4.1. Therapeutic indications

Amisulpride is indicated for the treatment of acute and chronic schizophrenic disorders with:

• positive symptoms (such as delusions, hallucinations, thought disorders, hostility, suspiciousness), and/or

• negative symptoms (deficit syndrome) such as blunted affect, emotional and social withdrawal

This includes patients with predominant negative symptoms.

4.2. Posology and method of administration

Posology

Positive symptoms:

For acute psychotic episodes, a daily dose between 400 mg and 800 mg is recommended.

In individual cases, the daily dose may be increased up to 1200 mg. Doses above 1200 mg/day have not been extensively evaluated for safety and therefore should not be used.

No specific titration is required when initiating treatment. 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.

Predominant negative symptoms (deficit syndrome)

A daily dose between 50 mg and 300 mg is recommended. Doses should be adjusted individually.

Amisulpride can be administered once daily at doses up to 300 mg, higher doses should be administered twice daily.

The minimum effective dose should be used.

Special populations

Elderly patients over 65 years

Treatment of elderly patients is not recommended. The safety of amisulpride has been examined in a limited number of elderly patients. If treatment with amisulpride is absolutely necessary, particular caution is required due to a possible risk of hypotension or sedation. Reduction in dosage may also be required because of renal insufficiency.

Paediatric population

The efficacy and safety of amisulpride in children and adolescents under 18 years of age have not been established. There are only limited data available on the use of amisulpride in adolescents in schizophrenia. Therefore, amisulpride should not be used in adolescents from 15 to 18 years of age until further data are available. If absolutely required, treatment of adolescents must be initiated and performed by a physician experienced in treating schizophrenia in this age group. The use of amisulpride is contraindicated in children and adolescents under 15 years of age (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), amisulpride should not be used in these patients (see section 4.4).

Hepatic insufficiency

Since amisulpride is weakly metabolised, a dosage reduction should not be necessary.

Duration of treatment

Data from controlled clinical trials covering a period of 1 year is available. The duration of treatment should be determined by the treating physician.

To avoid withdrawal symptoms treatment should be discontinued gradually (see section 4.4).

Method of administration

For oral use.

Tablets should be swallowed whole or halved, with a sufficient amount of liquid.

Amisulpride can be administered independently from meals.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Concomitant prolactin-dependent tumours e.g. pituitary gland prolactinomas or breast cancer.

• Severe hypertensive crises have been reported in patients with phaeochromocytoma with anti-dopaminergic medicinal products, including certain benzamides; therefore, it is wise to refrain from prescribing this product to patients with known or suspected phaeochromocytoma.

• Children and adolescents under 15 years of age (see section 4.2).

• In combination with levodopa (see section 4.5).

• In combination with the following medicinal products which could induce torsade de pointes (see section 4.5):

o dopaminergics not used for Parkinson's disease (cabergoline and quinagolide);

o citalopram, escitalopram, domperidone, hydroxyzine, piperaquine (see section 4.5).

o class Ia antiarrhythmics such as quinidine and disopyramide

o class III antiarrhythmics such as amiodarone and sotalol

o other medicinal products such as bepridil, cisapride, sultopride, thioridazine, methadone, erythromycin (intravenous application), vincamine (intravenous application), halofantrine, pentamidine, sparfloxacin, azole antifungals

4.4. Special warnings and precautions for use

Hepatotoxicity

Severe liver toxicity has been reported with amisulpride use. Patients should be instructed to immediately report 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).

Potentially fatal neuroleptic malignant syndrome

As with other neuroleptics, neuroleptic malignant syndrome (NMS) may occur. This condition is characterized by hyperthermia, muscle rigidity, autonomic dysfunction, clouded consciousness, rhabdomyolysis and elevated creatinine phosphokinase (CPK) blood levels, and it is potentially fatal.

If the patient develops signs and symptoms indicative for NMS, or an unexplained hyperthermia is present, particularly with high daily doses, administration of all antipsychotics including amisulpride has to be discontinued.

Rhabdomyolysis has also been observed in patients without neuroleptic malignant syndrome.

Prolongation of the QT interval:

Amisulpride induces a dose-dependent prolongation of the QT interval (see section 4.8). This effect is known to potentiate the risk of serious ventricular arrhythmias such as torsade de pointes. Before any administration, and if possible according to the patient's clinical status, it is recommended to exclude the following factors which could favour the occurrence of this rhythm disorder:

• bradycardia less than 55 bpm

• cardiac disease or family history of sudden death or QT prolongation

• electrolyte imbalance, in particular hypokalaemia

• congenital prolongation of the QT interval

• on-going treatment with a medicinal product likely to produce pronounced bradycardia (< 55 bpm), hypokalaemia, decreased intracardiac conduction, or prolongation of the QT interval (see section 4.5).

Baseline ECG is recommended prior to treatment in all patients especially in the elderly and patients with a positive personal or family history of cardiac disease or abnormal findings on cardiac clinical examination. During therapy, the need for ECG monitoring (e.g. at dose escalation) should be assessed on an individual patient basis. The dose of amisulpride should be reduced if QT is prolonged and discontinued if QTc is >500ms.

Periodic electrolyte monitoring is recommended particularly if the patient is taking diuretics or during inter-current illness.

Concomitant use with antipsychotics should be avoided (see section 4.5).

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 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 drugs, 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. 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 about 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.

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.

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.

Hyperglycaemia/metabolic 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.

Seizures

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

Special populations

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).

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.

Withdrawal syndrome

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.

Hyperprolactinaemia

Amisulpride can increase prolactin levels (see section 4.8). Patients with a history of hyperprolactinaemia and/or a tumour that is potentially prolactin-dependent should be closely monitored during treatment with amisulpride (see section 4.3).

Benign pituitary tumour:

Amisulpride may increase prolactin levels. Cases of benign pituitary tumours such as prolactinoma have been observed during amisulpride therapy (see section 4.8). In case of very high levels of prolactin or clinical signs of pituitary tumour (such as visual field defect and headache), pituitary imaging should be performed. If the diagnosis of pituitary tumour is confirmed, the treatment with amisulpride must be stopped (see section 4.3).

Other

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.

Amisulpride contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Sedative medicinal products

Consideration should be given to the fact that the depressant effects of many medicinal products or substances on the central nervous system may be cumulative and contribute to decreased attention. These include opioids (antitussives and replacement therapies), neuroleptics, non-benzodiazepine anxiolytics (for example, meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), baclofen and thalidomide.

The use of a torsadogenic medicinal product with another torsadogenic medicinal product is contraindicated as a general rule.

However, some of them, due to their unavoidable nature, are an exception to the rule, as they are only not recommended with other torsadogenics. These include methadone, hydroxychloroquine, anti-parasitics (chloroquine, halofantrine, lumefantrine and pentamidine) and neuroleptics.

However, citalopram, escitalopram, domperidone, hydroxyzine and piperaquine do not follow this exception and are contraindicated with all torsadogenics.

Table 1: Contraindicated combinations (see also section 4.3):

Medicinal products

Interaction effect

Dopaminergics not used for Parkinson's disease (cabergoline, quinagolide)

Reciprocal antagonism of the dopaminergic agonist and neuroleptics.

Citalopram, escitalopram, domperidone, hydroxyzine, piperaquine

Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Class Ia antiarrhythmics such as quinidine, hydroquinidine and disopyramide.

Class III antiarrhythmics such as amiodarone, dronedarone, dofetilide, ibutilide and sotalol.

Other medicinal products such as bepridil, cisapride, sultopride, thioridazine, methadone, erythromycin (intravenous application), vincamine (intravenous application), halofantrine, pentamidine, sparfloxacin, azole antifungals.

Medicinal products which could induce torsade de pointes.

Levodopa

Reciprocal antagonism of effects between levodopa and neuroleptics. Amisulpride may oppose the effect of dopamine agonists e.g. bromocriptine, ropinirole.

Table 2: Combinations not recommended

Medicinal products

Interaction effect

Anti-parasitics: chloroquine, halofantrine, lumefantrine, pentamidine

- Increased risk of ventricular arrhythmias, particularly torsades de pointes.

- If possible, discontinue one of the two treatments.

- If the combination cannot be avoided, prior QT interval check and supervised ECG monitoring.

Dopaminergic anti-parkinsonian agents:amantadine, apomorphine, bromocriptine, entacapone, lisuride, pergolide, piribedil, pramipexole, rasagiline, ropinirole, rotigotine, selegiline and tolcapone

- Reciprocal antagonism of the dopaminergic agent and neuroleptics.

- The dopaminergic agent may cause or aggravate psychotic disorders. If neuroleptic treatment is necessary for a Parkinson's patient treated with dopaminergics, the latter should be gradually reduced until discontinuation (their abrupt discontinuation exposes the patient to a risk of "neuroleptic malignant syndrome").

Arsenic compounds: diphemanil, intravenous dolasetron, intravenous erythromycin, levofloxacin, mequitazine, mizolastine, prucalopride, intravenous vincamine, moxifloxacin, intravenous spiramycin, toremifene, vandetanib

- Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Neuroleptics: chlorpromazine, cyamemazine, droperidol, flupenthixol, fluphenazine, levomepromazine, pipamperone, pipotiazine, sulpiride, sultopride, tiapride, zuclopenthixol

- Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Sodium oxybate

Increase in central nervous system depression. Impaired attention may make it dangerous to drive and use machines.

Hydroxychloroquine

- Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Bradycardia-inducing medicinal products such as beta-blockers, bradycardia-inducing calcium channel blockers such as diltiazem and verapamil, clonidine, guanfacine; and digitalis

Medicinal products which induce hypokalaemia or electrolyte imbalance: hypokalemic diuretics, stimulant laxatives, amphotericin B (intravenous application), glucocorticoids, and tetracosactides.

Antipsychotics such as pimozide, and haloperidol

Imipramine antidepressants

Lithium

Some antihistamines such as astemizole, and terfenadine

Mefloquine

Medicinal products which enhance the risk of torsade de pointes or could prolong the QT interval.

- Hypokalaemia should be corrected.

Alcohol

- Amisulpride may enhance the effects of alcohol. Therefore, alcohol should not be consumed during treatment.

- Alcohol increases the sedative effect of these substances.

- Impaired attention may make it dangerous to drive and use machines.

- The consumption of alcoholic beverages and medicinal products containing alcohol should be avoided.

Table 3: Combinations which require precautions for use

Medicinal products

Interaction effect and monitoring recommendations

Anagrelide

- Increased risk of ventricular arrhythmias, particularly torsades de pointes.

- Clinical and ECG monitoring during the combination.

Azithromycin, ciprofloxacin, clarithromycin, levofloxacin, norfloxacin and roxithromycin.

- Increased risk of ventricular arrhythmias, particularly torsades de pointes.

- Clinical and ECG monitoring during the combination.

Beta blockers in cardiac failure (bisoprolol, carvedilol, metoprolol and nebivolol).

- Increased risk of ventricular arrhythmias, particularly torsades de pointes.

- In addition, a vasodilator effect and risk of hypotension, especially orthostatic (additive effect).

- Clinical and ECG monitoring.

Bradycardia-inducing medicinal products (particularly class Ia anti-arrhythmics, beta blockers, certain class III anti-arrhythmics, certain calcium channel blockers, cardiac glycosides, pilocarpine and cholinesterase inhibitors).

- Increased risk of ventricular arrhythmias, particularly torsades de pointes.

- Clinical and ECG monitoring.

Potassium-depleting medicinal products (potassium-depleting diuretics, alone or combined, stimulant laxatives, glucocorticoids, tetracosactide and intravenous amphotericin B).

- Increased risk of ventricular arrhythmias, particularly torsades de pointes.

- Any hypokalaemia before administering the product should be corrected and and clinical, electrolyte and ECG monitoring should be carried out.

Ondansetron

Increased risk of ventricular arrhythmias, particularly torsades de pointes.

- Clinical and ECG monitoring during the combination.

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

- Can lead to potentiation of the effect.

Antihypertensive drugs and other hypotensive medications.

- Can lead to potentiation of the effect.

Clozapine

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

Table 4: Other combinations to take into account

Medicinal products

Interaction effect

Other sedative medicinal products

- Increase in central nervous system depression.

- Impaired attention may make it dangerous to drive and use machines.

Orlistat

- Risk of therapeutic failure in the case of concomitant treatment with orlistat.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is only limited amount of data from the use of amisulpride in pregnant women. The safety of amisulpride during pregnancy has not been established.

The 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.

Amisulpride crosses the placenta.

Studies in animals have shown reproductive toxicity (see section 5.3).

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.

Breast-feeding

Amisulpride is excreted in breast milk in rather large amounts, above the accepted value of 10% of the maternal weight-adjusted dosage in some cases, but blood concentrations in breastfed infants have not been evaluated. There is insufficient information on the effects of amisulpride in newborns/infants. A decision must be made whether to discontinue breast-feeding or to abstain from amisulpride therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

A decrease in fertility linked to the pharmacological effects of the medicinal product (prolactin-mediated effect) was observed in treated animals.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Adverse reactions have been ranked under headings of frequency using the following convention:

Very common (≥1/10);

Common (≥1/100 to <1/10);

Uncommon (≥1/1,000 to <1/100);

Rare (≥1/10,000 to <1/1,000);

Very rare (<1/10,000);

Not known (cannot be estimated from the available data).

System Organ Class

Frequency

Adverse Drug Reaction

Blood and Lymphatic system disorders

Uncommon

Leukopenia, neutropenia (see section 4.4)

Rare

Agranulocytosis (see section 4.4)

Immune system disorders

Uncommon

Allergic reactions

Endocrine disorders

Common

Increase in plasma prolactin levels which is reversible after discontinuation of amisulpride. This may result in:

- galactorrhoea,

- amenorrhoea or menstrual disorders,

- gynaecomastia,

- breast pain or enlargement,

- erectile dysfunction.

Rare

Benign pituitary tumour such as prolactinoma (see section 4.3 and section 4.4).

Metabolism and nutrition disorders

Uncommon

Hyperglycaemia (see section 4.4), hypertriglyceridaemia and hypercholesterolaemia.

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 symptoms1 may occur:

- tremor,

- rigidity,

- hypokinesia,

- hypersalivation,

- akathisia,

- dyskinesia.

Common

Acute dystonia (spasm torticollis, oculogyric crisis, trismus) may appear.2

Somnolence.

Uncommon

Tardive dyskinesia characterised by rhythmic, involuntary movements primarily of the tongue and/or face has been reported, usually after long-term administration.3

Seizures.

Rare

Neuroleptic malignant syndrome symptom (see section 4.4), which is a potentially fatal complication.

Not known

Restless leg syndrome

Eye disorders

Common

Blurred vision (see section 4.7)

Cardiac disorders

Uncommon

Bradycardia.

Rare

QT interval prolongation. Ventricular arrhythmias such as torsade de pointes, ventricular tachycardia, which may result in ventricular fibrillation or 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 (see section 4.4).

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

Not known

Drug withdrawal syndrome neonatal (see section 4.6)

Investigations

Common

Weight gain

Uncommon

Elevations of hepatic enzymes, mainly transaminases

Not known

Increased creatine phosphokinase blood level.

Injury, poisoning and procedural complications

Not known

Fall due to adverse reactions disturbing the body's balance

1 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 50-300mg/day.

2 This is reversible without discontinuation of amisulpride upon administration of antiparkinsonian medication.

3 Antiparkinsonian medication should not be used as it is ineffective and may induce aggravation of the symptoms.

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 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 has been reported. These include drowsiness, sedation, hypotension, extrapyramidal symptoms, and coma. Fatal outcomes have been reported mainly in combination with other psychotropic agents.

In cases of acute overdose, 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 QT interval until the patient recovers.

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