Amisulpride 400 mg Film-coated Tablets

Each film-coated tablet contains 400 mg amisulpride

Excipients: 190.00 mg lactose/film-coated tablet

For a full list of excipients, see section 6.1.

Film-coated tablet

White to off white, oval (18 mm length and 8 mm width) film-coated tablet with score line. The film-coated tablet can be divided into equal halves.

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

- positive symptoms such as delusions, hallucinations, thought disorders, hostility, suspiciousness

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

This includes patients with predominant negative symptoms.

Posology

For acute psychotic episodes, oral doses between 400 mg/day and 800 mg/day are 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 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 in example between 400-800mg/day.

Maintenance treatment should be established individually with the minimally effective dose.

For patients characterised by predominant negative symptoms, oral doses between 50 mg/day and 300 mg/day are recommended. Doses should be adjusted individually.

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

The minimum effective dose and appropriate strength tablets should be used.

Special populations

Elderly patients over 65 years: Treatment of elderly patients is not recommended as there is no sufficient clinical experience. If treatment with amisulpride is absolutely necessary particular caution is required due to a possible risk of hypotension or sedation.

Children and adolescents: 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 impairment: Amisulpride is eliminated by the renal route. In renal insufficiency, the dose should be reduced to half in patients with creatinine clearance (CR_CL) between 30-60 ml/min and to a third in patients with CR_CL between 10-30 ml/min.

As there is no experience in patients with severe renal impairment (CR_CL < 10 ml/min) amisulpride should not be used in these patients (see section 4.4).

Hepatic impairment: 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.

Method of administration

Amisulpride can be administered with or without food. The tablets should be taken without chewing with a sufficient amount of water.

Note

For doses not realizable/practicable with this strength, other strengths of this medicinal product are available.

- hypersensitivity to the active substance or to any of the excipients of the medicinal product

- concomitant prolactin-dependent tumours, e.g. pituitary gland prolactinomas and breast cancer

- phaeochromocytoma

- children and adolescents under 15 years of age

- lactation (see section 4.6)

- combination with levodopa (see section 4.5)

- combination with the following medicinal products which could induce torsades de pointes :

As with other antipsychotics, neuroleptic malignant syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated CPK, may occur. In the event of hyperthermia, particularly with high daily doses, all antipsychotic medicinal products including amisulpride should be discontinued.

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).

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

In elderly patients (over 65 years), amisulpride, like other antipsychotics, should be used with particular caution because of a possible risk of hypotension or sedation.

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 antipsychotic treatment cannot be avoided.

Acute withdrawal symptoms including nausea, vomiting and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotics. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.

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 torsades 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 antipsychotics should be avoided (see section 4.5).

Stroke

In randomized 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.

Increased mortality in elderly people with dementia

Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.

Amisulpride is not licensed for the treatment of dementia-related behavioural disturbances.

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 preventive measures undertaken.

Lactose

Amisulpride film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Combinations which are contraindicated (see also section 4.3)

Medicinal products which could induce torsades de pointes :

- class I antiarrhythmics such as quinidine, disopyramide, procainamide, flecainide and propafenone

- class III antiarrhythmics such as amiodarone and sotalol

- other medicinal products such as bepridil, cisapride, sultopride, thioridazine, methadone, IV erythromycin , IV vincamine , halofantrine, pentamidine, sparfloxacin, azole antifungals.

Levodopa : reciprocal antagonism of effects between levodopa and antipsychotics.

Combinations which are not recommended

Medicinal products which enhance the risk of torsades de pointes or could prolong the QT interval:

- 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, IV amphotericin B, glucocorticoids, and tetracosactides.

Hypokaliaemia should be corrected.

- antipsychotics such as pimozide, and haloperidol

- imipramine antidepressants

- lithium

- some antihistamines such as astemizole, and terfenadine.

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

Combinations which require precautions for use

Concomitant use of the following agents can lead to potentiation of the effect:

- CNS depressants including narcotics, anaesthetics, analgesics, sedative H1 antihistamines, barbiturates, benzodiazepines and other anxiolytic drugs, clonidine and derivatives

- antihypertensive and other hypotensive medicinal products

Pregnancy

In animals, amisulpride did not show reproductive toxicity. A decrease in fertility linked to it's pharmacological effects (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 this medicinal product is not recommended during pregnancy unless the benefits justify the potential risks. If amisulpride is used during pregnancy, neonates may show adverse effects of amisulpride and thus appropriate monitoring should be considered.

For women of childbearing potential, effective contraception should be fully discussed with the physician prior to treatment.

Lactation

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

This medicinal product can have minor or moderate influence on the ability to drive and use machines.

Even used as recommended, amisulpride may affect reaction time (e.g. caused by somnolence) so that the ability to drive vehicles or operate machinery can be impaired (see section 4.8). This effect is enhanced by the consumption of alcohol.

The following frequency estimates are used in assessing adverse effects:

CLINICAL TRIALS DATA

The following adverse effects have been observed in controlled clinical trials. It should be noted that in some instances it can be difficult to differentiate adverse events from symptoms of the underlying disease.

Immune system disorders

Uncommon:

Allergic reaction

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 breast enlargement, prolactinoma (see section 4.3) and erectile dysfunction.

Metabolism and nutrition disorders

Uncommon:

Hyperglycemia (see section 4.4)

Psychiatric disorders

Common:

Insomnia, anxiety, agitation, orgasmic dysfunction

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 should not be used as it is ineffective or may induce aggravation of the symptoms. Seizures

Cardiac disorders

Uncommon:

Bradycardia

Vascular disorders

Common:

Hypotension

Gastrointestinal disorders

Common:

Constipation, nausea, vomiting, dry mouth

General disorders

Very rare:

Acute withdrawal symptoms including nausea, vomiting and insomnia after abrupt cessation of high doses, also recurrence of psychotic symptoms, emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) (see section 4.4).

Investigations

Common:

Weight gain

Uncommon:

Elevations of hepatic enzymes, mainly transaminases

POST MARKETING DATA

In addition, cases of the following adverse reactions have been reported through spontaneous reporting only:

Nervous system disorders

Not known:

Neuroleptic malignant syndrome (see section 4.4)

Cardiac disorders

Not known:

QT interval prolongation and 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

Not known:

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs.

Skin and subcutaneous tissue disorders

Not known:

Angioedema, urticaria

Symptoms

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

Fatal outcomes have been reported mainly in combination with other psychotropic agents.

Treatment

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 it. 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.

Pharmacotherapeutic group: antipsychotics: benzamides

ATC code: N05AL05

Amisulpride binds selectively with a high affinity to human dopaminergic D₂/D₃ receptor subtypes whereas it is devoid of affinity for D₁, D₄ and D₅ receptor subtypes. Unlike classical and atypical antipsychotics, amisulpride has no affinity for serotonin, alpha-adrenergic, histamine H₁ and cholinergic receptors. In addition, amisulpride does not bind to sigma sites. In animal studies, at high doses, amisulpride blocks dopamine receptors located in the limbic structures in preference to those in the striatum. At low doses it preferentially blocks pre-synaptic D₂/D₃ receptors, producing dopamine release responsible for its disinhibitory effects.

This pharmacological profile explains the clinical efficacy of amisulpride against both negative and positive symptoms of schizophrenia.

In man, amisulpride shows two absorption peaks: one which is attained rapidly, one hour post-dose and a second between 3 and 4 hours after administration. Corresponding plasma concentrations are 39 ± 3 ng/ml and 54 ± 4 ng/ml after a 50 mg dose.

The volume of distribution is 5.8 l/kg bodyweight, plasma protein binding is low (16%) and no drug interactions are suspected.

Absolute bioavailability is 48%. Amisulpride is weakly metabolised: two inactive metabolites, accounting for approximately 4% of the dose, have been identified. There is no accumulation of amisulpride and its pharmacokinetics remain unchanged after the administration of repeated doses. The elimination half-life of amisulpride is approximately 12 hours after an oral dose.

Amisulpride is eliminated unchanged in the urine. Fifty percent of an intravenous dose is excreted via the urine, of which 90% is eliminated in the first 24 hours. Renal clearance is in the order of 20 l/h or 330 ml/min.

A carbohydrate rich meal (containing 68% fluids) significantly decreases the AUCs, T_max and C_max 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 impairment

Since amisulpride is weakly metabolised a dosage reduction should not be necessary in patients with hepatic insufficiency.

Renal impairment

The elimination half-life is increased in patients with renal insufficiency while systemic clearance is reduced by a factor of 2.5 to 3. The AUC of amisulpride in mild renal failure increased two fold and almost tenfold in moderate renal failure (see section 4.2). Experience is however limited and there is no data with doses greater than 50 mg.

Amisulpride is very weakly dialysed.

Elderly patients over 65 years

Limited pharmacokinetic data in this patient group show that a 10-30% rise occurs in C_max, T_½ and AUC after a single oral dose of 50 mg. No data are available after repeat dosing.

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/day) and dog (120 mg/kg/day) respectively in terms of AUC. No carcinogenic risk, relevant to man, was identified in the rat at up to 1.5 to 4.5 times the expected human AUC. A mouse carcinogenicity study (120 mg/kg/day) and reproductive studies (160, 300 and 500 mg/kg/day respectively in rat, rabbit and mouse) were performed. The exposure of the animals to amisulpride during these latter studies was not evaluated.

Tablet core:

Lactose monohydrate

Magnesium stearate

Methylcellulose

Microcrystalline cellulose

Sodium starch glycolate (type A)

Tablet coat:

Macrogol 6000

Magnesium stearate

Basic butylated methacrylate copolymer (Eudragit E 100)

Talc

Titanium dioxide (E 171)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVC/Aluminium blister

Pack sizes of 10, 12, 14, 20, 21, 30, 42, 50, 60, 98, 100, 150 and 198 film-coated tablets

Not all pack sizes may be marketed.

No special requirements.

Sandoz Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

PL 04416/1254

21/06/2010

12/2010