Clopine

New Zealand - English - Medsafe (Medicines Safety Authority)

Buy It Now

Active ingredient:
Clozapine 200 mg;  ;  ;  
Available from:
Douglas Pharmaceuticals Limited
INN (International Name):
Clozapine 200 mg
Dosage:
200 mg
Pharmaceutical form:
Tablet
Composition:
Active: Clozapine 200 mg       Excipient: Lactose monohydrate Magnesium stearate Microcrystalline cellulose Povidone Purified water Sodium starch glycolate
Units in package:
Blister pack, PVC/PVDC/Al, 50 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Taizhou Xingming Pharmaceutical Co., Ltd
Therapeutic indications:
The use of clozapine is indicated in the treatment of resistant schizophrenic patients only, i.e. schizophrenic patients who are non-responsive to or intolerant of classical antipsychotics. Non-responsiveness is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two marketed antipsychotics prescribed for adequate durations. Intolerance is defined as the impossibility of achieving adequate clinical benefit with classical antipsychotic drugs because of severe and untreatable neurological adverse reactions (extrapyramidal side effects or tardive dyskinesia).
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PVDC/Al - 50 tablets - 36 months from date of manufacture stored at or below 30°C - Blister pack, PVC/PVDC/Al - 100 tablets - 36 months from date of manufacture stored at or below 30°C - Bottle, plastic, HDPE with PP tamper evident and child resistant cap - 50 tablets - 36 months from date of manufacture stored at or below 30°C - Bottle, plastic, HDPE with PP tamper evident and child resistant cap - 100 tablets - 36 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-6231c
Authorization date:
2003-06-25

Consumer Medicine Information

CLOPINE®

Clozapine

25, 50, 100 and 200 mg tablets

50 mg/mL oral suspension

What is in this leaflet

Please read this leaflet carefully before you start

taking CLOPINE.

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.

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 tablets and suspension belong 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 only used in patients with

schizophrenia for whom other antipsychotic

medicines have not worked or have caused

severe side effects.

This medicine is thought to work by correcting

the chemical imbalances in the brain, which may

cause mental illness.

Your doctor may have prescribed it for another

reason.

Ask your doctor if you have any questions about

why this medicine has been prescribed for you.

This medicine is available only with a doctor's

prescription.

There is no evidence that this medicine is

addictive.

CLOPINE 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.

Before you take CLOPINE

When you must not take it

Do not take this medicine if you have an allergy

to:

the active ingredient, clozapine

any of the other ingredients listed at the

end of this leaflet.

Symptoms of an allergic reaction to this medicine

may include:

breathing problems such as shortness of

breath, wheezing, difficulty breathing

skin rash, itching or hives

swelling of the face, lips, tongue or other

parts of the body

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 use

of a medicine.

CLOPINE can cause agranulocytosis. With this

condition, the number of white blood cells (which

are needed to fight infections) is reduced. If you

have a low white blood cell count or have had

one in the past, you must not take this medicine.

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 CLOPINE if you have or have had

any of the following medical conditions:

any blood disorder that may lower your

red blood cell or platelet count

a low white blood cell count (e.g.,

leucopenia or agranulocytosis), especially

if this was caused by medicines.

symptoms of active liver disease such as

jaundice (yellowing of the skin and eyes,

feeling sick, loss of appetite) or liver

failure

problems with your kidneys

inflammation of heart muscle

(myocarditis) or any other heart disorder

uncontrolled epilepsy (fits or seizures)

paralytic ileus, a condition where your

bowel does not work properly, and

severe constipation or obstruction

bone marrow disorder

acute mental illness caused by alcohol or

another drug.

circulatory collapse which may occur as a

result of severe shock

CLOPINE must not be given to anyone who is

unconscious or in a coma.

Do not take this medicine if the expiry date

(EXP) shown on the outer container, on the

blister strip or on the bottle has passed. Do not

use if the tablets or suspension show signs of

deterioration or if the packaging shows signs of

tampering.

If you take this medicine after the expiry date has

passed, it may not work as well or you may feel

unwell.

If you are not sure whether you should start

taking this medicine, talk to your doctor or

pharmacist.

Before you start to take it

Tell your doctor if:

1.

you have allergies to:

any other medicines

any other substances such as foods,

preservatives or dyes

2.

you have or have had any medical

conditions, especially the following:

heart disease or a family history of

heart disease or disorders

chest pain which maybe a symptom of

heart attack or inflammation of the

heath muscle.

family history of an abnormal

conduction in the heart called

‘prolongation of QT interval’

neuroleptic malignant syndrome

(NMS) - a reaction to some medicines

with a sudden increase in body

temperature, sweating, fast heart

heartbeat, muscle stiffness and

fluctuating blood pressure, which may

lead to coma

a condition called tardive dyskinesia

characterised by uncontrollable

twitching or jerking of the arms or legs

diseases of liver or kidneys or family

history of liver and kidney problems

glaucoma (raised pressure in the eye)

enlargement of the prostate or

prostate problems or difficulty

urinating

fits or epilepsy that is under control

seizures, drowsiness, fainting, muscle

weakness, which may lead to falls

diabetes

chronic constipation or abdominal

pain

large intestine diseases

stroke

anticholinergic effects -confusion and

excitement especially in the elderly

dementia

blood clots or family history of blood

clots, as medicines like these have

been associated with formation of

blood clots.

any other medical condition

Your doctor may want to take special

precautions if you have any of these

conditions.

3.

you are pregnant or are thinking of

becoming pregnant during treatment with

CLOPINE.

There is limited information on the safety of

clozapine in pregnancy. Your doctor will

discuss the risks and benefits of taking this

medicine during pregnancy.

The following symptoms may occur in

newborn babies, of mothers that have used

clozapine in the last trimester (last three

months of their pregnancy): shaking, muscle

stiffness and/or weakness, sleepiness,

agitation, breathing problems, and difficulty

in feeding. If your baby develops any of

these symptoms you may need to contact

your doctor.

4.

Make sure you use a contraceptive to

prevent pregnancy during treatment with

CLOPINE.

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 clozapine.

5.

you are breast-feeding or plan to breast-

feed.

It is recommended that you do not breast-

feed while taking CLOPINE, as clozapine may

pass into breast milk and affect your baby.

6.

you smoke and how often you have drinks

containing caffeine (e.g., coffee, tea, cola).

Nicotine and caffeine can affect the amount

of clozapine in your body. Sudden changes in

your usual smoking or coffee drinking habits

can also change the effects of this medicine.

7.

you will be in a hot environment or you do a

lot of vigorous exercise.

Clozapine may make you sweat less; causing

your body to overheat.

8.

you are lactose intolerant.

This medicine contains lactose.

Taking other medicines

Tell your doctor or pharmacist if you are taking

any other medicines, including any that you buy

without a prescription from your pharmacy,

supermarket or health food shop.

You should also tell any health professional who

is prescribing a new medication for you that you

are taking CLOPINE.

Some medicines and CLOPINE may interfere with

each other. These include:

medicines that may decrease the number

of blood cells produced by your body

other medicines for schizophrenia, mental

disorders, depression or mood swings

such as lithium, paroxetine, sertraline,

fluoxetine, citalopram, MAO inhibitors,

perazine, fluvoxamine

medicines used to treat anxiety and sleep

disturbances such as benzodiazepines

epilepsy medicines e.g. phenytoin,

carbamazepine, valproic acid

warfarin or heparin - medicines used to

prevent blood clots

strong pain killers e.g. morphine

St John's wort (Hypericum perforatum) - a

herbal remedy

antihistamines - medicines used to control

and prevent symptoms of allergies such as

hay fever

anticholinergic medicines used to relieve

stomach cramps, spasms and travel

sickness

Parkinson's disease medicines

high blood pressure medicines

medicines used to treat a fast or irregular

heartbeat e.g. digoxin

medicines used for stomach ulcers e.g.

cimetidine, omeprazole

medicines used to treat bacterial

infections e.g. erythromycin, rifampicin

medicines used to treat fungal and viral

infections.

nicotine in medicines used to help you

quit smoking e.g. nicotine patches or

chewing gum

atropine - a medicine which may be used

in some eye drops or cough preparations

adrenaline - a drug used in emergency

situations

oral contraceptives (birth-control tablets)

These medicines may be affected by CLOPINE or

may affect how well CLOPINE work. Your doctor

will advise you.

Your doctor and pharmacist may have more

information on medicines to be careful with or

avoid while taking this medicine.

How to take CLOPINE

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.

Carefully follow all directions given to you by

your doctor. Their directions 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.

How much to take

Your doctor will determine the most appropriate

dose for you.

Take CLOPINE exactly as prescribed by your

doctor.

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 exceed the prescribed dose. 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.

Swallow CLOPINE tablets with a full glass of

water or other liquid.

CLOPINE suspension may be taken alone or in

water if required.

When to take it

Take your medicine at about the same time each

day.

Taking your tablets or suspension at the same

time each day will have the best effect. It will also

help you to remember when to take the

medicine.

It does not matter if you take this medicine

before or after food.

If you forget to take it

If 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 your medicine as you would

normally.

If you miss a dose of CLOPINE, do not take a

double dose to make up for the missed dose.

If you have stopped taking CLOPINE 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 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.

How long to take it

Take this medicine until your doctor tells you to

stop. Your doctor will check your progress and

decide how long to continue your treatment. 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.

Do not lower the dosage, even if you are feeling

better, unless your doctor tells you to do so.

Your condition may worsen if you suddenly stop

taking it. Your doctor will gradually reduce the

amount you take each day before stopping the

medicine completely.

Do not let yourself run out of over the weekend

or on holidays.

If you have any concerns, talk to your doctor.

While you are taking CLOPINE

Things you must do

You must have strict and regular blood tests

while taking this medicine. 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. Severe cases of agranulocytosis have

resulted in deaths. Only regular blood tests can

tell the doctor if you are at risk of

agranulocytosis. Therefore, agranulocytosis can

be detected early, and if this medicine is stopped

as soon as possible, the white blood cell numbers

should return to normal.

After starting on this medicine, 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

once a month for as long as you are taking this

medicine, and for one month after stopping.

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 (e.g. twice a

week). Your doctor will talk to you about this.

If the number of your white blood cells falls

below a safe level, this medicine must be

stopped immediately and you must never take

any medicines containing clozapine again.

Other monitoring

If you suffer from diabetes (a high level of sugar

in the blood) your doctor may regularly check

your level of sugar in the blood.

Contact your doctor immediately if:

you develop a fast or irregular heartbeat

that is present even when you are resting,

accompanied by rapid breathing,

shortness of breath, dizziness or light

headedness, or chest pain. These

symptoms could be signs of myocarditis,

an inflammation of the heart muscle, or

another heart condition.

you have muscle weakness, fever, fast or

irregular heartbeat and excessive

sweating. These are symptoms of a very

rare condition called Neuroleptic

Malignant Syndrome (NMS) - a reaction to

some medicines, which can cause a

sudden increase in body temperature.

you have uncontrolled movements of the

tongue, jaw (such as puffing at the

cheeks, chewing movements, puckering

of the mouth), face and mouth. These are

symptoms of a very rare condition called

tardive dyskinesia - a condition more likely

to happen during long term treatment,

especially in older women.

you develop a sore throat, mouth ulcers,

fever, any "flu-like" symptoms such as

swollen glands or other signs of infection

as these symptoms may be an early sign

of agranulocytosis. Flu-like symptoms may

also be a sign of myocarditis.

If you become pregnant while taking this

medicine, tell your doctor immediately.

Be sure to keep all of your doctor's

appointments so that your progress can be

checked.

Tell any other doctors, dentists, and pharmacists

who are treating you that you are taking

CLOPINE or if you are about to be started on any

new medicines or if you plan to have surgery

Things you must not do

Do not give the medicine to anyone else even if

their symptoms seem similar or they have the

same condition as you.

Do not take this medicine to treat any other

complaints unless your doctor tells you to.

You might get withdrawal reactions if you stop

CLOPINE abruptly such as sweating, headache,

nausea (feeling sick), vomiting (being sick) and

diarrhoea. Those signs may be followed by more

serious side effect so do not stop taking CLOPINE

without asking your doctor.

Things to be careful of

Be careful driving or operating machinery until

you know how this medicine affects you. You

may feel tired, drowsy, dizzy or you may feel faint

while taking this medicine, especially during the

early stages of treatment. If you have any of

these symptoms, do not drive, operate

machinery or do any tasks where you need to be

alert.

If the tablets or suspension make you feel dizzy,

light-headed or faint, be careful when getting up

from a sitting or lying position. This medicine

may lower your blood pressure, especially at the

start of treatment. Getting up slowly and flexing

leg muscles and toes to get the blood circulating

can usually prevent these symptoms. When

getting out of bed, dangle your legs over the side

for a minute or two before standing up.

Be careful when drinking alcohol or when taking

antihistamines (medicines used for hay fever,

allergies or colds), sleeping tablets or tablets to

relieve pain while taking this medicine.

Clozapine can increase drowsiness caused by

alcohol and by medicines affecting your nervous

system.

Clozapine may cause weight gain or affect your

blood lipid levels. Your doctor may monitor your

weight and blood lipid levels.

Tell your doctor if you will be in a hot

environment or you do a lot of vigorous

exercise. Clozapine 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 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.

In case of overdose

If you take too much (overdose)

Immediately telephone your doctor or the

National Poisons Centre (telephone 0800 POISON

or 0800 764 766), or go to accident and

emergency at your nearest hospital, if you think

that you or anyone else may have taken too

much CLOPINE.

The most common signs and symptoms of

clozapine overdose include drowsiness, confusion

and coma; light-headedness; shallow breathing or

breathing more slowly; fast or irregular heartbeat

and dribbling. Occasionally, fits have also been

reported

Side effects

Tell your doctor or pharmacist as soon as possible

if you do not feel well while you are using

CLOPINE.

All medicines can have side effects. Sometimes

they are serious, most of the time they are not.

You may need medical treatment if you get some

of the adverse effects.

If you are over 60 years old, you may have an

increased chance of getting side effects. You may

be more likely to get some of the side effects of

clozapine, 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

adverse 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 and they worry you:

Very common (affects more than 1 in 10 people):

tiredness and drowsiness

dizziness, fainting, light-headedness

constipation (if it seems to be getting

worse, check with your doctor

immediately)

excessive saliva

fast heartbeat

Common (affects up to 1 in 10 people):

nausea, vomiting

headache

dry mouth

weight gain

blurred vision

tremor, stiffness, restlessness

increased or decreased sweating

high blood pressure

faintness or light-headedness after

changing position

problems in passing or holding urine

changes in the way your body reacts to

temperature changes

speech disorders (e.g. slurred speech)

changes in ECG heart machine

abnormalities in liver function tests

High level of white blood cells

(leukocytosis), high level of a specific type

of white blood cell (eosinophilia)

Uncommon (affects up to 1 in 100 people):

lack of white blood cells (agranulocytosis)

speech disorders (e.g. stuttering)

falls

Rare (affects up to 1 in 1,000 people):

low level of red blood cells (anaemia)

high level of sugar in the blood, diabetes

mellitus

restlessness, agitation

confusion, delirium

difficulty in swallowing

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

abdominal discomfort, heartburn

swelling of the glands in the cheeks

very high levels of triglycerides or

cholesterol in the blood

obsessive thoughts and compulsive

repetitive behaviours

Other side effects

skin reactions, including rash or itching

profuse sweating, headache, nausea,

vomiting and diarrhoea

irresistible urge to move your legs or

arms, usually accompanied by

uncomfortable sensations during periods

of rest, especially in the evening or at

night and temporarily relieved by

movement (restless legs syndrome)

symptoms of low blood pressure such as

light-headedness, dizziness, fainting,

blurred vision, unusual fatigue, cold and

clammy skin or nausea

stuffy nose

diarrhoea, abdominal discomfort,

heartburn

muscle pain

night-time bedwetting

ejaculatory disorder if you are a male

skin discolouration

If any of the following happen, tell your doctor

immediately or go to your nearest Accident &

Emergency department or clinic:

Very common (affects more than 1 in 10 people):

constipation is very common, however,

tell your doctor immediately if you have

severe constipation. Your doctor will have

to treat this in order to avoid further

complications

Common (affects up to 1 in 10 people):

if you get signs of a cold, fever, flu-like

symptoms, sore throat or any other

infection. You will have to have an urgent

blood test to check if your symptoms are

related to your CLOPINE.

if you experience seizures (fits).

Uncommon (affects up to 1 in 100 people):

if you have a sudden rapid increase in

body temperature, rigid muscles which

may lead to unconsciousness (neuroleptic

malignant syndrome) as you may be

experiencing a serious side effect which

requires immediate treatment

sore throat, mouth ulcers, fever, any "flu-

like" symptoms such as swollen glands or

other signs of infection as these

symptoms may be an early sign of

agranulocytosis.

Rare (affects up to 1 in 1,000 people):

if you get signs of a respiratory tract

infection or pneumonia such as fever,

coughing, difficulty breathing, wheezing.

if you experience nausea (feeling sick),

vomiting (being sick) and/or loss of

appetite. Your doctor will need to check

your liver.

if you have fast and irregular heartbeat,

even when you are at rest, palpitations,

breathing problems, chest pain or

unexplained tiredness. Your doctor will

need to check your heart and if necessary,

refer you to a cardiologist immediately.

signs of loss of blood sugar control such as

excessive thirst, passing large amounts of

urine, dry mouth and skin

if you get signs of blood clots in the veins

especially in the legs (symptoms include

swelling, pain and redness in the leg),

which may travel through blood vessels to

the lungs causing chest pain and difficulty

in breathing.

signs of becoming obese or increasing

obesity

develop a fast or irregular heartbeat that

is present even when you are resting,

accompanied by rapid breathing,

shortness of breath, dizziness or light

headedness, or chest pain. These

symptoms could be signs of myocarditis,

an inflammation of the heart muscle, or

another heart condition.

interruption in breathing with or without

snoring during sleep

signs of a respiratory tract infection or

pneumonia such as fever, coughing,

difficulty breathing, wheezing.

severe, burning, upper abdominal pain,

extending to the back accompanied by

nausea and vomiting due to inflammation

of the pancreas

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

if you are a man and experience

persistent painful erection of the penis.

This is called priapism. If you have an

erection which lasts more than 4 hours

immediate medical treatment may be

needed in order to avoid further

complications.

spontaneous bleeding or bruising, which

might be signs of a decrease in numbers

of blood platelets.

abdominal pain, cramping, swollen

abdomen, vomiting, constipation and

failure to pass gas which may be signs and

symptoms of bowel obstruction.

loss of appetite, swollen abdomen,

abdominal pain, yellowing of the skin,

severe weakness and malaise. These

symptoms may be signs that you are

starting to develop a liver disorder.

nausea, vomiting, fatigue, weight loss

which may be symptoms of inflammation

of the kidney

if you have uncontrolled movements of

the tongue, jaw (such as puffing at the

cheeks, chewing movements, puckering of

the mouth), face and mouth.

These are serious side effects. You may need

urgent medical treatment.

Other side effects not listed above may occur in

some patients. Tell your doctor or pharmacist if

you notice anything else that is making you

unwell.

After taking CLOPINE

Storage

Keep your medicine in the original container

until it is time to take them.

If you take the tablets or suspension out of the

original container they will not keep well.

Keep your tablets in a cool dry place away from

light where the temperature stays at or below

30°C.

Keep your suspension in a cool dry place away

from light where the temperature stays at or

below 25°C.

Heat and dampness can destroy medicines, so do

not store CLOPINE in the bathroom or near a sink.

Do not leave it in the car or on a windowsill.

As with all medicines, you should store them out

of the reach of children. A locked cupboard at

least one-and-a-half metres above the ground is a

good place to store medicines.

Discard any remaining suspension 3 months

after opening.

Disposal

If your doctor tells you to stop taking this

medicine or they have passed their expiry date,

ask your pharmacist what to do with any that

are left over.

Product description

What it looks like

CLOPINE 25 – 25 mg tablets are small, round,

yellow tablets with "25" embossed over a

breakline on one face, the other side is plain.

CLOPINE 50 – 50 mg tablets are small, round,

yellow tablets with "50" embossed over a

breakline on one face, the other side is plain.

CLOPINE 100 – 100 mg tablets are small, round,

yellow tablets with "100", embossed over a

breakline on one face, the other side is plain.

CLOPINE 200 – 200 mg tablets are oval shaped

yellow tablets with "200" embossed on one side

and a breakline on the other side.

CLOPINE 50 mg/mL - a free flowing yellow

suspension.

Pack Sizes:

Not all pack sizes may be marketed.

CLOPINE tablets come in packs of 50 or 100

tablets.

CLOPINE 50 mg/mL Suspension is available in a

bottle containing 100 mL.

Your doctor will determine the quantity provided

to you by the pharmacy.

Ingredients

Active ingredient(s)

clozapine

Inactive ingredients

Tablets:

povidone, microcrystalline cellulose, lactose

monohydrate, sodium starch glycollate,

magnesium stearate.

Suspension:

glycerol, hydrochloric acid, monobasic sodium

phosphate dihydrate, povidone, purified water,

sodium hydroxide, sodium methyl

hydroxybenzoate, sodium propyl

hydroxybenzoate, sorbitol, xanthan gum.

Sponsor details

CLOPINE is supplied in New Zealand by:

Douglas Pharmaceuticals Ltd

P O Box 45 027

Auckland 0651

New Zealand

Phone: (09) 835 0660

Date of preparation

15 June 2020

(based on data sheet dated 07 May 2020)

1

| P a g e

New Zealand Data Sheet

Clopine® can cause agranulocytosis. Its use should be limited to patients:

with schizophrenia who are non-responsive to or intolerant of classical antipsychotic

agents, or with schizophrenia or schizoaffective disorder who are at risk of recurrent

suicidal behaviour (see section 4.1),

who have initially normal leukocyte findings (white blood cell count (WBC) ≥ 3500/mm

(3.5 x 10

/L), and absolute neutrophil counts (ANC) ≥ 2000/mm

(2.0 x 10

/L)),

and in whom regular white blood cell counts and absolute neutrophil counts can be

performed as follows: weekly during the first 18 weeks of therapy, and at least every 4

weeks

thereafter

throughout

treatment.

Monitoring

must

continue

throughout

treatment and for 4 weeks after complete discontinuation of Clopine (see section 4.4).

Prescribing physicians should comply fully with the required safety measures. At each

consultation, a patient receiving Clopine 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 a sore throat and to other evidence of

infection, which may be indicative of neutropenia (see section 4.4). Close monitoring of

bowel

habits

also

recommended

signs

constipation

gastrointestinal

hypomotility.

Clopine must be prescribed and dispensed in accordance with appropriate local guidelines.

The following conditions apply to the sale, supply and use of Clopine in New Zealand under

the consent notice from Medsafe. Douglas draws prescribers, nurses and patients’ attention

to the following criteria:

Clozapine may only be initiated and prescribed by:

Registered medical practitioners as defined in the Health Practitioners Competence

Assurance Act 2003 who are certified by the Medical Council of New Zealand as

competent in the scope of practice of psychiatry (i.e. psychiatrist);

Medical practitioners employed as registrars in the branch of psychiatry who are under

the supervision of the persons referred to above;

Medical officers who:

are in the employment of a District Health Board; and

are under the supervision of persons who are registered medical practitioners as

defined in the Health Practitioners Competence Assurance Act 2003 who are

certified by the Medical Council of New Zealand as competent in the scope of

practice of psychiatry.

Clozapine prescription may only be continued by:

Registered medical practitioners as defined in the Health Practitioners Competence

Assurance Act 2003 who are registered with the Medical Council of New Zealand within

the vocational scope of practice of general practice. The general practitioner can

continue the prescribing of clozapine for a specific patient whose illness is well-

controlled in collaboration, or following consultation, with the relevant community

mental health service.

2

| P a g e

Due to the risk of agranulocytosis, all patients prescribed Clopine in New Zealand must be

registered to ClopineCentral™, the Clopine Monitoring System by a registered medical

practitioner.

Additionally,

prescribing physicians

must

also

register themselves

onto

ClopineCentral™

access

patient

information.

Brand

swapping

between

clozapine

products is discouraged and should occur on the advice of a clinician.

Prescribers and dispensers should verify that the patient has not previously developed an

adverse reaction to clozapine that contraindicates further use of any clozapine containing

product.

Clozapine is associated with an increased risk of myocarditis which has, in rare cases, been

fatal. The increased risk of myocarditis is greatest in the first two months of treatment. Fatal

cases of cardiomyopathy have also been reported rarely. Myocarditis and cardiomyopathy

should be suspected in patients who experience persistent tachycardia at rest especially in

the first two months of treatment and/or palpitations, arrhythmias, chest pain and other

signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea) or

symptoms that mimic myocardial infarction. If myocarditis or cardiomyopathy is suspected,

Clopine treatment should promptly be stopped and the patient immediately referred to a

cardiologist.

1.

PRODUCT NAME

Clopine® 25 mg tablet

Clopine® 50 mg tablet

Clopine® 100 mg tablet

Clopine® 200 mg tablet

Clopine® 50 mg/mL oral suspension

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Clopine 25 mg tablet contains 25 mg of clozapine

Each Clopine 50 mg tablet contains 50 mg of clozapine

Each Clopine 100 mg tablet contains 100 mg of clozapine

Each Clopine 200 mg tablet contains 200 mg of clozapine

Each 1 mL of Clopine 50 mg/mL oral suspension contains 50 mg of clozapine

Excipient(s) with known effects

Clopine

tablets

contain

lactose.

Clopine

suspension

contains

sorbitol

hydroxybenzoates. For a full list of excipients, see section 6.1.

3

| P a g e

3.

PHARMACEUTICAL FORM

The tablet can be divided into equal doses using the break line.

Clopine 25 mg tablets are round yellow flat bevel-edged tablets engraved "25" over a

pressure sensitive break line on one face, the other face plain.

Clopine 50 mg tablets are round yellow flat bevel-edged tablets engraved "50" over a

pressure sensitive break line on one face, the other face plain.

Clopine 100 mg tablets are round yellow flat bevel-edged tablets engraved "100" over a

pressure sensitive break line on one face, the other face plain.

Clopine 200 mg tablets are oval shaped, yellow tablets engraved "200" on one face, and

a pressure sensitive break line on the other face.

Clopine 50 mg/mL oral suspension is a free-flowing yellow suspension.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

Treatment-resistant schizophrenia.

Clopine is indicated in patients with treatment-resistant schizophrenia, i.e. patients with

schizophrenia who are non-responsive to or intolerant of classic antipsychotics.

Non-responsiveness is defined as a lack of satisfactory clinical improvement despite the

use of adequate doses of at least two marketed antipsychotics prescribed for adequate

durations.

Intolerance is defined as the impossibility of achieving adequate clinical benefit with

classic antipsychotics because of severe and untreatable neurological adverse reactions

(extrapyramidal side effects or tardive dyskinesia).

Clopine tablets and Suspension are only indicated in patients aged 16 years and above.

4.2.

Dose and method of administration

Brand swapping between clozapine products is discouraged and should only occur on the

advice of a clinician.

Dose

The dosage must be adjusted individually. For each patient, the lowest effective dose

should be used. Cautious titration and a divided dosage schedule are necessary to

minimise the risks of hypotension, seizure, and sedation.

Initiation of clozapine treatment must be restricted to those patients with a white blood

cell (WBC) count ≥ 3500/mm³ (3.5 x 10

/L) and an absolute neutrophil count (ANC) ≥

2000/mm³ (2.0 x 10

/L) and within standardised normal limits.

Dose adjustment is indicated in patients who are also receiving medicinal products that

have pharmacokinetic interactions with clozapine, such as benzodiazepines or selective

serotonin reuptake inhibitors (see section 4.5).

4

| P a g e

In patients with a history of seizures or suffering from renal or cardiovascular disorders

(note: severe renal or cardiovascular disorders are contraindications) the initial dose

should be 12.5 mg given once on the first day, and dosage increase should be slow and in

small increments.

Switching from a previous antipsychotic therapy to Clopine

It is generally recommended that clozapine should not be used in combination with other

antipsychotics. When clozapine therapy is to be initiated in a patient undergoing oral

antipsychotic therapy, it is recommended that the dosage of other antipsychotics be

reduced or discontinued by gradually tapering it downwards. Based on the clinical

circumstances, the prescribing physician should judge whether or not to discontinue the

other antipsychotic therapy before initiating treatment with Clopine.

Treatment-resistant schizophrenia

Starting therapy Clopine should be started with 12.5 mg once or twice on the first day,

followed by 25 mg to 50 mg on the second day. If well tolerated, the daily dose may then

be increased slowly in increments of 25 mg 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 mg to 100 mg at

half-weekly

preferably,

weekly

intervals.

Therapeutic dose range

In most patients, antipsychotic efficacy can be expected with 200 to 450 mg/day given in

divided doses. Some patients may be treated with lower doses, and some patients may

require doses up to 600 mg/day. The total daily dose may be divided unevenly, with the

larger portion being taken at bedtime.

Maximum dose

To obtain a full therapeutic benefit, a few patients may require larger doses, in which case

judicious increments (not exceeding 100 mg) are permissible up to 900 mg/day. The

possibility of increased adverse reactions (in particular seizures) occurring at doses over

450 mg/day must be borne in mind.

Maintenance dose

After achieving maximum therapeutic benefit, patients can be maintained effectively on

lower doses.

Careful

downward titration

therefore

recommended to

lowest

effective dose for the individual patient. Treatment should be maintained for at least 6

months. If the daily dose does not exceed 200 mg, once daily administration in the

evening may be appropriate.

Ending therapy

In the event of planned termination of Clopine therapy, a gradual reduction in dose over

a 1- to 2-week period 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 4.4).

5

| P a g e

Re-starting therapy

In patients in whom the interval since the last dose of Clopine exceeds 2 days, treatment

should be reinitiated with 12.5 mg given once or twice on the first day. If this dose is well

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) , but was then

able to be successfully titrated to a therapeutic dose, re-titration should be done with

extreme caution.

Special populations

Cardiovascular disorders

In patients suffering from cardiovascular disorders (note: severe cardiovascular disorders

are contraindications, see section 4.3) the initial dose should be 12.5 mg given once on

the first day, and dosage increase should be slow and in small increments.

Renal impairment

In patients with mild to moderate renal impairment the initial dose should be 12.5 mg

given once on the first day, and dosage increase should be slow and in small increments.

Hepatic impairment

Patients with hepatic impairment should receive Clopine with caution along with regular

monitoring of liver function tests (see section 4.4).

Patients 60 years of age and older

It is recommended that treatment in patients 60 years and older is initiated at a

particularly low dose (12.5 mg given once on the first day) with subsequent dose

increments restricted to 25 mg/day.

Clopine is not approved for the treatment of dementia-related behavioural disturbances

(see section 4.4).

Paediatric population

No paediatric studies have been performed.

Children and adolescents

The safety and efficacy of clozapine in children and adolescents up to 16-years of age have

not been established.

Method of Administration

Clopine is administered orally.

4.3.

Contraindications

Known hypersensitivity to clozapine or to any of the excipients of Clopine (see section

6.1).

Patients unable to undergo regular blood tests.

History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception

of granulocytopenia/agranulocytosis from previous chemotherapy).

6

| P a g e

Drug induced agranulocytosis

Impaired bone marrow function.

Uncontrolled epilepsy.

Alcoholic and other toxic psychoses, drug intoxication, comatose conditions.

Circulatory collapse and/or CNS depression of any cause.

Severe renal or cardiac disorders (e.g. myocarditis).

Active liver disease associated with nausea, anorexia or jaundice; progressive liver

disease, hepatic failure.

Paralytic ileus.

4.4.

Special warnings and precautions for use

Agranulocytosis

Prescribers and dispensers should verify that the patient has not previously developed an

adverse reaction to clozapine that contraindicates further use of any clozapine containing

product.

Because of the association of clozapine with agranulocytosis, the following precautionary

measures are mandatory:

Medicines known to have a substantial potential to depress bone marrow function should

not be used concurrently with Clopine. In addition, the concomitant use of long-acting

depot antipsychotics should be avoided because of the impossibility of removing these

medications, which may be potentially myelosuppressive, from the body rapidly in

situations where this may be required, e.g. granulocytopenia.

Patients with a history of primary bone marrow disorders may be treated only if the

benefit outweighs the risk. They should be carefully reviewed by a haematologist prior to

starting Clopine.

Patients

have

white

blood

cell

(WBC)

counts

because

benign

ethnic

neutropenia should be given special consideration and may be started on Clopine after

agreement of a haematologist.

Clopine must be dispensed under strict medical supervision in accordance with official

recommendations.

White Blood Cell (WBC) counts and Absolute Neutrophil Count (ANC) monitoring

White blood cell (WBC) and differential blood counts must be performed within 10 days

prior to starting Clopinetreatment to ensure that only patients with normal leukocyte and

absolute neutrophil counts (WBC ≥ 3500/mm

(≥ 3.5 x 10

/L) and ANC ≥ 2000/mm

(≥ 2.0

x 10

/L)) will receive Clopine. After the start of Clopine treatment, regular WBC count and

ANC must be performed and monitored weekly for 18 weeks, and thereafter at least every

four weeks throughout treatment, and for 4 weeks after complete discontinuation of

Clopine.

Prescribing physicians should comply fully with the required safety measures. At each

consultation,

patient

should

reminded

contact

treating

physician

immediately if any kind of infection begins to develop. Particular attention should be paid

to flu-like complaints such as fever, or a sore throat and to other evidence of infection,

7

| P a g e

which may be indicative of neutropenia. A differential blood count must be performed

immediately if any symptoms or signs of an infection occur.

Low WBC count and/or ANC

If during Clopinetherapy, either the WBC count falls to between 3500/mm

(3.5 x 10

and 3000/mm

(3.0 x 10

/L) or the ANC falls to between 2000/mm

(2.0 x 10

/L) and

1500/mm

(1.5 x 10

/L), haematological evaluations must be performed at least twice

weekly until the patients WBC count and ANC stabilise within the range 3000 – 3500 /

(3.0 – 3.5 x 10

/L) and 1500 – 2000/mm

(1.5 – 2.0 x 10

/L), respectively, or higher.

In addition, if, during Clopine therapy, the WBC count is found to have dropped by a

substantial amount from baseline, a repeat WBC count and a differential blood count

should be performed.

A substantial drop is defined as a single drop of 3000 mm

(3.0 x 10

/L) or more in the

WBC count or a cumulative drop of 3000 mm

(3.0 x 10

/L) or more within three weeks.

Immediate

discontinuation

Clopine

mandatory

if the

count

less

than

3000/mm

(3.0 x 10

/L) or the ANC is less than 1500/mm

(1.5 x 10

/L). 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 Clopine, haematological evaluation is required until haematological

recovery has occurred.

If Clopine has been withdrawn and WBC count falls further to below 2000/mm

(2.0 x

/L) and/or the ANC falls below 1000/mm

(1.0 x 10

/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 and the

administration of GM-CSF (granulocyte-macrophage colony stimulating factor) or G-CSF

(granulocyte colony stimulating factor) may be indicated. It is recommended that the

colony stimulating factor therapy to be discontinued when the neutrophil count has

returned to a level above 1000/mm

(1.0 x 10

/L).

Patients in whom Clopine has been discontinued as a result of white blood cell deficiencies

(see above) must not be re-exposed to Clopine.

It is recommended that the haematological values be confirmed by performing two blood

counts on two consecutive days; however, Clopine should be discontinued after the first

blood count.

Table 1: Blood monitoring during Clopine therapy

Blood cell count

Action required

WBC/mm

3

(/L)

ANC/mm

3

(/L)

≥ 3500 (≥ 3.5 x 10

≥ 2000 (≥ 2.0 x 10

Continue Clopine treatment.

Between ≥ 3000 and < 3500

(≥ 3.0 and < 3.5 x 10

Between ≥ 1500 and < 2000

(≥ 1.5 x 10

and < 2.0 x 10

Continue

Clopine

treatment,

sample

blood

twice

weekly

until

counts

stabilise

increase.

< 3000 (< 3.0 x 10

< 1500 (< 1.5 x 10

Immediately

stop

Clopine

treatment, sample blood daily

8

| P a g e

(<3.0 x 10

(<1.5 x 10

until

haematological

abnormality

resolved,

monitor for infection. Do not

re-expose the patient.

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

Patients who have been on Clopine 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 Clopine

treatment has been interrupted for 4 weeks or longer, weekly monitoring is required for

the next 18 weeks of treatment, see section 4.2.

Other precautions

Eosinophilia

In the event of eosinophilia, discontinuation of Clopine is recommended if the eosinophil

count rises above 3000/mm

(3.0 x 10

/L). Therapy should be re-started only after the

eosinophil count has fallen below 1000/mm

(1.0 x 10

/L).

Thrombocytopenia

In the event of thrombocytopenia, discontinuation of Clopine is recommended if the

platelet count falls below 50 000/mm

(50.0 x 10

/L).

Cardiovascular disorders

In patients suffering from cardiovascular disorders (note: severe cardiovascular disorders

are contraindications, see section 4.3) the initial dose should be 12.5 mg given once on

the first day, and dosage increase should be slow and in small increments (see section 4.2).

Orthostatic hypotension

Orthostatic hypotension, with or without syncope, can occur during clozapine treatment.

Rarely (about one case per 3,000 clozapine-treated patients), collapse can be profound

and may be accompanied by cardiac and/or respiratory arrest. Such events are more likely

to occur during initial titration in association with rapid dose escalation; on very rare

occasions they occurred even after the first dose. Therefore, patients commencing

Clopinetreatment require close medical supervision.

Myocarditis and cardiomyopathy

Tachycardia that persists at rest, accompanied by arrhythmias, shortness of breath or

signs and symptoms of heart failure, may rarely occur during the first month of treatment

and very rarely thereafter. The occurrence of these signs and symptoms necessitates an

urgent diagnostic evaluation for myocarditis, especially during the titration period.

Therefore, the possibility of myocarditis should be considered in patients receiving

Clopine who present with unexplained fatigue, dyspnoea, tachypnoea, fever, chest pain,

tachycardia, palpitations, other signs and symptoms of heart failure, ECG changes (such

as ST-T wave abnormalities) or arrhythmias. It is not known whether eosinophilia is a

reliable predictor of myocarditis. The incidence of myocarditis reported globally is rare

(<0.1%) during the first month of therapy and very rare (<0.01%) thereafter. Some cases

9

| P a g e

of myocarditis have been reported to be fatal (incidence approximately 0.2 cases/100,000

patient years). Most reported cases of myocarditis have occurred in the first month of

therapy, therefore there should be a high index of suspicion in the first 6-8 weeks of

therapy.

If the diagnosis of myocarditis is confirmed, Clopine should be discontinued. There have

been post-marketing reports of myocarditis including fatal cases. Later in treatment, the

same signs and symptoms may very rarely occur and may be linked to cardiomyopathy.

Further

investigation

should

performed

diagnosis

confirmed,

treatment should be stopped unless the benefit clearly outweighs the risk to the patient.

If patients are diagnosed with cardiomyopathy while on Clopine 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).

Monitoring of standing and supine blood pressure is necessary during the first weeks of

treatment in patients with Parkinson’s disease.

Patients with clozapine-induced myocarditis or cardiomyopathy should not be re-exposed

to Clopine.

Myocardial infarction

In addition, there have been post-marketing reports of myocardial infarction including

fatal cases. Causality assessment was difficult in the majority of these cases because of

serious pre-existing cardiac disease and plausible alternative causes.

Seizures

Clozapine may lower seizure threshold. In patients with a history of seizures, the initial

dose should be 12.5 mg given once on the first day, and dosage increase should be slow

and in small increments (see section 4.2).

Anticholinergic effects

Clozapine exerts anticholinergic activity, which may produce adverse effects throughout

the body. Careful supervision is indicated in the presence of prostatic enlargement and

narrow-angle glaucoma.

Gastrointestinal hypomotility and constipation

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

intestinal

infarction/ischaemia (see section 4.8). On rare occasions these cases have proved fatal.

Since complications have been associated with delayed diagnosis, patients should be

questioned about their bowel habits. Careful monitoring during treatment with clozapine

identify

early,

onset

constipation,

followed

effective

management

constipation are recommended to prevent complications.

Particular care is necessary in patients who are receiving concomitant medications known

to cause constipation (especially those with anticholinergic properties such as some

antipsychotics,

antidepressants

antiparkinsonian treatments), have

history

1 0

| P a g e

colonic disease or a history of lower abdominal surgery as these may exacerbate the

situation. It is vital that constipation is recognised, and actively treated. The risk for

constipation may be greater with higher levels of clozapine. Prophylactic treatment with

laxatives may be considered for patients at high risk for constipation or who may not be

able to adequately describe symptoms of constipation”.

Fever

During Clopine therapy, patients may experience transient temperature elevations above

38°C, with the peak incidence within the first 3 weeks of treatment. This fever is generally

benign. Occasionally, it may be associated with an increase or decrease in the WBC count.

Patients with fever should be carefully evaluated to rule out the possibility of an

underlying infection or the development of agranulocytosis. In the presence of high fever,

the possibility of neuroleptic malignant syndrome (NMS) must be considered.

Neuroleptic Malignant Syndrome (NMS)

If the diagnosis of NMS is confirmed, Clopine should be discontinued immediately and

appropriate medical measures should be administered.

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.

Metabolic changes

Atypical antipsychotic drugs, including clozapine, have been associated with metabolic

changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes

include

hyperglycaemia,

dyslipidemia,

body

weight

gain.

While

atypical

antipsychotic drugs may produce some metabolic changes, each drug in the class has its

own specific risk profile.

Hyperglycaemia and Diabetes Mellitus

Hyperglycaemia,

some

cases

extreme

associated

with

ketoacidosis

hyperosmolar coma or death, has been reported in patients 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 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 studied. Precise risk estimates for hyperglycaemia-related adverse

events in patients treated with atypical antipsychotics are not available. The available data

are insufficient to provide reliable estimates of differences in hyperglycaemia related

adverse event risk among the marketed atypical antipsychotics. Glucose levels returned

1 1

| P a g e

to normal in most patients after discontinuation of clozapine, and re-challenge produced

a recurrence of hyperglycaemia in a few cases.

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 baseline and periodically during treatment. Any patient treated with atypical

antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia,

polyuria, polyphagia, or 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 Clopine should be considered.

There is a risk of altering the metabolic balance resulting in slight impairment of glucose

homoeostasis 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 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.

Risk of thromboembolism

Since clozapine may cause sedation and weight gain, thereby increasing the risk of

thromboembolism, immobilisation of patients should be avoided.

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. Clopine should be used with caution in patients with risk factors for stroke.

Prolongation of QT interval

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 Clopine is prescribed with

medicines known to increase the QTc interval.

Parkinson’s Disease

1 2

| P a g e

Physicians should weigh the risks versus the benefits when prescribing clozapine to

patients with Parkinson’s Disease or dementia with Lewy Bodies (DLB) since both groups

may be at increased risk of Neuroleptic Malignant Syndrome as well as having an

increased sensitivity to antipsychotics. Manifestation of this increased sensitivity can

include confusion, obtundation, postural instability with frequent falls, in addition to

extrapyramidal symptoms.

Suicide

The possibility of a suicide attempt is inherent in schizophrenia and close supervision of

high-risk patients should accompany therapy.

Smoking

Stopping or starting smoking (but not nicotine replacement therapy or vaping) affects the

plasma concentration of clozapine (see section 4.5).

Special populations

Hepatic impairment

Patients with stable pre-existing liver disorders may receive Clopine but must undergo

regular liver function tests. Such tests should be performed immediately in patients who

develop symptoms of possible liver dysfunction such as nausea, vomiting and/or anorexia

during Clopine treatment. If the elevation of the values is clinically relevant or if symptoms

of jaundice occur, treatment with Clopine must be discontinued. It may be resumed (see

section 4.2) only when the results of liver function tests are normal. In such cases, liver

function should be closely monitored after re-introduction of Clopine.

Renal impairment

patients

suffering

from

mild

moderate

renal

impairment,

initial

dose

12.5 mg/day (half a 25 mg tablet) is recommended (see section 4.2).

Patients aged 60 years and older

It is recommended that treatment be initiated at a particularly low dose (12.5 mg given

once on the first day) and subsequent dose increments be restricted to 25 mg/day.

Clinical studies with clozapine did not include sufficient numbers of subjects aged 60 years

and over to determine whether or not they respond differently from younger subjects.

Orthostatic hypotension can occur with clozapine treatment and there have been rare

reports of tachycardia, which may be sustained, in patients taking Clopine. Patients aged

60 years and over, particularly those with compromised cardiovascular function, may be

more susceptible to these effects.

Patients aged 60 years and over may also be particularly susceptible to the anticholinergic

effects of clozapine, such as urinary retention and constipation.

Patients aged 60 years and older with Dementia-related Psychosis

In patients aged 60 years and over with dementia-related psychosis, the efficacy and

safety of clozapine have not been studied. Observational studies suggest that patients

aged 60 years and over with dementia-related psychosis treated with antipsychotic drugs

1 3

| P a g e

are at an increased risk of death. In the published literature, risk factors that may

predispose

this

patient

population

increased

risk

death

when

treated

with

antipsychotics

include

sedation,

presence

cardiac

conditions

(e.g.

cardiac

arrhythmias) or pulmonary conditions (e.g. pneumonia, with or without aspiration).

Clopine is not approved for the treatment of dementia-related behavioural disturbances.

Rebound, withdrawal effects

If abrupt discontinuation of Clopine 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 such as profuse sweating, headache, nausea, vomiting and

diarrhoea.

4.5.

Interaction with other medicines and other forms of interaction

Pharmacodynamic-related Interactions

Anticipated pharmacodynamic interactions resulting in concomitant use not being

recommended

Medicinal products known to have a substantial potential to depress bone marrow

function should not be used concurrently with Clopine (see section 4.4).

As with other antipsychotics, caution should be exercised when Clopine is prescribed with

medicines known to increase the QTc interval or cause electrolyte imbalance.

Observed pharmacodynamic interactions to be considered

Particular caution is recommended when Clopine therapy is initiated in patients who are

receiving (or have recently received) a benzodiazepine or any other psychotropic agent,

as these patients may have an increased risk of circulatory collapse, which, on rare

occasions, can be profound and may lead to cardiac and/or respiratory arrest.

Concomitant

lithium

other

CNS-active

agents

increase

risk

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 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.

Anticipated pharmacodynamic interactions to be considered

Clozapine

enhance

central

effects

alcohol,

inhibitors

depressants such as narcotics, antihistamines, and benzodiazepines.

Because of the possibility of additive effects, caution is essential when substances

possessing

anticholinergic,

hypotensive,

respiratory

depressant

effects

given

concomitantly.

Owing to its anti-alpha-adrenergic properties, clozapine may reduce the blood pressure,

increasing the effect of noradrenaline, or other predominantly alpha-adrenergic agents

and reverse the pressor effect of adrenaline.

Pharmacokinetic-related Interactions

1 4

| P a g e

Clozapine is a substrate for many CYP 450 isoenzymes, in particular 1A2 and 3A4. The risk

of metabolic interactions caused by an effect on an individual isoform is therefore

minimised. Nevertheless, caution is called for in patients receiving concomitant treatment

with other substances that are either inhibitors or inducers of these enzymes.

clinically

relevant

interactions

have

been

observed

thus

with

tricyclic

antidepressants, phenothiazines or type 1C anti-arrhythmics, which are known to bind to

cytochrome P450 2D6.

Observed pharmacokinetic interactions to be considered

Concomitant administration of substances known to induce cytochrome P450 enzymes

may decrease the plasma levels of clozapine.

Substances known to induce the activity of 3A4 and with reported interactions with

clozapine include, for instance, carbamazepine, phenytoin and rifampicin.

Concomitant administration of substances known to inhibit the activity of cytochrome

P450 isozymes may increase the plasma levels of clozapine.

Substances known to inhibit the activity of the major isozymes involved in the

metabolism

clozapine

with

reported

interactions

include,

instance,

cimetidine, erythromycin (3A4), fluvoxamine (1A2), perazine (1A2), ciprofloxacin (1A2)

and oral contraceptives (1A2, 3A4, 2C19).

The plasma concentration of clozapine is increased by caffeine (1A2) intake and

decreased by nearly 50% following a 5-day caffeine-free period.

Elevated

clozapine

plasma

concentrations

also

have

been

reported

patients

receiving the substances in combination with selective serotonin re-uptake inhibitors

(SSRIs) such as paroxetine (1A2), sertraline, fluoxetine or citalopram.

Anticipated pharmacokinetic interactions to be considered

Concomitant administration of substances known to induce cytochrome P450 enzymes

may decrease the plasma levels of clozapine.

Known inducers of 1A2 include, for instance, omeprazole and tobacco smoke. In cases

of sudden cessation of tobacco smoking, the plasma clozapine concentration may be

increased, which may result in an increased risk of adverse drug reactions. Dose

reduction is strongly recommended in the first week with therapeutic monitoring and

further adjustment over the next four weeks, see local guidelines.

Concomitant administration of substances known to inhibit the activity of cytochrome

P450 isozymes may increase the plasma levels of clozapine.

Potent inhibitors of CYP3A, such as azole antimycotics and protease inhibitors, could

potentially also increase clozapine plasma concentrations; no interactions have been

reported to date, however.

4.6.

Fertility, pregnancy and lactation

Women of childbearing potential and contraceptive measures

1 5

| P a g e

Some female patients treated with antipsychotics other than clozapine may become

amenorrheic. A return to normal menstruation may occur as a result of switching from

other antipsychotics to Clopine. Adequate contraceptive measures must, therefore, be

ensured in women of childbearing potential.

Pregnancy

Reproduction studies in animals have revealed no evidence of impaired fertility or harm

to the foetus due to clozapine. However, the safe use of clozapine in pregnant women has

not been established. Therefore, Clopine should be used during pregnancy only if the

expected benefit clearly outweighs any potential risk.

Non-teratogenic effects

Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at

risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been

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

intensive care unit support and prolonged hospitalisation.

Antipsychotic drugs, including clozapine, should be used during pregnancy only if the

potential benefit justifies the potential risk to the foetus.

Breast-feeding

Animal studies suggest that clozapine is excreted in breast milk and has an effect in the

suckling offspring; therefore, mothers receiving Clopine should not breast-feed.

Fertility

No data available. For pre-clinical fertility data refer to section 5.3.

4.7.

Effects on ability to drive and use machines

Owing to the ability of clozapine to cause sedation and lower the seizure threshold,

activities such as driving or operating machinery should be avoided, especially during the

initial weeks of treatment.

4.8.

Undesirable effects

The adverse effects of clozapine are most often predictable based on its pharmacological

properties with the exception of agranulocytosis (see section 4.4).

The most serious adverse reactions experienced with clozapine are agranulocytosis,

seizure, cardiovascular effects and fever (see section 4.4). 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 (from 7.1 to 15.6%) were discontinued treatment due to an adverse

event, including only those that could be reasonably attributed to clozapine. The more

1 6

| P a g e

common

events

considered

causes

discontinuation

were

leukopenia;

somnolence; dizziness (excluding vertigo); and psychotic disorder.

Table

2:

Treatment-emergent

adverse

experience

frequency

estimate

from

spontaneous and clinical trial reports

Adverse reactions are ranked by MedDRA system organ class under headings of frequency

using the following convention: Very common (≥1/10); common (≥1/100 to <1/10);

uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000),

including isolated reports.

Blood and lymphatic system disorders

Common:

Leukopenia/decreased WBC/neutropenia,

eosinophilia,

leukocytosis

Uncommon:

Agranulocytosis

Rare:

Anaemia

Very rare:

Thrombocytopenia, thrombocythaemia

Metabolism and nutrition disorders*

Common:

Weight gain

Rare:

Impaired glucose tolerance, new onset diabetes, diabetes

aggravated, obesity

Very rare:

Ketoacidosis,

hyperosmolar

coma,

severe

hyperglycaemia,

hypercholesterolemia,

hypertriglyceridemia

Psychiatric disorders

Common:

Dysarthria

Uncommon:

Dysphemia

Rare:

Agitation, restlessness

Very rare

Obsessive compulsive symptoms

Nervous system disorders

Very common:

Drowsiness/sedation, dizziness

Common:

Headache,

tremor,

rigidity,

akathisia,

extrapyramidal

symptoms, seizures/convulsions/myoclonic jerks,

Uncommon:

Neuroleptic malignant syndrome

Rare:

Confusion, delirium

Very rare:

Tardive dyskinesia

Eye disorders

Common:

Blurred vision

1 7

| P a g e

Cardiac disorders **

Very common:

Tachycardia

Common:

ECG changes

Rare:

Circulatory

collapse,

arrhythmias,

myocarditis**,

pericarditis

Very rare:

Cardiomyopathy

Vascular disorders

Common:

Hypertension, postural hypotension, syncope

Rare:

Thromboembolism

Respiratory, thoracic and mediastinal disorders

Rare:

Aspiration of ingested food, sleep apnoea syndrome,

pneumonia and lower respiratory tract infection which

may be fatal

Very rare:

Respiratory depression/arrest

Gastrointestinal disorders

Very common:

Constipation, hypersalivation

Common:

Nausea, vomiting, dry mouth

Rare:

Dysphagia

Very rare:

Parotid

gland

enlargement,

intestinal

obstruction/

ileus/faecal impaction, abdominal discomfort, heartburn

Hepatobiliary disorders

Common:

Elevated liver enzymes

Rare:

Hepatitis, cholestatic jaundice, pancreatitis

Very rare:

Fulminant hepatic necrosis

Skin and subcutaneous tissue disorders

Very rare:

Skin reactions

Renal and urinary disorders

Common:

Urinary incontinence, urinary retention

Very rare:

Turbolointerstitialnephritis, nocturnal enuresis

Reproductive system and breast disorders

Very rare:

Priapism

General disorders and administration site conditions

Common:

Fatigue,

benign

hyperthermia,

disturbances

sweating/temperature regulation

1 8

| P a g e

Very rare:

Sudden unexplained death

Injury, poisoning and procedural complications

Uncommon:

Falls

(associated

with

clozapine-induced

seizures,

somnolence, postural hypotension, motor

and sensor instability)

Investigations

Rare:

Increased CPK

* Occasionally patients with pre-existing hyperglycaemia have had an exacerbation

**The prompt discontinuation of Clopine therapy is warranted upon suspicion of myocarditis (see

section 4.4).

Very rare events of ventricular tachycardia 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.

AEs from spontaneous reports and literature (frequency unknown)

following

post-marketing

adverse

effects

were

derived

from

experience

with

clozapine via spontaneous case reports and literature cases and have been categorised

according to MedDRA system organ class (Table 4). Because these have been reported

voluntarily from a population of uncertain size and are subject to confounding factors,

these post-marketing AEs have been categorised with a frequency of “unknown” since it

is not possible to reliably estimate their frequency. Adverse effects are listed according to

system organ classes (SOC) in MedDRA.

Within each system organ class, AEs are presented in order of decreasing seriousness.

Table 3: Adverse drug reactions from spontaneous reports and literature (frequency not

known)

Infections and infestations

Sepsis

Immune system disorders

Drug rash with eosinophilia and systemic symptoms (DRESS), angioedema,

leukocytoclastic vasculitis

Endocrine disorders

Pseudophaeochromocytoma

Nervous system disorders

Cholinergic syndrome, EEG changes, pleurothotonus, restless legs syndrome

Cardiac disorders

Myocardial infarction sometimes fatal, myocarditis sometimes fatal, chest

1 9

| P a g e

pain/angina pectoris, palpitations, atrial fibrillation, mitral valve incompetence

associated with clozapine-related cardiomyopathy

Vascular disorders

Hypotension

Respiratory, thoracic and mediastinal disorders

Pleural effusion, nasal congestion

Gastrointestinal disorders

Megacolon sometimes fatal, intestinal infarction/ischaemia sometimes fatal,

intestinal necrosis sometimes fatal, intestinal ulceration sometimes fatal,

intestinal

perforation

sometimes

fatal,

diarrhoea,

abdominal

discomfort/heartburn/dyspepsia, colitis

Hepatobiliary disorders

Hepatic steatosis, hepatic necrosis, hepatotoxicity, hepatic fibrosis, hepatic

cirrhosis,

liver

disorders

including

those

hepatic

events

leading

life-

threatening consequences such as liver injury (hepatic, cholestatic and mixed),

liver failure which may be fatal and liver transplant

Skin and subcutaneous tissue disorders

Pigmentation disorder

Musculoskeletal & connective tissue disorders

Rhabdomyolysis, muscle weakness, muscle spasms, muscle pain, systemic

lupus erythematosus

Renal and urinary disorders

Renal failure, nocturnal enuresis

Reproductive system and breast disorders

Retrograde ejaculation

General disorders and administration site conditions

Polyserositis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important.

It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

professionals

asked

report

suspected

reactions

https://nzphvc.otago.ac.nz/reporting/

4.9.

Overdose

2 0

| P a g e

In cases of acute intentional or accidental clozapine overdosage, for which information on

the outcome is available, to date, the mortality is about 12%. Most of the fatalities were

associated with cardiac failure or pneumonia caused by aspiration and occurred at doses

above 2000 mg.

There have been reports of patients recovering from an overdose in excess of 10,000 mg.

However, in a few adult individuals, 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. In young children, the intake of 50 mg to 200 mg resulted in strong

sedation or coma without being lethal.

Signs and symptoms

Drowsiness,

lethargy,

areflexia,

coma,

confusion,

hallucinations,

agitation,

delirium,

extrapyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred

vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration

pneumonia, dyspnoea, respiratory depression or failure.

Treatment

There are no specific antidotes for clozapine.

The administration of activated charcoal within the first 6 hours after Clopine ingestion.

(Peritoneal

dialysis

haemodialysis

unlikely

effective.)

Symptomatic

treatment under continuous cardiac monitoring, surveillance of respiration, establishing

and maintaining an airway, monitoring of electrolytes and acid-base balance. The use of

adrenaline should be avoided in the treatment of hypotension because of the possibility

of a reverse adrenaline effect. Close medical supervision is necessary for at least 5 days

because of the possibility of delayed reactions.

For further advice on the management of overdose please contact the National Poisons

Centre on 0800 POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties

Pharmacotherapeutic group: Antipsychotic agent (ATC code NO5A H02)

Mechanism of action

Clozapine has been shown to be an antipsychotic agent that is different from classic

antipsychotics. In pharmacological experiments, the compound does not induce catalepsy

or inhibit apomorphine- or amphetamine-induced stereotyped behaviour. It has only

weak dopamine receptor-blocking activity at D

and D

receptors, but shows high

potency for the D

receptor, in addition to potent anti-alpha-adrenergic, anticholinergic,

antihistaminic, and arousal reaction-inhibiting effects. It has also been shown to possess

antiserotoninergic properties.

Pharmacodynamic effects

Clinically clozapine produces rapid and marked sedation and exerts antipsychotic effects

in patients with schizophrenia resistant to other antipsychotic agents. In such cases,

2 1

| P a g e

Clozapine has proven effective in relieving both positive and negative schizophrenic

symptoms in short- and long-term trials

Clozapine is unique in that it produces virtually no major extrapyramidal reactions such as

acute dystonia and tardive dyskinesia. Furthermore, parkinsonian-like side effects and

akathisia are rare. In contrast to classical antipsychotics, clozapine produces little or no

prolactin elevation, thus avoiding adverse effects such as gynaecomastia, amenorrhoea,

galactorrhoea, and impotence.

Potentially serious adverse reactions caused by clozapine therapy are granulocytopenia

and agranulocytosis occurring at an estimated incidence of 3% and 0.7% respectively (see

section 4.4).

Clinical efficacy and safety

In a double-blind clinical trial performed in 319 treatment-resistant patients, clinically

relevant improvement was observed within 6 weeks in about 30% of the clozapine-

treated patients (see Clozapine Study 30 below).

Two open-label trials in which patients were treated for 12 months, showed clinically

relevant improvement in 37% of patients within the first 6 weeks of treatment and in an

additional 39%-44% of patients by the end of 12 months. The improvement was defined

as a reduction of more than 20% from baseline in Brief Psychiatric Rating Scale Score. In

addition, improvement in some aspects of cognitive dysfunction has been described.

See sections 4.4 and 4.8 for safety related information.

Clozapine Study 30

The efficacy of clozapine was evaluated in a randomized, double-blind, multicentre,

parallel group, 6- week, comparative study of clozapine versus chlorpromazine plus

benztropine.

study

population

included

treatment-resistant

schizophrenic

patients, between the ages of 18 - 60 years, who met DSM-III criteria for schizophrenia,

with a well-documented history of being refractory to treatment.

Eligible patients were randomly assigned to receive clozapine alone (up to 900 mg/day)

or chlorpromazine plus benztropine (up to 1800 mg/day of chlorpromazine, plus 6 mg/day

of benztropine).

Efficacy was assessed using the BPRS score, Clinical Global Impression (CGI) scale, and

Nurses’ Observation Scale for Inpatient Evaluation (NOSIE-30) Scale.

At the end of 6 weeks, clozapine was significantly superior to chlorpromazine in all

“Positive”, “Negative” and general symptoms of BPRS (p < 0.001) except ‘Grandiosity’ and

‘BPRS total score’. Clozapine showed a significantly superior change in CGI scale compared

chlorpromazine

starting

week

<

0.001).

Clozapine

superior

chlorpromazine on all six NOSIE-30 factors and total assets starting at either week 1 or 2

(p-value ranging from p < 0.05 to 0.001). Clozapine was statistically significant in the

following NOSIE factors, social competence, social interest and personal neatness, and

total assets (p < 0.001), as well as irritability and motor retardation (p < 0.01 and p < 0.05,

respectively).

2 2

| P a g e

In summary, superiority of clozapine was not confined to a particular aspect or dimension

of psychopathology; clozapine demonstrated broad-spectrum therapeutic effect on all

major psychotic signs and symptoms.

5.2.

Pharmacokinetic properties

Absorption

The absorption of orally administered clozapine is 90% to 95%; neither the rate nor the

extent of absorption is influenced by food. Clozapine is subject to 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), and the volume of distribution is 1.6 L/kg. Clozapine

is approximately 95% bound to plasma proteins.

Biotransformation/metabolism

Clozapine is almost completely metabolised before excretion by CYP1A2 and 3A4, and to

some

extent

CYP2C19

2D6.

main

metabolites,

only

desmethyl

metabolite was found to be

active.

pharmacological

actions

resemble

those

clozapine but are considerably weaker and of short duration.

Elimination

Its elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6 to 26 hours).

After single doses of 75 mg, the mean terminal half-life was 7.9 hours; it increased to 14.2

hours when steady-state conditions were reached by administering daily doses of 75 mg

for at least 7 days.

Only

trace

amounts

unchanged

drug

detected

urine

faeces,

approximately 50% of the administered dose being excreted as metabolites in the urine

and 30% in the faeces.

Linearity/non-linearity

Dosage increases from 37.5 mg to 75 mg and 150 mg given twice daily were found to

result during steady state in linearly dose-proportional increases in the area under the

plasma

concentration/time

curve

(AUC)

peak

minimum

plasma

concentrations.

5.3.

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of

safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential

Mutagenicity

Clozapine and/or its metabolites were devoid of genotoxic potential when investigated

for induction of gene mutations, chromosome aberrations and primary DNA-damage in a

spectrum of in vitro mutagenicity tests. No clastogenic activity was observed in vivo (bone

marrow micronucleus test in mice).

2 3

| P a g e

Carcinogenicity

In Sprague-Dawley (CD) rats treated in the diet for 24 months, maximum tolerated doses

of 35 mg/kg per day revealed no carcinogenic potential of clozapine. Likewise, no

evidence of tumorigenic effects was obtained in two 78-week feeding studies in Charles

River (CD) mice. In the first study, oral dose levels of up to 64 mg/kg were administered

to males, and of up to 75 mg/kg to females respectively. In the second study, the drug

intake achieved for both sexes was 61 mg/kg per day.

Reproductive toxicity

No embryotoxic or teratogenic potential of clozapine was observed in rats or rabbits at

daily oral doses of up to 40 mg/kg. In male rats treated for 70 days prior to mating, fertility

was unaffected.

In female rats, fertility as well as pre- and postnatal development of the offspring was not

adversely affected by oral clozapine treatment prior to mating (up to 40 mg/kg per day).

When rats were treated during the later part of pregnancy and during lactation, survival

rates of the young from lactating dams, treated at dose levels up to 40 mg/kg body weight,

were lowered and the young were hyperactive. However, there was no lasting effect on

pup development after weaning.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients

Clopine tablets contain the following excipients:

Lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, purified

water, sodium starch glycolate

Clopine 50 mg/mL oral suspension contains the following excipients:

Glycerol, hydrochloric acid, monobasic sodium phosphate dihydrate, povidone, purified

water,

sodium

hydroxide,

sodium

methyl

hydroxybenzoate,

sodium

propyl

hydroxybenzoate, sorbitol, xanthan gum

6.2.

Incompatibilities

Not applicable.

6.3.

Shelf life

Clopine tablets: 36 months from date of manufacture.

Clopine 50 mg/mL oral suspension:

Unopened: 6 months from date of manufacture.

Opened: 3 months after opening.

6.4.

Special precautions for storage

2 4

| P a g e

Clopine tablets: Store at or below 30°C, Protect from light.

Clopine 50 mg/mL oral suspension: Store at or below 25°C.

6.5.

Nature and contents of container

Clopine tablets:

Transparent PVC/PVDC/ Aluminium Foil Blister Strips in a cardboard carton containing 50

or 100 tablets.

HDPE bottles with polypropylene child-resistant, a tamper-evident cap containing 50 or

100 tablets.

Not all pack sizes may be marketed.

Clopine 50 mg/mL oral suspension:

Bottle, glass, 125 mL amber bottle, polypropylene child-resistant, tamper-evident cap

packaged with a graduated oral dispenser.

6.6.

Special precautions for disposal and other handling

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

7.

MEDICINE SCHEDULE

Prescription Medicine.

8.

SPONSOR

Douglas Pharmaceuticals Ltd

P O Box 45 027

Auckland 0651

New Zealand

Phone: (09) 835 0660

9.

DATE OF FIRST APPROVAL

Clopine tablets: 03 June 2010

Clopine 50 mg/mL oral suspension: 30 August 2012

10.

DATE OF REVISION OF THE TEXT

07 May 2020

2 5

| P a g e

Summary table of changes

Section

Changed

Summary of new information

Change in therapeutic dosage from 300mg-450mg/day to 200mg- 450mg/day.

Additional statement: “Clopine is not approved for the treatment of

dementia-related behavioural disturbances (see section 4.4).”

Addition of contraindication “Drug induced agranulocytosis”.

Revised information regarding monitoring of low WBC count and/or ANC.

Deletion of Table 2.

Additional information regarding constipation precaution.

Additional information regarding smoking precaution

Further information on smoking-clozapine interaction.

Removal of duplicate listed adverse effects Blurred vision and Neuroleptic

malignant syndrome in Table 2.

Removal of gastric lavage and addition of “establish and maintain airway”.

Clinical studies information updated.

Updated reproductive toxicity information

Similar products

Search alerts related to this product

Share this information