Posted by ed_uk on December 19, 2004, at 13:23:33
In reply to Re: SSRI/dopamine antagonism - Amisulpride - Ed, posted by KaraS on December 19, 2004, at 12:51:53
Hi Kara,
Here is the UK data sheet for amisulpride. I hope that it provides you with the information that you need.
1. NAME OF THE MEDICINAL PRODUCT
Solian 50Solian 100
Solian 200
Solian 400
Solian Solution, 100 mg/ml
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient: Amisulpride (INN) 50 mg, 100 mg, 200 mg or 400 mg per tablet; Solian Solution: Amisulpride (INN) 100 mg/ml.For excipients, see 6.1
3. PHARMACEUTICAL FORM
Solian 50, 100, 200, 400: TabletSolian Solution: Oral Solution. A clear yellow liquid in appearance.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Solian 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/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 Solian. 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.
Solian can be administered once daily at oral doses up to 300 mg, higher doses should be administered bid.
Elderly: Solian should be used with particular caution because of a possible risk of hypotension or sedation.
Children: Solian is contra-indicated in children under 15 years of age as its safety has not yet been established.
Renal insufficiency: Solian 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.
Solian Solution: 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.
4.3 Contraindications
Hypersensitivity to the active ingredient or to other ingredients of the drugConcomitant 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 medications 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
(see 4.5 Interactions with other medical products and other forms of interaction)
4.4 Special warnings and special 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 Solian should be discontinued.Solian is eliminated by the renal route. In cases of severe renal insufficiency, the dose should be decreased and intermittent treatment should be prescribed (see 4.2 Posology and method of administration).
Solian can lower the seizure threshold. Therefore patients with a history of epilepsy should be closely monitored during Solian therapy.
In elderly patients, Solian, 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 Solian to patients with Parkinson's disease since it may cause worsening of the disease. Solian 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.
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 (<55bpm), hypokalaemia, decreased intracardiac conduction, or prolongation of the QTc interval (see 4.5 Interaction with other medicinal products and other forms of interaction).
4.5 Interaction with other medicinal products and other forms of Interaction
COMBINATIONS WHICH ARE CONTRAINDICATEDMedications which could induce 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 WHICH ARE NOT RECOMMENDED
Solian 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: hypokalemic diuretics, stimulant laxatives, IV amphotericin B, glucocorticoids, tetracosactides.
Neuroleptics such as pimozide, haloperidol ; 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
In animals, Solian 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 Solian were noted.The safety of Solian during human pregnancy has not been established. Therefore, use of the drug is contraindicated during pregnancy and in women of child bearing potential unless using adequate contraception.
It is not known whether Solian 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, Solian 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:
Solian 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 Solian.
Acute dystonia (spasm torticolis, oculogyric crisis, trismus) may appear. This is reversible without discontinuation of Solian 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 Solian 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.
Acute withdrawal reactions have very rarely been reported (see Section 4.4 Special warnings and special precautions for use).
Allergic reactions, elevations 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 Section 4.4 Special warnings and special precautions for use).
4.9 Overdose
Experience with Solian 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 Solian is weakly dialysed, hemodialysis should not be used to eliminate the drug.
There is no specific antidote to Solian. 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
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, -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 Solian 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 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 Solian 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
Solian 50, 100 and 200: Potato starch, lactose monohydrate, methylcellulose, colloidal hydrated silica, magnesium stearate.Solian 400: Sodium starch glycollate, lactose monohydrate, microcrystalline cellulose, hypromellose, magnesium stearate, polyoxyl 40 stearate, titanium dioxide (E171).
Solian Solution: Saccharin sodium, sodium gluconate, glucono delta lactone, hydrochloric acid, methyl parahydroxybenzoate, propyl parahydroxybenzoate, potassium sorbate, caramel flavour (tonka beans extract, vanillin, benzaldehyde, acetyl methyl carbinol, gamma and delta decalactones, esters from acetic, butyric and 2 methyl butyric acid, esters from ethyl and cinnamyl alcohol, propylene glycol and ethyl alcohol), purified water
6.2 Incompatibilities
None known.
6.3 Shelf life
Solian 50, 100, 200, 400: 3 yearsSolian Solution;
Shelf life of the medicinal product as packaged for sale: 3 years
Shelf life after first opening the container: 2 months
Dispose of within two months of opening
6.4 Special precautions for storage
Solian 50 and 200: Store in a dry place below 25oC in its original container.Solian 100, 400 and Solution: No special precautions (for storage).
6.5 Nature and contents of container
Solian 50, 100, 200 and 400: PVC/aluminium foil blister packs containing 60 tabletsSolian Solution: 60 ml brown glass bottle (type III) and child resistant cap with a PVDC/PE seal, with a 5ml graduated oral syringe
6.6 Instructions for use and handling
No special precautions
7. MARKETING AUTHORISATION HOLDER
Sanofi-SynthelaboPO Box 597
Guildford
Surrey
8. MARKETING AUTHORISATION NUMBER(S)
Solian 50: PL 11723/0308Solian 100: PL 11723/0355
Solian 200: PL 11723/0309
Solian 400: PL 11723/0356
Solian Solution: PL 11723/0377
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Solian 50: 1 February 2001Solian 100: 5 September 2000
Solian 200: 29 January 2001
Solian 400: 5 September 2000
Solian Solution: 16 May 2001
10. DATE OF REVISION OF THE TEXT
Solian 50: March 2003Solian 100: March 2004
Solian 200: March 2004
Solian 400: March 2004
Solian Solution: October 2004
Legal category: POM
poster:ed_uk
thread:428740
URL: http://www.dr-bob.org/babble/20041217/msgs/431672.html