Amisulpride 200mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
AMISULPRIDE 200mg TABLETS
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 200mg Amisulpride.
For excipients, see 6.1
3 PHARMACEUTICAL FORM
Tablet.
White to off-white, round tablets with a break line, diameter 12.5mm and impressed “C” and “AM” on one face.
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
For acute psychotic episodes, oral doses between 400 mg per day and 800 mg per day are recommended. In individual cases, the daily dose may be increased up to 1200 mg per day. Doses above 1200 mg per 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. 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 per day and 300 mg per day 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 twice daily.
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 (see 4.4 Special warnings and precautions for use)
Hepatic insufficiency: since Amisulpride is weakly metabolised a dosage reduction should not be necessary.
For oral use.
4.3 Contraindications
Hypersensitivity to amisulpride or to any of the excipients.
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 age unless adequate contraception is used.
Combination with the following medicines which could induce torsades de pointes:
- Class Ia anti arrhythmic 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
(see 4.5 Interactions with other medical products and other forms of interaction)
4.4 Special warnings and precautions for use
As with other neuroleptics, Neuroleptic Malignant Syndrome, 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 medicines 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 therapy with Amisulpride.
Concomitant neuroleptics should be avoided (see section 4.5)
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.
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 Interactions with other medicinal products and other forms of interaction).
Caution should be used in patients with cardiovascular disease or a family history of QT prolongation.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 contra-indicated
Medicines which could induce QT prolongation and torsades de pointes:
- Class Ia antiarrhythmic agents such as quinidine, disopyramide,
procainamide.
- Class III antiarrhythmic agents such as amiodarone, sotalol.
- Others 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 not recommended
Amisulpride may enhance the central effects of alcohol.
Combinations to be used with caution
Medicines 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.
- Medicines which cause electrolyte imbalance such as hypokalemic diuretics, stimulant laxatives, IV amphotericin B, glucocorticoids, tetracosactide.
- Concomitant use of neuroleptics such as pimozide and haloperidol, and also antidepressants and lithium should be avoided.
Combinations to be considered
CNS depressants including narcotics, anaesthetics, analgesics, sedative H1
antihistamines, barbiturates, benzodiazepines and other anxiolytic drugs,
clonidine and derivatives
Antihypertensive drugs and other hypotensive medicines.
Dopamine agonists (eg: levodopa) since it may attenuate their action.
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.
Lactation
It is not known whether Amisulpride is excreted in breast milk, breast-feeding is therefore contra-indicated.
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.
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
Adverse reactions 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 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 Special warnings and
precautions for use).
Cardiovascular disorders:
Common: Hypotension.
Investigations:
Common: Weight gain.
Uncommon: Elevations of hepatic enzymes, mainly transaminases.
Immune system disorders:
Uncommon: Allergic reactions.
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
Special warnings and precautions for use).
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 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 section 4.6)
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 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.
If severe extrapyramidal symptoms occur, anticholinergic agents should be administered.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Benzamide antipsychotic 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, 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 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 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
Maize starch,
Lactose monohydrate, Methylcellulose Colloidal anhydrous silica Magnesium stearate
6.2 Incompatibilities
None known.
6.3 Shelf life
3 years
6.4 Special precautions for storage
No special precautions for storage.
6.5 Nature and contents of container
Blisters comprising of 25pm Al foil and 250pm PVC contained within a printed carton box.
Pack sizes: 10, 20, 28, 30, 50, 56, 60, 84, 90,100 or 150.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
MARKETING AUTHORISATION HOLDER
7
Actavis UK Limited (Trading style: Actavis)
Whiddon Valley
Barnstaple
North Devon
EX32 8NS
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00142/0586
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
01/11/2009
10 DATE OF REVISION OF THE TEXT
06/02/2012