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Amisulpride 400mg Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

AMISULPRIDE 400mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 400mg Amisulpride.

Excipients: Each tablet contains 200mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Film-coated tablet.

White to off-white, ovoidal-shaped, biconvex, film-coated tablets with a break line, 18mm long and 8mm wide.

The tablet can be divided into equal halves.

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.

4.2. Posology and method of administration

For acute psychotic episodes, oral doses between 400 mg per day and 800 mg per day are recommended. In individual cases, the daily dose may be increased up to 1200 mg per day. Doses above 1200 mg per 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 50 mg per day and 300 mg per 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 twice daily.

Elderly: Amisulpride should be used with particular caution because of a possible risk of hypotension or sedation.

Children: Amisulpride is contra-indicated in children under 15 years of age 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)

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

For doses not achievable/feasible with this strength, other strengths of this active ingredient are available.

Method of administration For oral use.

Amisulpride may be taken without regard to meals. The tablets should be taken unchewed, with a sufficient amount of fluid.

4.3. Contraindications

•    Hypersensitivity to amisulpride or to any of the excipients.

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

•    Phaeochromocytoma

•    Children under 15 years of age

•    Lactation

•    Combination with the following medicines which could induce torsades de pointes:

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

o Class III antiarrhythmic agents such as amiodarone, sotalol.

o Other medications such as bepridil, cisapride, sultopride, thioridazine, IV erythromycin, IV vincamine, halofantrine, pentamidine, sparfloxacin. (This list is not exhaustive.)

• Combination with levodopa (see section 4.5)

4.4. Special warnings and precautions for use

As with other neuroleptics, 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 medicines including Amisulpride should be discontinued.

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

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

Concomitant neuroleptics should be avoided (see section 4.5).

Hyperglycaemia has been reported during treatment with some atypical antipsychotics including amisulpride. Patients on amisulpride with or at risk of diabetes should monitor their glucose levels regularly.

In elderly patients (over 65 years of age), Amisulpride, like other neuroleptics, 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 neuroleptic treatment cannot be avoided.

Prolongation of the QT interval

Amisulpride induces a dose-dependent prolongation of the QT interval. This effect, known to potentiate the risk of serious ventricular arrhythmias such as torsades de pointes, is enhanced by the pre-existence of bradycardia, hypokalaemia, congenital or acquired long QT interval.

Hypokalaemia should be corrected.

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,

•    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 QTc interval (see section 4.5).

Caution should be used in patients with cardiovascular disease or a family history of QT prolongation.

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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Stroke

In randomized clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic medicines, a 3fold 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.

Acute withdrawal symptoms including nausea, vomiting and insomnia have been rarely described after abrupt cessation of high doses of antipsychotic agents. 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.

Cases of venous thrombolembolism (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 risperidone and preventative measures undertaken.

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

Combinations contra-indicated

Medicines which could induce QT prolongation and 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, IV erythromycin, methadone, IV vincamine, halofantrine, pentamidine, sparfloxacin.

(This list is not exhaustive.)

Levodopa: reciprocal antagonism of effects between levodopa and neuroleptics.

Combinations not recommended

Amisulpride may enhance the central effects of alcohol.

Combinations to be used with caution

Medicines which enhance the risk of torsades de pointes:

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

•    Medicines which cause electrolyte imbalance such as hypokalaemia: hypokalemic diuretics, stimulant laxatives, IV amphotericin B, glucocorticoids, tetracosactides.

•    Neuroleptics such as pimozide, haloperidol; impipramine antidepressants; lithium concomitant use should be avoided.

Combinations to be considered

CNS depressants including narcotics, anaesthetics, analgesics, sedative H1

antihistamines, barbiturates, benzodiazepines and other anxiolytic drugs, clonidine

and derivatives.

Antihypertensive drugs and other hypotensive medicines.

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

4.6 Fertility, pregnancy and lactation Pregnancy and lactation

Pregnancy

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

Very limited clinical data on exposed pregnancies are available. Therefore, the safety of Solian 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.

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

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.

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 used as recommended, Amisulpride may affect reaction time so that the ability to drive vehicles or operate machinery can be impaired.

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).

•    Immune system disorders Uncommon: Allergic reaction

•    Platelet, bleeding and clotting disorders

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

•    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 impotence.

•    Psychiatric disorders

Common: Insomnia, anxiety, agitation, orgasmic dysfunction

•    Nervous System Disorders

Very common: 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 50-300mg/day.

Common: Acute dystonia (spasm torticolis, oculogyric crisis, trismus) may appear. This is reversible without discontinuation of Amisulpride upon treatment with an antiparkinsonian agent. Somnelence.

Uncommon: 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. Seizures.

Frequency not known: Neuroleptic Malignant Syndrome have been reported (see section 4.4).

•    Cardiovascular disorders Common: Hypotension Uncommon: Bradycardia

Frequency not known: QT prolongation, ventricular arrhythmias - VF, VT (rare), sudden unexplained death, cardiac arrest, Torsades de pointes.

•    Pregnancy, puerperium and perinatal conditions

Frequency not known: Drug withdrawal syndrome neonatal (See 4.6)

•    Gastrointestinal disorders

Common: Constipation, nausea, vomiting, dry mouth, weight gain

•    Investigations

Uncommon: Elevations of hepatic enzymes, mainly transaminases 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.

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

Since Amisulpride is weakly dialysed, hemodialysis 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.

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

5.    PHARMACOLOGICAL PROPERTIES

5.1.    Pharmacodynamic properties

Pharmacotheraputic group: Antipsychotic, benzamides ATC code: N05A L05

Amisulpride binds selectively with a high affinity to human dopaminergic D2/D3 receptor subtypes whereas it is devoid of affinity for Di, D4 and D5 receptor subtypes.

Unlike classical and atypical neuroleptics, amisulpride has no affinity for serotonin, a -adrenergic, histamine Hi 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.

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, 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, 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: since the drug is weakly metabolised 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 dialysed.

Limited pharmacokinetic data in elderly subjects (> 65 years) show that a 10-30 % rise occurs in Cmax, T1/2 and AUC after a single oral dose of 50 mg. No data are available after repeat dosing.

5.3. Preclinical safety data

The safety profile of amisulpride use is largely related to the pharmacologic effects of the active substance.

An overall review of the completed safety studies indicates that amisulpride is devoid of any general, organ-specific, teratogenic, or genotoxic risk.

Carcinogenicity studies in mice and rats revealed that treatment with amisulpride resulted in an increased incidence of hormone-dependent tumours with no clinical relevance in man.

Amisulpride treatment might be associated with decreased fertility presumably due to the pharmacological effects of the active substance (a prolactin-mediated effect), as observed in animals.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Tablet core

Lactose monohydrate,

methylcellulose,

sodium starch glycolate type A,

magnesium stearate,

microcrystalline cellulose.

Coating

Methacrylate polymers, titanium dioxide (E171), talc,

magnesium stearate, macrogol 6000.

6.2. Incompatibilities

None known.

6.3. Shelf life

3 years

6.4. Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blisters comprising of 25pm Al foil and 250pm PVC contained within a printed carton box.

Pack sizes: 10, 20, 28, 30, 50, 56, 60, 84, 90, 100 or 150. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Actavis UK Limited (Trading style: Actavis) Whiddon Valley BARNSTAPLE N Devon EX32 8NS

8. MARKETING AUTHORISATION NUMBER

PL 0142/0587

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

2nd November 2004

10 DATE OF REVISION OF THE TEXT

27/02/2012