Amisulpride 400mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Amisulpride 400mg Film-coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Film-coated tablet contains 400mg amisulpride.
Excipient(s):
Each tablet contains 200.0mg lactose.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated Tablet
White to off white, film coated ovoidal shaped tablets with a score line on one side and embossed ‘AM 400’ on the other.
The tablet can be divided into equal halves.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Amisulpride is indicated for the treatment of acute and chronic schizophrenic disorders with:
• positive symptoms such as delusions, hallucinations, thought disorders, hostility, suspiciousness
• primary negative symptoms (deficit syndrome) such as blunted affect, emotional and social withdrawal.
4.2 Posology and method of administration Positive symptoms
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 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 administration
<Amisulpride Tablets> can be administered independently of food intake once daily at oral doses up to 400 mg; higher doses should be administered in divided doses. The tablets should be taken without chewing, with a sufficient amount of fluid.
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.
Special populations:
Patients over 65 years
Treatment 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 years
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 is contraindicated (see section 4.3).
Renal insufficiency
Amisulpride 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 insufficiency
Since 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.
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients.
- Concomitant prolactin-dependent tumors e.g. pituitary gland prolactinomas and breast cancer
- Patients with severe renal insufficiency (creatine clearance less that 10 ml//min: lack of experience)
- Phaeochromocytoma
- Children until puberty
- Combination with levodopa (see section 4.5).
- Lactation (see section 4.6)
- Combination with the following medications which may cause severe cardiac arrhythmias (QT prolongation, torsades de pointes):
- Class I antiarrhythmic agents such as quinidine, disopyramide, procainamide, mexiletine, flecanide and propafenone
- Class III antiarrhythmic agents such as amiodarone, sotalol.
- Other medicines such as bepridil, cisapride, sultopride, thioridazine, methadone, intravenous (IV) erythromycin, IV vincamine, halofantrine, pentamidine, sparfloxacin, imidazole antifungals (see section 4.5).
This list is not exhaustive.
4.4 Special warnings and precautions for use
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 Amisulpride Tablets should be discontinued.
Amisulpride is eliminated by the renal route. In cases of mild-to-moderate renal insufficiency (creatine clearance >10ml/min), the daily dose should be decreased or intermittent treatment could be considered (see section 4.2).
Amisulpride Tablets may lower the seizure threshold. Therefore patients with a history of epilepsy should be closely monitored during therapy.
Amisulpride is not recommended for use in patients over 65 years of age, owing to a lack of experience. It may lead to sedation and hypotension in this patient population (see section 5.2).
As with other antidopaminergic agents, caution should also be exercised when prescribing Amisulpride Tablets to patients with Parkinson’s disease since it may cause worsening of the disease. Amisulpride Tablets should be used only if neuroleptic treatment cannot be avoided.
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 Tablets and preventative measures undertaken.
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 akathisa, 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. 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 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., 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.
Hyperglycaemia
Hyperglycaemia 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.
4.5 Interaction with other medicinal products and other forms of interaction
Combinations Which Are Contraindicated (see section 4.3)
Combination with the following medications which may cause severe cardiac arrhythmias (QT prolongation, torsades de pointes):
- Class I antiarrhythmic agents such as quinidine, disopyramide, procainamide, mexiletine, flecainide and propafenone.
- Class III antiarrhythmic agents such as amiodarone and sotalol.
- Others medicines such as bepridil, cisapride, sultopride, thioridazine, methadone, intravenous (IV) erythromycin, IV vincamine, halofantrine, pentamidine, sparfloxacin, imidazole antifungals (see section 4.5).
This list is not exhaustive.
Amisulpride should not be administered concomitantly with dopamine agonists (e.g. levodopa for Parkinson's disease) due to reciprocal antagonism (see section 4.3).
Combinations Which Are Not Recommended
Amisulpride 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 use
Caution 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.
4.6 Pregnancy and lactation
Fertility and pregnancy
There is only very limited clinical data on the use of amisulpride during pregnancy. Animal studies indicate that amisulpride exerts an influence on embryofetal development and growth without having teratogenic potential.
The safety of amisulpride during human pregnancy has not been established. Therefore, use is not recommended during pregnancy unless the benefits justify the potential risks.
Neonates exposed to amisulpride during pregnancy may exhibit adverse events and should therefore be monitored.
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.
A decrease in female fertility linked to the pharmacological effects of the substance (prolactin-mediated effect) was observed.
For women of childbearing potential, effective contraception should be fully discussed with the physician prior to treatment.
Lactation
It is not known whether amisulpride is excreted in breast milk, breast-feeding is therefore contraindicated.
4.7 Effects on ability to drive and use machines
Amisulpride has moderate influence on the ability to drive and use machines. Even when used as recommended, Amisulpride Tablets may affect reaction time (e.g. caused by somnolence) so that the ability to drive vehicles or operate machinery can be impaired (see section 4.8).
This is especially true when used concomitantly with alcohol.
4.8 Undesirable effects
Very common >1/10 Common >1/100 to <1/10
Uncommon >1/1,000 to <1/100
Rare >1/10,000 to <1/1,000
Very rare <1/10,000
Not known (cannot be estimated from the available data)
Clinical trials data
The 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 Uncommon: Allergic reactions
Endocrine 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)
Psychiatric disorders
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 50300 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.
Somnolence, dizziness
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. Seizures.
Cardiac disorders Uncommon: Bradycardia
Vascular disorders Common: Hypotension
Gastrointestinal disorders
Common: Gastrointestinal disorders such as constipation, nausea, vomiting,
dry mouth
Investigations
Common: Weight gain
Uncommon: Increased hepatic enzyme levels, especially transaminases
Post-marketing data
The 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.
Cardiac disorders
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).
Vascular disorders
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).
Experience 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.
Treatment
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 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Benzamides
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.
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.
5.2 Pharmacokinetic properties
In humans, 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 dose reduction should not be necessary in patients with hepatic insufficiency.
Renal insufficiency
The 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 patients
In 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.
5.3 Preclinical safety data
Studies of chronic toxicity in rats (up to 200 mg/kg BW/d) and dogs (up to 120 mg/kg bw/d revealed no organ-specific toxicity. Apathy, lethargy and tremor were observed. Increased cholesterol and fat plasma levels and transient tachycardia were observed in dogs only.
Animal studies indicate an influence of amisulpride on embryonal/fetal development, but no teratogenic potential. Adequate studies to assess the effects on the offspring were not performed.
Carcinogenicity studies in rat and mice showed an increased incidence of mammary, pituitary, adrenal and endocrine pancreatic tumours. A no-effect level dose could not be established. An increased incidence of tumours was observed in both animal species already at the lowest dose (30 mg/kg bw). The induction of tumours can be explained by the anti-dopaminergic and hyperprolactinaemic effect of amisulpride, and the particular sensitivity of rodents to these hormonal changes. The mechanism of this induction is known in rodents.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Methylcellulose 400 cP Sodium starch glycollate (type A)
Magnesium stearate Microcrystalline cellulose
Film-coating:
Basic Butylated Methylacrylate copolymer (Eudragit E100) Titanium dioxide (E-171)
Talc
Magnesium stearate Macrogol 6000
6.2 Incompatibilities
None known.
6.3 Shelf life
3 Years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Amisulpride 400mg Film-coated Tablets are packed in PVC/Aluminium blisters available in pack sizes of 20, 50, 60 or 100 tablets* * not all pack types will be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Arrow Generics Limited Whiddon Valley, Barnstaple,
Devon,
EX32 8NS United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 18909/0263
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17/02/2010
10 DATE OF REVISION OF THE TEXT
06/11/2013