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AMISULPRIDE 100 MG TABLETS

Active substance(s): AMISULPRIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Amisulpride 100 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains:
100 mg amisulpride
Excpient:
50 mg lactose monohydrate
For the full list of excipients, see Section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
Amisulpride 100 mg tablets are white and round with break line on one side and
embossed with A100 on the other side.
The tablets 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, 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.

4.2

Posology and method of administration

Posology
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 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/d
and 300 mg/d 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 patients: 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 or sedation. Reduction in dosage may also be required because of renal
insufficiency.
Paediatric population.
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).
Renal insufficiency: Amisulpride is eliminated by the renal route. In renal insufficiency, the
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)
particular care is recommended in these patients (see Section 4.4).
Hepatic insufficiency: since the drug is weakly metabolised a dosage reduction should not be
necessary.
Method of administration
Oral

4.3

Contraindications

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.
Phaeochromocytoma.
Children before the onset of puberty.

Lactation.
Combination with levodopa (see Section 4.5)

4.4

Special warnings and precautions for use

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
glycaemic monitoring.
Amisulpride is eliminated by the renal route. In cases of severe renal insufficiency, the dose
should be decreased and intermittent treatment should be prescribed (see Section 4.2).
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 or 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.
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.
Caution should be exercised when amisulpride is prescribed in patients with known
cardiovascular disease or family history of QT prolongation.
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. Amisulpride should be used with caution in patients with stroke risk factors.
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 preventive measures undertaken.
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, the Lapp lactase deficiency or
glucose-galactose malabsorption should not take this medicine.
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.

4.5

Interaction with other medicinal products and other forms of interaction

COMBINATIONS WHICH ARE CONTRAINDICATED
Levodopa: reciprocal antagonism of effects between levodopa and neuroleptics. Amisulpride
may oppose the effect of dopamine agonists e.g. bromocriptine, ropinirole.

COMBINATIONS WHICH ARE 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 anxiolytic drugs, 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 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).

4.6

Fertility, pregnancy and lactation

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.
For women of childbearing potential, effective contraception should be fully discussed with
the physician prior to treatment.
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
It is not known whether Amisulpride is excreted in breast milk, breast-feeding is therefore
contra-indicated

4.7

Effects on ability to drive and use machines
Even used as recommended, Amisulpride may cause somnolence so that the ability to
drive vehicles or operate machinery can be impaired (see Section 4.8).

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 (≥1/1000, <1/100)
Rare (≥ 1/10,000, <1/1,000)
Very rare (<1/10,000)
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 Section 4.4).
• 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:
•Blood and Lymphatic system disorders:
Frequency not known: Leukopenia, neutropenia and agranulocytosis (see section 4.4)
• Metabolism and

nutrition disorders:

Frequency not known: hypertriglyceridemia and hypercholesterolemia
• Psychiatris disorders:
Frequency not known: confusion
•Nervous system disorders:
Frequency not known: Neuroleptic Malignant Syndrome (see Section 4.4), which is a
potentially
fatal complication.
•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).
• Vascular disorders:
Frequency not known: Cases of venous thromboembolism, including cases of pulmonary
embolism, sometimes fatal, and cases of deep vein thrombosis have been reported with
antipsychotic drugs.
• Skin and subcutaneous tissue disorders:
Frequency not known: Angioedema, urticaria
• Pregnancy, puerperium and perinatal conditions:
Frequency not known: Drug withdrawal syndrome neonatal (see Section 4.6)
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 Yellow
Card Scheme (www.mhra.gov.uk/yellowcard).

4.9

Overdose

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

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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, αadrenergic, 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 against both
negative and positive symptoms of schizophrenia.

5.2

Pharmacokinetic properties

Absorption
In man, amisulpride shows two absorption peaks: one which is attained rapidly, one hour
postdose 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.
Distribution
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%.
Biotransformation
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.
Elimination
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 Section 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.

5.3

Preclinical safety data
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/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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate
Methylcellulose
Sodium starch glycolate (Type A)
Microcrystalline cellulose
Magnesium stearate

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
36 months

6.4

Special precautions for storage
No special precautions for storage.

6.5

Nature and contents of container
PVC/aluminium foil blister packs containing 60 tablets.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER

DOUBLE-E PHARMA Ltd.
17 Corrig Road, Sandyford
Dublin 18
IRELAND

8

MARKETING AUTHORISATION NUMBER(S)
PL 39891/0005

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15/02/2013

10

DATE OF REVISION OF THE TEXT
17/01/2018

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Source: Medicines and Healthcare Products Regulatory Agency

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