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Profile of Amisulpride

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Profile of Amisulpride Profile of Amisulpride Graylands Hospital Drug Bulletin 2002 Vol 10 No 2 July ISSN 1323-1251 Amisulpride (Solian) will become the Pharmacokinetics latest addition to the range of atypical Absorption antipsychotics available in Australia, Amisulpride is absorbed rapidly, within 3- though it has been available in parts of 4 hours of oral administration. Europe since the late 1980s. It belongs to the benzamide class and will be available Metabolism on the PBS for the treatment of Amisulpride undergoes minimal schizophrenia from 1st August 2002. metabolism to form two metabolites (both inactive). Hepatic metabolism plays a Pharmacology limited role in healthy patients. Although it shares clinical properties that characterise other atypical agents eg. Excretion decreased incidence of extrapyramidal Excretion is primarily via urine (mainly as symptoms (EPS), amisulpride is unusual in unchanged drug). The elimination half- that it lacks the combined antagonism of life is approximately 12 hours. Plasma protein binding is low, therefore drug 5HT2/D2 receptors which usually defines “atypicality”. interactions due to displacement are unlikely. At low doses, amisulpride enhances Efficacy dopaminergic neurotransmission by Recent reviews have concluded that preferentially blocking pre-synaptic D /D 2 3 amisulpride (400 to 1200mg/day) was as dopamine receptors. This may explain its effective as haloperidol (5 to 40mg/day), efficacy in the treatment of negative flupenthixol (25mg/day) and risperidone symptoms in schizophrenia. (8mg/day) in patients with acute exacerbations of schizophrenia with At higher doses, amisulpride antagonises predominantly positive symptoms (1,2). post-synaptic D /D dopamine receptors, 2 3 Amisulpride was found to be more reducing dopaminergic transmission, effective than haloperidol but equally as which may explain its efficacy against the effective as risperidone in controlling positive symptoms of schizophrenia. negative symptoms. Amisulpride has little affinity for other In patients with predominantly persistent dopamine receptor subtypes or other negative symptoms, low dosages of neurotransmitter receptors such as amisulpride (50 to 300mg/day) serotonin, α-adrenergic, histamine and significantly reduced negative symptoms muscarinic. It is selective for dopamine compared to placebo. receptors in the limbic system rather than Amisulpride has been shown to be the striatum, which should reduce its efficacious in long-term studies where it tendency to produce EPS. has been used as maintenance therapy in patients with chronic schizophrenia with Graylands Hospital Drug Bulletin 2002 Vol 10 No 2 July - 1 - mixed symptoms. Long-term use was also Mixed positive and negative symptoms: associated with improvements in measures adjust dose to obtain optimal control of of quality of life and social functioning. positive symptoms. Contraindications Amisulpride has been available in France to These include prolactin-dependant treat schizophrenia since 1986, where a group of clinicians have produced a dosage tumours, phaeochromocytoma and use in (3) combination with medications that may algorithm (see Figure 1 below). This induce torsade de pointes – see drug suggests management strategies according interactions. to symptoms and treatment setting. Due to its lack of sedative properties, it may Precautions be appropriate in the initial stages to use a Amisulpride shares similar warnings with benzodiazepine or sedative antipsychotic to other atypical antipsychotics regarding the help control the symptoms of a very rare events of neuroleptic malignant disturbed or aggressive patient. syndrome, seizures and the need for No specific titration is required for initiation caution in the elderly and Parkinson’s of therapy; adjust dosage to individual disease. response. Where the dose is above or equal In renal impairment, use a decreased dose to 400mg, administer twice daily. and consider intermittent treatment in Preferably give the dose before meals. severe cases. Use with caution in patients with moderate Renal impairment Dosage reduction will be or severe hepatic impairment – limited required in this patient group. data. Hepatic impairment Dosage reduction should not be necessary as the drug is Pregnancy and Lactation Pregnancy Category B3 – Contraindicated. weakly metabolised. Figure 1: Amisulpride dosage algorithm Adverse effects (based on extensive use in France). Similarly to risperidone, amisulpride appears to be linked with dose-related EPS ACUTE EPISODES and hyperprolactinemia. Unlike other Severe & recurrent Mild-moderate First episode atypicals however, sedation and Treated patients Out-patients Untreated patients Initial dose 800mg/d Initial dose 400mg/d Initial dose 600mg/d hypotension do not prominently feature in (up to 1200mg/d ↑by 200mg/d steps its side-effect profile. for in-patients) Adequate dose : 800mg/d Other commonly reported adverse events in clinical trials included insomnia, anxiety, agitation and weight gain. Cases of QT prolongation have been reported (dose dependant) and very rarely (<0.01%) SHORT-TERM FOLLOW-UP (3 months) torsade de pointes. According to symptom evolution No reference is made in the product Reduce dose Continue treatment Increase dose information to possible disturbances in by 200mg/d steps at same dose by 200mg/d steps glucose metabolism. During the period January 1997 to January 2002, the manufacturers received only 3 reports of this nature worldwide (Personal MAINTENANCE communication, Sanofi-Synthelabo). Modulation according to symptoms No positive symptoms Dosage and administration Patient stable The recommended dose varies according Dose reduced by 100-200mg/d every 2-3 months to which symptoms predominate. Usual maintenance dose: 400mg/d Acute positive symptoms: 400-800mg/day (two divided doses). May be increased to 1200mg/day in individual cases (no If +ve symptoms reappear If -ve symptoms present superior efficacy proven). Increase dose to previous Decrease dose to 100-300mg/d stabilising level for Usual dose 100mg/d Predominantly negative symptoms: 50- several months before 300mg/day given once daily. renewed dose reduction Adapted from Reference 3 Graylands Hospital Drug Bulletin 2002 Vol 10 No 2 July - 2 - Switching to amisulpride be enhanced by amisulpride. Concomitant Taper down existing antipsychotic and during use with levodopa is not recommended due this period, begin amisulpride at the to reciprocal antagonism of effects. therapeutic dose required; no titration is necessary. Overlapping periods of 1-4 weeks Conclusion – place in therapy have been described depending on the Amisulpride appears to offer no significant patient’s clinical state. benefit over the existing atypical agents. It may be associated with the least weight Drug Interactions gain of the atypicals (4) and has less Interactions via the CYP450 system are potential for interaction with other drugs, unlikely as amisulpride is not significantly due to its lack of hepatic metabolism. metabolised by the liver. Further trials are needed comparing it with the other atypical agents. Comparative The potential for increased risk of ventricular data with olanzapine should be available arrhythmias must be borne in mind. Use with later this year. Class IA and III antiarrhythmic agents eg. flecainide and amiodarone respectively, is Presentation contraindicated. Caution is required in the Manufacturer: Sanofi-Synthelabo concomitant use of drugs that may induce Brand name: Solian bradycardia or hypokalemia or other drugs Available in following tablet strengths: known to prolong the QT interval, such as 100mg, 200mg and 400mg (all breakable). thioridazine and droperidol. References Caution is advised when used with other 1. Curran MP and Perry CM. Amisulpride – A Review of its Use in the Management of Schizophrenia. Drugs renally cleared drugs eg. lithium, which may 2001;61(14):2123-2150. interfere with clearance of amisulpride. 2. Leucht S, Pitschel-Walz G, Engel RR, Kissling W. However, a study of the concomitant use of Amisulpride, an Unusual “Atypical” Antipsychotic: a lithium carbonate (500mg twice daily) with Meta-Analysis of Randomised Controlled Trials. Am J Psychiatry 2002;159:180-190. low dose amisulpride (100mg twice daily) in 3. Lecrubier Y, Azorin M, Bottai T, Dalery J, Garreau G, healthy young males, showed no effect of Lemperiere T et al. Consensus on the Practical Use of amisulpride on the pharmacokinetics of Amisulpride, an Atypical Antipsychotic, in the Treatment lithium. of Schizophrenia. Neuropsychobiology 2001;44:41-46. 4. Taylor DM and McAskill R. Atypical Antipsychotics and Weight Gain – a Systematic Review. Acta Psychiatr The effects of CNS depressants eg. Scand. 2000;101(6):416-32. benzodiazepines, narcotics and alcohol may Serotonin syndrome – recognising the signs Serotonin syndrome (SS) is a condition ! concomitant use of agents that caused by drug-induced serotonin promote the release of serotonin from hyperstimulation. It is difficult to diagnose, presynaptic neurons eg. amphetamines usually mild and as a result may go largely ! pharmacokinetic interactions eg. unreported. SS may occur with co- CYP2D6 inhibition of tricyclic administration of drugs or lack of adequate antidepressant (TCA) metabolism by washout period when switching drugs. This agents such as paroxetine, bupropion, increases synaptic serotonin concentration leading to increased TCA plasma levels causing hyperstimulation of mainly 5HT1A ! inhibition of serotonin metabolism eg. receptors (other serotonin receptors may be
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