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AMISULPRIDE 100MG/ML ORAL SOLUTION

Active substance(s): AMISULPRIDE / AMISULPRIDE / AMISULPRIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Amisulpride 100mg/ml Oral Solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 1ml of solution contains 100mg of Amisulpride.
It also contains 1mg/ml methyl parahydroxybenzoate (E218), 0.5mg/ml propyl
parahydroxybenzoate (E216), sodium (4.02mg/ml) and ethanol (less than 0.5mg/ml).
For a full list of excipients, see Section 6.1.

3

PHARMACEUTICAL FORM
Oral Solution.
A colourless to brown yellowish clear solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Amisulpride Oral Solution 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
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 Oral Solution. Doses should be adjusted according to
individual response. Maintenance treatment should be established individually with
the minimally effective dose.
For patients with mixed positive and negative symptoms, doses should be adjusted
to obtain optimal control of positive symptoms i.e. between 400-800 mg/day.
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 Oral Solution can be administered once daily at oral doses up to 300 mg,
higher doses should be administered in two separate doses.
The minimum effective dose should be used.
Elderly: The safety of amisulpride has been examined in a limited number of elderly
patients. Amisulpride Oral Solution 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.

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).
Renal insufficiency: Amisulpride Oral Solution 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 4.4 Special warnings and
precautions for use).
Hepatic insufficiency: since the drug is weakly metabolised a dosage reduction should
not be necessary.
Method of administration (Amisulpride Oral Solution): The graduations on the
dosage syringe measure the millilitres of oral solution. 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 millilitres to be administered. The
oral solution should be drunk with a liquid, which does not contain alcohol.

4.3

Contraindications
- 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 up to puberty;
- Lactation.
- Combination with levodopa (see 4.5 Interactions with other medicinal products and
other forms of interaction).

4.4

Special warnings and precautions for use
As with other neuroleptics, Neuroleptic Malignant Syndrome, a potentially fatal
complication, characterised 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 Oral
Solution 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 Oral Solution 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).
Amisulpride Oral Solution may lower the seizure threshold. Therefore patients with a
history of epilepsy should be closely monitored during Amisulpride Oral Solution
therapy.
In elderly patients, Amisulpride Oral Solution, 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 also be exercised when
prescribing Amisulpride Oral Solution to patients with Parkinson’s disease since it
may cause worsening of the disease. Amisulpride Oral Solution should be used only
if neuroleptic treatment cannot be avoided.
Withdrawal symptoms including nausea, vomiting and insomnia have 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 dyskinesia) has been reported with
amisulpride. Therefore, gradual withdrawal is advisable.

Leukopenia, neutropenia and agranulocytosis have been reported with
antipsychotics, including Amisulpride Oral Solution. Unexplained infections
or fever may be evidence of blood dyscrasia (see Section 4.8), and requires
immediate haematological investigation.
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 randomised 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 Oral
Solution 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. Analysis 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.
Amisulpride Oral Solution 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 Oral Solution and preventative measures
undertaken.
Excipients with recognised action or effect
Amisulpride 100mg/ml Oral Solution contains methyl parahydroxybenzoate (E218)
and propyl parahydroxybenzoate (E216) which may cause allergic reactions (possibly
delayed).

This medicinal product contains 0.17mmol (4.02mg) sodium per 1ml of oral
solution. A dose of up to 500mg amisulpride contains less than 1mmol of
sodium, essentially sodium free. A dose of 600mg amisulpride or greater,
contains more than 1mmol of sodium. Care should be taken with patients on a
controlled sodium diet.
The flavouring used in this medicinal product contains a small amount of ethanol, less
than 0.5mg per 1ml of oral solution.

4.5

Interaction with other medicinal products and other forms of interaction
Contraindicated combinations

Levodopa: reciprocal antagonism of effects between levodopa and
neuroleptics. Amisulpride may oppose the effect of dopamine agonists e.g.
bromocriptine, ropinirole.
Combinations not recommended
Amisulpride Oral Solution 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 antiarrhythmics (e.g. quinidine, disopyramide) and class

III antiarrhythmics (e.g. amiodarone, sotalol), some antihistamines, some other
antipsychotics and some antimalarials (e.g. mefloquine) (see section 4.4).

4.6

Fertility, pregnancy and lactation
Pregnancy
In animals, amisulpride 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 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. If amisulpride is used during pregnancy, neonates
may show adverse effects of amisulpride and thus appropriate monitoring
should be considered.
For women of child bearing potential, effective contraception should be fully
discussed with the physician prior to treatment.Neonates exposed to
antipsychotics (including Amisulpride Oral Solution) 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.
Lactation
It is unknown whether amisulpride is excreted in breast milk, breast-feeding is
therefore contraindicated.

4.7

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

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 characterised 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).


Cadiovascular 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).


Nervous system disorders:

Frequency not known: Neuroleptic Malignant Syndrome (see 4.4 Special warnings
and precautions for use), 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 4.4 Special warnings and precautions for use).



Vascular disorders:

Frequency not known: Venous thromboembolism, including pulmonary
embolism, sometimes fatal, and deep vein thrombosis.
• Skin and subcutaneous tissue disorders:
Frequency not known: Angioedema, urticaria
• Pregnancy, puerperium and perinatal conditions:
Frequency not known: Drug withdrawal syndrome neonatal (see 4.6 Fertility,
pregnancy and lactation).
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 at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Experience with amisulpride in overdose is limited. Exaggeration of the known
pharmacological effects of the drug have been reported. These include drowsiness,
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, haemodialysis is of no use 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.

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,
α-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 against both
negative and positive symptoms of schizophrenia.

5.2

Pharmacokinetic properties
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. Experience is however limited and there is no data with doses greater
than 50mg.
Amisulpride is very weakly dialysed.
Limited pharmacokinetic data in elderly subjects (>65 years) shows that a 10-30 %
rise occurs in Cmax, T1/2 and AUC after a single oral dose of 50mg. 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 (200mg/kg/day) and dog
(120mg/kg/day) 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/day) and reproductive studies (160, 300
and 500 mg/kg/day 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
Saccharin sodium,
Sodium gluconate,
Gluconolactone,
Hydrochloric acid, concentrated (pH adjuster),
Methyl parahydroxybenzoate (E218),
Propyl parahydroxybenzoate (E216),
Potassium sorbate,
Caramel flavour, (containing glycerol (E422) and ethyl alcohol),
Purified water.

6.2

Incompatibilities
None known.

6.3

Shelf life
2 years unopened.
Once the bottle is opened, use within 2 months.

6.4

Special precautions for storage
The medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Amber (Ph. Eur. type III), 60ml glass bottle with a child resistant, tamper evident
plastic screw cap with a LDPE liner, and a 5ml graduated oral dosing syringe.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Focus Pharmaceuticals Ltd
Capital House,
85 King William Street,
London EC4N 7BL,
United Kingdom.

8

MARKETING AUTHORISATION NUMBER(S)
PL 20046/0074

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
22/02/2011

10

DATE OF REVISION OF THE TEXT
06/10/2016

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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