Consumer medicine information

APO-Amisulpride Tablets

Amisulpride

BRAND INFORMATION

Brand name

APO-Amisulpride

Active ingredient

Amisulpride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Amisulpride Tablets.

SUMMARY CMI

APO-Amisulpride Tablets

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 APO-Amisulpride?

APO-Amisulpride contains the active ingredient amisulpride. APO-Amisulpride is used to treat symptoms of schizophrenia.

For more information, see Section 1. Why am I using APO-Amisulpride? in the full CMI.

2. What should I know before I use APO-Amisulpride?

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

3. What if I am taking other medicines?

Some medicines may interfere with APO-Amisulpride and affect how it works. In particular, do not take this medicine, and tell your doctor if you are taking the following medicines: medicines used to treat irregular heart rhythm, other medicines used to treat heart problems, cisapride, sultopride, antibiotics, levodopa, methadone, thioridazine, vincamine, halofantrine, pentamidine and sparfloxacin. A full list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use APO-Amisulpride?

  • Your doctor will tell you how much you should take. The dosage is adjusted for each individual and can range from 50 mg to 800 mg a day, and in some cases up to 1200 mg a day. APO-Amisulpride should preferably be taken before meals.

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

5. What should I know while using APO-Amisulpride?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using APO-Amisulpride.
  • Call your doctor straight away if you have any suicidal thoughts or mental/mood changes.
  • Be careful taking antihistamines, sleeping tablets or tablets to relieve pain as APO-Amisulpride can increase drowsiness.
Things you should not do
  • Do not stop using this medicine unless your doctor tells you to.
  • Do not give APO-Amisulpride to anyone else.
Driving or using machines
  • Do not drive or operate machinery until you know how APO-Amisulpride affects you. APO-Amisulpride may cause drowsiness in some people.
Drinking alcohol
  • The effects of alcohol could be made worse while taking APO-Amisulpride. It is NOT recommended that you drink alcohol while taking this medicine.
Looking after your medicine
  • Store tablets below 25°C, in a cool dry place.

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

6. Are there any side effects?

You may need urgent medical attention if you notice any of these serious side effects: muscle symptoms including pain, weakness, twitching or stiffness, increased levels of an enzyme that measures breakdown of muscle (creatine phosphokinase) in the blood with impaired consciousness and an unexplained fever, abnormal movements, fever, unexplained infections, faster breathing, sweating, yellowing of the skin and eyes, light coloured bowel motions, dark coloured urine. After prolonged use in women, medicines of this type can cause: breast pain, milk secretion, an absence of their monthly period, changes in the regularity of their periods. After prolonged use in men, medicines of this type can cause breast enlargement or impotence.

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

APO-Amisulpride Tablets

Active ingredient(s): amisulpride

Consumer Medicine Information (CMI)

This leaflet provides important information about using APO-Amisulpride. 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 APO-Amisulpride.

Where to find information in this leaflet:

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

1. Why am I using APO-Amisulpride?

APO-Amisulpride contains the active ingredient amisulpride. APO-Amisulpride is an antipsychotic medication.

APO-Amisulpride is used to treat symptoms of schizophrenia. Schizophrenia is a condition which affects the way you think, feel and/or act. Schizophrenia may cause symptoms such as hallucinations (e.g. hearing, seeing or sensing things which are not there), delusions, unusual suspiciousness, emotional and social withdrawal. People with schizophrenia may also feel depressed, anxious or tense.

2. What should I know before I use APO-Amisulpride?

Warnings

Do not use APO-Amisulpride if:

  • you are allergic to amisulpride, or any of the ingredients listed at the end of this leaflet. Signs of an allergic reaction may include a skin rash, itching, shortness of breath or swelling of the face, lips or tongue. Always check the ingredients to make sure you can use this medicine.
  • you are breastfeeding or plan to breastfeed.
  • the packaging is torn or shows signs of tampering or the tablets do not look quite right.
  • you are taking the following medicines:
    - medicines used to treat irregular heart rhythm such as quinidine, disopyramide, amiodarone and sotalol
    - cisapride
    - antibiotics such as erythromycin and pentamidine, given as an injection into the veins
    - levodopa, a medicine used in Parkinson's disease
    - thioridazine, an antipsychotic
    - methadone, medicine used to treat pain or addiction

Check with your doctor if you:

  • take any medicines for any other condition
  • have any other medical conditions, including phaeochromocytoma, a rare tumour of the adrenal glands which sit near the kidneys, tumour of the pituitary gland, a small gland at the base of the brain, breast cancer, liver disease
  • have problems with the heart and blood vessels
  • have, or have a history of blood clots
  • have hyperglycaemia (high sugar levels in the blood) or a family history of diabetes. Your doctor may recommend monitoring your blood sugar levels while you are taking APO-Amisulpride.
  • suffer from dementia.
  • have mental/mood changes or suicidal thoughts. Patients (and caregivers of patients) need to monitor for any worsening of their condition and/or the development of thoughts of suicide, suicidal behaviour or thoughts of harming themselves. Seek medical advice immediately if these symptoms present.
  • have risk factors for stroke
  • have a history, or family history, of breast cancer
  • have a history of sleep apnoea.

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. Amisulpride is not recommended during pregnancy. If you need to take APO-Amisulpride during pregnancy you should discuss the benefits and risks of taking it with your doctor.

Babies exposed to antipsychotic medicines including amisulpride during the third trimester of pregnancy are at risk of experiencing breathing problems, difficulty in feeding, spasms, restlessness, involuntary movements and/or withdrawal symptoms following delivery.

Newborns of mothers who have taken amisulpride during pregnancy need to be carefully monitored.

Talk to your doctor if you are breastfeeding or intend to breastfeed. Amisulpride must not be used when breastfeeding

Use in children

  • This medicine must not be taken by children up to the age of puberty. There is limited information on the use of amisulpride in adolescents and its use is not recommended from puberty to the age of 18 years. If you are not yet 18 years of age, ask your doctor if this medicine is right for you.

3. What if I am taking other medicines?

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

Some medicines may interfere with APO-Amisulpride and affect how it works.

  • medicines used to treat irregular heart rhythm such as quinidine, disopyramide, amiodarone and sotalol
  • other medicines used to treat heart problems such as
  • diltiazem, verapamil, clonidine, digoxin and drugs known as beta blockers (e.g. propranolol)
  • intravenous amphotericin B (amphotericin), an anti-fungal
  • given by injection into the veins
  • other antipsychotics such as thioridazine, clozapine, chlorpromazine, trifluperazine, pimozide, haloperidol, imipramine and lithium
  • diuretics
  • stimulant laxatives
  • glucocorticosteroids
  • diagnostics drugs such as tetracosactides
  • medicines taken for anxiety or to help you sleep (central nervous system depressants)
  • anaesthetics (a medicine used during surgery)
  • medicines taken for depression
  • some strong pain killers
  • antihistamines, medicines to treat allergies, which cause drowsiness
  • some medicines taken to control blood pressure

The use of this medicine together with other antipsychotics, antidepressants and antianxiety agents increases the risk of drowsiness, low blood pressure, coma and death.

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

4. How do I use APO-Amisulpride?

How much to take

  • Your doctor will tell you how many tablets you should take. The dosage is adjusted for each individual and can range from 50 mg a day up to 800 mg a day. In some cases, your doctor may increase the dose to 1200 mg a day.
  • Tablets should be taken once or twice a day as advised by your doctor. Your doctor may increase or decrease your dose depending on your condition.
  • Do not take more than the dose your doctor has recommended.
  • Follow the instructions provided and use APO-Amisulpride until your doctor tells you to stop.

When to take APO-Amisulpride

  • This medicine should preferably be taken before meals. Take your prescribed dose at about the same time each day.

How to take APO-Amisulpride

  • This medicine should be swallowed whole with a glass of water.

If you forget to use APO-Amisulpride

APO-Amisulpride should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember.

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

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

If you use too much APO-Amisulpride

If you think that you have used too much APO-Amisulpride, you may need urgent medical attention.

You should immediately:

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

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

Show the doctor your pack of tablets.

If you have taken too much APO-Amisulpride, you may experience:

  • feeling restless or shaky
  • rigid muscles
  • feeling drowsy or sleepy
  • loss of consciousness leading to coma

5. What should I know while using APO-Amisulpride?

Things you should do

It is very important to continue taking APO-Amisulpride because it will help you stay well.

While you are taking APO-Amisulpride, tell your doctor or pharmacist before you start any new medicine.

Call your doctor straight away if you have any of the following suicidal thoughts or mental/mood changes:

  • thoughts or talk of death or suicide
  • thoughts or talk of self-harm or harm to others
  • any recent attempts of self-harm
  • increase in aggressive behaviour, irritability or agitation
  • depressed mood or worsening of depression

Occasionally, the symptoms of depression may include thoughts of suicide or self-harm. These symptoms may continue to get worse during the early stages of treatment until the effect of the medicine becomes apparent. All mentions of suicide or violence must be taken seriously.

Call your doctor straight away if you experience any of the following:

  • higher than normal body temperature (hyperthermia)
  • muscle stiffness
  • muscle pain in the shoulders, thighs or lower back, muscle weakness or trouble moving arms and legs, dark
  • red or brown urine or increased urination (symptoms of rhabdomyolysis)
  • dizziness upon standing, exercise intolerance, abnormal sweating, loss of appetite, bloating, diarrhoea, constipation, difficulty swallowing, trouble urinating including incomplete emptying of the bladder, ejaculation difficulties, difficult maintaining erections, blurry vision (symptoms of autonomic instability)

These are all symptoms of Neuroleptic Malignant Syndrome (NMS) which is potentially life threatening.

Remind any doctor, dentist or pharmacist you visit that you are using APO-Amisulpride.

Things you should not do

  • Do not stop using this medicine unless your doctor tells you. Do not stop taking your APO-Amisulpride just because you feel better. It is very important to continue APO-Amisulpride because it will help you stay well.
  • Do not drive or operate machinery until you know how this medicine affects you.
  • Do not give this medicine to anyone else. Your doctor has prescribed for you and your condition.

Things to be careful of

  • Be careful if you are elderly or unwell.
  • some people may experience side effects such as drowsiness, confusion, dizziness and unsteadiness. This medicine may affect your ability to move or balance. This may increase the risk of a fall, sometimes leading to fractures.
  • Be careful while taking antihistamines, sleeping tablets or tablets to relieve pain while taking this medicine. APO-Amisulpride can increase drowsiness caused by medicines affecting your nervous system.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APO-Amisulpride affects you.

APO-Amisulpride may cause drowsiness in some people

Drinking alcohol

Tell your doctor if you drink alcohol.

The effects of alcohol could be made worse while taking APO-Amisulpride. It is NOT recommended that you drink alcohol while taking APO-Amisulpride.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly. Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

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

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

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.

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
Heart related:
  • Dizziness. Some people may feel dizzy in the early stages of treatment, especially when getting up from a lying or sitting position. This side effect usually passes after taking this medicine for a few days.
  • drowsiness
Gastrointestinal related:
  • constipation
  • nausea
  • vomiting
  • dry mouth
Eye related:
  • blurred vision
Head and neurology related:
  • insomnia
  • anxiety
  • agitation
  • problems with orgasm
  • trembling*
Muscle related:
  • noticeable muscle stiffness or spasm*
  • slowness of movement
  • restlessness, an overwhelming urge to move and either distress or movements such as pacing, winging of the legs while seated, rocking from foot to foot, or both*
Metabolism and nutrition:
  • weight gain
  • increased appetite
  • excess saliva*
  • high blood sugar. Symptoms include passing more urine that normal, persistent excessive thirst, increased appetite with a loss in weight and weakness.
Other:
  • increased sensitivity to the sun or symptoms of sunburn (such as redness, itching, swelling, blistering) which may occur more quickly than normal
Rare:
  • sleepwalking
  • sleep eating
* These symptoms will usually be reduced if your dose is lowered by your doctor or if your doctor prescribes you an additional medicine.		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
  • muscle symptoms including pain,
  • weakness, twitching or stiffness
  • increased levels of an enzyme that measures breakdown of muscle (creatine phosphokinase) in the blood with impaired consciousness and an unexplained fever
  • abnormal movements mainly of the face, mouth or tongue (symptoms relating to Tardive Dyskinesia)
  • fever
  • unexplained infections
  • faster breathing
  • sweating
  • yellowing of the skin and eyes, also called jaundice
  • light coloured bowel motions
  • dark coloured urine or increased urination
  • higher than normal body temperature (hyperthermia)
  • dizziness upon standing, exercise intolerance, abnormal sweating, loss of appetite, bloating, diarrhoea, difficulty swallowing, trouble urinating including incomplete emptying of the bladder, ejaculation difficulties, difficult maintaining erections, blurry vision (symptoms relating to neuroleptic malignant syndrome)
  • alteration of the heart rhythm (electrical activity of the heart), very fast, uneven or forceful heartbeat (palpitations), weakness, fainting (symptoms relating to QT prolongation)
After prolonged use in women, medicines of this type can cause:
  • breast pain
  • milk secretion
  • an absence of their monthly period
  • changes in the regularity of their periods
Tell your doctor if your monthly periods are absent for six months or more.
After prolonged use in men, medicines of this type can cause breast enlargement or impotence.
Incidences of abnormal liver function have been occasionally reported.		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 APO-Amisulpride contains

Active ingredient
(main ingredient)		amisulpride
Other ingredients
(inactive ingredients)		lactose monohydrate
methylcellulose
sodium starch glycollate (type A)
microcrystalline cellulose
magnesium stearate
The 400 mg tablets also contain:
basic butylated methacrylate copolymer
titanium dioxide
purified talc
macrogol 6000.
Potential allergensContains sugars as lactose.

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

What APO-Amisulpride looks like

Amisulpride 50 mg tablets - white to off-white 6.0mm, round, bi-convex tablets with break line on one side.
AUST R 178900.

Amisulpride 100 mg tablets - white to off-white 8.0mm, round, flat tablets with break line on one side.
AUST R 178904.

Amisulpride 200 mg tablets - white to off-white 11.0mm, round, flat tablets with break line on one side.
AUST R 178902.

Amisulpride 400 mg tablets - white to off-white, 18 x 8mm capsule shaped, film-coated tablets with break line on one side. AUST R 178898.

Available in blister packs of 30, 50, 60, 90 or 100 tablets

*Not all strengths and/or pack sizes may be available.

Who distributes APO-Amisulpride

Arrotex Pharmaceuticals Pty Ltd
15 -17 Chapel Street
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in August 2024.

Published by MIMS December 2024

BRAND INFORMATION

Brand name

APO-Amisulpride

Active ingredient

Amisulpride

Schedule

S4

 

1 Name of Medicine

Amisulpride.

2 Qualitative and Quantitative Composition

Each tablet contains 50 mg, 100 mg, 200 mg or 400 mg amisulpride as the active ingredient.

Excipients with known effect.

Amisulpride tablets contain sugars as lactose.
Amisulpride tablets are gluten free.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

50 mg tablets.

White to off-white 6.0 mm, round, biconvex tablets with breakline on one side.

100 mg tablets.

White to off-white 8.0 mm, round, flat tablets with breakline on one side.

200 mg tablets.

White to off-white 11.0 mm, round, flat tablets with breakline on one side.

400 mg tablets.

White to off-white, 18 x 8 mm capsule shaped film-coated tablets with breakline on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Amisulpride is indicated for the treatment of acute and chronic schizophrenic disorders, in which positive symptoms (such as delusions, hallucinations, thought disorders) and/or negative symptoms (such as blunted affect, emotional and social withdrawal) are prominent, including patients characterised by predominant negative symptoms.

4.2 Dose and Method of Administration

Amisulpride tablets are intended for oral administration.
For acute psychotic episodes, oral doses between 400 mg/d and 800 mg/d are recommended. In individual cases, the daily dose may be increased up to 1200 mg/d. Doses above 1200 mg/d have not been extensively evaluated for safety and therefore should not be used. Doses above 800 mg/d have not been shown to be superior to lower doses and may increase the incidence of adverse events. No specific titration is required when initiating the treatment with amisulpride.
Doses should be adjusted according to individual response.
Doses should preferably be administered before meals.
Amisulpride should be administered twice daily for doses above 400 mg.
For patients with mixed positive and negative symptoms, doses should be adjusted to obtain optimal control of positive symptoms.
Maintenance treatment should be established individually with the minimally effective dose.
For patients characterised by predominant negative symptoms, oral doses between 50 mg/d and 300 mg/d are recommended. Doses should be adjusted individually.

Elderly.

Amisulpride should be used with particular caution because of a possible risk of hypotension or sedation.

Children.

Amisulpride is contraindicated in children up to puberty as its safety has not yet been established.

Renal impairment.

Amisulpride is eliminated by the renal route. In renal insufficiency, the dose should be reduced to half in patients with creatinine clearance (CRCL) between 30-60 mL/min and to a third in patients with CRCL between 10-30 mL/min. As there is no experience in patients with severe renal impairment (CRCL < 10 mL/min) particular care is recommended in these patients (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Since amisulpride is weakly metabolised, a dosage reduction should not be necessary (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Hypersensitivity to the active ingredient or to other ingredients of the product.
Concomitant prolactin-dependent tumours e.g. pituitary gland prolactinomas and breast cancer.
Phaeochromocytoma.
Children up to puberty.
Lactation.
In combination with the following medication which could induce torsades de pointes:
class Ia antiarrhythmic agents such as quinidine and disopyramide;
class III antiarrhythmic agents such as amiodarone and sotalol;
other medications such as bepridil, cisapride, sultopride, thioridazine, methadone, intravenous erythromycin, intravenous vincamine, halofantrine, pentamidine, sparfloxacin.
Levodopa; reciprocal antagonism between levodopa and neuroleptics (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In hepatic impairment, amisulpride may be contraindicated to avoid the possible risk of adverse events due to an influence of the disease on amisulpride metabolism.

4.4 Special Warnings and Precautions for Use

Neuroleptic malignant syndrome (NMS) is a potentially fatal syndrome that has been reported in association with anti-psychotic medicines, including amisulpride. Neuroleptic malignant syndrome is characterised by hyperthermia, muscle rigidity, rhabdomyolysis, autonomic instability, and elevated CPK, may occur. In the event of any symptoms which could suggest NMS, in particular hyperthermia, particularly with high daily doses, all antipsychotic medicines including amisulpride should be discontinued.
Rhabdomyolysis has also been observed in patients without NMS.
Amisulpride can lower the seizure threshold. Therefore patients with a history of seizures should be closely monitored during amisulpride therapy.
Withdrawal symptoms have been described after abrupt cessation of high therapeutic doses of antipsychotic drugs. The emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported with amisulpride. Therefore, gradual withdrawal of amisulpride is advisable.
Leucopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including amisulpride. Unexplained infections or fever may be evidence of blood dyscrasia and requires immediate haematological investigation.
Caution should be also exercised when prescribing amisulpride to patients with Parkinson's disease since it may cause worsening of the disease. Amisulpride should be used only if neuroleptic treatment cannot be avoided.
Amisulpride causes an increase in plasma prolactin levels which is reversible after discontinuation of the medicine. This may result in galactorrhoea, amenorrhoea, gynaecomastia, breast pain, orgasmic dysfunction and impotence.
Acute dystonia (spasm torticollis, oculogyric crisis, trismus) may appear. This is reversible without discontinuation of amisulpride upon treatment with an antiparkinsonian agent.
Extrapyramidal symptoms may occur: tremor, rigidity, hypokinesia, hypersalivation, akathisia. These symptoms are generally mild at optimal dosages and partially reversible without discontinuation of amisulpride upon administration of antiparkinsonian medication. The incidence of extrapyramidal symptoms which is dose related, remains very low in the treatment of patients with predominantly negative symptoms with doses of 50-300 mg/day.
The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and an increased risk of relapse.
Tardive dyskinesia characterised by rhythmic, involuntary movements primarily of the tongue and/or face have been reported, usually after long-term administration. Antiparkinsonian medication is ineffective or may induce aggravation of the symptoms.

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia has been reported in patients treated with some atypical antipsychotic agents, including amisulpride. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increase background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment emergent hyperglycaemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
In patients with significant treatment-emergent hyperglycaemia, discontinuation of amisulpride should be considered.

Prolongation of QT interval.

Amisulpride produces a dose-dependent prolongation of the QT interval (see Section 4.8 Adverse Effects (Undesirable Effects)). This effect is known to potentiate the risk of occurrence of serious ventricular arrhythmias such as torsades de pointes. Before any administration, and if possible according to the patient's clinical status, it is recommended to monitor factors which could favour the onset of this rhythm disorder, for example:
bradycardia less than 55 bpm;
electrolyte imbalance, in particular hypokalaemia;
congenital prolongation of the QT interval;
on-going treatment with a medication likely to produce pronounced bradycardia (< 55 bpm), hypokalaemia, slowing of the intracardiac conduction, or prolongation of the QTc interval (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Stroke.

In randomized clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic medicines, a 3-fold increase of the risk of cerebrovascular events has been observed. The mechanism of such risk increase is not known. An increase in the risk with other antipsychotic medicines, or other populations of patients cannot be excluded. Amisulpride should be used with caution in patients with stroke risk factors.

Venous thromboembolism.

Cases of venous thromboembolism, sometimes fatal, have been reported with antipsychotic drugs. Therefore, amisulpride should be used with caution in patients with risk factors for thromboembolism (see Section 4.8 Adverse Effects (Undesirable Effects)).

Sleep apnoea.

No cases of sleep apnoea clearly attributed to amisulpride have been reported and no epidemiology studies can substantiate this. However, sleep apnoea and related disorders have been reported in patients treated with other antipsychotic medicines, with or without prior history of sleep apnoea, in patients with or without concomitant weight-gain. Patients who have a history of or are at risk for sleep apnoea, or who are concomitantly using central nervous system depressants, should be medically monitored.

Suicide.

The possibility of a suicide attempt is inherent in schizophrenia and close supervision of high-risk patients should accompany therapy. Prescriptions for amisulpride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Breast cancer.

Amisulpride may increase prolactin levels. Therefore, caution should be exercised and patients with a history or a family history of breast cancer should be closely monitored during amisulpride therapy.

Benign pituitary tumour.

Amisulpride may increase prolactin levels. Cases of benign pituitary tumours, such as prolactinoma, have been observed during amisulpride therapy. In case of very high levels of prolactin or clinical signs of pituitary tumour (such as visual field defect and headache), pituitary imaging should be performed. If the diagnosis of pituitary tumour is confirmed, the treatment with amisulpride must be stopped (see Section 4.3 Contraindications).

Use in hepatic impairment.

The impact of hepatic impairment on hepatic metabolism and hepato-biliary excretion of amisulpride has not been studied. Amisulpride should be used with caution in patients with moderate or severe hepatic impairment.

Use in renal impairment.

Amisulpride is eliminated by the renal route. In cases of renal insufficiency, the dose should be decreased and intermittent treatment should be considered (see Section 4.2 Dose and Method of Administration).
There are limited data on the potential for renally-cleared medicines to interfere with the clearance of amisulpride. Therefore, amisulpride should be used with caution with other renally-excreted medicines, including lithium (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

In elderly patients, amisulpride therapy, like other neuroleptics, should be used with particular caution because of a possible risk of hypotension or sedation.

Elderly patients with dementia.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Although the causes of death in clinical trials with atypical antipsychotics were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Paediatric use.

The efficacy and safety of amisulpride from puberty to the age of 18 years have not been established: there are limited data available on the use of amisulpride in adolescents in schizophrenia. Therefore, the use of amisulpride from puberty to the age of 18 years is not recommended. In children up to puberty, the use of amisulpride is contraindicated (see Section 4.3 Contraindications).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

A number of medicines can increase the risk of ventricular arrhythmias including torsades de pointes.

Contraindicated combinations.

Medications which could induce torsades de pointes:
class Ia antiarrhythmic agents such as quinidine and disopyramide;
class III antiarrhythmic agents such as amiodarone and sotalol;
other medications such as bepridil, cisapride, sultopride, thioridazine, methadone, intravenous erythromycin, intravenous vincamine, halofantrine, pentamidine, sparfloxacin.
Levodopa: reciprocal antagonism of effects between levodopa and neuroleptics.

Combinations not recommended.

Amisulpride may enhance the effects of alcohol.
Medications which enhance the risk of torsades de pointes or could prolong the QT interval:
Medicines which induce bradycardia, such as bradycardia-inducing calcium channel blockers (diltiazem, verapamil), beta-blockers, clonidine, guanfacine, digitalis.
Medicines which can cause hypokalaemia, such as diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactides. Hypokalaemia should be corrected.
Neuroleptics such as thioridazine, chlorpromazine, trifluoperazine, pimozide, haloperidol, imipramine antidepressants, lithium.

Combinations to be taken into account.

Concomitant use of amisulpride with other anti-psychotics may increase the risk of developing neuroleptic malignant syndrome.
Co-administration of amisulpride and clozapine may lead to an increase in plasma levels of amisulpride.
Amisulpride may enhance the effects of the following medicines:
CNS depressants including narcotics, anaesthetics, analgesics, sedative, H1-antihistamines, barbiturates, benzodiazepines and other anxiolytic medicines, clonidine and derivatives;
antihypertensive medicines and other hypotensive medications.
A placebo-controlled study of concomitant use of lithium carbonate 500 mg twice daily and a low dose of amisulpride (100 mg) twice daily in healthy young male volunteers showed no effect of amisulpride on the pharmacokinetics of lithium. A small trend towards prolongation of the QTc interval was observed when lithium and amisulpride were co-administered but is not regarded as clinically important.
A study of the effect of concomitant use of cimetidine on amisulpride excretion has not been conducted.
In vitro studies using human liver microsomes and cryopreserved human hepatocytes did not show evidence of significant amisulpride metabolism. Based on these results, it is unlikely that drug interactions involving amisulpride would occur due to inhibition or induction of cytochrome P450-mediated metabolism.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Male rat fertility was unaffected by an amisulpride oral dose resulting in systemic drug exposure (plasma AUC) similar to that in humans, when treatment was carried out prior to mating. Female rat mating was reduced by concurrent amisulpride treatment, but it was normalised within days of cessation of dosing with overall fertility being unaffected, although some adverse effects were observed (see Use in pregnancy).
(Category C)
Neonates exposed to antipsychotic drugs (including amisulpride) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been post-market reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required additional medical treatment or monitoring. All newborns should be carefully monitored to assess the severity of adverse effects.
There was no evidence of teratogenicity in embryofoetal development studies in mice and rabbits following oral doses of up to 2 (mice) and 4 (rabbits) times the maximum recommended human dose based on body surface area, administered daily during the period of organogenesis. Oral treatment of female rats from prior to mating to late gestation or weaning, achieving systemic drug exposure (plasma AUC) similar to that in humans at the maximum dose, was associated with increased preimplantation loss, slight impairment of ossification and reduced pup weight gain to weaning. Teratogenicity was not observed.
Amisulpride crosses the placenta.
The safety of amisulpride during human pregnancy has not been established, and therefore use of this medicine is not recommended during pregnancy and in women of child bearing potential not using effective contraception, unless the benefits justifies the potential risks and the administered dose and duration of treatment should be as low and as short as possible.
 Amisulpride has been found in breast milk of treated women. Breast-feeding is contraindicated.

4.7 Effects on Ability to Drive and Use Machines

Even used as recommended, amisulpride may affect reaction time and/or cause somnolence and blurred vision so that the ability to drive vehicles or operate machinery can be impaired.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The following adverse effects have been observed in controlled clinical trials in at least 1% of treated patients (see Table 1). It should be noted that, in some instances, it can be difficult to differentiate adverse events from symptoms of the underlying disease.
The following CIOMS frequency rating is used, when applicable: very common ≥ 10%; common ≥ 1 and < 10%; uncommon ≥ 0.1 and < 1%; rare ≥ 0.01 and < 0.1%; very rare < 0.01%; not known (cannot be estimated from available data).
The following adverse reactions have been observed in controlled clinical trials and through spontaneous reporting. See Table 2.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems or contact Arrotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Experience with amisulpride in overdosage is limited. Exaggerations of the known pharmacological and adverse effects of amisulpride have been reported. These may include drowsiness, sedation, hypotension, extrapyramidal symptoms and coma.
Fatal outcomes have been reported mainly in combination with other psychotropic agents.

Treatment.

In cases of acute overdose, the possibility of multiple drug intake should be considered.
There is no specific antidote to amisulpride. Appropriate supportive measure should therefore be instituted: close supervision of vital functions and, because of the risk of prolongation of QT interval, continuous cardiac monitoring until the patient recovers.
If severe extrapyramidal symptoms occur, anticholinergic agents should be administered.
Since amisulpride is weakly dialysed, haemodialysis is not recommended as a method of elimination.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Class.

Neuroleptic of the benzamide class.
Amisulpride binds selectively to the human dopaminergic D2 (Ki 2.8 nanoM) and D3 (Ki 3.2 nanoM) receptor subtypes without any affinity for D1, D4 and D5 receptor subtypes (Ki > 1 microM). Unlike classical and atypical neuroleptics, amisulpride displays low affinity for serotonin, α-adrenergic, histamine receptor subtypes, muscarinic receptors and sigma sites.
In the rodent, it preferentially blocks post-synaptic D2 receptors located in the limbic structures as compared to those in the striatum as indicated by its reversal of d-amphetamine-induced hyperactivity without affecting stereotypies. In addition, it does not induce catalepsy and it does not produce D2 hypersensitivity after repeated treatment.
Moreover, it preferentially blocks pre-synaptic D2/D3 dopamine receptors, producing dopamine release responsible for its disinhibitory effects.
This atypical pharmacological profile may explain amisulpride's antipsychotic effect at higher doses through post-synaptic dopamine receptor blockade located in the limbic areas and its efficacy against negative symptoms, at lower doses, through presynaptic dopamine receptor blockade. In addition, the reduced tendency of amisulpride to produce extrapyramidal side effects may be related to its preferential limbic activity.

Clinical trials.

The efficacy of amisulpride in the treatment of schizophrenia has been established on the basis of eleven phase II and III studies conducted in 20 countries and involving 1933 patients (1247 treated with amisulpride) belonging to two distinct populations:
patients with acute exacerbations of schizophrenia;
patients with predominant negative schizophrenia.
These studies form the basis of the registration documentation for amisulpride. Seven of them are considered pivotal for efficacy and their results are summarized below.

Acute exacerbations of schizophrenia.

In four well-controlled double-blind studies versus reference medicines in patients with acute schizophrenia according to DSM III-R and DSM-IV criteria, amisulpride was at least as effective as haloperidol, flupenthixol and risperidone. In addition to its global antipsychotic activity, amisulpride significantly alleviated secondary negative symptoms as well as affective symptoms such as depressed mood and retardation.
1. A 4-week double-blind active-controlled trial (n = 319) compared four fixed doses of amisulpride (100 mg/d, 400 mg/d, 800 mg/d and 1200 mg/d) and a fixed dose of haloperidol (16 mg/d). A dose response relationship was clearly established in comparison to 100 mg/d, chosen as a potentially subtherapeutic dose in acute schizophrenia. Amisulpride at doses of 400 mg/d and 800 mg/d statistically significantly improved positive symptoms (BPRS total score, PANSS positive symptoms subscale) compared with amisulpride 100 mg/d. 800 mg/d of amisulpride was also statistically significantly superior to 100 mg/d for response rates based on the CGI.
2. Efficacy results were similar in the three other short-term controlled studies where 800 mg/d of amisulpride was compared with 20 mg/d of haloperidol (n = 191), 1000 mg/d of amisulpride with 25 mg/d of flupenthixol (n = 132) and 800 mg/d of amisulpride with 8 mg of risperidone (n = 228). On BPRS total score and PANSS positive subscale, amisulpride was not found to be different from haloperidol and flupenthixol and showed equivalent efficacy to risperidone. Additionally, amisulpride significantly improved the response rate with CGI versus haloperidol.

Predominant negative schizophrenia.

Three pivotal trials were conducted versus placebo in schizophrenic patients with predominant negative symptoms according to DSM III and DSM III-R, showing that low doses of amisulpride are active against negative symptoms.
1. In a six-week dose finding study (n = 104), amisulpride 100 mg/d and 300 mg/d were significantly better than placebo on the basis of the SANS total score.
2. In an additional 3-month dose finding study (n = 242) testing two fixed dose of amisulpride (50 mg/d and 100 mg/d) versus placebo, both doses of amisulpride were significantly more active in improving the negative symptoms than placebo on the SANS total score. Additionally, there was a significant improvement of the MADRS scores in the two amisulpride groups.
3. A medium/long-term placebo controlled study with amisulpride 100 mg/d over 6 months with the possibility of extension up to 12 months was conducted to demonstrate the maintenance of efficacy over time. Amisulpride improved negative symptoms (SANS total score) significantly compared with placebo, and the response rate with CGI was significantly higher in the amisulpride group versus placebo. The results were confirmed by the significant improvement of global functioning measured with the GAF. SANS total score remained stable over time up to 12 months, indicating that 100 mg/d not only maintains the improvement of negative symptoms but has also an effect on preventing the recurrence of positive symptoms.

5.2 Pharmacokinetic Properties

Absorption.

In man, amisulpride shows two absorption peaks: one which is attained rapidly, one hour post-dose and a second between 3 and 4 hours after administration. Corresponding plasma concentrations are 39 ± 3 and 54 ± 4 nanogram/mL after a 50 mg dose.

Distribution.

The volume of distribution is 5.8 L/kg. As plasma protein binding is low (16%), drug interactions due to displacement are unlikely.
The absolute bioavailability of amisulpride tablets is 48%. Amisulpride tablets are not interchangeable with amisulpride solution.

Metabolism.

Amisulpride is weakly metabolised: two inactive metabolites, accounting for approximately 4% of the dose, have been identified. The elimination half-life of amisulpride is approximately 12 hours after an oral dose.

Excretion.

Fifty percent of an intravenous dose is excreted via the urine, the majority as unchanged drug. Ninety percent of the intravenous dose is eliminated in the first 24 hours. Renal clearance is in the order of 20 L/h or 330 mL/min.
Following a single intravenous dose, about 20% of the dose was recovered from the faeces, about 70% of which was as unchanged amisulpride. Hepatic metabolism has a limited role in healthy patients.
A high-carbohydrate low-fat meal (14 g protein, 8 g fat, 108 g CHO) significantly decreases the AUC, Tmax and Cmax of amisulpride, but no changes were seen after a high fat meal. However, the significance of these findings in routine clinical use is not known.

Hepatic insufficiency.

See Section 4.4 Special Warnings and Precautions for Use.

Renal insufficiency.

In patients with renal insufficiency systemic clearance is reduced by a factor of 2.5 to 3. The AUC of amisulpride in mild renal failure increased two-fold and almost ten-fold in moderate renal failure. Experience is, however, limited and there is no data with doses greater than 50 mg.
Amisulpride is very weakly dialysed.
Limited pharmacokinetic data in elderly subjects (> 65 years) show that a 10-30% rise occurs in Cmax, T1/2 and AUC after a single oral dose of 50 mg. No data are available after repeat dosing.

5.3 Preclinical Safety Data

An overall review of the completed safety studies indicates that amisulpride is devoid of any general, organ-specific, teratogenic, mutagenic or carcinogenic risk. Changes observed in rats and dogs at doses below the maximum tolerated dose are either pharmacological effects or are devoid of major toxicological significance under these conditions. Compared with the maximum recommended dosages in man, maximum tolerated doses are 2 and 7 times greater in the rat (200 mg/kg/d) and dog (120 mg/kg/d) respectively in terms of AUC. No carcinogenic risk, relevant to man, was identified in the mouse (up to 120 mg/kg/d) and in the rat (up to 240 mg/kg/d), corresponding for the rat to 1.5 to 4.5 times the expected human AUC.
Reproductive studies performed in the rat, rabbit and mouse did not show any teratogenic potential.

Genotoxicity.

Amisulpride showed no genotoxicity in in vitro tests for bacterial gene mutation, or in in vitro and in vivo tests for clastogenic activity. Please also see Section 5.3 Preclinical Safety Data, Carcinogenicity.

Carcinogenicity.

In carcinogenicity studies, amisulpride was administered in the diet of mice and rats for up to two years. Treatment of mice was associated with increases in malignant mammary gland tumours and pituitary adenomas in females at all dose levels, but there was no tumourigenic response in males (doses were equivalent to 0.1, 0.2 and 0.5 times the maximum human dose of 1200 mg/day on a body surface area basis). Treatment of rats resulted in increased incidences of malignant mammary gland tumours in both sexes, malignant pituitary tumours and adrenal medullary phaeochromocytomas in males, and malignant pancreatic islet cell tumours in both sexes, at doses achieving lower systemic drug exposure (plasma AUC) than in humans at the maximal recommended dose. Increases in mammary gland, pituitary, adrenal and pancreatic endocrine tumours in rodents have been reported for other antipsychotic medicines, and are considered to result from increased prolactin secretion.
The relevance of prolactin-mediated endocrine tumours in rodents for human risk is unknown. In clinical trials, amisulpride substantially elevated plasma prolactin concentrations, although to date neither clinical nor epidemiological studies have shown an association between chronic administration of neuroleptic medicines and mammary tumourigenesis. However, since tissue culture experiments indicate that about one-third of human breast cancers are prolactin-dependent in vitro, amisulpride should be used cautiously in patients with previously-detected breast cancer or in patients with pituitary tumours (see Section 4.3 Contraindications).

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, methylcellulose, sodium starch glycollate type A, microcrystalline cellulose, magnesium stearate, basic butylated methacrylate copolymer (400 mg tablets only), titanium dioxide (400 mg tablets only), purified talc (400 mg tablets only), macrogol 6000 (400 mg tablets only).

6.2 Incompatibilities

No data available.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

50 mg tablets.

Blisters (Al/PVC) of 60, 90 or 100 tablets (AUST R number 178900).

100 mg tablets.

Blisters (Al/PVC) of 30, 50, 60, 90 or 100 tablets (AUST R number 178904).

200 mg tablets.

Blisters (Al/PVC) of 50, 60, 90 or 100 tablets (AUST R number 178902).

400 mg tablets.

Blisters (Al/PVC) of 10, 50, 60, 90 or 100 tablets (AUST R number 178898).
Not all strengths and/or pack sizes may be available.

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

Amisulpride is a white or almost white crystalline powder which is practically insoluble in water, freely soluble in methylene chloride, and sparingly soluble in anhydrous ethanol.

Chemical structure.


CAS number.

71675-85-9.
Chemical Name: (R, S)-4-Amino-N- [1-ethyl-2-pyrrolidinyl) methyl]-5-ethylsulfonyl-2-methoxybenxamide.
Molecular Formula: C17H27N3O4S.
Molecular Weight: 369.48.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes