SOLIAN 50

SOLIAN 100

SOLIAN 200

SOLIAN 400

Solian® Solution, 100mg/ml

Active ingredient: Amisulpride (INN) 50 mg, 100 mg, 200 mg or 400 mg per tablet; Solian Solution: Amisulpride (INN) 100 mg/ml.

For excipients, see 6.1.

Solian 50: White to off-white, round, flat-faced tablet engraved with AMI 50 on one face.

Solian 100: White to off-white, round, flat-faced tablet engraved AMI 100 on one face and with a breakable bar on the other face

Solian 200: White to off-white, round, flat-faced tablet engraved AMI 200 on one face and with a breakable bar on the other face

Solian 400: Tablet

Solian Solution: Oral Solution: A clear yellow liquid in appearance.

Solian 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.

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 Solian. 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 ie 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/d and 300 mg/d are recommended. Doses should be adjusted individually.

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

Children : Solian is contra-indicated in children under 15 years of age as its safety has not yet been established.

Renal insufficiency : Solian 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 4.4 Special warning and precautions for use).

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

Method of administration (Solian Solution): The graduations on the dosage pipette measure the milligrams of active ingredient. After introducing the measuring syringe into the bottle, draw the plunger of the measuring syringe up to the graduation mark corresponding to the number of milligrams to be administered. The oral solution should be drunk with a liquid, which does not contain alcohol.

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 under 15 years of age.

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)

As with other neuroleptics, Neuroleptic Malignant Syndrome, 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 Solian 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.

Solian 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).

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

In elderly patients, Solian, 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 Solian to patients with Parkinson's disease since it may cause worsening of the disease. Solian 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 is advisable.

Prolongation of the QT interval

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 Solian 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. Solian should be used with caution in patients with stroke risk factors.

COMBINATIONS WHICH ARE CONTRAINDICATED

Medications which could induce torsades de pointes :

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

- Class III antiarrhythmic agents such as amiodarone, sotalol.

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

This list is not exhaustive.

Levodopa : reciprocal antagonism of effects between levodopa and neuroleptics.

COMBINATIONS WHICH ARE NOT RECOMMENDED

Solian may enhance the central effects of alcohol.

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

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

Antihypertensive drugs and other hypotensive medications

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

Pregnancy

In animals, Solian 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 Solian 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.

Lactation

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

Even used as recommended, Solian may cause somnolence so that the ability to drive vehicles or operate machinery can be impaired (see Section 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).

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).

• 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 4.4 Special warnings and 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 4.4 Special warnings and precautions for use).

Experience with Solian 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 Solian is weakly dialysed, haemodialysis is of no use to eliminate the drug.

There is no specific antidote to Solian.

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.

Pharmcotherapeutic group: Antipsychotics, 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, -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 Solian 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 (see chapter 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.

An overall review of the completed safety studies indicates that Solian 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/d) and dog (120 mg/kg/d) 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/d) and reproductive studies (160, 300 and 500 mg/kg/d respectively in rat, rabbit and mouse) were performed. The exposure of the animals to amisulpride during these latter studies was not evaluated.

Solian 50mg,100mg & 200mg tablets

Sodium starch glycolate, lactose monohydrate, microcrystalline cellulose, hypromellose, magnesium stearate.

Solian 400mg tablets

Sodium starch glycollate, lactose monohydrate, microcrystalline cellulose, hypromellose, magnesium stearate, polyoxyl 40 stearate, titanium dioxide (E171).

Solian Solution

Saccharin sodium, sodium gluconate, glucono delta lactone, hydrochloric acid, methyl parahydroxybenzoate, propyl parahydroxybenzoate, potassium sorbate, caramel flavour (tonka beans extract, vanillin, benzaldehyde, acetyl methyl carbinol, gamma and delta decalactones, esters from acetic, butyric and 2 methyl butyric acid, esters from ethyl and cinnamyl alcohol, propylene glycol and ethyl alcohol), purified water.

None known.

Tablets 3 years

Solution Shelf life of the medicinal product as packaged for sale: 3 years

Shelf life after first opening the container: 2 months

Dispose of within two months of opening.

No special precautions.

Tablets PVC/aluminium foil blister packs containing 60 tablets

Solution 60 ml brown glass bottle (type III) and child resistant cap with a PVDC/PE seal, with a 5ml graduated oral syringe.

No special precautions

sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

50 mg, 100mg, 200mg tablets 7 February 2009

400mg tablets 12 June 2009

Solution 13 February 2009

50mg: 7 February 2009

Solution, 100mg, 200mg 400mg: 19 November 2009

POM