Amisulpride

Amisulpride 400 mg film-coated tablets

Each film-coated tablet contains:

400 mg amisulpride

Excipient:

200 mg lactose monohydrate

For the full list of excipients, see Section 6.1.

Film-coated tablets

Amisulpride 400 mg film-coated tablets are white to off white, and capsule shaped tablets with break line on one side.

The tablets can be divide into equal halves.

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.

Posology

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 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 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/day and 300 mg/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 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 (see section 4.3 contraindications).

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.

Method of administration

Oral

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Concomitant prolactin-dependent tumours (e.g. pituitary gland prolactinomas and breast cancer) (see section 4.4 and section 4.8).

Phaeochromocytoma.

Children up to puberty.

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

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 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).

Severe liver toxicity has been reported with Amisulpride use. Patients should be instructed to report immediately signs such as asthenia, anorexia, nausea, vomiting, abdominal pain or icterus to a physician. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately (see section 4.8)

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 cardiovascular disease or family history of QT prolongation, and concomitant use with neuroleptics 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.

Withdrawal symptoms including nausea, vomiting and insomnia have very rarely 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.

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.

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., hearth 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.

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 preventative measures undertaken.

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.

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.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption should not take this medicine

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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.

Co-administration of amisulpride and clozapine may lead to an increase in plasma levels of amisulpride.

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

Pregnancy

There are only limited data available from the use of amisulpride in pregnant women. The safety of amisulpride during human pregnancy has not been established.

Amisulpride crosses the placenta.

Studies in animals have shown reproductive toxicity (see section 5.3).

The use of amisulpride is not recommended during pregnancy and in women of childbearing potential not using effective contraception, unless the benefits justify the potential risks.

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.

Breast feeding

Amisulpride is excreted into breastmilk in rather large amounts above the accepted value of 10% of the maternal weight-adjusted dosage in some cases, but blood concentrations in breastfed infants have not been evaluated. There is insufficient information on the effects of amisulpride in newborns/infants.

A decision must be made whether to discontinue breast-feeding or to abstain from amisulpride therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

A decrease in fertility linked to the pharmacological effects of the drug (prolactin-mediated effect) was observed in treated animals.

Even when used as recommended, Amisulpride may cause somnolence and blurred vision 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 ( ≥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).

● Blood and lymphatic system disorders:

Uncommon: leukopenia, neutropenia (see Section 4.4).

Rare: agranulocytosis.

● Immune system disorders:

Uncommon: allergic reaction

● 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.

Rare: benign pituitary tumour such as prolactinoma (see Section 4.4).

● Metabolism and nutrition disorders:

Uncommon: hyperglycemia, hypertriglyceridemia and hypercholesterolemia.

Rare: hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

● Psychiatric disorders:

Common: insomnia, anxiety, agitation, orgasmic dysfunction.

Uncommon: confusion.

● 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.

Rare: Neuroleptic Malignant Syndrome (see Section 4.4), which is a potentially fatal complication.

Not known: restless legs syndrome.

●

Eye disorders:

Common: blurred vision.

● Cardiac disorders:

Uncommon: bradycardia.

Rare: QT interval prolongation, ventricular arrhythmias such as torsade de pointes, ventricular tachycardia, ventricular fibrillation, cardiac arrest, sudden death (see Section 4.4).

●

Vascular disorders:

Common: hypotension.

Uncommon: increase in blood pressure.

Rare: venous thromboembolism, including pulmonary embolism, sometimes fatal, and deep vein thrombosis

●

Respiratory, thoracic and mediastinal disorders:

Uncommon: nasal congestion, aspiration pneumonia (mainly in association with other antipsychotics and CNS depressants).

● Gastrointestinal disorders:

Common:constipation, nausea, vomiting, dry mouth.

● Hepatobilary disorders:

Uncommon: hepatocellular injury

● Skin and subcutaneous tissue disorders:

Rare: angioedema, urticaria.

Not known: photosensitivity reaction

.

● Musculoskeletal and connective tissue disorders:

Uncommon: osteopenia, osteoporosis.

● Renal and urinary disorders:

Uncommon: urinary retention

● Pregnancy, puerperium and perinatal conditions

Frequency not known: drug withdrawal syndrome neonatal (see Section 4.6)

● Injury, poisoning and procedural complications

Not Known: Fall as a consequence of adverse reactions compromising body balance

● Investigations:

Common: weight gain.

Uncommon: elevations of hepatic enzymes, mainly transaminases.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 should not be used 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 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, amisulpride 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 D ₂ 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 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. As 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.

A carbohydrate rich meal (containing 68% fluids) significantly decreases the AUC_s, 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 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 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 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 the rat at up to 1.5 - 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.

In animal trials amisulpride elicited an effect on foetal growth and development at doses corresponding to Human Equivalent Dose of 2000 mg/day and upwards for a 50-kg patient. There was no evidence for a teratogenic potential of amisulpride.

Studies on the impact of amisulpride on the behaviour of the offspring have not been conducted.

Core:

Lactose monohydrate

Methylcellulose

Sodium starch glycolate (Type A)

Microcrystalline cellulose

Magnesium stearate

Coating:

Eudragit (E100)

Titanium dioxide

Talc

Magnesium stearate

Macrogol 6000

Not applicable.

36 months

No special precautions for storage.

PVC/aluminium foil blister packs containing 60 tablets.

No special requirements.

Rivopharm UK Limited

100 Bishopsgate

London

EC2N 4AG

United Kingdom

PL 33155/0089

15/02/2013

25/06/2023