Consumer medicine information

Amipride 400

Amisulpride

BRAND INFORMATION

Brand name

Amipride 400

Active ingredient

Amisulpride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Amipride 400.

What is in this leaflet

This leaflet answers some common questions about AMIPRIDE.

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

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

Talk to your doctor or pharmacist if you have any concerns about taking this medicine.

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

What AMIPRIDE 400 is used for

AMIPRIDE belongs to a group of medicines called antipsychotics.

AMIPRIDE is used to treat the symptoms of schizophrenia.

Schizophrenia is a condition which can affect the way you think, feel and act. Schizophrenia may cause symptoms such as hallucinations (eg 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.

Your doctor may have prescribed AMIPRIDE for another reason.

Ask your doctor if you have any questions about why AMIPRIDE 400 has been prescribed for you.

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

Before you take it

When you must not take it

Do not take amisulpride if:

  • you have an ALLERGIC REACTION 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.
  • you are breastfeeding or plan to breastfeed.
  • 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
    - thioridazone, an antipsychotic
    - methadone, medicine used to treat pain or addiction
  • the packaging is torn or shows signs of tampering or the tablets do not look quite right.
  • the expiry date on the pack has passed.

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

  • 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

amisulpride 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 amisulpride is right for you.

Before you start to take it

Your doctor must know about all the following before you start to take Amipride 400.

Tell your doctor if:

  1. you have had an allergic reaction to any medicine which you have taken previously to treat your current condition.
  2. you are pregnant, think you may be pregnant or intend to become pregnant. Amipride 400. is not recommended for use in pregnancy. If you need to take Amipride 400 during pregnancy you should discuss the benefits and risks of taking it with your doctor. Newborns of mothers who have taken Amipride 400 during pregnancy need to be carefully monitored.
  3. you suffer from lactose intolerance because Amipride 400. tablets contain lactose.
  4. you have kidney or liver disease, Parkinson's disease or fits (seizures).
  5. you have problems with the heart and blood vessels.
  6. you have, or have a history of blood clots.
  7. you 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 Amipride 400.
  8. you suffer from dementia.
  9. you 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.
  10. you have risk factors for stroke.
  11. you have a history, or family history, of breast cancer.

Taking other medicines

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

Some medicines may be affected by AMIPRIDE 400, or may affect how well it works. These include:

  • 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, 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
  • 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

If you are unsure about any medicine you are taking, you should check with your doctor or pharmacist. They will have more information on medicines to be careful of while you are taking Amipride 400.

How to take AMIPRIDE 400

How much to take

Your doctor will tell you how many tablets you need to take each day and when to take them. The dosage is adjusted for each individual and can range from 50mg a day up to 800mg a day. In some cases your doctor may increase the dose to 1200mg a day.

Follow all directions given to you by your doctor and pharmacist carefully.

How to take it

Swallow the tablets with a glass of water. Tablets should preferably be taken before meals. Take your prescribed dose at about the same time each day.

If you forget to take it

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

Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

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

Ask your doctor or pharmacist if you are not sure what to do.

How long to take it for

It is important that you do NOT stop taking AMIPRIDE 400 unless your doctor tells you. Do not stop taking it, even if you feel better. It is very important to continue taking your medicine to help you stay well.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26) or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much AMIPRIDE 400. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much AMIPRIDE 400, you may feel drowsy or have slurred speech.

While you are taking it

Things you must do

It is very important to continue taking Amipride 400 because it will help you stay well.

Tell all doctors, dentists and pharmacists who are treating you that you are taking Amipride 400.

While you are taking Amipride 400, tell your doctor or pharmacist before you start any new medicine.

Make sure you use a contraceptive to prevent pregnancy during treatment with Amipride 400. If you become pregnant while taking this medicine, tell your doctor immediately.

Tell your doctor immediately, or go to the nearest hospital, 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.

Things to be careful of

Amipride 400 may cause drowsiness in some people.

Be careful driving or operating machinery until you know how Amipride 400 affects you.

Be careful if you are elderly or unwell. Some people may experience side effects such as drowsiness, confusion, dizziness and unsteadiness, which may increase the risk of a fall.

The effects of alcohol could be made worse while taking Amipride 400. It is NOT recommended that you drink alcohol while taking Amipride 400.

Be careful while taking antihistamines, sleeping tablets or tablets to relieve pain while taking this medicine. Amipride 400 can increase drowsiness caused by medicines affecting your nervous system.

Things you must NOT do

Do not drive or operate machinery until you know how Amipride 400 affects you.

Do not give Amipride 400 to anyone else. Your doctor has prescribed it for you and your condition.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Amipride 400.

Like other medicines, amipride 400 can cause some side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and may need medical attention. Some of the side effects are dose related, so it is important that you never exceed your prescribed dose.

While you are taking Amipride 400

Tell your doctor if you notice any of the following and they worry you:

  • drowsiness
  • weight gain
  • dizziness
  • increased appetite
  • nausea
  • vomiting
  • constipation
  • dry mouth
  • blurred vision
  • insomnia
  • anxiety
  • agitation
  • problems with orgasm

These are the most common side effects of Amipride 400.

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 Amipride 400 for a few days.

Sometimes trembling, noticeable muscle stiffness or spasm, slowness of movement, excess saliva, restlessness, an overwhelming urge to move and either distress or movements such as pacing, swinging of the legs while seated, rocking from foot to foot, or both can occur.

This will usually be reduced if your dose of amipride 400 is lowered by your doctor or if your doctor prescribes you an additional medicine.

High blood sugar has been reported in patients taking Amipride 400 Symptoms of high sugar levels in the blood include passing more urine than normal, persistent excessive thirst, increased appetite with a loss in weight and weakness.

Some people experience increased sensitivity to the sun or notice symptoms of sunburn (such as redness, itching, swelling, blistering) which may occur more quickly than normal.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • muscle twitching
  • abnormal movements mainly of the face or tongue
  • fever
  • unexplained infections
  • faster breathing
  • sweating
  • muscle stiffness
  • yellowing of the skin and eyes, also called jaundice
  • light coloured bowel motions
  • dark coloured urine

If this occurs, stop taking Amipride 400 immediately and contact your doctor.

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.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor if you notice any symptoms that worry you, even if you think the problems are not connected with the medicine or are not listed in this leaflet.

After using AMIPRIDE 400

Storage

Keep your medicine 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.

Keep your tablets in a cool, dry place where the temperature stays below 25°C.

Do not store this, or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking this medicine, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

AMIPRIDE 400 is a white to off white 18 x 8 mm capsule shaped, film coated tablet with a break line on one side.

Each pack contains 60 tablets.

Ingredients

The active ingredient in AMIPRIDE 400 is amisulpride. Each AMIPRIDE 400 tablet contains 400 mg of amisulpride.

The tablets also contain:

  • lactose monohydrate
  • methylcellulose
  • sodium starch glycollate
  • magnesium stearate
  • microcrystalline cellulose
  • Eudragit E100
  • purified talc
  • macrogol 6000
  • titanium dioxide.

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

Supplier

Arrow Pharma Pty Ltd
15 – 17 Chapel Street
Cremorne VIC 3121

Australian registration number:

AMIPRIDE 400 - AUST R 140231

This leaflet was revised in March 2021.

Published by MIMS April 2021

BRAND INFORMATION

Brand name

Amipride 400

Active ingredient

Amisulpride

Schedule

S4

 

1 Name of Medicine

Amisulpride.

2 Qualitative and Quantitative Composition

Amipride 400 tablets contain 400 mg of amisulpride.

Excipients with known effect.

Contains sugars as lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Amipride 400 tablets are a white to off white 18 x 8 mm capsule shaped, film coated tablet with a break line on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

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.

4.2 Dose and Method of Administration

For acute psychotic episodes, oral doses between 400 and 800 mg/day are recommended. In individual cases, the daily dose may be increased up to 1,200 mg/day. Doses above 1,200 mg/day have not been extensively evaluated for safety and therefore should not be used. Doses above 800 mg/day 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 bid (twice daily) for doses above 400 mg.

Chronic schizophrenic disorders.

Amipride 400 tablets are available as a 400 mg tablet only. It is recommended that Amipride 400 is used only for patients already established on amisulpride 400 mg tablets. It should not be used for initiation of treatment with amisulpride tablets or for dosage titration as different strength tablets may be required.

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 insufficiency.

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

Hepatic insufficiency.

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

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.

Neuroleptic malignant syndrome (NMS) is a potentially fatal syndrome that has been reported in association with antipsychotic drugs, including amisulpride. Neuroleptic malignant syndrome, characterised by hyperthermia, muscle rigidity, 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 drugs including amisulpride should be discontinued.

Use in patients with a history of seizures.

Amisulpride can lower the seizure threshold. Therefore patients with a history of seizures should be closely monitored during amisulpride therapy.

Antipsychotic drugs.

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.

Leukopenia, neutropenia and agranulocytosis.

Leukopenia, 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.

Use in patients with Parkinson's disease.

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.

Increase in plasma prolactin levels.

Amisulpride causes an increase in plasma prolactin levels which is reversible after drug discontinuation. This may result in galactorrhoea, amenorrhoea, gynaecomastia, breast pain, orgasmic dysfunction and impotence.

Acute dystonia.

Acute dystonia (spasm torticollis, oculogyric crisis, trismus) may appear. This is reversible without discontinuation of amisulpride upon treatment with an antiparkinsonian agent.

Extrapyramidal symptoms.

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 to 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.

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, 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 (beats per minute);
electrolyte imbalance, in particular hypokalaemia;
congenital prolongation of the QT interval;
ongoing 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 randomised 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 hepatobiliary 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, Renal insufficiency).
There are limited data on the potential for renally-cleared drugs to interfere with the clearance of amisulpride. Therefore, amisulpride should be used with caution with other renally excreted drugs, 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. Amisulpride is contra-indicated in children up to puberty (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, trifluperazine, pimozide, haloperidol, imipramine antidepressants, lithium.

Combinations to be taken into account.

Concomitant use of amisulpride with other antipsychotics 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 drugs.

CNS depressants including narcotics, anaesthetics, analgesics, sedative H1 antihistamines, barbiturates, benzodiazepines and other anxiolytic drugs, clonidine and derivatives;
antihypertensive drugs 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 coadministered 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 oral amisulpride 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 Section 4.6 Fertility, Pregnancy and Lactation, 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 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 embryofetal 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 amisulpride is not recommended during pregnancy and in women of child bearing potential not using effective contraception, unless the benefits justify 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: greater than or equal to 10%; common: > 1% to < 10%; uncommon: greater than or equal to 0.1% to < 1%; rare: greater than or equal to 0.01% to < 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.

Blood and lymphatic system disorders.

Uncommon: leukopenia, neutropenia.
Rare: agranulocytosis.

Immune system disorders.

Uncommon: allergic reactions.

Endocrine disorders.

Common: amisulpride causes an increase in plasma prolactin levels which is reversible after drug discontinuation. This may lead to galactorrhoea, amenorrhoea, gynaecomastia, breast pain, erectile dysfunction.
Rare: benign pituitary tumour, such as prolactinoma (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Metabolism and nutrition disorders.

Uncommon: hyperglycaemia (see Section 4.4 Special Warnings and Precautions for Use), hypertriglyceridaemia and hypercholesterolaemia.
Rare: hyponatraemia and syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Psychiatric disorders.

Common: insomnia, anxiety, agitation, orgasmic dysfunction.
Uncommon: confusion.

Nervous system disorders.

Very common: extrapyramidal sysmptoms may occur: tremor, rigidity, hypokinesia, hypersalivation, akathisia, dyskinesia. These symptoms are generally mild at optimal dosages and partially reversible without discontinuation of amisulpride upon administration of anti-Parkinson medication.
Common: acute dystonia (spasm torticollis, oculogyric crisis, trismus) may appear. This is reversible without discontinuation of amisulpride upon treatment with an anti-Parkinson agent. Somnolence.
Uncommon: tardive dyskinesia characterised by rhythmic, involuntary movements primarily of the tongue and/or face have been reported, usually after long-term administration. Anti-parkinsonian medication is ineffective or may induce aggravation of the symptoms. Seizures.
Rare: Neuroleptic Malignant Syndrome, which is a potentially fatal complication (see Section 4.4 Special Warnings and Precautions for Use).
Somnambulism (sleepwalking) and related behaviours including sleep-related eating disorder have been reported with the use of atypical antipsychotic medicines, including amisulpride.
Not known: restless legs syndrome with or without a context of akathisia.

Eye disorders.

Common: blurred vision.

Cardiac disorders.

Common: QT interval prolongation (see Section 4.4 Special Warnings and Precautions for Use).
Uncommon: bradycardia.
Rare: ventricular arrhythmias such as torsades de pointes, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest, sudden death (see Section 4.4 Special Warnings and Precautions for Use).

Vascular disorders.

Common: hypotension.
Uncommon: increase in blood pressure.
Rare: venous thromboembolism, including pulmonary embolism, sometimes fatal, and deep vein thrombosis have been reported (see Section 4.4 Special Warnings and Precautions for Use).

Respiratory, thoracic and mediastinal disorders.

Uncommon: nasal congestion, pneumonia aspiration (mainly in association with other antipsychotics and CNS depressants).

Gastrointestinal disorders.

Common: constipation, nausea, vomiting, dry mouth.

Hepatobiliary disorders.

Uncommon: hepatocellular injury.

Skin and subcutaneous tissue disorders.

Rare: angioedema and urticaria.
Not known: photosensitivity reaction.

Musculoskeletal and connective tissue disorders.

Uncommon: osteopenia and osteoporosis.

Renal and urinary disorders.

Uncommon: urinary retention.

Injury, poisoning and procedural complications.

Not known: fall as a consequence of adverse reactions compromising body balance.

Pregnancy, puerperium and perinatal conditions.

Frequency not known: neonatal drug withdrawal syndrome.

Investigations.

Common: weight gain.
Uncommon: elevations of hepatic enzymes, mainly transaminases.

Reporting suspected adverse effects.

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

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

Symptoms.

Experience with amisulpride in overdosage is limited. Exaggeration of the known pharmacological and adverse effects of amisulpride have been reported. These may include drowsiness, sedation, coma, hypotension and extrapyramidal symptoms.

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 the 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 the method of elimination.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 postsynaptic 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 stereotypes. In addition, it does not induce catalepsy and it does not produce D2 hypersensitivity after repeated treatment.
Moreover, it preferentially blocks presynaptic 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 postsynaptic 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 1,933 patients (1,247 treated with amisulpride). These studies form the basis of the registration documentation for amisulpride. Four of them are considered pivotal for efficacy in the treatment of acute exacerbations of schizophrenia and their results are summarised below.

Acute exacerbations of schizophrenia.

In four well controlled double blind studies versus reference drugs 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.
A four week double blind active controlled trial (n = 319) compared four fixed doses of amisulpride (100, 400, 800 and 1,200 mg/day) and a fixed dose of haloperidol (16 mg/day). A dose response relationship was clearly established in comparison to 100 mg/day, chosen as a potentially subtherapeutic dose in acute schizophrenia. Amisulpride at doses of 400 and 800 mg/day statistically significantly improved positive symptoms (BPRS total score, PANSS positive symptoms subscale) compared with amisulpride 100 mg/day. Amisulpride 800 mg/day was also statistically significantly superior to 100 mg/day for response rates based on the CGI.
Efficacy results were similar in the three other short-term controlled studies where amisulpride 800 mg/day was compared with haloperidol 20 mg/day (n = 191), amisulpride 1,000 mg/day with flupenthixol 25 mg/day (n = 132) and amisulpride 800 mg/day with risperidone 8 mg (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.

5.2 Pharmacokinetic Properties

Absorption.

In humans, amisulpride shows an absorption peak at 3.5 hours after administration. The corresponding plasma concentration is 1834 ± 706 nanogram/mL after a 400 mg dose.
A high carbohydrate (CHO), 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.

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%.

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.

50% of an intravenous dose is excreted via the urine, the majority as unchanged drug. 90% of the intravenous dose is eliminated in the first 24 hours. Renal clearance is in the order of 20 L/hour or 330 mL/minute.
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.

Hepatic insufficiency.

See Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment.

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 twofold and almost tenfold 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 to 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 humans, maximum tolerated doses are 2 and 7 times greater in the rat (200 mg/kg/day) and dog (120 mg/kg/day) respectively in terms of AUC. No carcinogenic risk relevant to humans was identified in the mouse (up to 120 mg/kg/day) and in the rat (up to 240 mg/kg/day), corresponding for the rat to 1.5 to 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.

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 tumorigenic response in males (doses were equivalent to 0.1, 0.2 and 0.5 times the maximum human dose of 1,200 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 drugs, 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 drugs and mammary tumorigenesis. 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

Amipride 400 tablets contain 400 mg of amisulpride. The tablets also contain the following excipients: lactose monohydrate, methylcellulose, sodium starch glycollate, microcrystalline cellulose, magnesium stearate, purified talc, macrogol 600, titanium dioxide and eudragit E100 (ARTG No. 1753).
The tablets are gluten free.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Amipride 400 tablets are available in PVC/Aluminium blister packs of 60 tablets.

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. Practically insoluble in water, freely soluble in methylene chloride, sparingly soluble in anhydrous ethanol.

Chemical structure.


CAS number.

CAS No.: 71675-85-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes