychotic drug is not a realistic option prior to institution of Clozaril, 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 Clozaril in increasing doses.

Administration.

Clozaril tablets are administered orally with water or other liquid.

4.3 Contraindications

Patients with a history of drug-induced granulocytopenia/agranulocytosis, or with bone marrow disorders, should not be treated with Clozaril.
Patients unable to undergo regular blood tests.
Circulatory collapse and/or CNS depression due to any cause.
Previous hypersensitivity to clozapine or to any other components of the formulation.
Alcoholic and other toxic psychoses; drug intoxication; comatose conditions.
Severe renal or cardiac disease (e.g. myocarditis).
Severe hepatic disease including active liver disease associated with nausea, anorexia or jaundice; progressive liver disease; hepatic failure.
Uncontrolled epilepsy.
Paralytic ileus.

4.4 Special Warnings and Precautions for Use

Special precautionary measures.

Agranulocytosis.

Clozaril can cause agranulocytosis. Its use should be limited to schizophrenic patients who are non-responsive to, or intolerant of other antipsychotic drugs:
who have initially normal leucocyte findings (white blood cell count > 3.5 x 109/L, normal differential blood count); and
in whom regular white blood cell (WBC) counts and absolute neutrophil counts (ANC) (weekly during the first 18 weeks, at least monthly thereafter throughout treatment, and for 1 month after complete discontinuation of Clozaril) can be performed.
Development of granulocytopenia and agranulocytosis is a risk inherent to Clozaril treatment. Although generally reversible on withdrawal of the drug, agranulocytosis 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, monitoring of the WBC count is mandatory.
Prescribing physicians should fully comply with the instituted safety measures. Because of the association of Clozaril with agranulocytosis, the following precautionary measures 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 Clozaril.
Drugs known to have a substantial potential to depress bone marrow function should not be used concurrently with Clozaril. 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 Clozaril treatment, a WBC and differential count (DC) must be performed within 10 days prior to starting Clozaril treatment to ensure that only patients with normal WBC counts and normal absolute neutrophil counts (ANC) will receive the drug. After the start of Clozaril treatment, the WBC and ANC must be performed and monitored weekly for 18 weeks. Thereafter, the WBC and ANC must be performed at least monthly throughout treatment, and for 1 month after complete discontinuation of Clozaril. At each consultation a patient receiving Clozaril should be reminded to contact the treating physician 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 Clozaril for more than 18 weeks and have had their treatment interrupted for more than 3 days but less than 4 weeks should have their WBC count and ANC monitored weekly for an additional 6 weeks. If no haematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed. If Clozaril treatment has been interrupted for 4 weeks or longer, weekly monitoring is required for the next 18 weeks of treatment.
If during Clozaril therapy, 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 below 3.5 x 109/L and/or reveal an absolute neutrophil granulocyte count of between 2.0 x 109/L and 1.5 x 109/L, the leucocytes and the granulocytes must be checked at least twice weekly. If the WBC falls below 3.0 x 109/L and/or the absolute neutrophil granulocyte count drops below 1.5 x 109/L, Clozaril must be withdrawn at once and the patients 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 Clozaril, haematological evaluation must be continued until haematological recovery has occurred.
If Clozaril has been withdrawn and a further fall of WBC below 2.0 x 109/L occurs and/or the neutrophil granulocytes 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 Clozaril has been discontinued as a result of white blood cell deficiencies (WBC count < 3.0 x 109/L and/or absolute neutrophil count < 1.5 x 109/L), must not be re-exposed to Clozaril.

Other precautions.

Myocardial infarction.

There have been postmarketing 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.

There have been cases of fatal myocarditis with clozapine treatment. Cases of myocarditis (with or without eosinophilia), 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, Clozaril treatment should be promptly stopped and the patient immediately referred to a cardiologist. If myocarditis is confirmed, Clozaril should be discontinued. If cardiomyopathy is diagnosed, Clozaril should be discontinued unless the benefit clearly outweighs the risk to the patient. If patients are diagnosed with cardiomyopathy while on Clozaril treatment, there is potential to develop mitral valve incompetence. Mitral valve incompetence has been reported in cases of cardiomyopathy related to Clozaril treatment. These cases of mitral valve incompetence reported either mild or moderate mitral regurgitation on two-dimensional echocardiography (2DEcho) (see Section 4.8 Adverse Effects (Undesirable Effects)). Most reported cases of myocarditis have occurred in the first month of treatment. Therefore, patients commencing Clozaril 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; see Section 4.8 Adverse Effects (Undesirable Effects)).
Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with Clozaril. However, if the benefit of Clozaril treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with Clozaril in consultation with a 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 Clozaril 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), Blood and lymphatic system disorders), it is recommended to discontinue Clozaril if the eosinophil count rises above 3.0 x 109/L, and to re-start 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), Blood and lymphatic system disorders), it is recommended to discontinue Clozaril if the platelet count falls below 50 x 109/L.

Orthostatic hypotension.

Tachycardia 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. 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 (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Treatment initiation.

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

Seizures.

Clozaril can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose dependent manner and may induce myoclonic jerks or generalised seizures. Caution should be used in administering Clozaril 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 patient 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 patient populations.

In patients with a history of seizures, or suffering from cardiovascular, renal or hepatic disorders (note: severe hepatic, renal or cardiovascular disorders, including active liver disease associated with nausea, anorexia or jaundice, progressive liver 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 or myocarditis (see Section 4.4 Special Warnings and Precautions for Use, Agranulocytosis; Section 4.4 Special Warnings and Precautions for Use, Myocarditis/ cardiomyopathy). The possibility of an underlying infectious process should also be considered.

Falls.

Clozaril 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 Clozaril (clozapine), either alone or in combination with lithium or other CNS-active agents (estimated incidence < 0.1%). If the diagnosis of NMS is confirmed, Clozaril should be discontinued immediately and appropriate medical measures should be administered.

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 intestinal obstruction, faecal impactions, megacolon, paralytic ileus and intestinal ischaemia or infarction (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 Clozaril, screen for constipation and treat as necessary. Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in clozapine-treated patients. Therefore, reassess bowel function frequency 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 (please see Boxed Warnings at the beginning of the document).
Clozapine is contraindicated in patients with paralytic ileus.

Anticholinergic effects.

Clozapine has potent anticholinergic effects. Treatment with Clozaril 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 affects can lead to significant adverse reactions. Where possible avoid concomitant use with other anticholinergic medications because the risk of 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 Clozaril, have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes may include hyperglycaemia, dyslipidaemia, 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 Clozaril in case reports and/or observational studies. When prescribing Clozaril all possible risk factors for VTE should be identified before and during treatment.

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 Clozaril was not included in this analysis.
Use of Clozaril 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. Clozaril 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 Clozaril treatment. There have been no reports of tardive dyskinesia directly attributable to Clozaril alone. However, the syndrome has been reported in a few patients who, prior to or concomitantly with Clozaril therapy, have been treated with other antipsychotic agents, so that a causal relationship to Clozaril 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 with atypical antipsychotics including Clozaril. 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 patients 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 Clozaril 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.

Dyslipidaemia.

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including Clozaril. 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 Clozaril. Clinical monitoring of weight is recommended.

Use in hepatic impairment.

Patients with stable pre-existing liver disorders may receive Clozaril but need regular liver function test monitoring. Patients who develop symptoms of possible liver dysfunction such as nausea, vomiting and/or anorexia during treatment with Clozaril 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 Clozaril 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 re-introduction of the drug.

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 leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting and diarrhoea (see Section 4.2 Dose and Method of Administration, Ending therapy).

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 Clozaril treatment and there have been reports of tachycardia, which may be sustained, in patients taking Clozaril. 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 Clozaril, such as urinary retention and constipation.

Use in the elderly with dementia-related psychosis.

In patients aged 60 years and older with dementia-related psychosis, the efficacy and safety of clozapine have 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). Clozaril should be used with caution in patients aged 60 years and older with dementia.

Paediatric use.

No paediatric studies have been performed. The safety and effectiveness in children and adolescents below 16 years of age have not been established. Clozaril 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 Clozaril (also see Section 4.4 Special Warnings and Precautions for Use, Special precautionary measures).
As with other antipsychotics, caution should be exercised when Clozaril is prescribed with medicines known to increase the QTc interval, or cause electrolyte imbalance.
Particular caution is advised when Clozaril 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.
Concomitant use of lithium or other CNS-active agents may increase the risk of development of neuroleptic malignant syndrome (NMS).
Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where Clozaril 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.
Clozaril may enhance the central effects of alcohol, MAO inhibitors and CNS depressants such as narcotics, antihistamines and benzodiazepines.
Because of the possibility of additive effects, caution in the concomitant administration of drugs with anticholinergic, hypotensive or respiratory depressant effects is essential.
In Clozaril-treated patients, the blood pressure increasing effect of adrenaline (epinephrine) and its derivatives may be reversed.

Pharmacokinetic-related interactions.

Clozapine is a substrate for many cytochrome P (CYP) 450 isoenzymes, in particular 1A2 and 3A4. Caution is called for in patients receiving concomitant treatment with other drugs which are either inhibitors or inducers of these enzymes.
With other drugs known to bind to the CYP450 2D6 isoenzyme, such as antidepressants, phenothiazine and type IC anti-arrhythmics, no clinically relevant interactions with Clozaril have been observed so far. On theoretical grounds, however, it is possible that the plasma levels of such drugs are increased by Clozaril, so it may be appropriate to use them at doses lower than usually prescribed.
Concomitant administration of phenytoin, carbamazepine, rifampicin, St John's wort (Hypericum perforatum) [drugs known to induce the activity of CYP450 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.
Competition for protein binding sites may lead to adverse effects as a result of changes in plasma levels of Clozaril or other highly protein-bound drugs such as warfarin and digoxin.
Concomitant administration of drugs known to inhibit the CYP450 enzyme system, may increase the plasma levels of clozapine, possibly resulting in adverse effects. Substances known to inhibit the activity of the major isozymes involved in the metabolism of clozapine and with reported interactions include: cimetidine, erythromycin and ciprofloxacin.
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.
In one study of 7 patients, the plasma concentration of clozapine was increased by caffeine (an inhibitor of CYP 450 1A2) intake and decreased by 29 to 80% following a 5-day caffeine-free period.
Discontinuation of the concomitant administration of carbamazepine has resulted in an increase of the clozapine plasma levels.
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).
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 2-fold), fluvoxamine (up to 10-fold) and with oral contraceptives (inhibits 1A2, 3A4 and 2C19 isozymes). Such patients should be monitored closely and dosage adjustment may be indicated.
Increased concentrations of clozapine have also been reported in patients who received clozapine in combination with venlafaxine.
Tobacco smoke, a known inducer of CYP450 1A2, may decrease the plasma levels of clozapine. In 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 CYP450 1A2, could potentially also decrease the plasma levels of clozapine.
Potent inhibitors of CYP450 3A, such as azole antimycotics and protease inhibitors, could potentially also increase clozapine plasma concentrations.

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 from studies 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.

Non-teratogenic class effect.

Neonates exposed to antipsychotic drugs (including Clozaril) 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.
Clozaril, should be used during pregnancy 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.
 Animal studies suggest that Clozaril 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 Clozaril should not breastfeed.

4.7 Effects on Ability to Drive and Use Machines

Owing to the ability of Clozaril 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 (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 are ranked under 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 Clozaril 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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

The most commonly reported signs and symptoms associated with Clozaril (clozapine) overdose are: altered state 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 Clozaril (clozapine) generally at doses above 2500 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 these drugs may exacerbate hypotension.
There are no specific antidotes for Clozaril (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.

Clozaril 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, Clozaril produces rapid and marked sedation, and exerts antipsychotic effects. In particular, the latter have been shown in schizophrenic patients resistant to other drug treatment. In such cases, Clozaril has proven effective in relieving both positive and negative schizophrenic symptoms, with about one-third of patients showing clinically relevant improvement. Clozaril 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 Clozaril alone. However, the syndrome has been reported in a few patients who prior to or concomitantly with Clozaril therapy have been treated with other antipsychotic agents, so that a causal relationship to Clozaril can neither be established nor excluded. In contrast to typical antipsychotic drugs, Clozaril 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 Clozaril therapy is granulocytopenia/ agranulocytosis. In view of this risk the use of Clozaril should be limited to patients who are treatment resistant (see Section 4.1 Therapeutic Indications) and in whom regular haematological examinations can be performed (see Section 4.4 Special Warnings and Precautions for Use, Special precautionary measures; 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 Clozaril is 90-95%; the rate or extent of absorption is not influenced by food.
Clozapine, the active ingredient of Clozaril, is subject to a moderate first-pass metabolism, resulting in an absolute bioavailability of 50-60%.

Distribution.

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

Metabolism.

Clozapine is almost completely metabolised prior to excretion by CYP1A2 and 3A4, and to some extent by CYP2C19 and 2D6. 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 12 hours (range: 4-66 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

Excipients: magnesium stearate, colloidal anhydrous silica, povidone, purified talc, maize starch, lactose monohydrate. The tablets contain no colouring agent.

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

Blister packs: Store below 30°C.
Bottle packs: Store below 25°C.
This medicinal product does not require any special storage precautions.

6.5 Nature and Contents of Container

Container type: PVC/PVDC/Al or PVC/PE/PVDC/Al blister packs of 28, 50 and 100 tablets.
Container type: HDPE bottle with a polypropylene child resistant closure of 100 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.

Australian Register of Therapeutic Goods (ARTG).

AUST R 50510 - Clozaril clozapine 25 mg tablet blister pack.
AUST R 50511 - Clozaril clozapine 100 mg tablet blister pack.
AUST R 79930 - Clozaril clozapine 100 mg tablet bottle.
AUST R 79932 - Clozaril clozapine 25 mg tablet bottle.

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

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.
Clozapine, a tricyclic dibenzodiazepine derivative, is a yellow crystalline powder, odourless or with a weak characteristic odour.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes