Consumer medicine information

Clopine

Clozapine

BRAND INFORMATION

Brand name

Clopine

Active ingredient

Clozapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Clopine.

What is in this leaflet

This leaflet answers some common questions about CLOPINE.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking CLOPINE against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What CLOPINE is used for

CLOPINE is used in patients with schizophrenia for whom other antipsychotic medicines have not worked or have caused severe side effects.

This medicine belongs to the group of medicines known as antipsychotics. This group of medicines is mainly used in the treatment of schizophrenia. Schizophrenia is a mental illness with disturbances in thinking, feelings and behaviour.

This medicine is thought to work by correcting the chemical imbalances in the brain which may cause mental illness.

Ask your doctor if you have any 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.

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

There is not enough information to recommend the use of this medicine in children under the age of 16 years.

Before you take CLOPINE

When you must not take it

Do not take CLOPINE if you have an allergy to:

  • any medicine containing clozapine
  • 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 think that you are allergic to Clopine, ask your doctor for advice before taking this medicine.

Do not take this medicine if you have a low white blood cell count, or if you have previously had a low white blood cell count caused by a drug treatment (except if it was following a treatment for cancer). CLOPINE can cause agranulocytosis. 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 CLOPINE.

Do not take CLOPINE 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.

Do not take this medicine if you have or have had any of the following medical conditions:

  • any disease of the blood which causes a reduced number of red blood cells or platelets
  • bone marrow disorder
  • severe kidney disease
  • severe heart disease
  • problems with the circulatory (blood) or nervous system
  • 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
  • myocarditis (an inflammation of the heart muscle) or any other heart problems
  • uncontrolled epilepsy (fits or seizures)
  • problems with alcohol or drug abuse
  • paralytic ileus, a condition in which the small and/or large bowel does not work properly, including severe constipation or obstruction.
  • severe constipation, obstruction of the bowel, or any other condition which has affected your large bowel

CLOPINE must not be given to anyone who is unconscious or in a coma, or who has an acute mental illness casued 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.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have any allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant. There is limited information on the safety of CLOPINE in pregnancy.

Your doctor will discuss the risks and benefits of taking this medicine during pregnancy.

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

Tell your doctor if you are breast-feeding or plan to breast-feed. You should not breast feed during CLOPINE treatment. This medicine may pass into breast milk and affect your baby.

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

  • heart disease or a family history of heart disease, including blood clots
  • stroke
  • joint-replacement, or other major surgery, or past major fractures or traumatic accidents
  • a job or pastime where you sit for long periods at a time, or if you travel sitting down for long periods
  • any issues with walking around (called "mobility")
  • any genetic conditions that cause abnormal blood clotting
  • serious lung disease, like pneumonia or obstructive pulmonary disease
  • liver or kidney problems
  • fits or epilepsy that is under control
  • diabetes or a family history of diabetes
  • prostate enlargement
  • glaucoma (raised pressure in the eye)
  • neuroleptic malignant syndrome, a reaction to some medicines with a sudden increase in body temperature, sweating, fast heart beat, 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)
  • chronic constipation
  • dementia, a condition in which there is a decline in all areas of mental ability
  • any other serious medical condition.

Your doctor may want to take special precautions if you have any of these conditions.

Tell your doctor if you will be in a hot environment or you do a lot of vigorous exercise. CLOPINE may make you sweat less, causing your body to overheat.

Tell your doctor if you smoke and how much coffee you drink. Smoking and caffeine can affect how CLOPINE affects your body. Sudden changes in your usual smoking or coffee drinking habits can also change the effects of CLOPINE and how much CLOPINE you need.

Tell your doctor if you are lactose intolerant. This medicine contains lactose.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking CLOPINE.

Taking other medicines

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

Some medicines and CLOPINE may interfere with each other. These include:

  • medicines which may decrease the number of blood cells produced by your body
  • strong pain killers such as morphine
  • antihistamines, medicines used to control and prevent symptoms of 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
  • medicines used to treat a fast or irregular heart beat such as digoxin
  • atropine, a medicine which may be used in some eye drops or cough preparations
  • adrenaline, a drug used in emergency situations
  • warfarin, a medicine used to prevent blood clots
  • medicines used for stomach ulcers and reflux oesophagitis such as cimetidine, pantoprazole, lansoprazole and omeprazole
  • medicines used to treat bacterial infections such as erythromycin, clarithromycin, azithromycin, norfloxacin, rifampicin, and ciprofloxacin
  • medicines used to treat epilepsy such as phenytoin, carbamazepine and valproic acid
  • other medicines for mental disorders such as schizophrenia, mood swings or depression
  • medicines to calm you and help you sleep such as benzodiazepines
  • medicines used to treat fungal and viral infections
  • St John's wort (Hypericum perforatum), a herbal remedy
  • birth-control tablets, or hormone-replacement therapy

These medicines may be affected by CLOPINE 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 CLOPINE.

How to take CLOPINE

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 label, ask your doctor or pharmacist for help.

Take CLOPINE exactly as prescribed by your doctor to help prevent unwanted side effects.

How much to take

Your dose of CLOPINE has been determined for you by your doctor. The dose will depend on how you respond to the medicine, other medicines you are taking, and other medical conditions that you may have. The dose may be altered from time to time.

When you first start taking CLOPINE, the usual 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 effects.

Do not take more or less CLOPINE than your doctor has prescribed. If you think the dose is too weak or too strong, talk to your doctor.

How to take it

The total daily amount of CLOPINE 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.

CLOPINE Tablets:

Swallow CLOPINE tablets with water or other liquid.

CLOPINE Suspension

24 HOURS BEFORE THE FIRST USE:

  1. Unscrew and remove the cap from the bottle.
  2. Push the bottle adaptor into the top of the bottle. Once the adaptor is in place it stays there.
  3. Replace the cap and ensure it is tightened.
  4. Before the first dose only, SHAKE THE BOTTLE for 90 seconds.
  5. Note the expiry date on the product label in permanent marker as 90 days from the date of opening.
  6. Leave the bottle to stand for 24 hours to ensure the bubbles formed during shaking have dissipated.

IMMEDIATELY BEFORE DISPENSING DOSES:

  1. Ensure the cap is tightened.
  2. SHAKE THE BOTTLE for 10 seconds.
  3. Remove the cap from the bottle.
  4. Draw air into the oral dispenser (syringe) equivalent to the volume of the dose required.
  5. Insert the oral dispenser into the opening of the bottle adaptor. Expel all the air from the oral dispenser into the bottle.
  6. Invert the bottle and slowly draw up the amount prescribed by your doctor
  7. Turn the bottle upright and detach the oral dispenser from the bottle adaptor.
  8. Invert the oral dispenser to prevent spillage. Swallow the contents of the oral dispenser.
  9. Leave the bottle adaptor in place on the bottle.
  10. Replace the bottle cap over the bottle adaptor after use.
  11. Wash the oral dispenser with warm soapy water after each use. Then rinse well with water.

When to take it

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.

It does not matter if you take this medicine before or after food.

How long to take it

Continue taking your medicine for as long as your doctor tells you. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

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 CLOPINE 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 CLOPINE 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 CLOPINE 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 have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much CLOPINE. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

The most common signs and symptoms of CLOPINE 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.

While you are using CLOPINE

Things you must do

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

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

This medicine can cause agranulocytosis. This is a condition where the number of white blood cells (which are necessary to fight infection in your body) 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 CLOPINE is stopped as soon as possible, the white blood cell numbers should return to normal.

After starting on CLOPINE, you must have a blood test at least once a week for the first 18 weeks of treatment (this is when the risk of agranulocytosis is greatest), thereafter at least every 4 weeks for as long as you are taking CLOPINE, and for one month after stopping the medicine.

Your doctor will advise if blood tests are required more often. These tests will tell the doctor if the white blood cell count is dropping.

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

If the number of your white blood cells falls below a critical level, CLOPINE 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 your level of sugar in the blood.

Watch for important side effects:

If you develop a fast or irregular heart beat 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. These symptoms could be signs of myocarditis, an inflammation of the heart muscle, or another heart condition. Your doctor may want to stop your CLOPINE and refer you to a cardiologist for further tests.

If at any stage during treatment with CLOPINE you develop a sore throat, mouth ulcers, fever, flu-like symptoms or other signs of infection, you must contact your doctor immediately. This is necessary, as these symptoms may be an early sign of agranulocytosis. Flu-like symptoms may also be a sign of myocarditis.

Some patients develop fever in the first few weeks of taking CLOPINE. 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.

If you notice any uncontrolled movements of the tongue, face, mouth or jaw, such as puffing of the cheeks, puckering of the mouth or chewing movements, tell your doctor immediately. 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.

If you are about to be started on any new medicines, remind your doctor and pharmacist that you are taking CLOPINE.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

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

Make sure you use a contraceptive to prevent pregnancy during treatment with CLOPINE. If you become pregnant while taking this medicine, tell your doctor immediately. Your doctor can discuss with you the risks of taking it while you are pregnant. 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.

If you suffer from severe stomach pain and constipation tell your doctor immediately. If you develop severe stomach pain it could be a sign of breakdown of part of the intestine.

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 must not do

Do not take CLOPINE to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it 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 let yourself run out of CLOPINE 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 CLOPINE.

Be careful driving or operating machinery until you know how CLOPINE affects you. This medicine 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. If you do have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

You should not drink alcohol while you are taking Clopine. Clopine may enhance the effects of alcohol.

Be careful when taking antihistamines (medicines used for hayfever, allergies or colds), sleeping tablets or tablets to relieve pain while taking this medicine. If you take some medicines, drowsiness, dizziness or light-headedness may be worse.

CLOPINE 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.

CLOPINE 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.

Keep cool in hot weather and keep warm in cool weather. This medicine may affect the way your body controls temperature, and it may prevent sweating even in very hot weather. Exercise, hot baths or saunas may make you feel dizzy or faint while you are taking this medicine.

Tell 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.

Tell your doctor if you are going to be hospitalised or on bed rest for a long period of time Being immobile for long periods of time can increase your risk of developing blood clots while taking CLOPINE.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking CLOPINE.

This medicine helps most people with schizophrenia, but it may have unwanted side effects in a few people. All medicines have side effects. Sometimes these are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

If you are over 65 years old, you may have an increased chance of getting side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following:

  • tiredness, drowsiness or fatigue
  • dizziness, fainting, light-headedness
  • too much saliva
  • difficulty in swallowing
  • dry mouth
  • nasal congestion
  • swelling of the glands in the cheeks
  • weight gain
  • nausea, vomiting
  • constipation (if it seems to be getting worse, check with your doctor immediately)
  • diarrhoea
  • abdominal discomfort, heartburn or dyspepsia
  • changes in sexual function
  • painful menstrual periods
  • problems in passing or holding urine, dark urine, excessive urination, nocturnal bedwetting
  • skin reactions or change in the colour of the skin
  • mild fever
  • headache
  • agitation, confusion, disorientation, vivid dreams
  • increased or decreased sweating
  • blurred vision
  • stuttering
  • rash, purplish-red spots usually associated with fever or itching
  • "butterfly" rash, joint pain, muscle pain, fever and fatigue
  • uncontrolled bending of the body to one side
  • repetitive and ritualised behaviour (obsessive compulsive symptoms)
  • 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
  • a strong urge to move the legs (restless legs syndrome) with an unpleasant feeling in the legs

If any of the following happen, tell your doctor immediately or go to Accident & Emergency at your nearest hospital:

  • fainting or loss of consciousness
  • falls due to seizure, drowsiness, fainting, muscle weakness
  • chest pain
  • sore throat, mouth ulcers, fever, any "flu-like" symptoms such as swollen glands or other signs of infection
  • signs of an allergic reaction such as itching, skin rash, hives, swelling of the face, lips or tongue, difficulty in swallowing or breathing
  • a sudden increase in body temperature, sweating, fast heart beat and muscle stiffness which may be symptoms of neuroleptic malignant syndrome
  • fast or irregular heart beat 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
  • 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, chest pain or shortness of breath.
  • uncontrolled movements of the tongue, jaw, face and mouth(such as puffing at the cheeks, chewing movements, puckering of the mouth, lipsmacking, grimacing and rapid eye blinking). These are symptoms of a very rare condition called tardive dyskinesia.
  • abnormal movements, inability to start moving, inability to stay still, inner feeling of restlessness, stiff limbs, trembling hands
  • signs of pneumonia or lower respiratory tract infection such as difficulty breathing, coughing, and chest pain
  • signs of sepsis such as shivering, fever, rapid breathing and heart rate, a change in your mental state sus confusion or disorientation
  • seizures or fits
  • jaundice, yellowing of the skin and/or eyes
  • urinary problems - difficulty passing urine (water) or blood in the urine; loss of bladder control
  • signs of loss of blood sugar control such as excessive thirst, passing large amounts of urine, dry mouth and skin
  • persistent painful erection
  • muscle spasms associated with fever and/or red-brown urine
  • loss of co-ordination, shaking or tremor, feeling unable to sit still, rigidity or muscle stiffness/spasms/weakness or pain
  • persistent painful erection or prolonged erection
  • abdominal or lower back pain
  • stomach pain accompanied by nausea and vomiting
  • severe or prolonged constipation, which may be accompanied by abdominal pain and bloating
  • unusual bruising or bleeding
  • cough, hiccups, rapid breathing, chest pain which can be associated with abdomen pain
  • pauses in breathing or periods of shallow breathing during sleep.

The above list includes serious side effects which may require medical attention.

Tell your doctor or pharmacist if you notice anything else that is making you unwell. Other side effects not listed above may also occur in some people.

Some side effects can only be found when your doctor does tests to check your progress.

These tests could show a reduction in white blood cells, red blood cells or changes in blood platelet levels. These tests could also show a change in liver enzymes, blood sugar and lipid levels.

After using CLOPINE

Storage

Keep your medicine in the original packaging until it is time to take it.

Tablets and Suspension:

Keep your tablets in a cool dry place where the temperature stays below 30°C. Protect from light.

Store the CLOPINE Suspension below 25°C. Recap the bottle tightly following each use. Discard the bottle 90 days after it has been opened.

Do not store CLOPINE tablets or suspension or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. 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.

Disposal

If your doctor tells you to stop taking CLOPINE or the medicine has passed its expiry date, ask your pharmacist what to do with any medicine that is left over. CLOPINE Suspension expires 90 days after first opening the bottle.

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

Product description

What it looks like

CLOPINE 25 are small, round, yellow tablets with "25" embossed over a breakline on one face, the other side is plain.

CLOPINE 50 are small, round, yellow tablets with "50" embossed over a breakline on one face, the other side is plain.

CLOPINE 100 are small, round, yellow tablets with "100" embossed over a breakline on one face, the other side is plain.

CLOPINE 200 are oval shaped yellow tablets with "200" embossed on one side and a breakline on the other side.

CLOPINE Suspension is a yellow mixture called a suspension in a glass amber bottle containing 100 mLs.

Pack Sizes:

CLOPINE 25, CLOPINE 50, CLOPINE 100 and CLOPINE 200 come in blister packs or bottles of 100 tablets.

CLOPINE Suspension comes in a 125 mL bottle containing 100 mLs of the suspension.

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

Ingredients

CLOPINE Tablets:

Active ingredient:

CLOPINE 25 tablets contain 25 mg of clozapine. CLOPINE 50 tablets contain 50 mg of clozapine. CLOPINE 100 tablets contain 100mg of clozapine. CLOPINE 200 tablets contain 200 mg of clozapine.

CLOPINE tablets also contain:

  • povidone
  • microcrystalline cellulose
  • lactose monohydrate
  • sodium starch glycollate
  • magnesium stearate.

CLOPINE Suspension:

Active ingredient:

Each 1 ml of CLOPINE Suspension contains 50 mg of clozapine.

CLOPINE suspension also contains:

  • sorbitol solution (70 per cent)
  • povidone
  • monobasic sodium phosphate dihydrate
  • sodium methyl hydroxybenzoate
  • sodium propyl hydroxybenzoate,
  • xanthan gum
  • glycerol
  • hydrochloric acid
  • sodium hydroxide
  • purified water

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

Supplier

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

CLOPINE is a registered trade mark of Douglas Pharmaceuticals Limited used under licence.

CLOPINE 25 in blister packs
AUST R 67947

CLOPINE 25 in bottles
AUST R 93972

CLOPINE 50 in blister packs
AUST R 95557

CLOPINE 50 in bottles
AUST R 95559

CLOPINE 100 in blister packs
AUST R 67948

CLOPINE 100 in bottles
AUST R 93973

CLOPINE 200 in blister packs
AUST R 95560

CLOPINE 200 in bottles
AUST R 95561

CLOPINE Suspension
AUST R 142239 (not supplied)

This leaflet was updated in
January 2020

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Clopine

Active ingredient

Clozapine

Schedule

S4

 

1 Name of Medicine

Clozapine.

6.7 Physicochemical Properties

Clopine tablets and suspension contain clozapine which is a tricyclic dibenzodiazepine derivative. This compound is practically insoluble in water.
Active: clozapine.
Chemical name: 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4] diazepine. Molecular formula: C18H19ClN4. Molecular weight: 326.83.

Chemical structure.


CAS number.

5786-21-0.

2 Qualitative and Quantitative Composition

Clopine 25: Each 25 mg tablet contains 25 mg clozapine.
Clopine 50: Each 50 mg tablet contains 50 mg clozapine.
Clopine 100: Each 100 mg tablet contains 100 mg clozapine.
Clopine 200: Each 200 mg tablet contains 200 mg clozapine.
Clopine suspension: Each 1 mL of suspension contains 50 mg clozapine.

Excipients with known effect.

Tablets.

Contains sugars (as lactose monohydrate).

Suspension.

Sorbitol solution (70 percent) (crystallising), sodium methyl hydroxybenzoate and sodium propyl hydroxybenzoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Clopine 25 - 25 mg tablets.

Round, yellow, flat, beveled edge tablets engraved with '25' over a pressure sensitive breakline on one face. The other face plain.

Clopine 50 - 50 mg tablets.

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

Clopine 100 - 100 mg tablets.

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

Clopine 200 - 200 mg tablets.

Oval shaped, yellow tablet with '200' on one side and a breakline on the other side.

Clopine suspension (50 mg/mL).

A free flowing yellow suspension.

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.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment with Clopine 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).

4.3 Contraindications

Clopine 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.
Clopine 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.

Agranulocytosis.

Clozapine can cause agranulocytosis. Its use should be limited to people with schizophrenia who are non-responsive to, or intolerant of, other antipsychotic drugs:
who have initially normal leucocyte findings (white blood cell count > 3500/mm3, 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 clozapine] can be performed.
Development of granulocytopenia and agranulocytosis is a risk inherent to clozapine 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 clozapine with agranulocytosis, 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 white blood cell (WBC) count and a differential count (DC) must be performed within ten days prior to starting clozapine treatment to ensure that only patients with normal leucocyte findings (WBC count > 3500/mm3, normal differential blood count), and normal absolute neutrophil counts (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 3,500/mm3, or has dropped by a substantial amount from baseline (even if the count is above 3,500/mm3), a repeat WBC count and a differential count should be done. Should the results confirm a WBC count below 3,500/mm3 and/or reveal an absolute neutrophil granulocyte count of between 2,000 and 1,500/mm3, the leucocytes and the granulocytes must be checked at least twice weekly. If the WBC count falls below 3,000/mm3 and/or the absolute neutrophil granulocyte count drops below 1,500/mm3, 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 2,000/mm3 occurs and/or the neutrophil granulocytes decrease below 1,000/mm3, 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 < 3,000/mm3 and/or ANC < 1,500/mm3) must not be re-exposed to clozapine.

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.

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 (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 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 3,000/mm3 and to restart therapy only after the eosinophil count has fallen below 1,000/mm3.

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

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 or myocarditis (see Boxed Warnings; Section 4.4 Special Warnings and Precautions for Use, Myocarditis/ cardiomyopathy; Section 4.4 Special Warnings and Precautions for Use, Agranulocytosis). 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 exerts anticholinergic activity which may produce undesirable effects throughout the body. Probably on account of its anticholinergic properties, clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, faecal impaction, paralytic ileus, megacolon and intestinal infarction/ischaemia (see Section 4.8 Adverse Effects (Undesirable Effects)). On rare occasions these cases have been fatal. Since complications have been associated with delayed diagnosis, patients should be questioned about their bowel habits. Careful monitoring during treatment with clozapine to early identify the onset of constipation, followed by effective management of constipation are recommended to prevent complications. Careful supervision is indicated in the presence of prostatic enlargement and narrow angle glaucoma. Clozapine is contraindicated in patients with paralytic ileus.

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 CYP1A2, CYP2D6 and CYP3A4. Caution is called for in patients receiving concomitant treatment with other drugs which are inhibitors or inducers 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 CYP1A2) intake and decreased by 29 to 80% following a 5-day caffeine-free period.
Potent inhibitors of CYP3A4, 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 CYP3A4] 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 CYP2D6 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 CYP1A2. Such patients should be monitored closely and dosage adjustments may be indicated.
Tobacco smoke, a known inducer of CYP1A2, 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 CYP1A2, 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 childbearing 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 breastfeed.

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 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.
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.

Postmarketing 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.

4.2 Dose and Method of Administration

(See Section 4.4 Special Warnings and Precautions for Use.)
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.
Clopine suspension must be administered by healthcare professionals who are staff at centres registered with the Clopine monitoring and support network - ClopineCentral.

Suspension: instructions for use.

All doses being measured should be given using an appropriate oral dispenser.

24 hours before the first use.

1. Push down and turn the cap to open the bottle. Remove the cap and push the bottle adaptor into the top of the bottle. Leave the bottle adaptor in place on the bottle.
2. Replace the cap over the bottle adaptor and ensure the cap is tightened.
3. To ensure the suspension is dispersed, before dispensing the first dose only, shake the bottle for a period of 90 seconds. This is important to ensure any sedimentation that may have occurred during storage has been re-suspended.
4. Note the expiry date on the product label in permanent marker as ninety (90) days from the date of first opening.
5. Leave the bottle of suspension to stand for 24 hours before dispensing the first dose to allow dissipation of air bubbles formed during shaking.

Immediately before dispensing doses.

1. Immediately before each dose, the bottle should be further shaken for 10 seconds to ensure the suspension is homogeneous.
2. Push down and turn the cap to open the bottle. Remove the cap from the bottle.
3. Draw air into the oral dispenser (syringe) equivalent to the volume of the dose required.
4. Insert the oral dispenser into the opening of the bottle adaptor. Expel all the air from the oral dispenser into the bottle.
5. Turn the bottle of Clopine suspension upside down and slowly draw the prescribed dose of liquid into the oral dispenser using the graduations displayed in millilitres.
6. Turn the bottle upright and detach the oral dispenser from the bottle adaptor. Invert the oral dispenser to prevent spillage.
7. Administer the Clopine suspension directly from the oral dispenser or add the suspension to a cup with some water. Stir and drink the entire mixture right away.
8. Replace the bottle cap. Do not remove the bottle adaptor before recapping.
9. Oral dispensers may be reused for the same patient only. Wash the oral dispenser in warm soapy water after each use. Rinse well with water.
Clopine suspension can be used for up to 90 days following the first opening.
Clopine suspension should be given undiluted, however, if dilution is required, Clopine suspension may only be mixed with water. Do not mix Clopine suspension with any other beverages as they may change the properties of the active drug.
The recommended dosages which follow are for oral administration.

Starting therapy.

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'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 (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.

Administration.

Clozapine tablets are administered orally with water or other liquids.

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.

4.9 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).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Clopine tablets (25 mg, 50 mg, 100 mg, 200 mg).

Lactose monohydrate, microcrystalline cellulose, povidone, sodium starch glycollate and magnesium stearate.

Clopine suspension (50 mg/mL).

Sorbitol solution (70 per cent) (crystallising), povidone, monobasic sodium phosphate dihydrate, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate, xanthan gum, glycerol, hydrochloric acid, sodium hydroxide and purified water.

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

Clopine tablets.

Store below 30°C in a cool dry place. Protect from light.

Clopine suspension.

Store below 25°C. Clopine suspension may be used for up to 90 days after first opening. Recap the bottle tightly following each use.

6.5 Nature and Contents of Container

Clopine 25, Clopine 50, Clopine 100 and Clopine 200 are available in blister packs or bottles, in pack sizes of either 50 (not marketed) or 100 tablets.
Clopine suspension (50 mg/mL) is available as 100 mL in 125 mL bottle (not marketed).

6.6 Special Precautions for Disposal

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

Summary Table of Changes