Silomes ®is indicated for the treatment of acute and chronic schizophrenic disorders, in which positive symptoms (such as delusions, hallucinations, and thought disorders) and/or negative symptoms (such as blunted affect, emotional and social withdrawal) are prominent, including patients characterised by predominant negative symptoms.

Route of administration: Orally.

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 Silomes ^®. 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/d and 300 mg/d are recommended. Doses should be adjusted individually.

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

The minimum effective dose should be used.

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.

Renal insufficiency: Silomes ^® 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) particular care is recommended in these patients.

Hepatic insufficiency: since the drug 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.

- Hypersensitivity to the active ingredient or to other ingredients of the medicinal product - Concomitant prolactin-dependent tumours (e.g. pituitary gland prolactinomas or breast cancer) - Phaeochromocytoma - Children before the onset of puberty - Lactation - Combination with levodopa - In combination with the following medicinal products which could induce torsade de pointes: - class Ia antiarrhythmics such as quinidine and disopyramide - class III antiarrhythmics such as amiodarone and sotalol - other medicinal products such as bepridil, cisapride, sultopride, thioridazine, methadone, erythromycin (intravenous application), vincamine (intravenous application), halofantrine, pentamidine, sparfloxacin, azole antifungals

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.

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.

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 or 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.

Acute 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. Therefore, gradual withdrawal of amisulpride is advisable.

Prolongation of the QT interval

Amisulpride induces a dose-dependent prolongation of the QT interval. 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.

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.

Stroke:

In 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. The extent to which the findings of increased mortality may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

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.

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.

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.

Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including Amisulpride. Unexplained infections or fever may be evidence of blood dyscrasia, and requires immediate haematological investigation.

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

Contraindicated combinations:

• Medicinal products which could induce torsade de pointes:

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.

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

Combinations not recommended:

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

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

o medicinal products which induce hypokalaemia or electrolyte imbalance: hypokalemic diuretics, stimulant laxatives, amphotericin B (intravenous application), glucocorticoids, and tetracosactides. Hypokalaemia should be corrected.

o antipsychotics such as pimozide, and haloperidol

o imipramine antidepressants

o lithium

o some antihistamines such as astemizole, and terfenadine

o mefloquine

• Amisulpride may enhance the 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 anxiolytics, clonidine and derivatives.

• Antihypertensive drugs and other hypotensive medications.

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.

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.

Even used as recommended, Amisulpride may cause somnolence and blurred vision so that the ability to drive vehicles or operate machinery can be impaired.

 

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).

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, and 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, and 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.

• Cardiovascular disorders

Common: Hypotension

Uncommon: Bradycardia

• Investigations:

Common: Weight gain

Uncommon: Elevations of hepatic enzymes, mainly transaminases

• Immune system disorders

Uncommon: Allergic reaction

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

• Blood and Lymphatic system disorders:

Frequency not known: Leukopenia, neutropenia and agranulocytosis

• Endocrine disorders:

Frequency not known: Benign pituitary tumour such as prolactinoma

• Metabolism and nutrition disorders:

Frequency not known: hypertriglyceridemia and hypercholesterolemia. Hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH)

• Psychiatric disorders:

Frequency not known: confusion

• Nervous system disorders:

Frequency not known: Neuroleptic Malignant Syndrome, which is a potentially fatal complication

• Eye disorders:

Frequency not known: Blurred vision.

• 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.

• Vascular disorders:

Frequency not known: Cases of venous thromboembolism, including cases of pulmonary embolism, sometimes fatal, and cases of deep vein thrombosis have been reported with antipsychotic drugs.

• Skin and subcutaneous tissue disorders:

Frequency not known: Angioedema, urticaria

• Musculoskeletal and connective tissue disorders:

Frequency not known: Osteopenia, osteoporosis

• Pregnancy, puerperium and perinatal conditions:

Frequency not known: Drug withdrawal syndrome neonatal

• Respiratory, thoracic and mediastinal disorders:

Frequency not known: Nasal congestion

 

To report any side effect(s):

·       Saudi Arabia:

-       National Pharmacovigilance & Drug Safety Centre (NPC): ·       Fax: +966-11-205-7662 ·       Call NPC at +966-11-2038222, Ext.: 2317-2356-2353-2354-2334-2340. ·       Toll free phone : 8002490000 ·       E-mail: npc.drug@sfda.gov.sa ·       Website: www.sfda.gov.sa/npc

-   Other GCC States:

Please contact the relevant competent authority.

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, 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 until the patient recovers.

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

 

Pharmacotherapeutic group: Antipsychotics

ATC Code: NO5A LO5

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, -adrenergic, histamine H₁ and cholinergic receptors. In addition, amisulpride does not bind to sigma sites. 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 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. 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 (> 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.

An overall review indicates that Amisulpride is devoid of any general, organ-specific, teratogenic, mutagenic or carcinogenic risk. Compared with the maximum recommended dosages in man, maximum tolerated doses are 2 and 7 times greater. No carcinogenic risk, relevant to man, was identified.

Lactose Regular

Sodium Starch Glycolate

Hydroxypropyl Methyl Cellulose

Microcrystalline Cellulose

Magnesium Stearate

Not applicable.

2 years.

Do not store above 30°C.

Silomes ® 400mg Tablets are packed in Aluminum foil, PVC coated with PVDC blisters, with a multi folded leaflet packed in registration box.

 

Pack sizes:

30 tablets

(10 tablets / blister, 3 blisters/ pack)

Hospital packs are also available.

Any unused product or waste should be disposed of in accordance with local requirements.