- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Positive symptomsFor 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 sufficiently evaluated for safety and therefore should not be used. No specific titration is required when initiating treatment with Amisulpride Tablets. 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.
Primary negative symptoms (deficit syndrome)For patients characterised by predominant negative symptoms, oral doses between 50 mg/day and 300 mg/day are recommended. Doses should be adjusted individually.
Method of administrationAmisulpride Tablets can be administered independently of food intake once daily at oral doses up to 400 mg; higher doses should be administeredin divided doses. The tablets should be taken without chewing, with a sufficient amount of fluid.
Duration of treatmentData from controlled clinical trials covering a period of 1 year is available. The duration of treatment should be determined by the treating physician.Special populations
Patients over 65 yearsTreatment of elderly patients is not recommended as there is no sufficient clinical experience. Treatment with amisulpride bears a possible risk of hypotension or sedation (see section 5.2).
Children and adolescents under 18 yearsThe 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 is contraindicated (see section 4.3).
Renal insufficiencyAmisulpride is eliminated by the renal route.The daily 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) amisulpride is contraindicated in these patients (see section 4.3).
Hepatic insufficiencySince the drug is weakly metabolised a dose reduction should not be necessary.For doses not realisable / practicable with this strength, other strengths of this medicinal product are available.
Prolongation of the QT intervalAmisulpride induces a dose-dependent prolongation of the QT interval. 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 exclude the following factors which could favour the occurrence of this rhythm disorder:- cardiac disorders or family history of sudden death,- bradycardia less than 55 bpm,- electrolyte imbalance, in particular,hypokalaemia, hypomagnesaemia,- 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).
Cerebrovascular accident (CVA)In randomised, placebo-controlled clinical trials in elderly patients with dementia treated with atypical antipsychotics, a three-fold increase was observed in the risk of cerebrovascular adverse events. The mechanism leading to this increase in risk is unknown. It cannot be excluded that this effect might occur with other antipsychotics or in other patient populations. Amisulpride should therefore be used with caution in patients at risk for CVA.
Elderly patients with dementiaElderly 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., 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.
HyperglycaemiaHyperglycaemia 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. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Combinations Which Are Not RecommendedAmisulpride is not recommended in combination with the following agents which increase the risk of serious cardiac arrhythmias (torsade de pointes) or which may affect cardiac conduction (QT prolongation):- Bradycardia-inducing medicines such as beta-blockers, some calcium channel blockers such as diltiazem and verapamil, clonidine, guanfacine; digitalis glycosides.- Medications which induce hypokalaemia or electrolyte imbalance such as hypokalaemic diuretics, stimulant laxatives, intravenous (IV) amphotericin B, glucocorticoids, tetracosactides. Hypokalaemia must be treated (see section 4.4)- Neuroleptics such as pimozide, haloperidol - tricyclic antidepressants such as imipramine - lithium- some antihistamines (astemizole, terfenadine).Amisulpride may potentiate the central effects of alcohol. Therefore, alcohol should not be consumed during treatment.
Combinations which require precautions for useCaution is required when using the following agents concomitantly (due to potentiation of effect):- CNS depressants including narcotics, anaesthetics, analgesics, sedative H1 antihistamines, barbiturates, benzodiazepines and other anxiolytic drugs, clonidine and derivatives.- Antihypertensive drugs and other hypotensive medicines.There is no data on interactions with H2 antagonists such as cimetidine.
|Common||≥1/100 to <1/10|
|Uncommon||≥1/1,000 to <1/100|
|Rare||≥1/10,000 to <1/1,000|
|Not known||(cannot be estimated from the available data)|
Clinical trials dataThe following adverse events 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.
|Immune system disorders|
|Common:||Increased plasma prolactin levels, reversible after discontinuation of amisulpride. This may result in galactorrhoea, amenorrhoea or menstrual disorders, gynaecomastia, breast pain or enlargement, prolactinoma and erectile dysfunction.|
|Metabolism and nutrition disorders|
|Uncommon:||Hyperglycaemia (see section 4.4)|
|Common:||Insomnia, anxiety, agitation, orgasm disorders|
|Nervous system disorders|
|Very common:||Extrapyramidal disorders such as 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 agents. 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 such as spasm torticollis, oculogyric crisis, trismus. This is reversible without discontinuation of amisulpride upon treatment with an antiparkinsonian agent.|
|Uncommon:||Tardive dyskinesia characterised by rhythmic, involuntary movements primarily of the tongue and/or face, usually after long term administration. Antiparkinsonian treatment should not be used as it is ineffective or may induce aggravation of the symptoms.|
|Common:||Gastrointestinal disorders such as constipation, nausea, vomiting, dry mouth|
|Uncommon:||Increased hepatic enzyme levels, especially transaminases|
Post-marketing dataThe following adverse events/reactions were spontaneously reported after market launch:
|Nervous system disorders|
|Not known:||Neuroleptic malignant syndrome (see section 4.4)|
|Skin and subcutaneous tissue disorders|
|Frequency not known: Angioedema, urticaria.|
|Not known:||QT prolongation, ventricular arrhythmias such as torsade de pointes and ventricular tachycardia, which can lead to fibrillation or cardiac arrest and sudden death (see section 4.4).|
|Not known - Cases of venous thromboembolism, including cases of pulmonary embolism, sometimes fatal and cases of deep vein thrombosis have been reported.|
|General disorders and administration site conditions|
|Rare:||Acute withdrawal symptoms including nausea, vomiting and insomnia after abrupt cessation of high doses, also recurrence of psychotic symptoms, emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) (see section 4.4).|
|Pregnancy, puerperium and perinatal conditions|
|Not known:||Drug withdrawal syndrome neonatal (see 4.6).|
SymptomsExperience with Amisulpride Tablets 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 antipsychotic agents.
TreatmentIn 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 Tablets.Appropriate supportive measures should therefore be instituted with close supervision of vital functions including continuous cardiac monitoring due to risk of prolongation of QT interval.If severe extrapyramidal symptoms occur, anticholinergic agents should be administered.
Pharmacotherapeutic group: Benzamides
ATC Code: NO5A LO5Amisulpride 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 Amisulpride Tablets against both negative and positive symptoms of schizophrenia.
Hepatic insufficiencySince the drug is weakly metabolised a dose reduction should not be necessary in patients with hepatic insufficiency.
Renal insufficiencyThe elimination half-life is increased 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.
Elderly patientsIn elderly patients (>65 years), slight changes were observed in the kinetic profile (10% increase in AUC) which are probably due to age-related changes in renal function.
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