Consumer medicine information

Amisolan

Amisulpride

BRAND INFORMATION

Brand name

Amisolan

Active ingredient

Amisulpride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Amisolan.

What is in this leaflet

This leaflet answers some common questions about AMISOLAN.

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 AMISOLAN against the benefits they expect it will have for you.

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

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

What AMISOLAN is used for

AMISOLAN is used to treat symptoms of schizophrenia.

Schizophrenia is a condition whichaffects the way you think, feel and/or 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.

AMISOLAN belongs to a group of medicines called antipsychotics.

Your doctor may have prescribed AMISOLAN for another reason.

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

AMISOLAN must not be taken by children up to the age of puberty. There is limited information on the use of AMISOLAN 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 AMISOLAN is right for you.

AMISOLAN is available only with a doctor's prescription.

Before you take AMISOLAN

When you must not take it

Do not take AMISOLAN if you are allergic to medicines containing amisulpride or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

Do not take AMISOLAN if 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 pentamidene, 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.

Do not take AMISOLAN if you are breastfeeding or planning to breastfeed.

Do not take AMISOLAN if the expiry date (Exp.) printed on the pack has passed.

Do not take AMISOLAN if the packaging is torn or shows signs of tampering.

Do not take AMISOLAN 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.

Before you start to take it

Tell your doctor if:

  • you have had an allergic reaction to any medicine which have taken previously to treat your current condition.
  • any other substances, such as foods, preservatives or dyes
  • you suffer from lactose intolerance because AMISOLAN tablets contain lactose.

Tell your doctor if you are pregnant or plan to become pregnant. AMISOLAN is not recommended for use in pregnancy. Your doctor will discuss the risks and benefits of taking AMISOLAN during pregnancy. Newborns and mothers who have taken AMISOLAN during pregnancy need to be carefully monitored.

Tell your doctor if you are breastfeeding or wish to breastfeed. Your doctor will discuss the risks and benefits of taking AMISOLAN when breastfeeding.

Tell your doctor if you have any medical conditions, especially the following:

  • kidney or liver disease, Parkinson’s disease or seizures
  • problems with the heart and blood vessels
  • a history of blood clots
  • 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 AMISOLAN.
  • suffer from dementia
  • mental/mood changes or suicidal thoughts. Patients (and care givers 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
  • risk factors for stroke
  • history or family history of breast cancer.

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

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

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 AMISOLAN, 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 treatheart problems such as diltiazem,verapamil, clonidine, digoxin anddrugs known as beta blockers(e.g. propranolol)
  • intravenous amphotericin B, ananti-fungal given by injection into the veins
  • other antipsychotics such asthioridazine, chlorpromazine,trifluperazine, pimozide,haloperidol, imipramine andlithium
  • diuretics
  • stimulant laxatives
  • glucocorticosteriods
  • diagnostics drug such as tetracosactides
  • medicines taken for anxiety or to help you sleep
  • medicines taken for depression
  • some strong pain killers
  • antihistamines, medicines to treat allergies, which cause drowsiness
  • some medicines taken to control blood pressure.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking AMISOLAN.

How to take AMISOLAN

How much to take

Your doctor will tell you how many tablets you need to take each day and when to take them. This depends on your condition and whether or not you are taking any other medicines. 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.

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

Do not take more than the dose your doctor has recommended.

How to take AMISOLAN

Swallow the tablets whole with a glass of water.

If you forget to take AMISOLAN

If you forget to take your medicine, take your dose as soon as you remember.

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

If you are not sure what to do, ask your doctor or pharmacist.

How long to take AMISOLAN for

It is important that you do NOT stop taking AMISOLAN unless your doctor tells you. Do not stop taking AMISOLAN just because you feel better. It is very important to continue AMISOLAN because it will help you stay well.

Keep taking AMISOLAN for as long as your doctor recommends.

If you take too much AMISOLAN (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 AMISOLAN. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much AMISOLAN, you may feel drowsy and have slurred speech.

While you are taking AMISOLAN

Things you must do

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

Before starting any new medicine, tell your doctor or pharmacist that you are taking AMISOLAN.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking AMISOLAN.

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 effect of the medicine becomes apparent. All mentions of suicide or violence must be taken seriously.

Visit your doctor regularly so they can check on your progress.

Things you must not do

Do not use AMISOLAN to treat any other conditions unless your doctor tells you to.

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

Things to be careful of

Be careful driving or operating machinery until you know how AMISOLAN affects you. AMISOLAN may cause drowsiness, dizziness or light headedness in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

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.

Be careful when drinking alcohol while taking AMISOLAN the effects may be worse. It is NOT recommended that you drink alcohol while taking AMISOLAN.

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

Side effects

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

Like all other medicines, AMISULPRIDE may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. Some side effects are dose related, so it is important that you never exceed your prescribed dose.

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

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

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
  • insomnia
  • anxiety
  • agitation
  • problems with orgasm.

These are the most common side effects of AMISOLAN.

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 AMISOLAN 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 AMISOLAN is lowered by your doctor or if your doctor prescribes you an additional medicine.

High blood sugar has been reported in patients taking AMISOLAN. 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.

Tell your doctor immediately or go to Accident and Emergency at the 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

If this occurs, stop taking AMISOLAN 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.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

After using AMISOLAN

Storage

Keep AMISOLAN 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 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.

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

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

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

Disposal

If your doctor tells you to stop taking AMISOLAN, 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

AMISOLAN comes in 3 strengths of tablets:

  • AMISOLAN 100 - White, round, flat tablets embossed MC on one side
  • AMISOLAN 200 - White, round, flat scored on one side tablets
  • AMISOLAN 400 - White, biconvex, capsule shaped tablets, scored on both sides.

The 100 mg, 200 mg and 400 mg strengths are available in pack sizes of 30, 60 and 90 tablets.

Ingredients

The active ingredient in AMISOLAN is amisulpride.

  • each AMISOLAN 100 tablet contains 100 mg of amisulpride
  • each AMISOLAN 200 tablet contains 200 mg of amisulpride.
  • each AMISOLAN 400 tablet contains 400 mg of amisulpride.

The tablets also contain:

  • microcrystalline cellulose
  • hypromellose
  • magnesium stearate
  • lactose monohydrate
  • sodium starch glycollate A.

The tablet contains sugars as lactose

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

Supplier

Southern Cross Pharma Pty Ltd
Suite 5/118 Church Street
Hawthorn, VIC 3122,
Australia

Australian registration numbers:

AMISOLAN 100
AUST R 234715

AMISOLAN 200
AUST R 234701

AMISOLAN 400
AUST R 234705

Date of preparation:
October 2018

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Amisolan

Active ingredient

Amisulpride

Schedule

S4

 

1 Name of Medicine

Amisulpride.

2 Qualitative and Quantitative Composition

Amisolan tablets come in four strengths and contain either 50 mg, 100 mg, 200 mg or 400 mg of amisulpride. Excipients with known effect: lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Amisolan 50 mg tablets.

White round flat tablet with diameter 7 mm.

Amisolan 100 mg tablets.

White round flat tablet with diameter 9.5 mm, embossed with MC on one side.

Amisolan 200 mg tablets.

White round flat tablet scored on one side with diameter 11.5 mm.

Amisolan 400 mg tablets.

White biconvex, capsule shaped tablet scored on both sides with dimensions 19 x 10 mm.

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

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 bid 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 insufficiency.

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

Hepatic insufficiency.

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, 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.
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 atypical antipsychotics 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.

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.

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)).

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.

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.

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.

See Section 4.8 Adverse Effects (Undesirable Effects).

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.

The use of the following medicines is contraindicated.

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.

Caution is required with the use of the following medicines.

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.
Concomitant use of amisulpride with other anti-psychotics may increase the risk of developing neuroleptic malignant syndrome.
Amisulpride may enhance the effects of alcohol.

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 C1)
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.
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.
The safety of amisulpride during human pregnancy has not been established, and therefore use of this medicine is not recommended during pregnancy unless the benefits justify the potential risks and the administered dose and duration of treatment should be as low and as short as possible.
1 Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
 It is not known whether amisulpride or its metabolites are excreted in animal or human breast milk. Breast-feeding is therefore contraindicated during amisulpride treatment.

4.7 Effects on Ability to Drive and Use Machines

Even used as recommended, amisulpride may affect reaction time and/or cause somnolence 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).

Central and peripheral nervous system disorders.

Very common: Extrapyramidal symptoms 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.

Cardiovascular disorders.

Common: Hypotension.
Uncommon: Bradycardia.

Body as a whole - general disorders.

Uncommon: Allergic reactions.

Investigations.

Common: Weight gain.
Uncommon: Elevations of hepatic enzymes, mainly transaminases.

Metabolism and nutrition disorders.

Uncommon: Hyperglycaemia (see Section 4.4 Special Warnings and Precautions for Use).

Psychiatric disorders.

Common: Insomnia, anxiety, agitation, orgasmic dysfunction.

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.

Gastrointestinal disorders.

Common: Constipation, nausea, vomiting, dry mouth.

Postmarketing data.

Leucopenia, neutropenia and agranulocytosis have been reported.
Very rare cases of neuroleptic malignant syndrome, which is a potentially fatal complication, have been reported (see Section 4.4 Special Warnings and Precautions for Use).
Cases of benign pituitary tumour, such as prolactinoma, have been reported.
Cases of hyponatraemia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported.
Cases of QT interval prolongation and ventricular arrhythmias such as torsades de pointes, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest, sudden death, have been reported (see Section 4.4 Special Warnings and Precautions for Use).
Hypertriglyceridemia and hypercholesterolemia have been reported.
Cases of venous thromboembolism, including pulmonary embolism, sometimes fatal and deep vein thrombosis have been reported (see Section 4.4 Special Warnings and Precautions for Use).
Angioedema and urticaria have been reported.
Osteopenia and osteoporosis have been reported.
Confusion has been reported.
Blurred vision has been reported.
Neonatal drug withdrawal syndrome has been reported.
Nasal congestion has been reported.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medical 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

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, 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 Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Class - Neuropleptic 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 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 subcale, 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 also has 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%.
Bioequivalence between the solution and the 200 mg tablet has been demonstrated (Cmax mean ratio 0.95, 90% confidence interval 0.81-1.12; AUC0-∞ mean ratio 0.89, 90% confidence interval 0.81-0.97). However, bioequivalence has not been demonstrated between the solution and the 400 mg tablet (Cmax mean ratio 0.88, 90% confidence interval 0.75-1.04; AUC0-∞ mean ratio 0.86, 90% confidence interval 0.78-0.94).

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 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 10-30% 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.

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

The tablets also contain microcrystalline cellulose, hypromellose, magnesium stearate, lactose monohydrate and sodium starch glycollate type A.

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

Amisolan 50 mg.

PVC/PE/PVDC/Al and PVC/PVDC/Al blister packs of 30, 60 and 90 tablets.

Amisolan 100 mg.

PVC/PE/PVDC/Al and PVC/PVDC/Al blister packs of 30, 60 and 90 tablets.

Amisolan 200 mg.

PVC/PE/PVDC/Al and PVC/PVDC/Al blister packs of 30, 60 and 90 tablets.

Amisolan 400 mg.

PVC/PE/PVDC/Al and PVC/PVDC/Al blister packs of 30, 60 and 90 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

Chemical Name: (R,S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-ethylsulfonyl-2-methoxybenzamide. Molecular Formula: C17H27N3O4S. Molecular Weight: 369.48.
Amisulpride is a white to off white powder, which is practically insoluble in water, sparingly soluble in ethanol, soluble in methanol and freely soluble in dichloromethane.
The tablets are gluten free.

Chemical structure.


CAS number.

71675-85-9.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes