Consumer medicine information

Solian, Solian 100, Solian 200 and Solian 400

Amisulpride

BRAND INFORMATION

Brand name

Solian

Active ingredient

Amisulpride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Solian, Solian 100, Solian 200 and Solian 400.

What is in this leaflet

This leaflet is designed to provide answers to some common questions about this medicine. It does not contain all the available information.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Solian against the benefits this medicine is expected to have for you.

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

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

What Solian is used for

The name of your medicine is Solian. It contains the active ingredient called amisulpride.

Solian belongs to a group of medicines called antipsychotics. Solian is used to treat symptoms of schizophrenia.

Schizophrenia is a condition which affects the way you think, feel and/or act. Schizophrenia may cause symptoms such as hallucinations (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 Solian for another reason.

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

Before taking it

When you must not take it

Do not take Solian if:

  • you have an ALLERGIC REACTION to Solian 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 Solian 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

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

Before you start to take it

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

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. Solian is not recommended for use in pregnancy. If you need to take Solian during pregnancy you should discuss the benefits and risks of taking it with your doctor. Newborns of mothers who have taken Solian during pregnancy need to be carefully monitored.
  3. you suffer from lactose intolerance because Solian 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 Solian.
  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
  12. you have a history of sleep apnoea

Taking other medicines

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

Some medicines and Solian may interfere with each other. 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 (amphotericin), an anti-fungal given by injection into the veins
  • other antipsychotics such as thioridazine, clozapine, chlorpromazine, trifluperazine, pimozide, haloperidol, imipramine and lithium
  • diuretics
  • stimulant laxatives
  • glucocorticosteroids
  • diagnostics drugs such as tetracosactides
  • medicines taken for anxiety or to help you sleep (central nervous system depressants)
  • anaesthetics (a medicine used during surgery)
  • medicines taken for depression
  • some strong pain killers
  • antihistamines, medicines to treat allergies, which cause drowsiness
  • some medicines taken to control blood pressure

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 Solian.

How to take it

How much to take

Your doctor will tell you how many Solian tablets you should take, or the amount of Solian Solution you should take. 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.

When taking Solian Solution, the dosage syringe supplied should be used to measure the correct dose. Each 1mL marking is equal to 100mg.

After introducing the measuring syringe into the bottle, draw the plunger of the measuring syringe up to the graduation mark corresponding to the number of milligrams to be administered.

Solian tablets and Solian Solution should be taken once or twice a day as advised by your doctor. Your doctor may increase or decrease your dose depending on your condition.

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

How to take it

Solian tablets should be swallowed whole with a glass of water.

Solian Solution is swallowed. It may be mixed with water if preferred.

When to take it

Solian tablets and Solian Solution should preferably be taken before meals. Take your prescribed dose at about the same time each day.

How long do I take it

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

If you forget to take it

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 that you missed.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much Solian. Show the doctor your pack of tablets or bottle. Do this even if there are no signs of discomfort or poisoning.

If you have taken too much Solian, the most common signs are drowsiness and slurred speech.

While you are using it

Things you must do

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

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

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

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

Solian may cause drowsiness in some people.

Be careful driving or operating machinery until you know how Solian 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 Solian. It is NOT recommended that you drink alcohol while taking Solian.

Be careful while taking antihistamines, sleeping tablets or tablets to relieve pain while taking this medicine. Solian 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 Solian affects you.

Do not give Solian 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 Solian.

Like other medicines, Solian 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 Solian

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 Solian.

Rare side effects include sleep walking and sleep eating.

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

High blood sugar has been reported in patients taking Solian. 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 Solian 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 taking it

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

Store Solian Solution in the original bottle. Solian Solution has an expiry of two months once opened. Any solution remaining after this should be discarded.

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

Solian Solution should be stored in a cool, dry place where the temperature stays below 25°C.

Do not store Solian 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.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

There will be an expiry date (month, year) on your Solian container. The medicine should not be taken after this date.

Disposal

If your doctor tells you to stop taking Solian or the tablets or Solution have passed their expiry date, ask your pharmacist what to do with the amount left over.

Product description

What it looks like

Solian tablets are available in three different strengths:

The 100 mg strength is a white, flat faced, breakable tablet, marked "AMI 100".

The 200 mg strength is a white, flat faced, breakable tablet, marked "AMI 200".

The 400 mg strength is a white, film-coated, breakable, oblong tablet, marked "AMI 400".

The 100 mg strength is available in a pack size of 30 tablets.

The 200 mg strength is available in a pack size of 60 tablets.

The 400 mg strength is available in a pack size of 60 tablets.

Solian Solution is a clear yellow coloured liquid. It is available in 60mL brown glass bottles.

Ingredients

Active Ingredient:

Solian 100 tablets - 100 mg amisulpride per tablet.

Solian 200 tablets - 200 mg amisulpride per tablet.

Solian 400 tablets - 400 mg amisulpride per tablet.

Solian Solution - 100mg amisulpride per mL.

Inactive Ingredients:

The tablets also contain:

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

The 400 mg tablets also contain:

  • PEG-40 stearate
  • titanium dioxide

The oral liquid also contains:

  • Gesweet® 2023
  • Hydrochloric acid
  • Methyl hydroxybenzoate
  • Propyl hydroxybenzoate
  • Potassium sorbate
  • Caramel Flavour® E_9422058
  • Purified water

Manufacturer

Solian is distributed in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Australia
Freecall No: 1800 818 806

Solian is distributed in New Zealand by:

sanofi-aventis new zealand limited
Level 8, 56 Cawley Street
Ellerslie, Auckland 1051
New Zealand
Freecall No: 0800 283 684

The Australian Registration numbers for Solian are as follows:

Solian 100*: AUST R 96422

Solian 200*: AUST R 96425

Solian 400*: AUST R 74272

Solian Solution 100mg/mL: AUST R 94484

*Not marketed in New Zealand

This leaflet was prepared in May 2020

solian- ccdsv13-cmiv17-may20

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Solian

Active ingredient

Amisulpride

Schedule

S4

 

1 Name of Medicine

Amisulpride.

6.7 Physicochemical Properties

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.
Chemical name: (R,S)-4-amino-N- [(1-ethyl-2-pyrrolidinyl) methyl]-5-ethylsulfonyl- 2-methoxybenzamide.
Molecular Weight: 369.48.
Molecular Formula: C17H27N3O4S.

Chemical structure.


CAS number.

71675-85-9.

2 Qualitative and Quantitative Composition

Tablets.

Solian Tablets contain amisulpride (50 mg, 100 mg, 200 mg and 400 mg).
Excipient with known effect: lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

Solution.

Solian Solution contains amisulpride 100 mg/mL.
Excipients with known effect: methyl hydroxybenzoate, potassium sorbate, and propyl hydroxybenzoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.

Solian 50: white to off white, flat-faced breakable tablet, engraved "AMI 50".
Solian 100: white to off white, flat-faced breakable tablet, engraved "AMI 100".
Solian 200: white to off white, flat-faced breakable tablet, engraved "AMI 200".
Solian 400: white, film-coated, breakable, oblong tablet, engraved "AMI 400".

Solution.

Solian Solution 100 mg/mL: a clear, yellow to yellow-brown coloured liquid.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: neuroleptic of the benzamide class.

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 stereotypies. 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 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.
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.
Efficacy results were similar in the three other short-term controlled studies where 800 mg/d of amisulpride was compared with 20 mg/d of haloperidol (n = 191), 1000 mg/d of amisulpride with 25 mg/d of flupenthixol (n = 132) and 800 mg/d of amisulpride with 8 mg of risperidone (n = 228). On BPRS total score and PANSS positive subscale, amisulpride was not found to be different from haloperidol and flupenthixol and showed equivalent efficacy to risperidone. Additionally, amisulpride significantly improved the response rate with CGI versus haloperidol.

Predominant negative schizophrenia.

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

5.2 Pharmacokinetic Properties

Absorption.

In man, amisulpride shows two absorption peaks: one which is attained rapidly, one hour postdose 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, T½ 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 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).

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.

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

Venous thromboembolism.

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

Sleep apnoea.

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

Suicide.

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

Breast cancer.

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

Benign pituitary tumour.

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

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).
There are limited data on the potential for renally cleared medicines to interfere with the clearance of amisulpride. Therefore, amisulpride should be used with caution with other renally excreted medicines, including lithium (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

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

Elderly patients with dementia.

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

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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

Contraindicated combinations.

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

Combinations not recommended.

Amisulpride may enhance the effects of alcohol.
Medications which enhance the risk of torsades de pointes or could prolong the QT interval: medicines which induce bradycardia, such as bradycardia inducing calcium channel blockers (diltiazem, verapamil), beta-blockers, clonidine, guanfacine, digitalis.
Medicines which can cause hypokalaemia, such as diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactides. Hypokalaemia should be corrected.
Neuroleptics such as thioridazine, chlorpromazine, 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 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 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 amisulpride oral dose resulting in systemic drug exposure (plasma AUC) similar to that in humans, when treatment was carried out prior to mating. Female rat mating was reduced by concurrent amisulpride treatment, but it was normalised within days of cessation of dosing with overall fertility being unaffected, although some adverse effects were observed (see Use in pregnancy).
(Category C)
Neonates exposed to antipsychotic drugs (including amisulpride) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been postmarket reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self limited, in other cases neonates have required additional medical treatment or monitoring. All newborns should be carefully monitored to assess the severity of adverse effects.
There was no evidence of teratogenicity in embryofoetal development studies in mice and rabbits following oral doses of up to 2 (mice) and 4 (rabbits) times the maximum recommended human dose based on body surface area, administered daily during the period of organogenesis. Oral treatment of female rats from prior to mating to late gestation or weaning, achieving systemic drug exposure (plasma AUC) similar to that in humans at the maximum dose, was associated with increased preimplantation loss, slight impairment of ossification and reduced pup weight gain to weaning. Teratogenicity was not observed.
Amisulpride crosses the placenta.
The safety of amisulpride during human pregnancy has not been established and, therefore, use of 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. Breastfeeding is contraindicated.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

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

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 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.
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.

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 reactions.

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

4.2 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 twice daily for doses above 400 mg.
For patients with mixed positive and negative symptoms, doses should be adjusted to obtain optimal control of positive symptoms.
Maintenance treatment should be established individually with the minimally effective dose.
For patients characterised by predominant negative symptoms, oral doses between 50 mg/d and 300 mg/d are recommended. Doses should be adjusted individually.
A graduated dosage syringe (pipette) is supplied for dispensing Solian Solution. Each one mL graduation is equivalent to 100 mg amisulpride.

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 (CRCL) between 30-60 mL/min and to a third in patients with CRCL between 10-30 mL/min. As there is no experience in patients with severe renal impairment (CRCL < 10 mL/min) particular care is recommended in these patients (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic insufficiency.

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

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.

4.9 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 Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Solian Tablets contain the following excipients:
50, 100 and 200 mg tablets: sodium starch glycollate type A, lactose monohydrate, microcrystalline cellulose, hypromellose, magnesium stearate.
400 mg tablets: sodium starch glycollate type A, lactose monohydrate, microcrystalline cellulose, hypromellose, magnesium stearate, PEG-40 stearate, titanium dioxide.
Solian Solution contains the following excipients: hydrochloric acid, methyl hydroxybenzoate, propyl hydroxybenzoate, potassium sorbate, and purified water, and the following proprietary ingredients: Gesweet 2023 (ARTG No. 10553) and Caramel Flavour E9422058 (ARTG No. 10645).

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

Tablets.

Store below 30°C.

Solution.

Store below 25°C. Once opened, discard after two months.

6.5 Nature and Contents of Container

Solian 50.

Packed in blister packs of 2, 5, 10, 15, 30, 50, 60, 90 and 100. (Not marketed.)

Solian 100.

Packed in blister packs of 2, 5, 10, 15, 30*, 50, 60, 90 and 100.

Solian 200.

Packed in blister packs of 2, 5, 10, 15, 30, 50, 60*, 90 and 100.

Solian 400.

Packed in blister packs of 2, 5, 10, 15, 30, 50, 60*, 90 and 100.

Solian solution 100 mg/mL.

Packed in 60 mL brown glass bottles.
* Marketed pack.

6.6 Special Precautions for Disposal

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

Summary Table of Changes