4/1/2015

CleviprexSummaryofProductCharacteristics(SPC)(eMC)
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Cleviprex
LastUpdatedoneMC30Dec2014Viewchanges|TheMedicinesCompanyUKLtdContactdetails

Thismedicinalproductissubjecttoadditionalmonitoring.Thiswillallowquick
identificationofnewsafetyinformation.Healthcareprofessionalsareaskedtoreport
anysuspectedadversereactions.Seesection4.8forhowtoreportadversereactions.
1.Nameofthemedicinalproduct
Cleviprex0.5mg/mlemulsionforinjection
2.Qualitativeandquantitativecomposition
1mlemulsionforinjectioncontains0.5mgclevidipine.
Onevialof50mlofemulsioncontains25mgofclevidipine
Onevialof100mlofemulsioncontains50mgofclevidipine
Contains10g/20gsoyabeanoilrefinedper50ml/100mlvial
Containslessthan1mmolsodium(23mg)pervial,i.e.essentially'sodiumfree'.
Forthefulllistofexcipients,seesection6.1.
3.Pharmaceuticalform
Emulsionforinjection
Whiteopaque,oilinwateremulsion
pH:6.08.0
Osmolarity:341mOsmols/kg
4.Clinicalparticulars
4.1Therapeuticindications
Cleviprexisindicatedfortherapidreductionofbloodpressureintheperioperativesetting.
Thissiteusescookies.Bycontinuingtobrowsethesiteyouareagreeingtoourpolicyontheuseofcookies.Continue
4.2Posologyandmethodofadministration

Findoutmorehere.

Adults/Elderly
Clevidipineisintendedforintravenoususe.Titratedrugtoachievethedesiredbloodpressurereduction.Individualise
dosagedependingonthebloodpressuretobeobtainedandtheresponseofthepatient.Bloodpressureandheartrate
mustbemonitoredcontinuallyduringtheinfusion,andthenuntilvitalsignsarestable.Patientswhoreceiveprolonged
clevidipineinfusionsandarenottransitionedtootherantihypertensivetherapiesshouldbemonitoredforthepossibility
ofreboundhypertensionforatleast8hoursafterinfusionisstopped.
Initialdose:Initiatetheintravenousinfusionofclevidipineat4ml/h(2mg/h)thedosemaybedoubledevery90
seconds.Continuetitrationuntildesiredtargetrangeisachieved.
Maintenancedose:Thedesiredtherapeuticresponseformostpatientsoccursatdosesof812ml/h(46mg/h).
Maximumdose:Mostpatientsinclinicalstudiesweretreatedwithdosesof32ml/h(16mg/h)orless.Themaximum
recommendeddoseis64ml/h(32mg/h).Thereislimitedclinicalexperienceindosesover64ml/h(32mg/h).Nomore
than1000mlofclevidipineinfusionisrecommendedintheinitial24hourperiodduetotheassociatedlipidload.There
islimitedexperiencewithclevidipineinfusiondurationsbeyond72hoursatanydose.
Transitiontoanoralantihypertensiveagent:Discontinueclevidipineortitratedownwardwhileappropriateoral
therapyisestablished.Whenanoralantihypertensiveagentisbeinginstituted,considerthelagtimeofonsetoftheoral
agent'seffect.Continuebloodpressuremonitoringuntildesiredeffectisachieved.DiscontinuationofCleviprexleadsto
areductioninantihypertensiveeffectswithin5to15minutes.
Instructionsforuse
StrictaseptictechniquemustbemaintainedwhilehandlingCleviprex.Cleviprexisasingleuseparenteralproductthat
containsphospholipidsandcansupportthegrowthofmicroorganisms.Donotuseifcontaminationissuspected.Once
thestopperispunctured,usewithin12hoursanddiscardanyunusedportion.
Cleviprexisasterile,whiteopaqueemulsion.Visuallyinspectforparticulatematteranddiscolourationpriortouse.
Solutionsthatarediscolouredorcontainparticulatemattershouldnotbeused.

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Gentlyinvertvialbeforeusetoensureuniformityoftheemulsionpriortoadministration.
Clevidipineshouldbeadministeredviaaventedspikeandinfusiondevice.
Clevidipinemaybeadministeredusingasyringeorvolumetricpump.Commerciallyavailablestandardplasticcannulae
maybeusedtoadministertheinfusion.Clevidipinecanbeadministeredviaacentrallineoraperipheralline.
Clevidipineshouldnotbeadministeredinthesameintravenouslineasothermedications.
HepaticImpairment
Dataregardingthedosageregimeninpatientswithhepaticimpairmentarelimitedandhavenotbeenspecifically
studied.Inclinicaltrials,78(6.0%)patientswithabnormalhepaticfunction(definedastotalbilirubin>1.5ULN,
AST/SGOT,and/orALT/SGPT>2ULNfornonsurgicalpatientsand>3ULNforsurgicalpatients)weretreatedwith
clevidipine.Nodoseadjustmentisrequiredinpatientswithhepaticimpairment.
RenalImpairment
Dataregardingthedosageregimeninpatientswithrenalimpairmentarelimitedandhavenotbeenspecificallystudied.
Inclinicaltrials121(9.2%)patientswithmoderatetosevererenalimpairmentweretreatedwithclevidipine.Nodose
adjustmentisrequiredinpatientswithrenalimpairment.
Paediatricpopulation
Thesafetyandefficacyofclevidipineinchildrenaged0to18yearsoldhasnotyetbeenestablished.Nodataare
available.
Patientsonotherlipidbasedtherapies
Cleviprexcontainsapproximately0.2goflipidperml(8.4kJ/2.0kcal).Inpatientswithlipidloadrestrictionsthe
quantityofconcurrentlyadministeredlipidsmayneedtobeadjustedtocompensatefortheamountoflipidinfusedas
partoftheclevidipineformulation.
4.3Contraindications
Hypersensitivitytotheactivesubstance,soybeans,soyabeanoilrefined,soyproducts,peanut,eggsoreggproducts
ortoanyoftheotherexcipientslistedinsection6.1.
Clevidipinemustnotbeusedinpatientswithdefectivelipidmetabolismsuchaspathologichyperlipemia,lipoid
nephrosis,oracutepancreatitisifitisaccompaniedbyhyperlipidemia.
4.4Specialwarningsandprecautionsforuse
Usestrictaseptictechniqueanddiscardanyunusedproductwithin12hoursofstopperpuncture.Failuretopractice
appropriateaseptictechniquemayleadtocontaminationofinfusedproductandthepotentialforsystemicinfection.
Hypotensionandreflextachycardia
Rapidpharmacologicreductionsinbloodpressuremayproducesystemichypotensionandreflextachycardia.Ifeither
occurswithclevidipine,considerdecreasingthedosebyhalforstoppingtheinfusion.
Patientswithaorticstenosis,hypertrophicobstructivecardiomyopathy,mitralstenosis,aorticdissectionor
pheochromocytomahavenotbeenstudiedinclinicaltrialswithclevidipine.
Clevidipineshouldnotbeusedinpatientswithuncorrectedcriticalaorticstenosisbecauseexcessiveafterload
reductioncanreducemyocardialoxygendelivery.Forpatientsundergoingsurgerytorelievetheirstenosiswitha
replacementvalve,clevidipinemaybeusefulinthepostoperativeperiodiftheabilitytocompensatefordecreasesin
bloodpressurehasbeenrestored.
Patientswithhypertrophicobstructivecardiomyopathyandmitralstenosismayalsobeatriskofreducedoxygen
delivery.
Clevidipineshouldbeusedwithcautioninpatientswhocannotincreasetheirheartrateadequatelytocompensatefor
reducedbloodpressuresuchasthosewithleftbundlebranchblockorprimaryventricularpacing.
Therearelimiteddataforuseofclevidipineinacutemyocardialinfarctionoracutecoronarysyndrome.
4.5Interactionwithothermedicinalproductsandotherformsofinteraction
Nointeractionstudieshavebeenperformedaspharmacokineticdruginteractionsareunlikelygivenclevidipineis
metabolisedbyhydrolysisinvivo.
InhibitionofCYPisoformswasdetectedininvitrostudiesatconcentrationsequivalenttoatleast10timesthehighest
concentrationtypicallyseenintheclinic.Atthedosesrecommended,clevidipineanditsmajordihydropyridine
metabolitedonothavethepotentialforinhibitingorinducinganyCYPenzyme.
PatientsreceivingoralorIVantihypertensiveagents,includingbetablockers,whileonclevidipineshouldbeobserved
closelyforincreasedantihypertensiveeffects.
4.6Fertility,pregnancyandlactation
Pregnancy
Therearenoadequatedatafromtheuseofclevidipineinpregnantwomen.
Studiesinanimalshaveshowneffectsonembryo/fetaldevelopmentandparturition(seesection5.3)
Clevidipineshouldnotbeusedduringpregnancyunlessclearlynecessary.
Lactation
Itisunknownwhetherclevidipineisexcretedinhumanbreastmilk.Theexcretionofclevidipineinmilkhasnotbeen
studiedinanimals.Adecisiononwhethertocontinue/discontinuebreastfeedingortocontinue/discontinuetherapywith
clevidipineshouldbemadetakingintoaccountthebenefitofbreastfeedingtothechildandthebenefitofclevidipine
therapytothewoman.
Fertility

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Clevidipinehadnoadverseeffectsonfertilityormatingbehaviourofmalerats.Pseudopregnancyandchangesin
oestruscyclewereobservedinfemalerats.
4.7Effectsonabilitytodriveandusemachines
Cleviprexhasmoderateinfluenceontheabilitytodriveandusemachines.
Clevidipinemaycausedizzinesswhichcouldinterferewiththeabilitytodriveoroperatemachineryhowever,patients
receivingCleviprexwillbeconfinedtohospitalforthedurationoftreatment.
4.8Undesirableeffects
Clevidipinehasbeenevaluatedforsafetyin1,423hypertensivepatients.Infusionratewasevaluatedfor1,326patients
amongwhom6%weretreatedwiththemeandoseof>32ml/h(16mg/h)anduptothemaximumrecommended
therapeuticdoseof64ml/h(32mg/h).Continuousinfusiondurationwasevaluatedfor1,380patients20%ofwhomwere
continuouslyinfusedformorethan15hoursandupto72hours.Theincidenceofadversereactionsshowedno
associationwithgender,age,raceorethnicity.
Atrialfibrillation,sinustachycardiaandhypotensionwereallfrequentlyobservedadverseeventsintheperioperative
population.Theseeventsmayalsoberelatedtothesurgicalproceduresbeingundertakenratherthanthedrug
treatment.
Inclinicalstudies,atotalof2.5%ofpatientsreceivingclevidipineexperiencedoxygensaturationdecrease(reportedas
hypoxia)comparedtoratesof1.5%fornitroglycerine(NTG)and,5.1%forsodiumnitroprusside(SNP)and5.7%for
nicardipine(NIC).
InallPhaseIIIclinicaltrialsoncardiacsurgicalpatients,theincidenceofatrialfibrillationinpatientstreatedwith
Cleviprexascomparedtoactivecomparatorsandplacebowas32.8%,32.9%,and12.0%,respectively,amongwhich
3.9%,2.5%,and0.0%wereconsideredtreatmentrelated.Theincidenceofsinustachycardiainperioperativepatients
treatedwithCleviprexascomparedtoactivecomparatorsandplacebowas25.5%,30.5%,and0.0%,respectively,
amongwhich1.3%,1.2%,and0.0%wereconsideredtreatmentrelated.Theincidenceofhypotensioninperioperative
patientstreatedwithCleviprexascomparedtoactivecomparatorsandplacebowas15.1%,14.9%,and1.0%,
respectively,amongwhich2.5%,2.5%,and0.0%wereconsideredtreatmentrelated.
Theadversereactions(Table1:Perioperativehypertension)reportedinexcess(>0.5%)inpatientsreceivingplacebo
andasmorethananisolatedcaseinpatientsreceivingclevidipineincontrolledclinicaltrialsarelistedbelowas
MedDRApreferredtermbysystemorganclassandabsolutefrequency.
Frequenciesaredefinedas:verycommon1/10common1/100,<1/10uncommon1/1000,<1/100rare1/10000,
<1/1000veryrare<1/10000notknown(cannotbeestimatedfromtheavailabledata).Withineachfrequencygrouping,
undesirableeffectsarepresentedinorderofdecreasingseriousness.
Table1:Adversedrugreactionsinperioperativehypertensionpatients
Nervoussystemdisorders
Uncommon:

Dizziness,Headache

Cardiacdisorders
Common:

Atrialfibrillation,Sinustachycardia

Uncommon:

Atrialflutter,Tachycardia,Cardiacfailurecongestive,Bradycardia,Atrioventricular
blockcomplete,Bundlebranchblock

Vasculardisorders
Common:

Hypotension

Generaldisordersandadministrationsiteconditions
Common:

Oedema,Chestpain

Respiratoryandmediastinaldisorders
Uncommon:

Hypoxia,Pulmonarycongestion

Gastrointestinaldisorders
Uncommon:

Constipation,Nausea,Vomiting

Rare:

Ileus

Inclinicalstudiesinpatientsinnonperioperativesettings(n=294)thefollowingadditionaladversereactionswereseen
inpatientstreatedwithclevidipine:hypersensitivity(uncommon),flushing(common),feelinghot(common)andpolyuria
(common).
Reportingofsuspectedadversereactions
Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinued
monitoringofthebenefit/riskbalanceofthemedicinalproduct.Healthcareprofessionalsareaskedtoreportany
suspectedadversereactionsviatheYellowCardScheme,Website:www.mhra.gov.uk/yellowcard.
4.9Overdose
Themaximumrecommendeddoseis64ml/h(32mg/h).Inclinicaltrials,1healthysubjectreceivedadoseof
clevidipineupto212ml/h(106mg/h)andexperiencedmildflushingandaslighttransientincreaseinserumcreatinine.
Asaresultofaweightbasedregimen,49patientsreceivedamaximumrateabove64ml/h(32mg/h)withoutany
clinicaldifferenceintheincidencesofadverseeventscomparedtothosewhoreceived64ml/h(32mg/h)orbelow.The
averagedoseinthesepatientswas82ml/h(41mg/h)withamaximumdoseof120ml/h(60mg/h).
Onecardiacsurgicalpatientreceivedabolusdoseofclevidipinepriortoaorticcannulationandexperienced
hypotension.

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Anoverdoseofclevidipinemayresultintachycardiaorexcessivereductioninbloodpressure.Ifeitheroccurswith
clevidipine,considerdecreasingthedosebyhalforstoppingtheinfusion.Discontinuationofclevidipineleadstoa
reductioninantihypertensiveeffectswithin5to15minutes.
5.Pharmacologicalproperties
5.1Pharmacodynamicproperties
Pharmacotherapeuticgroup:Dihydropyridinederivatives,ATCcode:(C08CA16).
Mechanismofaction:ClevidipineisadihydropyridineLtypecalciumchannelblocker.Ltypecalciumchannels
mediatetheinfluxofcalciumduringdepolarisationinarterialsmoothmuscle.Experimentsinanaesthetisedratsand
dogsshowthatclevidipinereducesmeanarterialbloodpressurebydecreasingsystemicvascularresistance.
Clevidipinedoesnotreducecardiacfillingpressure(preload),confirminglackofeffectsonthevenouscapacitance
vessels.
Pharmacodynamiceffects:Clevidipineistitratedtothedesiredreductioninbloodpressure.
Intheperioperativepatientpopulation,clevidipineproducesa45%reductioninsystolicbloodpressure(SBP)within24
minutesafterstartinga0.4mcg/kg/mininfusion(approximately24ml/h[12mg/h]).Instudiesupto72hoursthere
wasnoevidenceoftolerance.
Inmostpatients,fullrecoveryofbloodpressureisachievedin515minutesaftertheinfusionisstopped.Instudiesof
upto72hourstherewasnoevidenceofreboundhypertension.
Haemodynamics:Clevidipinecausesadosedependentdecreaseinsystemicvascularresistance.
Anincreaseinheartratecanbeanormalresponsetorapiddecreasesinbloodpressureinsomepatientstheheartrate
responsemaybepronounced.
Theeffectofclevidipineinanaesthetisedcardiacsurgerypatientsoncentralhaemodynamics,myocardialbloodflow
andmetabolismhavebeenstudied.Inthesepatients,cardiacoutputandstrokevolumeincreasedby10%.Asthedose
ofclevidipinewasescalated,myocardialoxygenextractiondecreasedsignificantly,indicatingpreservationof
myocardialperfusionandadirectcoronaryvasodilatoryeffect.Noincreaseinnetlactateproductionincoronarysinus
bloodwasobserved,confirmingtheabsenceofmyocardialischaemiaduetocoronarysteal.
ClinicalTrials
Perioperativepatients
ClevidipinewasevaluatedintwoPhase3doubleblind,randomised,placebocontrolledtrialsof105and110cardiac
surgerypatients(ESCAPE1,preoperative,andESCAPE2,postoperative,respectively)withperioperativehypertension
(SBP160mmHg).Themeancontinuousinfusiondurationwas30minutes(min4minutes,max1hour).Theprimary
endpointwas'bailout'definedbyprematureandpermanentdiscontinuationofstudydrug,withpatientstransferredto
alternativeopenlabeltherapy.
Ingreaterthan90%ofpatientstreatedwithclevidipine,bloodpressurewasloweredby15%within30minutes.Bailout
ratesinESCAPE1were7.5%clevidipinevs.82.7%placebo.SimilarlyESCAPE2hadbailoutratesof8.2%clevidipine
vs.79.6%forplacebo.
Thebloodpressureloweringeffectwithclevidipinewasseenwithin2minutes.Themediantimetoattainthetarget
SBPwas6minutesand5.3minutesforESCAPE1andESCAPE2,respectively.
TherewerenotreatmentemergentadversereactionsintheESCAPE1trial.Treatmentemergentadversereactionsfor
ESCAPE2wereatrialfibrillation(clevidipine1.6%placebo0%),andinsomnia(clevidipine1.6%placebo
0.0%).
InthreePhase3,activelycontrolled,openlabelclinicaltrials(ECLIPSE),1,506patientswererandomisedandreceived
clevidipine(n=752),nitroglycerine(perioperative,n=278),sodiumnitroprusside(perioperative,n=283),ornicardipine
(postoperative,n=193).Themeancontinuousinfusiondurationwas4hours(min1minute,max127hours).Theprimary
safetyendpointwasacomparisonoftheclinicaleventsofdeath,myocardialinfarction(MI),stroke,andrenal
dysfunctionat30dayspostsurgery.Theprimaryefficacyendpointwasbloodpressurecontroldefinedasthearea
underthecurve(AUC)capturingthemagnitudeanddurationofbloodpressureexcursionsoutsideofapredefinedrange.
DataregardingtheprimarysafetyendpointispresentedinTable2.
Table2.PrimaryendpointdatafortheECLIPSEtrials

Clevidipine

AllActiveComparators

(N=752)

(N=754)

Death

20/719(2.8%)

28/729(3.8%)

Stroke

8/700(1.1%)

12/705(1.7%)

MI

16/700(2.3%)

17/707(2.4%)

Renaldysfunction

56/712(7.9%)

56/710(7.9%)

Regardingefficacy,clevidipineprovidedbetterbloodpressurecontrolcomparedtonitroglycerine(AUCSBPmedian4.14
vs.8.87mmHgxmin/h,respectively,p=0.0006)andcomparedtosodiumnitroprusside(median4.37vs.10.50mmHgx
min/h,respectively,p=0.0027).Cleviprexdidnotshowsuperiorityovernicardipineintermsofbloodpressurecontrolin
thepostoperativesetting(median1.76vs.1.69mmHgxmin/h,respectively,p=0.8508).
Theadverseeventsobservedduringthetreatmentinfusionperiodupto1houraftertheendoftheinfusionweresimilar
inpatientswhoreceivedclevidipineandinthosewhoreceivedcomparatoragents.Theincidenceofadverseevents
leadingtostudydrugdiscontinuationinpatientswithperioperativehypertensionreceivingclevidipinewas5.9%versus
3.2%forallactivecomparators.
Othertrials
Additionalpreliminarystudieshavebeenconductedinpatientswithessentialhypertension,severehypertensionandin
acutelyhypertensivepatientswithacuteintracerebralhaemorrhage.
Thepharmacodynamicrelationshipbetweenclevidipineandbloodpressurewasmeasuredinarandomisedplacebo
controlled,singleblindtrialof61patientswithmildtomoderateessentialhypertension(MeanBloodPressureBP
151/86).Theresultsshowedclevidipinehadahighclearance,induceddosedependentreductionsinsystolicBP(SBP),
DiastolicBP(DBP)andMeanArterialPressure(MAP),andhadalinearrelationshipbetweenconcentrationandBP
response.
Theeffectofclevidipineonseverehypertension(BP>180/115)wasstudiedinanopenlabeltrialin126patients

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(VELOCITY).Meaninfusiondurationwas21hoursAmeandecreaseinSBPof21.1%wasachievedin89%of
patientswithinfirst30minutesmediantimetoachievetargetSBPwas10.9minutesmediandosetoachievetarget
BPwas8mg/hr.
Theuseofclevidipinein33patientswithintracerebralhaemorrhageandacuteelevatedbloodpressurewasstudiedin
anopenlabelclinicaltrial(ACCELERATE).Within30minutesofinitiationofclevidipineinfusion,systolicbloodpressure
wasreducedtowithinthetargetrange(140mmHgto160mmHg)inamediantimeof5.5minutes.Systolicblood
pressurewasreducedto160mmHgwithinthefirst30minutesafterinitiationofclevidipineinfusionin97%(32/33)
patients.
5.2Pharmacokineticproperties
Clevidipineisrapidlydistributedandmetabolised.Thearterialbloodconcentrationofclevidipinedeclinesina
multiphasicpatternfollowingterminationoftheinfusion.Theinitialphasehalflifeisapproximately1minute,and
accountsfor8590%ofclevidipineelimination.Theterminalhalflifeisapproximately15minutes.
Distribution:Clevidipineis>99.5%boundtoproteinsinplasmaat37C.Thesteadystatevolumeofdistributionis0.17
L/kginarterialblood.
Metabolismandelimination:Clevidipineisrapidlymetabolisedbyhydrolysisoftheesterlinkage,primarilyby
esterasesinthebloodandextravasculartissues,makingitseliminationunlikelytobeaffectedbyhepaticorrenal
dysfunction.Theprimarymetabolitesarethecarboxylicacidmetaboliteandformaldehydeformedbyhydrolysisofthe
estergroup.Thecarboxylicacidmetaboliteisinactiveasanantihypertensive.Thismetaboliteisfurthermetabolisedby
glucuronidationoroxidationtothecorrespondingpyridinederivative.Theclearanceoftheprimarydihydropyridine
metaboliteis0.03L/h/kgandtheterminalhalflifeisapproximately9hours.
Invitrostudiesshowthatclevidipineanditsmetaboliteattheconcentrationsachievedinclinicalpracticedonotinhibit
orinduceanyCYPenzyme.
Inaclinicalstudywithradiolabelledclevidipine,83%ofthedrugwasexcretedinurineandfaeces.Themajorfraction,
6374%isexcretedintheurine,722%inthefaeces.Morethan90%oftherecoveredradioactivityisexcretedwithin
thefirst72hoursofcollection.
5.3Preclinicalsafetydata
Nonclinicaldatarevealnospecialhazardforhumansbasedonstudiesofsafetypharmacology,repeateddosetoxicity
andgenotoxicity.
Findingsintherepeateddosestudiesweregenerallyrelatedtothepharmacologyofclevidipineand/orthe
administrationofhighquantitiesoflipidvehicle.Theseeffectsareconsideredoflittlerelevancetotheshorterterm
clinicaluse.
Clevidipinedisplayedpositivegenotoxicpotentialininvitroassays(Amestest,mouselymphomathymidinekinase
locusassay,chromosomalaberrationassay)butnotinvivointhemousemicronucleustest.Thepositiveinvitro
resultsareconsistentwiththeformationofformaldehyde,aminormetaboliteofclevidipine,whichisknowntobea
genotoxicinvitroandaprobablehumancarcinogen.However,humaninvivoexposuretoformaldehydeatthe
maximumclinicaldosesofclevidipine(64ml/h[32mg/h])isatleastseveralhundredtimeslessthannormaldaily
endogenousformaldehydegeneration,andisthereforenotofclinicalconcern.
Developmentandreproductivetoxicitystudiesshowednoadverseeffectsonfertilityormatingbehaviourofmalerats
pseudopregnancyandchangesinoestruscyclewereobservedinfemalerats.
Increasedpostimplantationlossesanddoserelateddecreasesinossificationwereseeninbothratsandrabbits.In
rats,areductioninossificationofpawswasobservedthatincludedpartiallyossifiedmetacarpals,metatarsalsand
phalangessuggestingdevelopmentalretardation.Renalpelviccavitationwasalsoobserved.Inaddition,malrotationsof
ahindlimbwereobservedthatwerenotconsideredrelatedtoskeletalalterations.
Rabbitsexhibitedareductioninossificationofsupraoccipitalbonesandsternebraeandunossifiedheadsoflonglimb
bones.Inaddition,anincreaseinfusedand/ormisalignedsternebraewereobserved.Theseeffectsaresimilarto
changesreportedwithothercalciumchannelantagonists.
Ratsdosedwithclevidipineduringlategestationandlactationexperienceddoserelatedincreasesinmortality,lengthof
gestationandprolongedparturition.
6.Pharmaceuticalparticulars
6.1Listofexcipients
Soyabeanoilrefined
Glycerol
Eggphospholipids
Oleicacid
Disodiumedetate
Waterforinjections
Sodiumhydroxide(forpHadjustment)
6.2Incompatibilities
ThismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinSection6.6.
6.3Shelflife
2yearsrefrigerated(28C)ofwhich2monthsmaybebelow25C
Donotreturntorefrigeratedstorageafterbeginning25Cstorage
Fromamicrobiologicalperspectivethestoppershouldbepuncturedimmediatelybeforeuseandanyremainingproduct
discardedafter12hours

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6.4Specialprecautionsforstorage
Storeandtransportrefrigerated(2C8C).Donotfreeze1.
Keepvialintheoutercartoninordertoprotectfromlight.
Forstorageconditionsafterfirstopeningofthemedicinalproduct,seesection6.3.
1ThefreezingpointofCleviprexisbetween1Cand0C

6.5Natureandcontentsofcontainer
Singleuse,premixed50mland100mlTypeIglassvials,sealedwithagreybromobutylrubberstopperandcapped
withaflipoffaluminiumoverseal.
Packsizes:10x50mlvialsor10x100mlvials.
Notallvialsizesmaybemarketed.
6.6Specialprecautionsfordisposalandotherhandling
Forsingleuseonly.
Lipidfilterswitha1.2micronporesizemaybeusedwhenadministeringCleviprex.
Cleviprexshouldnotbediluted.
Cleviprexshouldnotbeadministeredinthesamelineasothermedicationshowever,Cleviprexcanbeadministered
withthefollowing:
Waterforinjections
SodiumChloride(0.9%)Injection
5%glucosesolution
5%glucosesolutioninSodiumChloride(0.9%)Injection
5%glucosesolutioninRingersLactateInjection
LactatedRingersInjection
10%aminoacid
Compatibilitymayvarybetweenproductsfromdifferentsourcesandhealthcareprofessionalsareadvisedtocarryout
appropriatecheckswhenmixingCleviprexemulsionforinjectionwithotherparenteralsolutions.
Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.
7.Marketingauthorisationholder
TheMedicinesCompanyUKLtd
115LMiltonPark
Abingdon
Oxfordshire
OX144SA
UK
8.Marketingauthorisationnumber(s)
PL16881/0003
9.Dateoffirstauthorisation/renewaloftheauthorisation
Dateoffirstauthorisation:23November2011
10.Dateofrevisionofthetext
12/2014

Companycontactdetails
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www.themedicinescompany.com
Address
115LMiltonPark,Abingdon,
Oxfordshire,OX144SA,UK
Fax
+44(0)1235835561
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+44(0)8005874149
http://www.medicines.org.uk/emc/medicine/28128

Telephone
+44(0)1235448500
MedicalInformationDirectLine
+44(0)2036846344
MedicalInformationemail
medical.information@themedco.com
CustomerCaredirectline
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CustomerCaredirectline
+44(0)2036846344

+44(0)8005874149

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activeingredient.Pleasecheckthatthisisthecorrectcompanybeforecontactingthem.Why?

Activeingredients
clevidipine

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