Amisulpride 100 Mg/Ml Oral Solution
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Amisulpride 100 mg/ml Oral Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
1ml of Amisulpride Oral Solution contains 100mg of amisulpride.
1ml of Amisulpride Oral Solution also contains 1.0 mg of Methyl parahydroxybenzoate and 0.1mg of Propyl parahydroxybenzoate
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Oral Solution
A clear yellow liquid with an odour of caramel.
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, animosity, unusual suspiciousness
- and/or negative symptoms (deficit syndrome) such as blunted affect, emotional and social withdrawal.
This includes patients with predominant negative symptoms.
4.2 Posology and method of administration
Route of administration
Oral use
Method of administration
The graduations on the dosage pipette measure the milligrams of active ingredient. 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 milligrams to be administered. The oral solution should be drunk with a liquid, which does not contain alcohol.
Recommended dosage
Positive symptoms:
For acute psychotic episodes a daily dose of 400 mg to 800 mg of amisulpride is recommended.
In individual cases, the daily dose may be increased up to 1200 mg/day of amisulpride. Doses above 1200 mg/day have not been extensively evaluated for safety and should therefore not be used.
For daily doses over 300 mg/day amisulpride, the daily dose should be divided in several administrations.
No specific titration is required when initiating the treatment with amisulpride. For patients with mixed positive and negative symptoms, doses should be adjusted to obtain optimal control of positive symptoms i.e. between 400-800mg/day.
Maintenance treatment should be established individually with the minimally effective dose.
Predominant negative symptoms (defect syndrome):
A daily dose of 50 mg to 300 mg of amisulpride. Doses should be adjusted according to individual response.
Amisulpride can be administered once daily at oral doses up to 300 mg.
Dosage for particular patient groups
Patients with renal impairment:
The dose should be reduced to half in patients with creatinine clearance between 30 to 60 ml/min and to a third in patients with creatinine clearance between 10 to 30 ml/min. As there is no experience in patients with severe renal impairment (creatinine clearance < 10 ml/min), the use of amisulpride is not recommended in these patients (see section 4.4).
Patients with hepatic impairment:
Since the drug is weakly metabolized, a dosage reduction should not be necessary for patients with hepatic insufficiency.
Children and adolescents
Amisulpride is contra-indicated in children and adolescents under 15 years of age (see section 4.3)
Efficacy and safety of Amisulpride in children and adolescents under 18 years of age have not been established. There are only limited data available on the use of amisulpride in adolescents in schizophrenia. Therefore Amisulpride should not be used in adolescents from 15 to 18 years of age until further data are available. If absolutely required treatment of adolescents must be initiated and preformed by a physician experienced in treating schizophrenia in this age group.
Patients over 65 years
Treatment of elderly patients is not recommended as there is insufficient clinical experience. If treatment with amisulpride is absolutely necessary particular caution is required due to a possible risk of hypotension or sedation.
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.
4.3 Contraindications
Hypersensitivity to amisulpride or to other ingredients of the drug
Concomitant prolactin-dependent tumours: pituitary gland prolactinomas and breast cancer
Phaeochromocytoma
Children and adolescents under 15 years of age Lactation (see section 4.6)
Combination with levodopa (see section 4.5)
4.4 Special warnings and precautions for use
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 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 mild to moderate renal insufficiency, the dose should be decreased or intermittent treatment should be considered (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 (patients over 65 years), amisulpride should be used with caution in this patient group owing to a lack of experience. It may lead to sedation and hypotension in this patient population (see section 5.2).
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, 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.
Increased Mortality in Elderly people with Dementia:
Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
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.
Notice for Amisulpride Oral Solution
Allergic reactions can be caused by Methyl parahydroxybenzoate and Propyl parahydroxybenzoate (possibly delayed).
4.5 Interaction with other medicinal products and other forms of interaction
COMBINATIONS WHICH ARE CONTRAINDICATED (see section 43)
Levodopa: reciprocal antagomism of effects between levodopa and neuroleptics. In the case of neuroleptic-induced extrapyramidal symptoms, do not treat with a dopaminergic agonist but use an anticholinergic.
COMBINATIONS WHICH ARE NOT RECCOMMENDED
Amisulpride may enhance the central effects of alcohol. There fore 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 medications. Antihypertensive effect and increase risk of orthostatic hypotension (additive effect).
- 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 antihistaminics, some other antipsychotics and some antimalarials (e.g., mefloquine) (see section 4.4).
- Possible interactions with medicines causing electrolyte imbalance.
4.6 Fertility, Pregnancy and lactation
Pregnancy:
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.
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 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
This medicinal product can have minor or moderate influence on the 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). This is especially true when used concomitantly with alcohol.
4.8 Undesirable effects
Adverse events 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; I 1,000); very rare (<1/10,000); frequency 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 reaction Endocrine disorders
Common: Amisulpride causes an increase in plasma prolactin levels which is reversible after drug discontinuation. This may result in galactorrhoea, amenorrhoea or menstrual disorders, gynaecomastia, breast pain or enlargement, prolactinoma and erectile dysfunction.
Metabolism and nutrition disorders
Uncommon: Hyperglycemia (see section 4.4). Psychiatric disorders
Common: Insomnia, anxiety, agitation, orgasmic dysfunction 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 and dizziness.
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 should not be used as it is is ineffective or may induce aggravation of the symptoms. Seizures
Cardiovascular disorders
Common: Hypotension Uncommon: Bradycardia Gastrointestinal disorders
Common: Constipation, nausea, vomiting, dry mouth General disorders
Very 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.
Frequency not known: Drug withdrawal syndrome neonatal (see section 4.6) Investigations:
Common: Weight gain
Uncommon: Elevations of hepatic enzymes, mainly transaminases Post marketing data
In addition, cases of the following adverse reactions have been reported through spontaneous reporting only:
Nervous system disorders:
Frequency not known: Neuroleptic Malignant Syndrome (see section 4.4). 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: Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs.
Skin and subcutaneous tissue disorders Frequency not known: Angioedema, urticaria
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 (Website: www.mhra.gov.uk/yellowcard).
4.9 Overdose
Experience with amisulpride in over-dosage is limited. Exaggeration of the known pharmacological effects of the drug has been reported. These include drowsiness and sedation, coma, hypotension and extrapyramidal symptoms.
Actions to be taken by overdose
In cases of acute over-dosage, the possibility of intoxication by 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
Pharmcotherapeutic group: Antipsychotics, 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, a-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 remains 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 impairment: since the drug is weakly metabolised a dosage reduction should not be necessary in patients with hepatic insufficiency.
Renal impairment: The elimination half-life may increase 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.
Limited pharmacokinetic data in elderly subjects (> 65 years) show that a 1030 % 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
Propylene Glycol
Saccharin Sodium
Sodium Gluconate
Glucono-delta-lactone
Methyl parahydroxybenzoate (E218)
Propyl parahydroxybenzoate (E216)
Potassium Sorbate (E202)
Hydrochloric Acid (for pH-adjustment) Purified water
Caramel flavour consisting of the following: -
- Propylene glycol E1520 75,
- Nature-identical flavouring substance(s),
- Water,
- Flavouring preparation
- Ascorbic acid E300
6.2 Incompatibilities
Not applicable
6.3 Shelf life
Shelf life of the medicinal product as packaged for sale: 3 years Shelf life after first opening the container: 2 months
6.4 Special precautions for storage
Store in the original bottle.
6.5 Nature and contents of container
60ml Amber colored EP type III glass bottle with 28 mm polypropylene child resistance cap having tamper evident ring with a 4ml graduated oral syringe.
6.6
Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Auden Mckenzie Ltd.
Mckenzie House,
Bury Street,
Ruislip,
Middlesex,
HA4 7TL UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 17507/0229
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
26/11/2010
10 DATE OF REVISION OF THE TEXT
07/07/2015
11 DOSIMETRY (IF APPLICABLE)
12 INSTRUCTIONS FOR PREPARATION OF
RADIOPHARMACEUTICALS (IF APPLICABLE)