AMISULPRIDE MYLAN

Main information

  • Trade name:
  • AMISULPRIDE MYLAN
  • Dosage:
  • 400 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AMISULPRIDE MYLAN
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0577/125/004
  • Authorization date:
  • 28-08-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AmisulprideMylan400mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

AmisulprideMylancontains400mgamisulpridepertablet.

Excipient:

200mglactosemonohydrateperfilm-coatedtablet

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Whitetooffwhite,18x8mmcapsuleshaped,filmcoatedtabletwithbreaklineononeside.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

AmisulprideMylanisindicatedforthetreatmentofacuteandchronicschizophrenicdisorders:

Productivesymptomswithdelusions,hallucinations,thoughtdisorders,hostilityandsuspiciousbehavior.

Primarilynegativesymptoms(deficitsyndrome)withbluntedaffect,emotionalandsocialwithdrawal.

AmisulprideMylanalsocontrolssecondarynegativesymptomsinproductiveconditionsaswellasaffectivedisorders

suchasdepressivemoodorretardation.

4.2Posologyandmethodofadministration

Forproductiveconditions,therecommendedoraldoserangesfrom400to800mg/day.Dosesabove800mg/dayhave

notbeenassociatedwithgreaterefficacyandhaveinducedhigherratesofextrapyramidalsymptoms.Nospecific

titrationisrequiredwheninitiatingthetreatmentwithAmisulprideMylan.Dosesshouldbeadjustedaccordingto

individualresponse.Maintenancetreatmentshouldbeestablishedindividuallywiththeminimallyeffectivedose.

Forpatientswithmixedpositiveandnegativesymptoms,dosesshouldbeadjustedtoobtainoptimalcontrolofpositive

symptoms.

Forpatientscharacterizedbypredominantnegativesymptoms,oraldosesbetween50mg/dand300mg/dare

recommended.Dosesshouldbeadjustedindividually.

AmisulprideMylanmaybeadministeredoncedailyorallyatadoseupto300mg.Higherdosesshouldbedividedin

twodoses.

AmisulprideMylantabletscanbeadministeredindependentlyfromthemeals.Tabletsshouldbetakenwholeorhalved

withasufficientamountofliquid.

Elderly

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section5.2Pharmacokineticproperties).

Pediatricpatients

AmisulprideMylaniscontraindicatedinchildrenunder15yearsofageasitssafetyhasnotyetbeenestablished.

Renalinsufficiency

AmisulprideMylaniseliminatedbytherenalroute.Inrenalinsufficiency,thedoseshouldbereducedtohalfinpatients

withcreatinineclearance(CRCL)between30-60mL/minandtoathirdinpatientswithCRCLbetween10-30mL/min.

Asthereisnoexperienceinpatientswithsevererenalimpairment(CRCL<10mL/min),AmisulprideMylanis

contraindicatedinthesepatients(seesection4.3Contraindicationsandsection5.2Pharmacokineticproperties).

Hepaticinsufficiency

Sinceamisulprideisweaklymetabolized,adosagereductionshouldnotbenecessary.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Concomitantprolactin-dependenttumorse.g.pituitaryglandprolactinomasandbreastcancer.

Phaeochromocytoma.

Childrenupto15yearsofage.

Lactation.

Incombinationwiththefollowingmedicationwhichcouldinducetorsadesdepointesforexample:

ClassIaantiarrhythmicagentssuchasquinidine,disopyramide

ClassIIIantiarrhythmicagentssuchasamiodarone,sotalol

Othermedicationssuchasbepridil,cisapride,sultopride,thioridazine,methadone,intravenous

erythromycin,intravenousvincamine,halofantrine,pentamidine,sparfloxacin

Incombinationwithlevodopa.

Severerenalimpaiment(CRCL<10ml/min).

4.4Specialwarningsandprecautionsforuse

NeurolepticMalignantSyndrome

Aswithotherneuroleptics,NeurolepticMalignantSyndromecharacterizedbyhyperthermia,increasedmusclerigidity,

autonomicinstability,andelevatedCPK,mayoccur.Intheeventofhyperthermia,particularlywithhighdailydoses,

allantipsychoticmedicinesincludingAmisulprideMylanshouldbediscontinued.AmisulprideMylaniseliminatedby

therenalroute.

Incasesofrenalinsufficiency,thedoseshouldbedecreasedandintermittenttreatmentshouldbeconsidered(see

section4.2Posologyandmethodofadministration).

AmisulprideMylancanlowertheseizurethreshold.Thereforepatientswithahistoryofseizuresshouldbeclosely

monitoredduringamisulpridetherapy.

Inelderlypatients,amisulpridetherapy,likeotherneuroleptics,shouldbeusedwithparticularcautionbecauseofa

possibleriskofhypotensionorsedation.Reductionindosagemayalsoberequiredincaseofrenalinsufficiency.

CautionshouldbealsoexercisedwhenprescribingAmisulprideMylantopatientswithParkinson'sdiseasesinceitmay

causeworseningofthedisease.AmisulprideMylanshouldbeusedonlyifneuroleptictreatmentcannotbeavoided.

ProlongationofQTinterval

AmisulprideMylanproducesadose-dependentprolongationoftheQTinterval.Thiseffectisknowntopotentiatethe

riskofseriousventriculararrhythmiassuchastorsadesdepointes.Beforeanyadministration,andifpossibleaccording

tothepatient'sclinicalstatus,itisrecommendedtomonitorfactorswhichcouldfavortheonsetofthisrhythmdisorder,

forexample:

Bradycardialessthan55bpm

Electrolyteimbalance,inparticularhypokalaemia

CongenitalprolongationoftheQTinterval

On-goingtreatmentwithamedicationlikelytoproducepronouncedbradycardia(<55bpm),hypokalaemia,

decreasedintracardiacconduction,orprolongationoftheQT

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productsandotherformsofinteraction).

Stroke

Inrandomizedclinicaltrialsversusplaceboperformedinapopulationofelderlypatientswithdementiaandtreated

withcertainatypicalantipsychoticmedicines,a3-foldincreaseoftheriskofcerebrovasculareventshasbeenobserved.

Themechanismofsuchriskincreaseisnotknown.Anincreaseintheriskwithotherantipsychoticmedicines,orother

populationsofpatientscannotbeexcluded.AmisulprideMylanshouldbeusedwithcautioninpatientswithstrokerisk

factors.

VenousThromboembolism

Casesofvenousthromboembolism(VTE)havebeenreportedwithantipsychoticdrugs.Sincepatientstreatedwith

antipsychoticsoftenpresentwithacquiredriskfactorsforVTE,allpossibleriskfactorsforVTEshouldbeidentified

beforeandduringtreatmentwithAmisulprideMylanandpreventivemeasuresundertaken.

IncreasedMortalityinElderlypeoplewithDementia

Elderlypatientswithdementiatreatedwithatypicalantipsychoticshadanincreasedmortalitycomparedtoplaceboina

meta-analysisof17controlledtrialsofatypicalantipsychotics,howevernostudywithamisulpridewasincluded.

Theobservedriskofdeathwas1.6to1.7timestheriskofdeathinplacebo-treatedpatients.Therateofdeathinpatient

treatedwithatypicalantipsychoticwasabout4.5%,comparedtoarateofabout2.6%intheplacebogroupduringa

typical10-weekcontrolledtrial.Thereweredifferentcausesofdeathinclinicaltrialswithatypicalantipsychotics,but

mostofthedeathsappearedtobeeithercardiovascular(eg,heartfailure,suddendeath)orinfectious(eg,pneumonia)

innature.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethepossibilityofanincreased

riskforamisulpride.

AmisulprideMylanisnotapprovedforthetreatmentofpatientswithdementia-relatedbehaviouraldisturbances.

Other

Hyperglycemiahasbeenreportedinpatientstreatedwithsomeatypicalantipsychoticagents,includingAmisulpride

Mylan.Thereforepatientswithanestablisheddiagnosisofdiabetesmellitusorwithriskfactorsfordiabetes,whoare

startedonAmisulprideMylan,shouldgetappropriateglycaemicmonitoring.

Theconcomitantprescriptionofotherantipsychoticsshouldbeavoided.

Acutewithdrawalsymptomsincludingnausea,vomitingandinsomniahavebeenrarelydescribedafterabruptcessation

ofhighdosesofantipsychoticdrugs.Recurrenceofpsychoticsymptomsmayalsooccur,andtheemergenceof

involuntarymovementdisorders(suchasakathisia,dystoniaanddyskinesia)havebeenreported.Therefore,gradual

withdrawalisadvisable.

Lactose

Patientswithrarehereditaryproblemsofgalactoseintolerance,Lapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Contraindicatedcombinations:

Medicinalproductsthatmaycausetorsadesdepointes(seesection4.3Contraindications):

Levodopa:reciprocalantagonismofeffectsbetweenlevodopaandneuroleptics.

Combinationswhicharenotrecommended:

MedicinalproductsthatincreasetheriskoftorsadesdepointesormayprolongQTinterval:

Medicineswhichinducebradycardia,suchasbradycardia-inducingcalciumchannelblockers(diltiazem,

verapamil),beta-blockers,clonidine,guanfacine,digitalis.

Medicineswhichcancausehypokalaemia:hypokalemicdiuretics,stimulantlaxatives,intravenous

amphotericinB,glucocorticoids,tetracosactides.Hypokalaemiashouldbeadjusted.

Neurolepticssuchasthioridazine,chlorpromazine,trifluperazine,pimozide,haloperidol,imipramine

antidepressants,lithium.

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Combinationswhichmustbetakenintoaccount:

CNSdepressantsincludingnarcotics,anaesthetics,analgesics,sedativeH

-antihistamines,barbiturates,

benzodiazepinesandotheranxiolyticmedicines,clonidineandderivatives.

Incombinationwithotherantipsychoticsthepotentiationofcentraldepressanteffects(sedation,

somnolence,impairedcapacityofreaction)cannotbeexcluded.

Antihypertensivemedicinesandotherhypotensivemedications.

Amisulpridemayopposetheeffectofdopamineagonistse.g.bromocriptine,ropinirole.

4.6Fertility,pregnancyandlactation

Pregnancy

AmisulprideMylanwasdevoidofdirecteffectonreproductioninanimals.Lowerfertilityassociatedwith

pharmacologicaleffectoftheproduct(bymeansofprolactin)wasfound.Noteratogeniceffectwasnoted.

Thereisonlyverylimitedclinicaldataonadministrationofthemedicinalproductduringpregnancy.Thereforesafety

ofamisulprideduringpregnancyinhumanshasnotbeenconfirmed.Usingofthemedicinalproductduringpregnancy

isnotrecommendedunlessthebenefitoutweighsthepossiblerisk.Ifamisulprideisusedduringpregnancythe

newbornsmayexperiencerelatedundesirableeffectsandthereforeappropriatemonitoringshouldbeconsidered.

Neonatesexposedtoantipsychotics(includingamisulpride)duringthethirdtrimesterofpregnancyareatriskof

adversereactionsincludingextrapyramidaland/orwithdrawalsymptomsthatmayvaryinseverityandduration

followingdelivery.Therehavebeenreportsofagitation,hypertonia,hypotonia,tremor,somnolence,respiratory

distress,orfeedingdisorder.Consequently,newbornsshouldbemonitoredcarefully.

Lactation

Itisnotknownifamisulprideisexcretedinbreastmilk.Breast-feedingisthereforecontraindicated.

4.7Effectsonabilitytodriveandusemachines

AmisulprideMylancancausedrowsinessandthereforealsoreducetheabilitytodrivevehiclesandoperatemachines,

evenwhenusedatrecommendeddoses(seesection4.8Undesirableeffects).

4.8Undesirableeffects

Undesirableeffectsareclassifiedaccordingtotheirincidenceasfollows:

Verycommon(1/10);common(1/100,<1/10);uncommon(1/1000,<1/100);rare(1/10000,<1/1000);veryrare

(<1/10000);notknown(cannotbedeterminedfromavailabledata).

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Clinicaldata

Thefollowingadverseeffectshavebeenobservedincontrolledclinicaltrials.Itshouldbenotedthatinsomeinstances

itcouldbedifficulttodifferentiateadverseeventsfromsymptomsoftheunderlyingdisease.

Investigations:

Common:Weightgain

Uncommon:Elevationsofhepaticenzymes,mainlytransaminases

Cardiacdisorders:

Common:Hypotension

Uncommon:Bradycardia

Nervoussystemdisorders:

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dyskinesia.Thesesymptomsaregenerallymildatoptimaldosagesandpartiallyreversiblewithoutdiscontinuationof

amisulprideuponadministrationofantiparkinsonianmedication.Theincidenceofextrapyramidalsymptoms,whichis,

doserelated,remainsverylowwhenadministeringclinicallyeffectivedosestopatientswithdeficitschizophrenia(50-

300mg/day).

Common:

-Acutedystonia(spasmtorticolis,oculogyriccrisis,trismus)mayappear.Thisisreversiblewithoutdiscontinuationof

amisulprideuponadministrationofantiparkinsonianmedication.

-Drowsiness

Uncommon:

-Tardivedyskinesiacharacterizedbyrhythmic,involuntarymovementsprimarilyofthetongueand/orfacehasbeen

reported,usuallyafterlong-termadministration.Antiparkinsonianmedicationisineffectiveandmayinduce

aggravationofthesymptoms.

-Seizures

Gastrointestinaldisorders:

Common:Constipation,nausea,vomiting,drymouth

Endocrinedisorders:

Common:Amisulpridecausesanincreaseinplasmaprolactinlevels,whichisreversibleafterdrugdiscontinuation.This

mayresultingalactorrhoea,amenorrhoeaormenstrualdisorder,gynaecomastia,breastpain,orgasmicand

erectiledysfunction.

Metabolismandnutritiondisorders:

Uncommon:Hyperglycemia(seesection4.4Specialwarningsandprecautionsforuse)

Immunesystemdisorders:

Uncommon:Allergicreactions

Psychiatricdisorders:

Common:Sleeplessness,anxiety,agitation,orgasmicdysfunction

Postmarketingsurveillance:

Thefollowingundesirableeffectswerealsoreported(spontaneousreports):

Cardiacdisorders:

Notknown:prolongationoftheQTintervalandventriculararrhythmiasuchas“Torsadesdepointes“,ventricular

tachycardia,whichcouldleadtoventricularfibrillationorcardiacarrest,suddendeath(seesection4.4Special

warningsandprecautionsforuse).

Vasculardisorders:

Notknown:Casesofvenousthromboembolism,includingcasesofpulmonaryembolismandcasesofdeepvein

thrombosishavebeenreportedwithantipsychoticdrugs

Nervoussystemdisorders:

Notknown:Neurolepticmalignantsyndromesymptom(seesection4.4Specialwarningsandprecautionsforuse)

Pregnancy,puerperiumandperinatalconditions

Notknown:Drugwithdrawalsyndromeneonatal(see4.6)

4.9Overdose

Experiencewithoverdoseislimited.Exaggerationofpharmacologicaleffectsofthedrughasbeenreportedwith

symptomssuchasdrowsinessandsedation,coma,hypotensionandextrapyramidalsymptoms.

Incasesofacuteoverdose,thepossibilityofmultipledrugintakesshouldbeconsidered.

Sinceamisulprideisweaklydialysed,hemodialysisisofnousetoeliminatethedrug.

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closesupervisionofvitalfunctionsincludingcontinuouscardiacmonitoringduetotheriskofprolongationoftheQT

interval,untilcompleterecoveryofthepatient.

Ifsevereextrapyramidalsymptomsoccur,anticholinergicagentsshouldbeadministered.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:antipsychotics

ATCcode:N05AL05

AmisulpridebindsselectivelywithahighaffinitytohumandopaminergicD2/D3receptorsubtypeswhereasitisdevoid

ofaffinityforD1,D4andD5receptorsubtypes.

Unlikeclassicalandatypicalneuroleptics,amisulpridehasnoaffinityforserotonin,alpha-adrenergic,H1-histamineand

cholinergicreceptors.Inaddition,amisulpridedoesnotbindtosigmareceptors.

Inanimalstudies,athighdoses,amisulprideblocksdopaminereceptorslocatedprimarilyoutsidestriatuminthe

mesolimbicsystem.Asopposedtoclassicalneuroleptics,itdoesnotcausecatalepsy.Duringrepeateduse,itdoesnot

develophypersensitivitytod2dopaminereceptors.Atlowdosesitpreferentiallyblockspre-synapticD2/D3receptors,

producingdopaminereleaseresponsibleforitsdisinhibitoryeffects.

Thisatypicalpharmacologicalprofilecanexplainamisulpride’santipsychoticeffectathigherdosesthroughpost-

synapticdopaminereceptorblockadeanditseffectonnegativesymptomsatlowerdosescausedbytheinhibitionof

pre-synapticdopaminereceptors.Decreasedincidenceofundesirableextrapyramidalsymptomscanbecausedbythe

preferentialactivityinthelimbicsystem.

Inclinicalstudies,whichmonitoredpatientswithacuteexacerbationofschizophrenia,amisulpridesignificantly

reducedsecondarynegativesymptomsaswellasaffectivesymptomsandpsychomotorslow-down.

5.2Pharmacokineticproperties

Inman,amisulprideshowstwoabsorptionpeaks:onewhichisattainedrapidly,onehourpost-doseandasecond

between3and4hoursafteradministration.Correspondingplasmaconcentrationsare39±3and54±4ng/mlaftera50

mgdose.Thevolumeofdistributionis5.8l/kg,plasmaproteinbindingislow(16%)andnodruginteractionsare

known.Absolutebioavailabilityis48%.Amisulprideisweaklymetabolised:twoinactivemetabolites,accountingfor

approximately4%ofthedose,havebeenidentified.Thereisnoaccumulationofamisulprideanditspharmacokinetics

remainsunchangedaftertheadministrationofrepeateddoses.Theeliminationhalf-lifeofamisulprideisapproximately

12hoursafteranoraldose.Amisulprideiseliminatedunchangedintheurine.50%ofanintravenousdoseisexcreted

viatheurine,ofwhich90%iseliminatedinthefirst24hours.Renalclearanceisintheorderof20l/hor330ml/min.A

carbohydraterichmeal(containing68%fluids)significantlydecreasestheAUCs,TmaxandCmaxofamisulpridebut

nochangeswereseenafterahighfatmeal.However,thesignificanceofthesefindingsinroutineclinicaluseisnot

known.

Hepaticinsufficiency:sincethedrugisweaklymetabolized,thedosageneedsnottobereducedinpatientswithhepatic

insufficiency.

Renalinsufficiency:Theeliminationhalf-lifeisunchangedinpatientswithrenalinsufficiencywhilesystemicclearance

isreducedbyafactorof2.5to3.TheAUCofamisulprideinmildrenalfailureincreasedtwofoldandalmosttenfoldin

moderaterenalfailure(seesection4.2Posologyandmethodofadministration).Experienceishoweverlimitedand

thereisnodatawithdosesgreaterthan50mg.

Amisulprideisveryweaklydialysed.

Limitedpharmacokineticdatainelderlysubjects(>65years)showthata10-30%riseoccursinCmax,T1/2andAUC

afterasingleoraldoseof50mg.Nodataareavailableafterrepeatdosing.

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Anoverallreviewofthecompletedsafetystudiesindicatesthatamisulprideisdevoidofanygeneral,organ-specific,

teratogenic,mutagenicorcarcinogenicrisk.Changesobservedinratsanddogsatdosesbelowthemaximumtolerated

doseareeitherpharmacologicaleffectsoraredevoidofmajortoxicologicalsignificanceundertheseconditions.

Comparedwiththemaximumrecommendeddosagesinman,maximumtolerateddosesare2and7timesgreaterinthe

rat(200mg/kg/d)anddog(120mg/kg/d),whichcorrespondsto1.5–4.5higherAUCinratthaninhuman.

Reproductivestudiesperformedinrats,rabbitsandmicedidnotshowanyteratogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core

Lactosemonohydrate

Methylcellulose

Sodiumstarchglycolate(typeA)

Cellulose,microcrystalline

Magnesiumstearate

Filmcoating

Basicbutylatedmethacrylatecopolymer

Titaniumdioxide

Talc

Magnesiumstearate

Macrogol6000

6.2Incompatibilities

Notapplicable

6.3Shelflife

36months

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/Aluminiumblisterof30,60or100film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLtd/t/aGerardLaboratories

35/36BaldoyleIndustrialEstate

GrangeRoad

Dublin13

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8MARKETINGAUTHORISATIONNUMBER

PA577/125/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28August2009

10DATEOFREVISIONOFTHETEXT

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