Consumer medicine information

Clopixol

Zuclopenthixol acetate

BRAND INFORMATION

Brand name

Clopixol

Active ingredient

Zuclopenthixol acetate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Clopixol.

SUMMARY CMI

Clopixol®

Consumer Medicine Information (CMI) summary

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

1. Why am I using Clopixol?

Clopixol Tablet, Acuphase and Depot contain the active ingredient Zuclopenthixol hydrochloride, Zuclopenthixol acetate and Zuclopenthixol decanoate, respectively. Clopixol tablets are used for the acute and long-term treatment of schizophrenia and other mental illnesses, and to treat the manic phase of manic-depressive illness. Clopixol Acuphase injection is used for the initial treatment of acute episodes of mental disorders and to treat mania. Clopixol Depot injection is used to prevent further episodes of your illness. For more information, see Section 1. Why am I using Clopixol? in the full CMI.

2. What should I know before I use Clopixol?

Do not use if you have ever had an allergic reaction to Zuclopenthixol hydrochloride, Zuclopenthixol acetate or Zuclopenthixol decanoate or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Clopixol? in the full CMI.

3. What if I am taking other medicines?

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

4. How do I use Clopixol?

  • Clopixol tablets: the usual dose is 10 to 50 mg per day; Clopixol Acuphase injection: the usual dose is 50 to 150 mg (1 to 3 mL) every 2 to 3 days; Clopixol Depot injection: the usual dose is 200 to 400 mg (1 to 2 mL) every second to fourth week.
  • Clopixol tablets should be swallowed whole with a full glass of water; Clopixol injections should only be given by a doctor, nurse or other trained healthcare professional.

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

5. What should I know while using Clopixol?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Clopixol.
  • Protect your skin when you are in the sun, especially between 10am and 3pm.
  • Call your doctor straight away if you become pregnant while using Clopixol or notice any worm-like movements of the tongue, or other uncontrolled movements of the tongue, mouth, cheeks or jaw.
Things you should not do
  • Do not stop using Clopixol, or lower the dosage, without checking with your doctor.
  • Do not take any medicines that cause drowsiness while you are using Clopixol.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Clopixol affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Be careful when drinking alcohol while you are using this medicine.
Looking after your medicine
  • Keep Clopixol in the outer carton in order to protect from light.
  • Keep the medicine in a cool dry place where the temperature stays below 25°C.

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

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, contact your doctor or nurse.
For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Clopixol® (clo-PIK-sol)
Clopixol® Tablets 10 mg, Clopixol® Acuphase Injection 50 mg/mL, Clopixol® Depot Injection 200 mg/mL

Active ingredient(s): Zuclopenthixol hydrochloride (zoo-clo-PEN-thic-sol high-dro-CLOR-ride); Zuclopenthixol acetate (zoo-clo-PEN-thic-sol AS-se-tate); Zuclopenthixol decanoate (zoo-clo-PEN-thic-sol deck-can-OH-ate)


Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Clopixol?

Clopixol Tablet, Acuphase and Depot contains the active ingredients Zuclopenthixol hydrochloride, Zuclopenthixol acetate and Zuclopenthixol decanoate, respectively. Clopixol belongs to a group of medicines called thioxanthene neuroleptics. It helps to correct chemical imbalances in the brain, which may cause mental illness.

Clopixol tablets are used for the acute and long-term treatment of schizophrenia and other mental illnesses with disturbances in thinking, emotional reactions and behaviour.

It is also used to treat the manic phase of manic-depressive illness. A manic phase is a mood of excitement, over-activity and uninhibited behaviour.

Clopixol Acuphase injection is used for the initial treatment of acute episodes of mental disorders. It is also used to treat mania (a mental condition characterised by episodes of overactivity, elation or irritability) and used in case of worsening of chronic mental conditions.

Clopixol Depot injection is usually used to prevent further episodes of your illness.

2. What should I know before I use Clopixol?

Warnings

Do not use Clopixol if:

  • you are allergic to ingredients Zuclopenthixol hydrochloride, Zuclopenthixol acetate or Zuclopenthixol decanoate, or any of the ingredients listed at the end of this leaflet.
    - Always check the ingredients to make sure you can use this medicine.
    - 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, or rash, itching or hives on the skin.
  • you have collapsed due to very low blood pressure
  • you have diminished consciousness due to any cause
  • you have brain damage
  • you have diseases of the blood with abnormal or reduced number of red or white blood cells or platelets
  • you have phaeochromocytoma, a rare tumour of the adrenal gland which sits near the kidney

Do not give Clopixol to a child or adolescent.

There is no experience with its use in children or adolescents under 18 years old.

Do not use it after the expiry date printed on the pack.

If you use it after the expiry date has passed, it may not work as well. The expiry date refers to the last day of the month.

Do not use it if the packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • have allergies to any other substances such as foods, preservatives or dyes.
  • take any medicines for any other condition
  • you have, or have had, the following medical conditions:
    - arteriosclerosis, a disease affecting the arteries
    - convulsions, fits or seizures
    - decreased blood supply to the brain
    - diabetes, a disorder of metabolism in which the amount of sugar in the blood is too high
    - feeling lethargic, indifferent, lost or remote
    - glaucoma, a condition in which there is usually a build-up of pressure in the eye
    - heart and blood vessel problems
    - kidney problems
    - liver problems
    - low potassium and/or low magnesium levels in the blood
    - organic brain syndrome
    - parkinsonism, a disease of the brain affecting movement
    - risk factors for stroke
    - tardive dyskinesia, a reaction to some medicines with worm-like movements of the tongue, or other uncontrolled movements of the mouth, tongue, cheeks or jaw which may progress to the arms and legs.
    - treatment for cancer
    - sleep apnoea (a sleep disorder where your breathing is interrupted during sleep)
    - if you or someone else in your family has a history of blood clots, as medicines like these have been associated with formation of blood clots

Also tell your doctor if you will be in a hot environment or you do a lot of vigorous exercise.

Clopixol may make you sweat less, causing your body to overheat.

Tell your doctor if you are exposed to pesticides that contain phosphorus.

The risk of you experiencing a side effect may be increased.

If you are lactose intolerant, contact your doctor before taking Clopixol tablets.

Clopixol tablets contain lactose.

If you have not told your doctor about any of the above, tell them before you use Clopixol.

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

Pregnancy and breastfeeding

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

Animal studies have shown that Clopixol affects fertility. If you are intending to start a family, ask your doctor for advice.

Like most medicines of this kind, Clopixol is not recommended for use during pregnancy unless clearly necessary. The general condition of your baby might be affected by the use of this medicine.

The following symptoms may occur in newborn babies of mothers who have used Clopixol in the 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 should contact your doctor.

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

It is not recommended that you breast-feed while using Clopixol. Its active ingredient passes into breast milk and therefore there is a possibility that your baby might be affected.

3. What if I am taking other medicines?

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

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

  • tricyclic antidepressants and lithium, medicines used to treat depression or mood swings
  • medicines used to treat strong pain
  • medicines used to produce calmness or to help you sleep
  • medicines used to treat high blood pressure (hypertension), such as guanethidine
  • levodopa, a medicine used to treat Parkinson's disease
  • medicines which stimulate the body, getting it ready for action, such as adrenaline
  • metoclopramide, a medicine used to relieve nausea and vomiting
  • piperazine, a medicine used to treat worm infections
  • medicines known to inhibit the activity of certain liver enzymes
  • medicines used to treat changes in the rhythm or rate of the heart beat, e.g. quinidine, amiodarone, sotalol and dofetilide
  • antipsychotics, a class of medicines used to treat certain mental and emotional conditions, e.g. thioridazine
  • certain medicines used to treat infections, such as erythromycin, gatifloxacin and moxifloxacin
  • medicines used to relieve the symptoms of allergy, including terfenadine and astemizole
  • cisapride, used to treat stomach problems
  • medicines that disturb water or salt balance e.g. thiazide diuretics, also called fluid or water tablets
  • medicines used to relieve stomach cramps or spasms, to prevent travel sickness and to treat Parkinson's disease, such as atropine or related medicines.
  • medicines used to treat cancer

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

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

4. How do I use Clopixol?

How much to take / use

Clopixol tablets

The usual dose is 10 to 50 mg per day.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Clopixol may not work as well and your condition may not improve.

Clopixol Acuphase injection

The usual dose is 50 to 150 mg (1 to 3 mL) every 2 to 3 days or as instructed by your doctor.

The duration of the treatment should not be more than 2 weeks.

The maximum dose should not be more than 400 mg and the total number of injections should not be more than 4 per course of treatment.

Clopixol Depot injection

The usual dose is 200 to 400 mg (1 to 2 mL) every second to fourth week.

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight and your response to the medicine. Generally, your doctor will start you on smaller doses which will be gradually increased until a dose is reached where Clopixol works best for you.

Your doctor may have prescribed a different dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. Follow the instructions they give you.

They will tell you exactly how much you will be given.

Elderly patients

The dosage of Clopixol may need to be reduced in elderly patients.

When to use Clopixol

You may be given Clopixol tablets or injections which both have the same effects on your illness, although they last for different lengths of time.

Clopixol tablets

Clopixol tablets only work for a short time, so they need to be taken every day.

Take Clopixol tablets once a day at about the same time.

Taking them at the same time each day will also help you remember when to take the tablets.

Take Clopixol tablets before or after food.

Clopixol injections

Clopixol Acuphase injection has to be given every 2-3 days, while Clopixol Depot injection lasts several weeks, so it is given once every 2-4 weeks.

Your doctor will advise you.

How to use it

Clopixol tablets

Swallow the tablets whole with a full glass of water.

To open this child resistant bottle, please hold, twist and turn the bottle.

Clopixol injections

Clopixol is given as an injection into a large muscle where it is slowly released over time. The injection should only be given by a doctor, nurse or other trained person.

How long to use it

Continue taking your tablets and/or having your injections for as long as your doctor tells you to.

Clopixol helps control your condition, but does not cure it. Therefore, you will need regular treatment.

If you forget to use Clopixol

Clopixol tablets

  • If it is almost time for your next dose, skip the dose you missed and take the next dose when you are meant to.
  • Do not take a double dose to make up for the dose you have missed.
  • If there is still a long time to go before your next dose, take it as soon as you remember, and then go back to taking it as you would normally.
  • If you are not sure what to do, ask your doctor or pharmacist.
  • If you have trouble remembering when to take your medicine, ask your pharmacist for hints.

Clopixol injections

  • If you forget to keep an appointment, contact your doctor as soon as you remember, so that you can make another one.

If you use too much Clopixol

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

You should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26 for Australia and Tel: 0800 764 766 for New Zealand), or
  • contact your doctor, or
  • go to Accident and Emergency at your nearest hospital, if
    - you think you or anyone else may have taken too many Clopixol tablets.
    - you experience any side effects after being given Clopixol injections.

You may need urgent medical attention.

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

As Clopixol injections are given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

Symptoms of an overdose may include sleepiness, coma, cramps, convulsions, low blood pressure and extremely high or low body temperature. Uncontrollable movements may develop and collapse due to very low blood pressure may occur. Changes in the rhythm or rate of the heartbeat have been seen in Clopixol overdose when medicines known to affect the heart have also been taken.

5. What should I know while using Clopixol?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using Clopixol.

Tell any other doctors, dentists and pharmacists who treat you that you are using Clopixol.

Tell your doctor if you notice any soreness of the mouth, gums, throat or other flu-like symptoms.

Talk to your doctor or mental health professional if you are thinking or talking about death, suicide, self-harm or harm to others.

These may be signs of changes or worsening in your mental illness.

If you are going to have surgery, tell the surgeon or anaesthetist that you are using this medicine.

Clopixol may affect other medicines used during surgery.

If you are about to have any blood tests, tell your doctor that you are using this medicine.

It may interfere with the results of some tests.

Protect your skin when you are in the sun, especially between 10am and 3pm.

If you are outdoors, wear protective clothing and use a 30+ sunscreen.

If your skin appears to be burning, tell your doctor.

Clopixol may cause your skin to be much more sensitive to sunlight than it is normally. This could cause skin rash, itching, redness, or severe sunburn.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some blood and liver tests from time to time, particularly during the first months of therapy, to make sure the medicine is working and to prevent unwanted side effects.

Call your doctor straight away if you:

  • become pregnant while using Clopixol.
  • notice any worm-like movements of the tongue, or other uncontrolled movements of the tongue, mouth, cheeks or jaw which may progress to the arms and legs.
    These are symptoms of a condition called tardive dyskinesia, which may develop in people taking similar medicines, including Clopixol.
    This condition is more likely to occur during long-term treatment with Clopixol, especially in elderly women. In very rare cases, this may be permanent. However, if detected early, these symptoms are usually reversible.

Things you should not do

  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not use Clopixol to treat any other complaints unless your doctor tells you to.
  • Do not take any medicines that cause drowsiness while you are using Clopixol, unless recommended by your doctor.
  • Do not stop using Clopixol, or lower the dosage, without checking with your doctor.
  • Do not miss any injections, even if you feel better.
    Clopixol helps control your condition, but does not cure it. Therefore, you will need regular injections.
  • Do not stop using Clopixol suddenly.
    If Clopixol is stopped suddenly, you may experience symptoms such as nausea, vomiting, loss of appetite, diarrhoea, runny nose, sweating, aching muscles, pins and needles, sleeplessness, restlessness, anxiety, or agitation.
    Your doctor may want to gradually reduce the amount you are using before stopping completely.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

Standing up slowly 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.

Driving or using machines

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

It may cause drowsiness, tiredness, sleepiness or blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery, or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

If you drink alcohol, drowsiness or sleepiness may be worse.

Be careful when drinking alcohol while you are using this medicine.

Looking after your medicine

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

Keep Clopixol in the pack until it is time to use it.

If you take the tablets or the ampoules out of the pack, they may not keep well.

Keep Clopixol in the outer carton in order to protect from light.

Store it in a cool dry place below 25°C away from moisture, heat or sunlight; for example, do not store it:

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

Heat and damp 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.

When to discard your medicine

If your doctor tells you to stop using this medicine, or the expiry date has passed, ask your pharmacist what to do with any that is left over.

Getting rid of any unwanted medicine

Return any unused medicine to your pharmacist.

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

It helps most people with mental illness, but it may have unwanted side effects in a few people.

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

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

Less serious side effects

Less serious side effectsWhat to do
  • drowsiness, sleepiness
  • inability to sleep
  • abnormal dreams
  • headache
  • fatigue
  • depressed mood
  • anxiousness
  • nervousness, agitation
  • headaches
  • nasal congestion
  • dry mouth
  • constipation or diarrhoea
  • increased salivation or increased sweating
  • nausea, vomiting, dyspepsia
  • weight and appetite changes
  • change in your menstrual periods
  • impaired sexual function
  • swelling of hands, ankles or feet
  • skin rash, itching.
  • abnormal sensations, such as burning or prickling
  • changes in attention and memory
  • dizziness or spinning sensation
  • painful or weak muscles
  • pain at the injection site
  • feeling generally unwell
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • sudden onset of unusual movements, including trembling and shaking of the hands and fingers, twisting movements of the body, or shuffling walk and stiffness of the arms and legs
  • worm-like movements of the tongue or other uncontrolled movements of the mouth, tongue, cheeks or jaws, which may progress to the arms and legs
  • inability to keep still
  • increased, slowed or unusual muscle movements
  • feeling dizzy when standing up
  • irregular heart beat and changes in heart rate and blood pressure
  • fainting
  • blurred vision or difficulty focusing
  • difficulty passing urine
  • increased urination or other urinary disorder
  • high pressure in the eye
  • unusual secretion of breast milk
  • breast enlargement in men
  • difficult or painful breathing
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily than normal, nosebleeds
  • yellowing of the skin and/or eyes, also called jaundice
  • severe pain in the stomach with bloating, gut cramps and vomiting.
  • 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. If you notice any of these symptoms seek medical advice immediately.
  • In elderly people with dementia, a small increase in the number of deaths has been reported for patients taking antipsychotics compared with those not receiving antipsychotics.
These may be serious side effects of Clopixol. You may need urgent medical attention.
Tell your doctor straight away if you notice any of these serious side effects.
  • serious allergic reaction (symptoms of an allergic reaction may include swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing, or hives)
  • sudden increase in body temperature, unusual stiffness of the muscles and changes in consciousness, especially in conjunction with fast heart rate and sweating. This may be due to a very rare condition called neuroleptic malignant syndrome, which has been reported with various antipsychotic medicines.
These are very serious side effects. You may need urgent medical attention or hospitalisation.
These side effects are generally rare.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

Other side effects not listed here may occur in some people.

Reporting side effects

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

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

7. Product details

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

What Clopixol contains

Active ingredient
(main ingredient)
  • Clopixol 10 mg tablets - 10 mg zuclopenthixol (as hydrochloride) per tablet
  • Clopixol Acuphase 50 mg/mL injection - 50 mg zuclopenthixol acetate per 1 mL or 100 mg zuclopenthixol acetate per 2 mL
  • Clopixol Depot 200 mg/mL injection - 200 mg zuclopenthixol decanoate per 1 mL.
Tablets
Other ingredients
(inactive ingredients)

hydrogenated castor oil

microcrystalline cellulose

glycerol

hypromellose

iron oxide red

lactose monohydrate

macrogol 6000

magnesium stearate

copovidone

potato starch

purified talc

titanium dioxide.

Injections
Other ingredients
(inactive ingredients)

fractionated coconut oil.

Potential allergens

Clopixol tablets do not contain gluten, sucrose, tartrazine or any other azo dyes.

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

What Clopixol looks like

Clopixol comes as tablets and in two types of injections:

  • Clopixol 10 mg film-coated tablets - light red brown, round biconvex tablets. (AUST R 45077)
  • Clopixol Acuphase 50 mg/mL solution for injection - clear, yellowish oil. (AUST R 46061)
  • Clopixol Depot 200 mg/mL solution for injection - clear, yellowish oil. (AUST R 45082)

The tablets are available in bottles of 100 tablets and the injections come in boxes of 5 ampoules.

Who distributes Clopixol?

Clopixol is made by H. Lundbeck A/S, Denmark.

Distributed in Australia by:

Lundbeck Australia Pty Ltd
1 Innovation Rd
North Ryde NSW 2113
Ph: +61 2 8669 1000

Distributed in New Zealand by:

Healthcare Logistics
PO Box 62027
Mt Wellington, Auckland
Ph: +64 9 9185100

This leaflet was prepared on 23 February 2022.

Published by MIMS May 2022

BRAND INFORMATION

Brand name

Clopixol

Active ingredient

Zuclopenthixol acetate

Schedule

S4

 

1 Name of Medicine

Clopixol tablets.

Zuclopenthixol hydrochloride.

Clopixol Acuphase injection.

Zuclopenthixol acetate.

Clopixol Depot injection.

Zuclopenthixol decanoate.

2 Qualitative and Quantitative Composition

Clopixol tablets.

Film-coated tablets containing 10 mg zuclopenthixol as zuclopenthixol hydrochloride.

Clopixol Acuphase injection.

The 1 mL solution for injection contains 50 mg zuclopenthixol acetate equivalent to 45.25 mg zuclopenthixol.
The 2 mL solution for injection containing 100 mg zuclopenthixol acetate equivalent to 90.50 mg zuclopenthixol.

Clopixol Depot injection.

The 1 mL solution for injection contains 200 mg zuclopenthixol decanoate equivalent to 144.4 mg zuclopenthixol.

Excipients with known effect in the tablets.

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

3 Pharmaceutical Form

Clopixol tablets.

Film-coated tablets. Clopixol 10 mg tablets are light red brown, round biconvex film-coated tablets.

Clopixol Acuphase injection.

Solution for injection. Clopixol Acuphase injection presents as a clear, yellowish oil.

Clopixol Depot injection.

Solution for injection. Clopixol Depot injection presents as a clear, yellowish oil.

4 Clinical Particulars

4.1 Therapeutic Indications

Clopixol tablets.

Acute and chronic schizophrenia and other psychoses, especially those with symptoms such as hallucinations, delusions, thought disturbances, agitation, restlessness, hostility or aggressiveness.
Manic phase of manic depressive illness.

Clopixol Acuphase injection.

Initial treatment of acute psychoses, mania and exacerbation of chronic psychoses.

Clopixol Depot injection.

Maintenance treatment. May be an advantage in the treatment of noncompliant patients.

4.2 Dose and Method of Administration

Adults.

Clopixol tablets. Dosage should be adjusted individually. In general, small doses should be used initially and increased to the optimal effective level as rapidly as possible based on the response. The maintenance dose can usually be given as a single dose at bedtime.
Concomitant intake of food enhances the bioavailability by approximately 20% of Clopixol tablets without influencing its absorption rate. Cmax, tmax and elimination half-life (t1/2) are not altered. The postulated mechanism for this effect is that food reduces the presystemic clearance of zuclopenthixol. This effect is of doubtful clinical relevance and it does not appear that Clopixol tablets need to be given with regard to meals.

Acute schizophrenia and other acute psychoses; severe, acute states of agitation, mania.

Usually 10-50 mg/day orally. In moderate to severe cases, initially 20 mg/day increasing if necessary by 10-20 mg every 2-3 days to 75 mg or more daily.

Chronic schizophrenia and other chronic psychoses.

The usual maintenance dose is 20-40 mg/day orally.
Clopixol Acuphase injection. Dosage should be individually adjusted according to the patient's condition. Clopixol Acuphase is administered by intramuscular injection. Local tolerability is good.
The dose range is usually 50-150 mg (1-3 mL) i.m., repeated if necessary, preferably at intervals of 2 to 3 days. In some cases, an additional injection may be needed 24 to 48 hours following the first injection.
Clopixol Acuphase is not intended for long-term use and the duration of treatment should not be more than 2 weeks. The maximum accumulated dosage in a course should not exceed 400 mg and the total number of injections should not exceed 4.
In the maintenance therapy, treatment should be continued with oral Clopixol or Clopixol Depot i.m. according to the following guidelines.

1. Change to oral Clopixol 2 to 3 days after the last injection of Clopixol Acuphase.

If the patient has been treated with 100 mg Clopixol Acuphase, oral treatment should be started at a dosage of about 40 mg daily, possibly in divided dosages. If necessary the dose can be further increased by 10-20 mg every 2 to 3 days up to 75 mg or more.

2. Change to maintenance treatment with Clopixol Depot.

Concomitantly with the last injection of Clopixol Acuphase, 200-400 mg (1-2 mL) of Clopixol Depot should be given intramuscularly and repeated every second week. Higher doses or shorter intervals may be needed.
Clopixol Depot injection. The usual maintenance dose is 200-400 mg (1-2 mL) every second to fourth week. A few patients may need higher doses or shorter intervals between doses.
When changing medication from oral Clopixol or Clopixol Acuphase to maintenance treatment with Clopixol Depot, the following guidelines should be used.

1. Change from oral Clopixol to Clopixol Depot i.m.

mg Clopixol orally daily x 8 = mg Clopixol Depot i.m. every second week.
Oral Clopixol should be continued during the first week after the first injection but in diminishing dosage.

2. Change from Clopixol Acuphase i.m. to Clopixol Depot i.m.

Concomitantly with the last injection of Clopixol Acuphase, 200-400 mg (1-2 mL) of Clopixol Depot should be given intramuscularly and repeated every second week. Higher doses or shorter intervals between injections may be needed.

Elderly patients.

The dosage may need to be reduced in elderly patients.

Children.

Since the safety and efficacy of Clopixol in children have not been established, its use is not recommended in this age group.

Reduced hepatic function.

Clopixol should be used with caution in patients with mild to moderate liver disease (see Section 4.4 Special Warnings and Precautions for Use).

Reduced renal function.

Since approximately 10% of a zuclopenthixol dose is excreted via the renal system, patients with renal dysfunction may require dosage adjustment during long-term treatment (see Section 4.4 Special Warnings and Precautions for Use).

Clinical particulars.

If a rapid and pronounced reduction in psychotic symptoms is required, it is recommended to start treatment parenterally with Clopixol Acuphase 50 mg/mL (zuclopenthixol acetate). Clopixol Acuphase has a duration of action of 2 to 3 days and 1 or 2 injections are usually sufficient prior to the introduction of maintenance treatment with Clopixol tablets or Clopixol Depot injection solution (see Section 4.2 Dose and Method of Administration).
In the maintenance treatment of psychotic patients, particularly where compliance with oral medication is a problem, it may be beneficial to continue treatment with Clopixol Depot 200 mg/mL (zuclopenthixol decanoate) which is administered at intervals of 2-4 weeks.
In addition to its antipsychotic effect, zuclopenthixol also has a nonspecific sedative effect on accompanying symptoms such as agitation, restlessness, hostility or aggression.
Zuclopenthixol induces dose dependent sedation. Tolerance to the nonspecific sedative effect develops rapidly. Significant sedation occurs within 2 hours of injection of Clopixol Acuphase, reaching a maximum after 8 hours then declining to a low level, despite repeated injection.

Instructions to patients.

1. Ambulant patients should be warned not to drive or operate machinery during the use of Clopixol.
2. Patients should be forewarned and reassured concerning the possible occurrence of extrapyramidal symptoms.
3. Patients should be instructed to report any soreness of the mouth, gums, throat or other symptoms which may indicate suppression of the immune system.

4.3 Contraindications

Known hypersensitivity to the thioxanthenes. The possibility of cross sensitivity between the thioxanthenes and phenothiazine derivatives should be kept in mind.
Known hypersensitivity to any of the excipients of the particular Clopixol presentation (see Section 2 Qualitative and Quantitative Composition).
Acute alcohol, barbiturate or opiate intoxication.
Circulatory collapse, depressed level of consciousness due to any cause, coma, suspected or established subcortical brain damage.
Blood dyscrasias.
Phaeochromocytoma.
Leukopenia and/or previous agranulocytosis.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Neuroleptic malignant syndrome.

A potentially fatal syndrome called neuroleptic malignant syndrome (NMS) has been reported on occasion with antipsychotic drugs. The syndrome is characterised by muscle rigidity, fever, hyperthermia, altered consciousness and autonomic instability (e.g. tachycardia, labile blood pressure, profuse sweating, dyspnoea). The management of neuroleptic malignant syndrome should include immediate discontinuation of antipsychotic drugs, intensive monitoring of symptoms and treatment of any associated medical problems. Symptoms may persist for more than a week after oral neuroleptics are discontinued and somewhat longer when associated with the depot forms of the drugs.

Initiation of therapy.

Severe adverse reactions requiring immediate medical attention may occur and are difficult to predict. Therefore, the evaluation of tolerance and response, and establishment of adequate maintenance therapy require careful stabilisation of each patient under continuous, close medical observation and supervision.

Suicide.

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

Dyskinesia.

The possibility of the development of irreversible dyskinesia should be borne in mind when patients are on prolonged therapy with Clopixol.

Photosensitivity reactions.

Photosensitivity reactions have been reported with related drugs.

Ophthalmological.

Pigmentary retinopathy and lenticular and corneal deposits have been reported with related drugs. Lens opacity has been reported rarely with zuclopenthixol.

Anaphylactoid reactions.

The possibility of anaphylactoid reactions occurring in some patients should be borne in mind.

Psychoses with apathy or withdrawal.

Clopixol is unsuitable for patients whose psychoses are accompanied by features of apathy or withdrawal.

Parkinsonism.

Clopixol should be used with caution in patients with Parkinsonism.

Arteriosclerosis.

Clopixol should be used with caution in patients with severe arteriosclerosis.

Organic brain syndrome.

Like other neuroleptics, Clopixol should be used with caution in patients with organic brain syndrome.

Stroke.

An approximate 3-fold increase in risk of cerebrovascular adverse events has been seen in randomised placebo controlled clinical trials 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. Therefore, zuclopenthixol should be used with caution in patients with risk factors for stroke.

Cerebrovascular insufficiency.

Patients who have cerebrovascular insufficiency should be closely monitored during treatment with Clopixol.

Convulsions.

Clopixol should be used with caution in patients with a history of convulsions since it may lower the convulsive threshold.

Anticholinergic effects.

Although its anticholinergic properties are weak, zuclopenthixol should be used with caution in patients who are known to have or suspected of having glaucoma, those who might be exposed to extreme heat or organophosphorus insecticides and those who are receiving atropine or related drugs. Paralytic ileus has occasionally been reported (particularly in the elderly) when several drugs with anticholinergic effects have been used simultaneously.

White blood cell disorders.

Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including zuclopenthixol.
Long acting depot antipsychotics should be used with caution in combination with other medicines known to have a myelosuppressive potential, as these cannot rapidly be removed from the body in conditions where this may be required.

Laboratory tests required.

Blood dyscrasias and liver damage have been reported with this class of drugs (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, routine blood counts and hepatic function tests are advisable, particularly during the first months of therapy. Should either of these disorders occur, supportive treatment should be instituted and administration of the drug ceased.

Cellular depression.

If any soreness of the mouth, gums or throat, or any symptoms of upper respiratory infection occur and confirmatory leukocyte count indicates cellular depression, therapy should be discontinued and other appropriate measures instituted immediately.

Cardiac disorders.

Caution should be observed when using a drug of this category in patients who have advanced cardiovascular disease or those who may have a propensity for development of cardiac conduction defects.
As with other drugs belonging to the therapeutic class of antipsychotics, zuclopenthixol may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, zuclopenthixol should be used with caution in susceptible individuals (with hypokalaemia, hypomagnesaemia or genetic predisposition) and in patients with a history of cardiovascular disorders, e.g. QT prolongation, significant bradycardia (< 50 beats per minute), recent acute myocardial infarction, uncompensated heart failure or cardiac arrhythmia. Concomitant treatment with other antipsychotics should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Venous thromboembolism (VTE).

Cases have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with zuclopenthixol and preventive measures undertaken.

Increased mortality in elderly people with dementia.

Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
Zuclopenthixol is not approved for the treatment of dementia related behavioural disturbances.

Diabetes.

As described for other psychotropics, zuclopenthixol may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients.

Surgery.

Patients on large doses of zuclopenthixol who are undergoing surgery should be carefully observed for possible hypotensive phenomena. Dosages of anaesthetic or central nervous system depressant drugs may need to be reduced.

Monitoring.

To lessen the likelihood of adverse reactions related to drug accumulation, patients on long-term therapy or receiving high doses of zuclopenthixol should be monitored carefully and evaluated periodically in order to determine whether the maintenance dosage can be lowered or drug therapy discontinued.

Antiemetic effect.

The antiemetic effect observed with zuclopenthixol in animal studies may also occur in man. Therefore, the drug may mask signs of toxicity due to overdosage of other drugs, or it may mask symptoms of disease, such as brain tumour or intestinal obstruction.

Sleep apnoea.

No cases of sleep apnoea clearly attributed to zuclopenthixol have been reported and no epidemiology studies can substantiate this. However, sleep apnoea and related disorders have been reported in patients treated with other atypical antipsychotic medications, with or without prior history of sleep apnoea, and in patients 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, zuclopenthixol should be used with caution.

Excipients.

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not receive this medicine. They also contain hydrogenated castor oil which may cause stomach upset and diarrhoea.

Use in hepatic impairment.

Clopixol should be used with caution in patients with liver disease. Patients with compromised hepatic function should be given half the recommended dose and serum levels monitored (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

Since only about 0.1% of a zuclopenthixol dose is excreted unchanged via the renal system, patients with mild to moderate renal dysfunction can receive Clopixol in the usual dosage. In patients with renal failure the dosage should be reduced to half the usual dose and close monitoring instituted.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

The safety and efficacy of Clopixol in children have not been established, therefore, its use cannot be recommended in this age group.

Effects on laboratory tests.

Transient slight alterations in liver function tests have infrequently been reported.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Tricyclic antidepressants.

Tricyclic antidepressants and classical neuroleptics mutually inhibit the metabolism of each other.

Lithium.

Concomitant use of neuroleptics and lithium increases the risk of neurotoxicity.

Alcohol, other CNS depressant drugs.

Zuclopenthixol enhances the sedative response to alcohol and the effects of barbiturates and other CNS depressants.

Hypnotics.

As with phenothiazines, Clopixol should not be used concomitantly with large doses of hypnotics due to the possibility of potentiation.

Antihypertensives.

Zuclopenthixol should not be given concomitantly with guanethidine or similar acting compounds since neuroleptics such as zuclopenthixol may block their antihypertensive effects.

Levodopa, adrenergic drugs.

Zuclopenthixol may reduce the effects of levodopa and adrenergic drugs.

Metoclopramide, piperazine.

Concomitant use of metoclopramide or piperazine increases the risk of extrapyramidal disorder.

Medicines metabolised by CYP2D6.

Since zuclopenthixol is partly metabolised by CYP2D6, concomitant use of drugs known to inhibit this enzyme may lead to decreased clearance of zuclopenthixol.

Drugs known to increase the QT interval.

Increases in the QT interval related to antipsychotic treatment may be exacerbated by the coadministration of other drugs known to significantly increase the QT interval. Coadministration of such drugs should be avoided. Relevant classes include:
class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide);
some antipsychotics (e.g. thioridazine);
some macrolides (e.g. erythromycin);
some antihistamines (e.g. terfenadine, astemizole);
some quinolone antibiotics (e.g. gatifloxacin, moxifloxacin).
The above list is not exhaustive and other individual drugs known to significantly increase the QT interval (e.g. cisapride, lithium) should be avoided.
Drugs known to cause electrolyte disturbances such as thiazide diuretics (hypokalaemia) and drugs known to increase the plasma concentration of zuclopenthixol should also be used with caution as they may increase the risk of QT prolongation and malignant arrhythmias (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In humans, adverse events such as hyperprolactinaemia, galactorrhoea, amenorrhoea, erectile dysfunction and ejaculation failure have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). These events may have a negative impact on female and/or male sexual function and fertility.
If clinical significant hyperprolactinaemia, galactorrhoea, amenorrhoea or sexual dysfunctions occur, a dose reduction (if possible) or discontinuation should be considered.
Administration of zuclopenthixol to male and female rats were associated with a slight delay in mating. In an experiment where zuclopenthixol was administered via the diet, impaired mating performance and reduced conception rate was noted.
(Category C)
The safety of Clopixol in pregnant women has not been established. Clopixol should not be administered to women of childbearing potential unless, in the opinion of the physician, the expected benefit to the patient outweighs the potential risk to the foetus.
Animal studies have shown reproductive toxicity.
In a three generation study in rats a delay in mating was noted. In an experiment where zuclopenthixol was administered via the diet, impaired mating performance and reduced conception rate was noted.
Zuclopenthixol crosses the placental barrier in small amounts.

Nonteratogenic class effect.

Neonates exposed to antipsychotic drugs (including zuclopenthixol) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been postmarket 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.
Zuclopenthixol should be used during pregnancy only if the anticipated benefit outweighs the risk and administered dose and duration of treatments should be as low and short as possible.
Oral administration of the drug to rats during the peri/ postnatal period at dose levels of 5 and 15 mg/kg/day resulted in an increase in the number of stillbirths, reduced pup survival and delayed development of pups. The clinical significance of these findings is unclear and it is possible that the effect on pups was due to neglect by the dams who were exposed to doses of zuclopenthixol producing maternal toxicity.
Zuclopenthixol passes into breast milk in small amounts; the milk/ serum concentration ratio in women is on average 0.3.
Safe use of Clopixol by nursing mothers has not been established, therefore, it is recommended that breastfeeding be discontinued in women taking Clopixol.

4.7 Effects on Ability to Drive and Use Machines

Zuclopenthixol is a sedative drug. Patients who are prescribed psychotropic medication may be expected to have some impairment in general attention and concentration and should be cautioned about their ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

The most common adverse reaction reported with zuclopenthixol has been extrapyramidal disorder.
Clopixol has been marketed extensively overseas for many years. Adverse events listed below reflect those which have been observed during clinical trials, published reports and in the overseas postmarketing period. Events described as "rarely" are those which were reported on 1-3 occasions irrespective of the formulation used and without regard to causality, while those described as "occasionally" were reported on 4-10 occasions. Other events were reported more frequently (see also the adverse events in Table 1).
Because zuclopenthixol shares many of the pharmacological properties of other thioxanthenes and phenothiazines, the possible occurrence of the known adverse effects of these drug classes exists.

Autonomic nervous system.

Dry mouth, blurred vision, constipation, excessive salivation, excessive perspiration, nausea, difficulty in micturition and urinary retention have been observed.
Miosis, mydriasis, paralytic ileus, polyuria, nasal congestion and glaucoma have been reported with related drugs.

Cardiovascular.

Orthostatic dizziness may occur. Tachycardia, palpitations and fainting have been observed.
Hypotension, hypertension, fluctuations in blood pressure, nonspecific ECG changes and cardiac arrhythmias have been reported with related drugs.
If hypotension occurs, adrenalin should not be used as a pressor agent since a paradoxical further lowering of blood pressure may result.
As with other drugs belonging to the therapeutic class of antipsychotics, rare cases of QT prolongation, ventricular arrhythmias, ventricular fibrillation, ventricular tachycardia, torsade de pointes and sudden unexplained death have been reported for zuclopenthixol (see Section 4.4 Special Warnings and Precautions for Use).

Central nervous system.

Extrapyramidal symptoms, including hypokinetic and hyperkinetic states, tremor, pseudoparkinsonism, dystonia, hypertonia, rigidity, akathisia, oculogyric crises, opisthotonos, hyper-reflexia and tardive dyskinesia (see below).
These symptoms, if they occur, usually appear within the first few days of treatment and can usually be controlled or totally curtailed by reduction in dosage and/or standard antiparkinsonian medication. However, the routine prophylactic use of antiparkinsonian medication is not recommended. Extrapyramidal reactions may be alarming and patients should be forewarned and reassured (see Section 4.2 Dose and Method of Administration). Reduction in dosage or, if possible, discontinuation of zuclopenthixol therapy is recommended. Other CNS effects include drowsiness and somnolence.

Metabolic and endocrine.

Weight change and menstrual disturbance have been reported. Transient galactorrhoea has been reported occasionally. Gynaecomastia, thyroid disorder and impotence have been observed rarely.
Related drugs have been associated with breast enlargement, menstrual irregularities, false positive pregnancy tests, peripheral oedema, hypo- and hyperglycaemia and glycosuria.

Persistent tardive dyskinesia.

As with all antipsychotic agents, tardive dyskinesia may appear in some patients during long-term use or may occur after drug therapy has been discontinued. Elderly patients on high dose therapy, especially elderly females, may be at greater risk. The symptoms may be persistent and, in some patients, appear to be irreversible.
The syndrome is characterised by rhythmical, involuntary movements of the tongue, face, mouth or jaw (e.g. protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of the extremities.
There is no known effective treatment for tardive dyskinesia; antiparkinsonian agents usually do not alleviate the symptoms of this syndrome. If these symptoms appear, it is suggested that all antipsychotic agents be discontinued. Should it be necessary to reinstitute treatment, increase dosage or change the antipsychotic agent, the syndrome may be masked.
If manifestations are recognised, particularly in patients over the age of fifty, the risk of this syndrome developing may be reduced by avoiding unnecessary neuroleptic medication, reducing the dose or discontinuing the drug altogether (if possible).
It has been reported that if the medication is stopped at the first signs of fine vermicular movements of the tongue, which may be an early manifestation, the syndrome may not develop.

Toxic and allergic.

Alterations in liver function, particularly increased bilirubin levels, have been observed. Transient increases in ALT and ALP values may occur. Transient, benign leukopenia has been reported rarely. Peripheral oedema has occasionally been reported. Skin reactions such as pruritus, rash and erythema have been reported rarely.
Eosinophilia, jaundice and increased levels of alkaline phosphatase have been reported with related drugs. Other antipsychotic drugs have been associated with leukopenia, agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura, haemolytic anaemia and pancytopenia.

Discontinuation.

Abrupt discontinuation of zuclopenthixol may be accompanied by withdrawal symptoms. The most common symptoms are nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgias, paraesthesias, insomnia, restlessness, anxiety and agitation. Patients may also experience vertigo, alternate feelings of warmth and coldness and tremor. Symptoms generally begin within 1 to 4 days of withdrawal and abate within 7 to 14 days.

Miscellaneous.

Lens opacity has been reported rarely.

Other post-marketing events.

Post-marketing events from literature and spontaneous reporting for which frequencies have been further defined are provided in Table 1. Frequencies are defined as: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000), or not known (cannot be estimated from the available data).

Reporting suspected adverse effects.

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

4.9 Overdose

In general, the main therapy for all overdoses is supportive and symptomatic care.

Symptoms.

Overdosage may cause somnolence, coma, cramps, convulsions, extrapyramidal symptoms, shock, decreased blood pressure and hyperthermia/ hypothermia.
ECG changes, QT prolongation, torsade de pointes, cardiac arrest and ventricular arrhythmias have been reported when zuclopenthixol has been taken or has been administered in overdose together with drugs known to affect the heart.
The highest orally administered dose of zuclopenthixol in clinical trials was 450 mg daily.

Treatment.

Treatment is symptomatic and supportive. No further doses of zuclopenthixol should be administered. Measures to support the respiratory and cardiovascular systems should be instituted. If severe hypotension occurs, an i.v. vasopressor drug should be administered immediately. Epinephrine (adrenaline) should not be used as further lowering of blood pressure may result. Convulsions may be treated with diazepam and extrapyramidal symptoms with an antiparkinsonian medication.
For information on the management of overdose, contact the Poison Information Centre (Tel: 13 11 26 for Australia and Tel: 0800 764 766 for New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Zuclopenthixol is a potent neuroleptic of the thioxanthene series. The antipsychotic effect of neuroleptics is related to their dopamine receptor blocking activity. The thioxanthenes have high affinity for both the adenylate cyclase coupled dopamine D1-receptors and for the dopamine D2-receptors; in the phenothiazine group the affinity for D1-receptors is much lower than for D2-receptors, whereas butyrophenones, diphenylbutylpiperidines and benzamides only have affinity for D2-receptors.
In the traditional tests for antipsychotic effect, e.g. antagonism of stereotypic behaviour induced by dopamine agonists, the mentioned chemical groups of neuroleptics exhibit equal but dose dependent activity. However the antistereotypic effect of butyrophenones, diphenylbutylpiperidines and benzamides is strongly counteracted by the anticholinergic drug scopolamine, that of the phenothiazines less so, while the antistereotypic effect of the thioxanthenes, e.g. zuclopenthixol, is not, or only very slightly influenced by concomitant treatment with anticholinergics. Like most other neuroleptics, zuclopenthixol increases the serum prolactin level.

Clinical trials.

A clear relationship between serum levels and clinical effects of zuclopenthixol has not been established. However, data from open trials of zuclopenthixol in the treatment of mania and acute paranoid psychosis indicate that the minimum effective serum levels are 5 nanogram/mL (12.5 nanomol/L) in acute mania patients of moderate severity, 3-4 nanogram/mL (7.5-10 nanomol/L) in moderately psychotic patients (BPRS 26-30 points) and 6-8 nanogram/L (15-20 nanomol/L) in severely psychotic patients (BPRS 31-38 points). Clopixol tablets, when given within the dosage recommendation, provide adequate zuclopenthixol serum levels for effective control of psychoses.

5.2 Pharmacokinetic Properties

Absorption.

Clopixol tablets.

The absolute bioavailability after oral administration of Clopixol 10 mg tablets is 49%. Maximum serum concentrations are reached after approximately 4 hours (2-12 hours). The mean steady-state serum level corresponding to 20 mg/day zuclopenthixol (as the dihydrochloride) p.o. is about 13 nanogram/mL (33 nanomol/L). The biological half-life is approximately 20 hours.
Concomitant intake of food enhances the bioavailability by approximately 20% of Clopixol tablets without influencing its absorption rate. Cmax, tmax and elimination half-life (t1/2) are not altered. The postulated mechanism for this effect is that food reduces the presystemic clearance of zuclopenthixol. This effect is of doubtful clinical relevance and it does not appear that Clopixol tablets need to be given with regard to meals.

Clopixol Acuphase injection.

The acetate ester is rather slowly released from the oil and is rapidly hydrolysed to the active substance, zuclopenthixol, upon reaching the body water.
Maximum serum concentrations of zuclopenthixol are reached, on average, 24 to 36 hours after i.m. injection, followed by a gradual decline. Average maximum serum concentration of zuclopenthixol corresponding to a 100 mg i.m. dose of zuclopenthixol acetate is 41 nanogram/mL (102 nanomol/L). 3 days following injection, serum levels are approximately one-third of the maximum.

Clopixol Depot injection.

The decanoate ester is slowly released from the oil depot and is rapidly hydrolysed to the active substance, zuclopenthixol, upon reaching the body water phase. Whereas zuclopenthixol itself is relatively short acting, the decanoate ester in oil provides a predictable, slow release preparation of the active constituent.
Maximum serum concentrations of zuclopenthixol are reached 3 to 7 days following i.m. injection. The serum concentration curve declines exponentially with a half-life of 19 days, reflecting the rate of release from the depot. The average steady-state preinjection serum level of zuclopenthixol corresponding to a 200 mg dose of zuclopenthixol decanoate every 2 weeks is approximately 10 nanogram/mL (25 nanomol/L).
As no first pass metabolism occurs when a drug is administered parenterally, zuclopenthixol decanoate can be administered in lower doses than oral zuclopenthixol.
A dose of 200 mg/2 weeks or 400 mg/4 weeks zuclopenthixol decanoate is expected to be equivalent to a daily dose of 25 mg zuclopenthixol (as the dihydrochloride).

Distribution.

As for other neuroleptics, zuclopenthixol is distributed with highest concentrations of drug and metabolites in liver, lungs, intestines and kidneys and lower concentrations in heart, spleen, brain and blood. The apparent volume of distribution is 20 L/kg and protein binding is approximately 98% at concentrations above the therapeutic range.

Metabolism.

The metabolism of zuclopenthixol is mainly by means of sulphoxidation, side chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of psychopharmacological activity.

Excretion.

Excretion is mainly via the faecal route and to a smaller degree (about 10%) via the urine. Only about 0.1% of the dose is excreted unchanged in the urine, so the drug load on the kidneys is negligible. The systemic clearance is approximately 0.9 L/min.

Linearity.

The kinetics appear to be linear, since highly significant correlations exist between dose and serum level, and between dose and area under the serum concentration curve, respectively.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Chronic administration of zuclopenthixol (30 mg/kg/day for 2 years) in rats resulted in small but significant increases in the incidence of thyroid parafollicular carcinomas and, in females, of mammary adenocarcinomas and of pancreatic islet cell adenomas and carcinomas. An increase in the incidence of mammary adenocarcinomas is a common finding for D2-antagonists which increase prolactin secretion when administered to rats. An increase in the incidence of pancreatic islet cell tumours has been observed for some other D2-antagonists. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear.

6 Pharmaceutical Particulars

6.1 List of Excipients

Clopixol tablets.

They contain the following excipients: potato starch, lactose monohydrate, microcrystalline cellulose, copovidone, glycerol, purified talc, hydrogenated castor oil and magnesium stearate, with a coating of hypromellose and macrogol 6000, coloured with titanium dioxide and iron oxide red.

Clopixol Acuphase injection.

It contains the following excipient: fractionated coconut oil.

Clopixol Depot injection.

It contains the following excipient: fractionated coconut oil.

6.2 Incompatibilities

Clopixol Acuphase and Clopixol Depot should not be mixed with depot preparations formulated with a sesame oil vehicle since this will produce changes in pharmacokinetic properties.
Zuclopenthixol acetate should only be mixed with zuclopenthixol decanoate which is also dissolved in coconut oil, and vice versa.

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

Clopixol tablets.

Store below 25°C. Protect from light.

Clopixol Acuphase injections and Clopixol Depot injection.

Store below 25°C. Protect from light. Do not remove from carton except immediately prior to use.

6.5 Nature and Contents of Container

Clopixol tablets.

HDPE bottles with a PP child resistant closures of 100 tablets.

Clopixol Acuphase injection.

1 and 2 mL glass ampoules in packs of 5 ampoules.

Clopixol Depot injection.

1 mL glass ampoules in packs of 5 ampoules.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Clopixol tablets.

Chemical name: (Z)-2-4-[3-(2-chlorothioxanthene-9-ylidene) propyl] piperazin-1-ylethanol dihydrochloride.
Physical properties: Clopixol tablets contain zuclopenthixol hydrochloride, an off-white, granular powder. It is very soluble in water, sparingly soluble in ethanol (96%), slightly soluble in chloroform and very slightly soluble in ether.
Molecular formula: C22H25ClN2OS,2HCl.
Molecular weight: 473.9.

Clopixol Acuphase injection.

Chemical name: (Z)-2-4-[3-(2-chlorothioxanthene-9-ylidene) propyl] piperazin-1-ylethyl acetate.
Physical properties: Clopixol Acuphase contains the acetate ester of zuclopenthixol. Zuclopenthixol acetate is a yellowish, viscous oil. It is very slightly soluble in water, very soluble in ethanol (96%), ether and dichloromethane.
Molecular formula: C24H27ClN2O2S.
Molecular weight: 443.0.

Clopixol Depot injection.

Chemical name: 2-[4-[3-[(Z)-2-chloro-9H-thioxanthen-9-ylidene] propyl] piperazin-1-yl] ethyl decanoate.
Physical properties: Clopixol Depot contains the decanoate ester of zuclopenthixol. Zuclopenthixol decanoate is a yellow viscous oily liquid. It is very slightly soluble in water, very soluble in alcohol and methylene chloride.
Molecular formula: C32H43ClN2O2S.
Molecular weight: 555.3.

Chemical structure.


CAS number.

Clopixol tablets.

633-59-0.

Clopixol Acuphase injection.

85721-05-7.

Clopixol Depot injection.

64053-00-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes