SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Amisulpride 400 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Amisulpride 400 mg per tablet For excipients, see 6.1.

3 PHARMACEUTICAL FORM

White to off-white, film-coated, capsule-shaped tablet, with a break line on one side, plain on the other.

4 CLINICAL PARTICULARS

4.1    Therapeutic indications

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

•    productive symptoms such as delusions, hallucinations, thought disorders, hostility, paranoid delusions,

•    predominant negative symptoms (deficit syndrome) 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 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. No specific titration is required when

initiating the treatment with Amisulpride. Doses should be adjusted according to individual response.

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

•    For patients characterised by predominant negative symptoms (deficit syndrome), oral doses between 50 mg/d and 300 mg/d are recommended. Doses should be adjusted individually.

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

•    For patients with mixed positive and negative symptoms, doses should be adjusted to obtain optimal control of positive symptoms.

•    The minimum effective dose should be used.

Special populations

•    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.

•    Renal insufficiency : Amisulpride is eliminated by the renal route. In renal insufficiency, the dose should be reduced to half in patients with creatinine clearance (CR_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 (CRCL < 10 ml/min) particular care is recommended in these patients (see 4.4 Special warning and precautions for use).

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

Paediatric population

•    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)

4.3 Contraindications

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

Concomitant prolactin-dependent tumours (e.g. pituitary gland prolactinomas and breast cancer)

Phaeochromocytoma.

Children up to puberty.

Lactation.

Combination with the following medications which could induce torsades de pointes :

-    Class Ia antiarrhythmic agents such as quinidine, disopyramide, procainamide.

-    Class III antiarrhythmic agents such as amiodarone, sotalol.

-    Others medications such as bepridil, cisapride, sultopride, thioridazine, methadone, IV erythromycin, IV vincamine, halofantrine, pentamidine, sparfloxacin.

This list is not exhaustive.

Combination with levodopa (see 4.5 Interactions with other medical products and other forms of interaction)

4.4 Special warnings and precautions for use

•    Neuroleptic Malignant Syndrome

As with other neuroleptics, Neuroleptic Malignant Syndrome, a potentially fatal complication, characterized 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 drugs including amisulpride should be discontinued.

•    Parkinson’s disease

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 Amisulpride induces a dose-dependent prolongation of the QT interval (see Section 4.8 Undesirable effects). 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 monitor 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 medication likely to produce pronounced bradycardia (< 55 bpm), hypokalaemia, decreased intracardiac conduction, or prolongation of the QT interval (see Section 4.5 Interaction with other medicinal products and other forms of interaction).

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.

•    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.

•    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 drugs as opposed to some characteristic(s) of the patient is not clear.

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.

•    Hyperglycaemia

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.

•    Epilepsy

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

•    Renal insufficiency

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).

•    Elderly

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.

•    Leukopenia, neutropenia and agranulocytosis

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.

•    Withdrawal

Acute withdrawal symptoms have been described after abrupt cessation of high therapeutic doses of antipsychotic drugs. Withdrawal symptoms including nausea, vomiting and insomnia have very rarely been described after abrupt cessation of high 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. Lactose warning: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Contraindicated combinations

• Levodopa : reciprocal antagonism of effects between levodopa and neuroleptics. Amisulpride may oppose the effect of dopamine agonists e.g. bromocriptine, ropirinol.

Medications which could induce torsades de pointes:

•    Medications such as bepridil, cisapride, sultopride, thioridazine, methadone, IV erythromycin, IV vincamine, halofantrine, pentamidine, sparfloxacin. This list is not exhaustive.

Combinations not recommended

•    Amisulpride may enhance the central effects of alcohol.

Combinations to be taken into account

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

•    Antihypertensive drugs and other hypotensive medications.

Medications which could induce torsades de pointes:

Caution is advised when prescribing amisulpride with medicines known to prolong the QT interval, e.g., class IA antiarrhythmics (e.g., quinidine, disopyramide, procainamide) and class III antiarrhythmics (e.g., amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g., mefloquine) (see section 4.4). This list is not exhaustive.

Combinations which require precautions for use

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

•    Bradycardia-inducing medications such as beta-blockers, bradycardia-inducing calcium channel blockers such as diltiazem and verapamil, clonidine, guanfacine ; digitalis.

•    Medications which induce hypokalaemia or electrolyte imbalance : hypokalemic diuretics, stimulant laxatives, IV amphotericin B , glucocorticoids, tetracosactides.

•    Neuroleptics such as pimozide, haloperidol ; imipramine, antidepressants, lithium.

Combinations to be taken into account

•    Dopamine agonists (eg : levodopa) since it may attenuate their action

4.6 Fertility, pregnancy and lactation

Pregnancy

In animals, amisulpride did not show 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. If amisulpride is used during pregnancy, neonates may show adverse effects of amisulpride and thus appropriate monitoring should be considered.

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.

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.

4.7 Effects on ability to drive and use machines

Even used as recommended, amisulpride may cause somnolence 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 I 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).

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.

*    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

*    Psychiatric disorders:

Common: Insomnia, anxiety, agitation, orgasmic dysfunction

*    Gastrointestinal disorders

Common: Constipation, nausea, vomiting, dry mouth

*    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. •Metabolism and nutrition disorders

Uncommon: Hyperglycemia (see 4.4 Special warnings and precautions for use).

•    Cardiac disorders Uncommon: Bradycardia

•    Vascular disorders Common:Hypotension

•Investigations:

Common: Weight gain

Uncommon: Elevations of hepatic enzymes, mainly transaminases

•    Immune system disorders Uncommon: Allergic reaction Post marketing data

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

• Blood and lymphatic system disorders_

Not known: Leukopenia, neutropenia and agranulocytosis (see section 4.4)

•Nervous system disorders:

Frequency not known: Neuroleptic Malignant Syndrome (see 4.4 Special warnings and precautions for use) , which is a potentially fatal complication. •Cardiac disorders:

Frequency 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 4.4 Special warnings and precautions for use).

•Vascular disorders:

Frequency not known: Venous thromboembolism, including pulmonary embolism, sometimes fatal, and deep vein thrombosis •Skin and subcutaneous tissue disorders:

Frequency not known: Angioedema, urticaria •Pregnancy, puerperium and perinatal conditions:

Not Known: Drug withdrawal syndrome neonatal (see section 4.6)

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 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: close supervision of vital functions and 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antipsychotics, psychopharmaca, neuroleptics 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 neuroleptics, amisulpride has no affinity for serotonin, a-adrenergic, histamine H₁ and cholinergic receptors. In addition, amisulpride does not bind to sigma sites.

In animals, at high doses it blocks post-synaptic D2 receptors located in the limbic structures in preference to those in the striatum. Unlike classical neuroleptics it does not induce catalepsy and hypersensitivity of D2 dopamine receptors does not develop after repeated treatment.

At low doses it preferentially blocks pre-synaptic D2/D3 receptors, producing dopamine release responsible for its dis-inhibitory effects.

This atypical pharmacological profile may explain amisulpride's antipsychotic effect at higher doses through post-synaptic dopamine receptor blockade and its efficacy against negative symptoms, at lower doses, through pre-synaptic dopamine receptor blockade. In addition, the reduced tendency of amisulpride to produce extrapyramidal side effects may be related to its preferential limbic activity.

In clinical studies including schizophrenic patients with acute exacerbations, amisulpride significantly alleviated secondary negative symptoms as well as affective symptoms such as depressed mood.

5.2 Pharmacokinetic properties

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

The volume of distribution is 5.8 l/kg. As plasma protein binding is low (16%) drug

Absolute bio-availability is 48%. Amisulpride is weakly metabolized: 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.

Kinetic profile of amisulpride is not influenced by diet.

A carbohydrate rich meal (containing 68% fluids) significantly decreases the AUC_s, 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 insufficiency: since the drug is weakly metabolized a dosage reduction should not be necessary in patients with hepatic insufficiency.

Renal insufficiency: The elimination half-life is unchanged 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 dialyzed.

Limited pharmacokinetic data in elderly subjects (> 65 years) show that a 10-30 % rise occurs in C_max, T_1/2 and AUC after a single oral dose of 50 mg. No data are available after repeat dosing.

5.3 Preclinical safety data

An overall review of the completed safety studies indicates that amisulpride is devoid of any general, organ-specific, teratogenic, mutagenic or carcinogenic risk. Changes observed in rats and dogs at doses below the maximum tolerated dose are either pharmacological effects or are devoid of major toxicological significance under these conditions. Compared with the maximum recommended dosages in man, maximum tolerated doses are 2 and 7 times greater in rats (200 mg/kg/d) and dogs (120 mg/kg/d) respectively in terms of AUC. No carcinogenic risk, relevant to man, was identified in mice (up to 120 mg/kg/d) and rats (up to 240 mg/kg/d), corresponding for the rat to 1.5 to 4.5 times the expected human AUC. Reproductive studies performed in rats, rabbits and mice did not show any teratogenic potential.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium starch glycolate Lactose monohydrate

Methycellulose

Microcrystalline cellulose (E460)

Magnesium stearate (E572)

Film-Coating

Basic butylated methacrylate polymers (Eudragit E100) Titanium dioxide (E171)

Talc

Magnesium Stearate Macrogol 6000

6.2 Incompatibilities

None known.

6.3 Shelf life

3 years

6.5 Nature and contents of container

PVC/aluminium foil blister packs containing 60 tablets

6.6 Special precautions for disposal

No special precautions.

7    MARKETING AUTHORISATION HOLDER

Norton Healthcare Limited

T/A IVAX Pharmaceuticals UK Limited

Ridings Point, Whistler Drive, Castleford,

West Yorkshire, WF10 5HX

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0730

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/04/2009

10 DATE OF REVISION OF THE TEXT

28/10/2013