Posted by michael on May 29, 2000, at 17:10:52
In reply to Re: Amisulpride and MAOI -- AndrewB, posted by michael on May 29, 2000, at 16:21:37
I somehow lost some of the info I meant to post.... having difficulty getting the whole msg to post... this is most of the interesting stuff - plus some not so interesting stuff.
One comment - it seems to me that a lot of (most)the concerns/cautions raised below are more relevant to high-dosage use, rather than to the low-dose use that Andrew has referred to in the past.
Oh yeah - one more thing, check out this web site also: http://solian.com.ph/ Lots more info.
Here's what I meant to post originally:
Clinical particularsTherapeutic 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.
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 nega- tive 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 childen 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.
Hepatic insufficiency: Since the drug is weakly metabolised a dosage reduction should not be necessary.
Contra-indications: 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.
Childen under 15 years of age.
Pregnancy or lactation.
Women of childbearing potential unless using adequate contraception.
Special warnings and special 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 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 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.
Interaction with other medicaments and other forms of interaction: Solian may enhance the central effects of alcohol.
Caution should be exercised with the concomitant administration of drugs such as: 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 (e.g. levodopa) since it may attenuate their action.
Pregnancy and lactation:
Pregnancy: 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 contra-indicated during pregnancy and in women of child bearing potential unless using adequate contraception.
Lactation: It is not known whether Solian is excreted in breast milk, breast-feeding is therefore contra- indicated.
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.
Undesirable effects: The following adverse effects have been observed in controlled cinical 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 50-300 mg/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 as well as an isolated case of QT prolongation.
Allergic reactions and cases of seizures have been reported occasionally.
Rare cases of Neuroleptic Malignant Syndrome have been reported (see Special warnings and special precautions for use).
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, close supervision of vital functions and cardiac monitoring is recommended until the patient recovers.
If severe extrapyramidal symptoms occur, anticholinergic agents should be administered.
Pharmacological properties
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, ;in-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.
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 ten-fold in moderate renal failure (see Posology and method of administration). Experience is however limited and there is no data with doses greater than 50 mg.
Amisulpride is very weakly dialysed.
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.
Incompatibilities: None known.
poster:michael
thread:34862
URL: http://www.dr-bob.org/babble/20000526/msgs/35138.html