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.

Amisulpride also regulates secondary negative symptoms in productive state, as well as affective disorders such as depressive mood.

4.2. Posology and method of administration

For acute psychotic episodes: Oral doses between 4 ml/day (400 mg/day) and 8 ml/day (800 mg/day) are recommended. In individual cases, the daily dose may be increased up to 12 ml/day (1200 mg/day). Doses above 12 ml/day (1200 mg/day) have not been extensively evaluated for safety and therefore should not be used. No specific titration is required when initiating the treatment with Amisulpride. Doses should be adjusted according to individual response.

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 0.5 ml/day (50 mg/day) and 3 ml/day (300 mg/day) are recommended. Doses should be adjusted individually.

Amisulpride can be administered once a day at oral doses up to 400mg, higher dose should be split into two separate doses.

Elderly: The safety of amisulpride has been examined in a limited number of elderly patients. Amisulpride should be used with particular caution because of a possible risk of hypotension and sedation. Reduction in dosage may also be required because of renal insufficiency.

Children: 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 amisulpride is contraindicated, as its safety has not yet been established (see section 4.3).

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 Special Precautions for Use).

Hepatic insufficiency: since the drug is weakly metabolised a dosage reduction should not be necessary.

Method of administration

For oral use only.

The oral solution should be drunk with a liquid, which does not contain alcohol.

4.3. Contraindications

• Hypersensitivity to the active ingredient or to other ingredients of the product.

• Concomitant prolactin-dependent tumours (e.g. pituitary gland prolactinomas or breast cancer) (see section 4.4 and section 4.8).

• Phaeochromocytoma.

• Children up to puberty.

• Combination with levodopa (see section 4.5 Interactions with other medicinal products and other forms of interactions).

4.4. Special warnings and precautions for use

As with other neuroleptics, neuroleptic malignant syndrome (NMS) may occur. This condition is characterised by high fever, muscle rigidity, autonomic dysfunction, clouding of consciousness, rhabdomyolysis and elevated CPK values, and it is potentially fatal. If a patient develops signs and symptoms indicative for NMS or presents with unexplained hyperthermia, particularly at high daily doses, all antipsychotic agents including amisulpride must be discontinued.

Rhabdomyolysis has also been observed in patients without Neuroleptic Malignant Syndrome.

Hyperglycaemia has been reported in patients treated with some atypical antipsychotic agents, including amisulpride, therefore patients with an established diagnosis of diabetes mellitus or with risk factors for diabetes who are started on amisulpride, should get appropriate glycaemic monitoring.

Amisulpride is eliminated by the renal route. In cases of renal insufficiency, the dose should be decreased or intermittent treatment could be considered (see section 4.2 Posology and method of administration).

Severe liver toxicity has been reported with amisulpride use. Patients should be instructed to report immediately signs such as asthenia, anorexia, nausea, vomiting, abdominal pain or icterus to a physician. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately (see section 4.8)

Amisulpride may lower the seizure threshold. Therefore, patients with a history of epilepsy should be closely monitored during amisulpride therapy.

In elderly patients, amisulpride, like other neuroleptics, should be used with particular caution because of a possible risk of hypotension and sedation. Reduction in dosage may also be required because of renal insufficiency.

As with other antidopaminergic agents, 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.

Prolongation of the QT interval

Caution should be exercised when amisulpride is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and concomitant use with neuroleptics should be avoided.

Stroke:

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

Withdrawal symptoms including nausea, vomiting and insomnia have been described after abrupt cessation of high therapeutic doses of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and 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 (see Section 4.8), and requires immediate haematological investigation.

Elderly patients with dementia:

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared to a rate of 2.6% in the placebo group. 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.

Breast cancer:

Amisulpride causes an increase in plasma 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. Amisulpride is contraindicated in patients with breast cancer (see section 4.3 and 4.8).

Venous thromboembolism:

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with amisulpride and preventative measures undertaken.

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.

Excipients warnings

This product contains methyl parahydroxybenzoate (E218), which may cause allergic reactions (possibly delayed).

4.5. Interaction with other medicinal products and other forms of interaction

CONTRAINDICATED COMBINATIONS

Levodopa: reciprocal antagonism of effects between levodopa and neuroleptics.

COMBINATIONS NOT RECOMMENDED

Amisulpride may enhance the central effects of alcohol.

COMBINATIONS TO BE TAKEN INTO ACCOUNT

• CNS depressants including narcotics, anaesthetics, analgesics, sedative H1 antihistamines, barbiturates, benzodiazepines and other anxiolytics, clonidine and derivatives.

• Antihypertensive drugs and other hypotensive medications.

• Co-administration of amisulpride and clozapine may lead to an increase in plasma levels of amisulpride.

• Caution is advised when prescribing amisulpride with medicines known to prolong the QT interval, e.g., class IA antiarrythmics(e.g., quinidine, disopyramide) and class III antiarrhytmics (e.g., amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g., mefloquine) (see section 4.4)

Amisulpride may oppose the effect of dopamine agonists e.g. bromocriptine, ropirinole.

4.6. Fertility, pregnancy and lactation

Pregnancy

In animals, amisulpride did not show direct reproductive toxicity. A decrease in fertility linked to the pharmacological effects of the drug (prolactin mediated effect) was observed. No teratogenic effects of amisulpride were noted.

Very limited clinical data on exposed pregnancies are available. Therefore, the safety of amisulpride during human pregnancy has not been established. Use of the drug is not recommended during pregnancy unless the benefits justify the potential risks.

Neonates exposed to antipsychotics, including amisulpride, during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery (see Section 4.8). There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Lactation

It is not known whether amisulpride is excreted in breast milk, breast-feeding is therefore contra-indicated.

4.7. Effects on ability to drive and use machines

Even when used as recommended, amisulpride may cause somnolence and blurred vision so that the ability to drive vehicles or operate machinery can be impaired (see section 4.8 Undesirable Effects).

4.8. Undesirable effects

Adverse effects have been ranked under headings of frequency using the following convention: very common (≥ 1/10); common (≥ 1/100; <1/10); uncommon (≥ 1/1,000;<1/100); rare (≥ 1/10,000;<1/1,000); very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

Uncommon: leukopenia, neutropenia (see Section 4.4).

Rare: agranulocytosis.

Immune system disorders:

Uncommon: allergic reaction

Endocrine disorders:

Common: amisulpride causes an increase in plasma prolactin levels which is reversible after drug discontinuation. This may result in galactorrhoea, amenorrhoea, gynaecomastia, breast pain, and erectile dysfunction.

Rare: benign pituitary tumour such as prolactinoma (see Section 4.4).

Metabolism and nutrition disorders:

Uncommon: hyperglycaemia, hypertriglyceridemia and hypercholesterolemia.

Rare: hyponatraemia, 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 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.

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

Uncommon: tardive dyskinesia characterized 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.

Seizures.

Rare: Neuroleptic Malignant Syndrome (see Section 4.4), which is a potentially fatal complication.

Not known: restless legs syndrome.

Eye disorders:

Common: blurred vision.

Cardiac disorders:

Uncommon: bradycardia.

Rare: QT interval prolongation, ventricular arrhythmias such as torsade de pointes, ventricular tachycardia, ventricular fibrillation, cardiac arrest, sudden death (see Section 4.4).

Vascular disorders:

Common: hypotension.

Uncommon: increase in blood pressure.

Rare: venous thromboembolism, including pulmonary embolism, sometimes fatal, and deep vein thrombosis

Respiratory, thoracic and mediastinal disorders:

Uncommon: nasal congestion, aspiration pneumonia (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, urticaria.

Not known: photosensitivity reaction.

Musculoskeletal and connective tissue disorders:

Uncommon: osteopenia, osteoporosis.

Not known: rhabdomyolysis.

Renal and urinary disorders:

Uncommon: urinary retention

Pregnancy, puerperium and perinatal conditions

Frequency not known: drug withdrawal syndrome neonatal (see Section 4.6)

Injury, poisoning and procedural complications:

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

Investigations:

Common: weight gain.

Uncommon: elevations of hepatic enzymes, mainly transaminases.

Not known: blood creatine phosphokinase increased.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme Website at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

In cases of acute overdosage, the possibility of multiple drug intake should be considered.

Since Amisulpride is weakly dialysed, haemodialysis is of no use to eliminate the drug.

There is no specific antidote to Amisulpride. Appropriate supportive measures should therefore be instituted with close supervision of vital functions including continuous cardiac monitoring due to the risk of prolongation of the QT interval until the patient recovers.

If severe extrapyramidal symptoms occur, anticholinergic agents should be administered.