1. Name Of The Medicinal Product
Amisulpride 50mg Tablets
2. Qualitative And Quantitative Composition
Each tablet contains 50mg Amisulpride
3. Pharmaceutical Form
Tablet
White to off-white round tablets with break line on one side and '50' on other.
4. Clinical Particulars
4.1 Therapeutic Indications
Amisulpride 50mg Tablets are 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/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.
Elderly:
Amisulpride should be used with particular caution because of a possible risk of hypotension or sedation.
Children:
Amisulpride is contra-indicated in children under 15 years of age as its safety has not yet been established.
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.
Hepatic insufficiency:
Since the drug is weakly metabolised a dosage reduction should not be necessary.
4.3 Contraindications
• Hypersensitivity to the active ingredient or to other ingredients of the drug
• Concomitant prolactin-dependent tumours e.g. pituitary gland prolactinomas and breast cancer
• Phaeochromocytoma
• Children under 15 years of age
• Pregnancy or lactation
• Women of childbearing potential unless using adequate contraception
• Combination with the following medication which could induce torsades de pointes:
- Class Ia antiarrhythmic agents such as quinidine, disopyramide, procainamide#
- Class III antiarrhythmic agents such as amiodarone, sotalol
- Other medications such as bepridil, cisapride, sultopride, thioridazine, IV erythromycin, IV vincamine, Halofantrine, pentamidine, sparfloxacin
This list is not exhaustive
• Combination with levodopa
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 should be discontinued.
Amisulpride is eliminated by the renal route. In cases of severe renal insufficiency, the dose should be decreased and intermittent treatment should be considered (see 4.2 Posology and method of administration).
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.
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 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, known to potentiate the risk of serious ventricular arrhythmias such as torsades de pointes is enhanced by the pre-existence of bradycardia, hypokalaemia, congenital or acquired long QT interval.
Hypokalaemia should be corrected.
Before any administration, and if possible according to the patient's clinical status, it is recommended to monitor factors which could favour the occurrence of this rhythm disorder:
- bradycardia less than 55 bpm,
- hypokalaemia,
- 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 QTc interval (see 4.5 Interaction with other medicinal products and other forms of interaction).
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
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
COMBINATIONS WHICH ARE CONTRAINDICATED
Medications which could induce torsades de pointes:
- Class Ia antiarrhythmic agents such as quinidine, dispyramide, procainamide
- Class III antiarrhythmic agents such as amiodarone, sotalol
- Other medications such as bepridil, cisapride, sultopride, thioridazine, IV erythromycin, IV vincamine, Halofantrine, pentamidine, sparfloxacin
This list is not exhaustive
Levodopa: reciprocal antagonism of effects between levodopa and neuroleptics.
COMBINATIONS WHICH ARE NOT RECOMMENDED
Amusulpride may enhance the central effects of alcohol
COMBINATIONS WHICH REQUIRE PRECAUTIONS FOR USE
Medications which enhance the risk of torsades de pointes:
- Bradycardia-inducing medications such as beta-blockers, bradycardia-inducing calcium channel blockers such as diltiazem and verapamil, clonidine, guanfacine; digitalis
- Medications which induce hypokalaemia: hypokalaemic diuretics, stimulant laxatives, IV amphotericin B, glucocortocoids, tetracosactides
- Neuroleptics such as pimozide, haloperidon; imipramine, antidepressants; lithium
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
Dopamine agonists (eg: levodopa) since it may attenuate their action
4.6 Pregnancy And Lactation
Neonates exposed to antipsychotics including Amisulpride tablets 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.
4.7 Effects On Ability To Drive And Use Machines
Even used as recommended, amisulpride may affect reaction time so that the ability to drive vehicles or operate machinery can be impaired.
4.8 Undesirable Effects
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.
Common adverse effects (5-10 %):
insomnia, anxiety, agitation
Less common adverse effects (0.1-5 %):
somnolence
gastrointestinal disorders such as constipation, nausea, vomiting, dry mouth.
In common with other neuroleptics:
Amisulpride causes an increase in plasma prolactin levels which is reversible after drug discontinuation. This may result in galactorrhoea, amenorrhoea, gynaecomastia, breast pain, orgasmic dysfunction and impotence.
Weight gain may occur under therapy with amisulpride.
Acute dystonia (spasm torticolis, oculogyric crisis, trismus) may appear. This is reversible without discontinuation of amisulpride upon treatment with an antiparkinsonian agent.
Extrapyramidal symptoms may occur: tremor, rigidity, hypokinesia, hypersalivation, akathisia. 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 50-300mg/day.
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.
Hypotension and bradycardia have been reported occasionally.
Cases of QT prolongation and very rare cases of torsades de pointes have been reported.
Allergic reactions, elevation of hepatic enzymes, mainly transaminases and cases of seizures have been very rarely reported.
Very rare cases of Neuroleptic Malignant Syndrome have been reported (see special warnings and special precautions for use).
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown
Pregnancy, puerperium and perinatal conditions:
Drug withdrawal syndrome neonatal (see 4.6) / not known
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.
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 risk of prolongation of the QT interval.
If severe extrapyramidal symptoms occur, anticholinergic agents should be administered.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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 serotonic, 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 structure 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 schizopheria.
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 50mg 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 (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 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
Each tablet contains the following excipients:
Maize starch
Lactose monohydrate
Methylcellulose 400cP
Colloidal silica anhydrous
Magnesium stearate
6.2 Incompatibilities
None
6.3 Shelf Life
24 months
6.4 Special Precautions For Storage
Do not store above 25°C. Store in original package.
6.5 Nature And Contents Of Container
The tablets are packed in blisters constituted from a PVC and aluminium foil.
6.6 Special Precautions For Disposal And Other Handling
None
No Data Held
7. Marketing Authorisation Holder
Milpharm Limited,
Ares,
Odyssey Business Park,
West End Road,
South Ruislip HA4 6QD,
United Kingdom
8. Marketing Authorisation Number(S)
PL 16363/0145
9. Date Of First Authorisation/Renewal Of The Authorisation
14 May 2004
10. Date Of Revision Of The Text
October 2011
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