sanofi-aventis

Solian 400mg Film-Coated Tablets

Amisulpride 400 mg per tablet

Also contains lactose monohydrate 130.25mg per tablet.

For a full list of excipients, see section 6.1

Film Coated Tablet.

A white film-coated scored tablet engraved AMI 400. The scoreline/breakline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

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.

Amisulpride also regulates secondary negative symptoms in productive state, as well as affective disorders such as depressive mood.

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/day. Doses above of 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. 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 (deficit syndrome), oral doses between 50 mg/day and 300 mg/day are recommended. Doses should be adjusted individually.

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

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 amilsulpride is contraindicated 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 (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 (see section 4.4 Special Warnings and Special Precautions for Use).

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

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

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

Phaeochromocytoma.

Children up to puberty.

Lactation.

Combination with levodopa (see section 4.5 Interactions with other medicinal products and other forms of interactions).

As with other neuroleptics, Neuroleptic Malignant Syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, 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 glycemic 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 Posology and method of administration).

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 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.

Prolongation of the QT interval

Caution should be exercised when amisulpride is prescribed in patients with known cardiovascukar disease or family history of QT prolongation, and concomitant use with neuroleptics should be avoided.

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 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.

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 dyskinsia) has been reported with amisulpride. Therefore, gradual withdrawal of amisulpride is advisable.

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 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.

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

CONTRAINDICATED COMBINATIONS

Levodopa: reciprocal antagonism of effects between levodopa and neuroleptics.

COMBINATIONS NOT RECOMMENDED

Amisulpride may enhance the central effects of alcohol.

COMBINATIONS TO BE TAKEN INTO ACCOUNT

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

- Antihypertensive drugs and other hypotensive medications

- Caution is advised when prescribing amisulpride with medicines known to prolong the QT interval, e.g., class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g. amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g., mefloquine) (see section 4.4).

Amisulpride may oppose the effect of dopamine agonists e.g. bromocriptine, ropirinole.

Pregnancy

In animals, amisulpride did not show direct 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.

Lactation

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

Even when 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).

Clinical Trial 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.

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).

Clinical trial 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 section 4.4 Special Warnings and Special Precautions for Use).

- Cardiovascular disorders:

Common: Hypotension.

Uncommon: Bradycardia.

- 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:

- Nervous system disorders

Frequency not known: Neuroleptic Malignant Syndrome (see section 4.4 Special Warnings and Special Precautions for Use).

- 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 section 4.4 Special Warnings and Special Precautions for Use).

- Vascular disorders

Frequency not known: Venous thromboembolism, including pulmonary embolism, sometimes fatal, and deep vein thrombosis (see section 4.4 Special Warnings and Special Precautions for Use).

- Skin and subcutaneous tissue disorders:

Frequency not known: Angioedema, urticaria

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 overdosage, 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 cardiac monitoring (risk of prolongation of QT interval) until the patient recovers.

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

Pharmacotherapeutic group: Antipsychotics, psychopharmaca, neuroleptics

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 D₁, D₄ and D₅ receptor subtypes.

Unlike classical and atypical neuroleptics, amisulpride has no affinity for serotonin, α-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 disinhibitory effects.

This atypical pharmacological profile may explain amisulpride's antipsychotic effect at higher doses through post-synaptic dopamine receptor blockage and its efficacy against negative symptoms, at lower doses through presynaptic dopamine receptor blockage. 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.

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. A plasma protein binding is low (16%) drug interactions are unlikely.

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.

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 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 for dosing recommendations). 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 C_max, T_1/2 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 mice (up to 120mg/kg/day) and rats (up to 240mg/kg/day), 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.

Sodium starch glycollate

Lactose monohydrate

Microcrystalline cellulose

Hypromellose

Magnesium stearate

Macrogol stearate

Titanium dioxide (E171).

Not applicable.

3 years

No special precautions for storage

PVC/aluminium foil blister packs containing 30, 60 or 90 tablets

Not all pack sizes may be marketed.

No special precautions for storage

sanofi-aventis Ireland Ltd.

Citywest Business Campus

Dublin 24

Ireland

PA 540/158/4

Date of first authorisation: 27^th July 1998

Date of last renewal: 1st September 2009

September 2010