Closiver Injection

Main information

  • Trade name:
  • Closiver Injection
  • Pharmaceutical form:
  • Solution for injection
  • Medicine domain:
  • Animals
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • Closiver Injection
    United Kingdom
  • Language:
  • English

Therapeutic information

  • Therapeutic group:
  • ivermectin, combinations
  • Therapeutic area:
  • Cattle Females, Cattle Food

Other information

Status

  • Source:
  • HMA - Europe
  • Authorization number:
  • UK/V/0277/001
  • Authorization date:
  • 25-11-2011
  • EU code:
  • UK/V/0277/001
  • Last update:
  • 09-08-2016

Summary of Product characteristics: dosage,interactions,side effects

Revised:May2013

AN:00417/2012

Page1of10

SUMMARYOFPRODUCTCHARACTERISTICS

1. NAMEOFTHEVETERINARYMEDICINALPRODUCT

Closiver5mg/ml/125mg/mlSolutionforInjectionforCattleandSheep(UK&IE)

Closamectin5mg/ml/125mg/mlSolutionforInjectionforCattleandSheep(AT,

BE,CZ,ES,SK)

Closamectine5mg/ml/125mg/mlSolutionforInjectionforCattleandSheep(FR)

ClosamectinFF5mg/ml/125mg/mlSolutionforInjectionforCattleandSheep

(PT)

Closivet5mg/ml/125mg/mlSolutionforInjectionforCattleandSheep(IT)

Ivermectin/Closantel

2. QUALITATIVEANDQUANTITATIVECOMPOSITION

Onemloftheproductcontains:

ActiveSubstances

Ivermectin 5mg

Closantel(asclosantelsodiumdihydrate) 125mg

(equivalentto135,9mgofclosantelsodiumdihydrate)

Excipients

SodiumFormaldehydeSulphoxylate 5mg

ForafulllistofexcipientsseeSection6.1

3. PHARMACEUTICALFORM

Solutionforinjection.

Aclearambersolution.

4. CLINICALPARTICULARS

4.1 TargetSpecies

CattleandSheep.

4.2 IndicationsforUse(SpecifyingtheTargetSpecies)

Cattle:

Forthetreatmentofmixedtrematode(fluke)andnematodeorarthropod

infestationsduetothefollowinggastrointestinalroundworms,lungworms,

eyeworms,warbles,mitesandlice:

Gastrointestinalroundworms

Ostertagiaostertagi(includinginhibitedlarvalstages),Ostertagialyrata(adult),

Haemonchusplacei(adultandimmature),Trichostrongylusaxei(adultand

immature),Trichostrongyluscolubriformis(adultandimmature),Cooperia

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oncophora(adultandimmature),Cooperiapunctata(adultandimmature),

Cooperiapectinata(adultandimmature),Oesophagostomumradiatum(adultand

immature),Nematodirushelvetianus(adult),Nematodirusspathiger(adult),

Strongyloidespapillosus(adult),Bunostomumphlebotomum(adultandimmature),

Toxocaravitulorum(adult),Trichurisspp.

Lungworms

Dictyocaulusviviparus(adultand4 th

stagelarvae)

LiverFluke(trematodes)

Fasciolagigantica,Fasciolahepatica

Treatmentofflukeat12weeks(mature)>99%efficacy.

Treatmentofflukefrom7weeks(lateimmature)>90%efficacy

Eyeworms(adult)

Thelaziaspp

Cattlegrubs(parasiticstages)

Hypodermabovis,Hypodermalineatum

Lice

Linognathusvituli,Haematopinuseurysternus,Solenopotescapillatus

MangeMites

Psoroptesovis(synPcommunisvarbovis),Sarcoptesscabieivarbovis

Theveterinarymedicinalproductmayalsobeusedasanaidinthecontrolofthe

bitinglouseDamaliniabovisandthemangemiteChorioptesbovis,butcomplete

eliminationmaynotoccur.

Sheep:

Forthetreatmentofmixedtrematode(fluke)andnematodeorarthropod

infestationsduetogastrointestinalroundworms,trematodes,lungworms,nasal

botsandmitesofsheep.

Gastrointestinalroundworms

Teladorsagiacircumcincta(includinginhibitedL4),Teladorsagiatrifurcata(adult

andL4),Haemonchuscontortus(includinginhibitedL4),Trichostrongylusaxei

(adult),Trichostrongyluscolubriformis(adultandL4),T.vitrinus(adult)Cooperia

curticei(adultandL4),Oesophagostomumcolumbianum(adultandL4),O.

venulosum(adult)Chabertiaovina(adultandL4)Nematodirusfilicollis(adultand

L4),Trichurisovis(adult).

[L4=fourthstagelarave]

Lungworms

Dictyocaulusfilaria(adultand4 th

stagelarvae)

Protostrongylusrufescens(adult)

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LiverFluke(Adultsand7weeksimmature)

Fasciolagigantica,Fasciolahepatica

NasalBots

Oestrusovis

MangeMites

Psoroptesovis(Treatmentrequireasecondinjectionofanivermectin-onlyproduct

7dayslater.Seesections4.4and4.9)

Benzimidazole –resistantstrainsofHaemonchuscontortusandTeladorsagia

circumcinctaarealsocontrolled.

4.3 Contraindications

Donotusebyintramuscularorintravenousroute.

Donotuseinanimalswithknownhypersensitivitytotheactiveingredientsorto

anyoftheexcipients.

Avermectinsmaynotbewelltoleratedinallnon-targetspecies(casesof

intolerancewithfataloutcomearereportedindogs –especiallyCollies,Bobtails,

OldEnglishSheepdogsandrelatedbreedsorcrosses,andalsoin

turtles/tortoises).

PleaserefertoSection4.7and4.8oftheSPC.

4.4 SpecialWarningsforEachTargetSpecies

Careshouldbetakentoavoidthefollowingpracticesbecausetheyincreasethe

riskofdevelopmentofresistanceandcouldultimatelyresultinineffectivetherapy:

Toofrequentandrepeateduseofanthelminticsfromthesameclass,overan

extendedperiodoftime.

Underdosingwhichmaybeduetounderestimationofbodyweight,

misadministrationoftheproduct,orlackofcalibrationofthedosingdevice.

Suspectedclinicalcasesofresistancetoanthelminticsshouldbefurther

investigatedusingappropriatetests(e.g.FaecalEggCountReductionTest).

Wheretheresultsofthetestsstronglysuggestresistancetoaparticular

anthelmintic,ananthelminticbelongingtoanotherpharmacologicalclassand

havingadifferentmodeofactionshouldbeused.

ResistancetoivermectinhasbeenreportedinCooperiasppincattleandthere

havealsobeenisolatedgeographicalreportsofresistanceinOstertagiaostertagi

inCattle.Thereforetheuseofthisproductshouldbebasedonlocal

epidemiologicalinformationaboutthesusceptibilityoftheCooperiasppand

Ostertagiaspp.andrecommendationsonhowtolimitfurtherselectionfor

resistancetoanthelmintics.

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ResistancetoivermectinandclosantelhasbeenreportedinHaemonchus

contortusinsheep.Thereforetheuseofthisproductshouldbebasedonlocal

epidemiologicalinformationaboutthesusceptibilityoftheHaemonchuscontortus

andrecommendationsonhowtolimitfurtherselectionforresistanceto

anthelmintics.

Insheeptreatmentofpsoropticmange(sheepscab)withoneinjectionofthis

productwillnotbeeffectiveineliminatingallthemites.Asuitableivermectin –only

injectableproductmustbeadministeredsevendaysafterthetreatmentwiththis

producttotreatclinicalsignsandtoeliminatethemites.

Sheepscab(Psoroptesovis)isanextremelycontagiousexternalparasiteof

sheep.Toensurecompletecontrolgreatcaremustbetakentoavoidre-

infestation,asmitesmaybeviableforupto15daysoffthesheep.Itisimportant

thatallsheepwhichhavebeenincontactwithinfectedsheeparetreatedwithan

appropriateproduct.Contactbetweentreated,infectedanduntreatedflocksmust

beavoideduntilatleastsevendaysaftertreatment.

4.5 SpecialPrecautionsforUse

i. Specialprecautionsforuseinanimals

Dosesofmorethan10mlshouldbeinjectedintwodifferentsitesinorderto

reducethetransitorydiscomfortorreactionsattheinjectionsite.

DuetothepotentialforsecondaryreactionsduetodeathofHypoderma

larvae,itisnotadvisabletoadministertheproductwhenHypoderma

lineatumlarvaearelocalisedintheperiaesophagicregion,orwhen

Hypodermabovislarvaearesituatedinthespinalcanal.Seektheadviceof

yourveterinariantodeterminethebestperiodofuse.

ii. Specialprecautionstobetakenbythepersonadministeringthemedical

veterinaryproducttoanimals

Donotsmoke,eatordrinkwhilehandlingtheproduct.

Avoiddirectcontactoftheproductwiththeskin.Incaseofspillageontothe

skinrinseimmediatelywithfreshwater.

Washhandsafteruse.

Takecaretoavoidself-injection.Inadvertentself-injectionmayresultin

localirritationand/orpainattheinjectionsite.

Incaseofaccidentalself-injection,seekmedicaladviceimmediatelyand

showthepackageleaflettothephysician.

iii. OtherPrecautions

Ivermectinisverytoxictoaquaticorganismsanddunginsects.Treated

cattleshouldnothavedirectaccesstoponds,streamsorditchesfor14

daysaftertreatment.Longtermeffectsondunginsectscausedby

continuousorrepeatedusecannotbeexcluded.Thereforerepeated

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treatmentofanimalsonapasturewithanivermectin-containingproduct

withinaseasonshouldonlybegivenintheabsenceofalternative

treatmentsorapproachestomaintainanimal/flockhealth,asadvisedbya

veterinarian.

4.6 AdverseReactions(FrequencyandSeriousness)

Transitorydiscomforthasbeenobservedinsomecattlefollowingsubcutaneous

administration.Tissueswellingsattheinjectionsitearecommonupto48hours

afterinjectionwhichresolvethereafterwithouttreatment.Hardnessonpalpation

maybeobservedupto7daysfollowingadministration.

Transitoryswellinghasoccasionallybeenobservedinsheepattheinjectionsite.

Occasionallythisswellingisaccompaniedbypainanddiscomfort.Thisswelling

resolvescompletelywithin14daysfollowingtreatment.

4.7 UseDuringPregnancy,LactationorLay

Theveterinarymedicinalproductcanbeadministeredtocattleandsheepatany

stageofpregnancyorlactationprovidedthatthemilkisnotintendedforhuman

consumption.

BeforeuseindairyanimalsseeSection4.11.

4.8 InteractionswithOtherMedicamentsandOtherFormsofInteraction

Donotadministerconcomitantlywithchlorinatedcompounds.TheeffectofGABA

agonistsareincreasedbyivermectin.

4.9 AmountstobeAdministeredandAdministrationRoute

Theveterinarymedicinalproductshouldbeadministeredatadosagerateof200

givermectinperkgbodyweightand5mgclosantelperkgbodyweight(1mlper

25kg).Itshouldonlybeinjectedsubcutaneouslyintotheneck.Amaximumdose

of10mlshouldbeadministeredatanyonesitewithanyresidualvolume

administeredatanothersiteintheneck.Asterile16-gauge,one-inchneedleis

recommended.

Assessbodyweightcarefullypriortoadministration.

Thisproductdoesnotcontainanantimicrobialpreservative.Swabseptumbefore

removingeachdose.Useadrysterileneedleandsyringe.For250mland500ml

packsizes,useofamultipledosesyringeisrecommended.Torefillthesyringe,

useofadraw-offneedleisrecommendedtoavoidexcessivebroachingofthe

stopper.

Donotexceed40broachingspervial.Ifmorethan40broachingsarerequired,

useofadrawoffneedleisrecommended.

Thetimingfortreatmentshouldbebasedonepidemiologicalfactorsandshouldbe

customisedforeachindividualfarm.Professionalveterinaryadviceshouldbe

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soughtonappropriatedosingprogrammesandstockmanagementtoachieve

adequateparasitecontrolandreducethelikelihoodofresistancedeveloping.

Toensureadministrationofacorrectdose,bodyweightshouldbedeterminedas

accuratelyaspossible;accuracyofthedosingdeviceshouldbechecked.

Ifanimalsaretobetreatedcollectivelyratherthanindividuallytheyshouldbe

groupedaccordingtotheirbodyweightanddosedaccordingly,inordertoavoid

under-oroverdosing.

Forthetreatmentandcontrolofsheepscabaninjectionoftheveterinary

medicinalproductmaybeadministeredbutmustbefollowedwithasecond

injectionofanivermectinonlyproductsevendaysaftertheinitialinjectiontotreat

clinicalsignsofscabandtoeliminatemites.Thisinjectionshouldbeadministered

attheothersideoftheneck.

4.10Overdose(Symptoms,EmergencyProceduresandAntidotes)(ifnecessary)

Doselevelsapproaching4.0mg/kgivermectin(20timestherecommended

dosage)administeredsubcutaneously,resultinataxiaanddepressionincattleand

sheep.

Closantellikeothersalicylanilidesisapotentuncouplerofoxidative

phosphorylationandthesafetyindexisnotashighasisthecaseofmanyother

anthelmintics.Howeverwhereusedasdirectedthereareunlikelytobeany

untowardeffects.Signsofoverdosagecanincludelossofappetite,decreased

vision,loosefaecesandincreasedfrequencyofdefaecation.Highdosesmay

causeblindness,hyperventilation,hyperthermia,generalweakness,inco-

ordination,convulsions,tachycardiaandinextremecasesdeath.

Noantidotehasbeenidentifiedforeitherivermectinorclosanteloverdosage.

Symptomatictreatmentmaybebeneficial.

Oralclosanteldosesinexcessof82.5mg/kgincattlemaycauseblindness,

hyperventilation,hyperthermia,generalweakness,incoordination,convulsions,

tachycardiaandinextremecases,death.

Followingintramuscularadministrationofclosantelinacutetoxicitystudies,the

firstdeathsincattlewerenotedat35mg/kg.

Thelethaldose(LD

)ofclosantelinsheep,afterasingleintramusculardose,was

higherthan40mg/kg.Moreover,somestudiesconductedinsheepreportedsigns

ofoverdosewithdosesofaround4timesthetherapeuticdose(bothinjectableand

oral).

4.11WithdrawalPeriod

Cattle:

Meatandoffal:49days.

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Milk:Notauthorisedforuseincattleproducingmilkforhumanconsumption

includingduringthedryperiod.Donotuseduringthelasttrimesterofpregnancy

inheiferswhichareintendedtoproducemilkforhumanconsumption

Sheep:

Meatandoffal:28days.

Milk:Notauthorisedforuseinewesproducingmilkforhumanconsumption

includingduringthedryperiod.Donotusewithin1yearpriortothefirstlambing

inewesintendedtoproducemilkforhumanconsumption

5. PHARMACOLOGICALPROPERTIES

Pharmacotherapeuticgroup:Endectocides,Macrocycliclactones,Avermectins,

ivermectin,combinations

ATCvetCode:QP54AA51

5.1 PharmacodynamicProperties

Ivermectinisanendectocidewithactivityagainstawiderangeofinternaland

externalparasites.Ivermectinisamacrocycliclactoneandactsbyinhibitingnerve

impulses.Itbindsselectivelyandwithhighaffinitytoglutamate-gatedchlorideion

channelswhichoccurininvertebratenerveandmusclecells.Thisleadstoan

increaseinthepermeabilityofthecellmembranetochlorideionswith

hyperpolarizationofthenerveormusclecell,resultinginparalysisanddeathof

therelevantparasites.Compoundsofthisclassmayalsointeractwithother

ligand-gatedchloridechannels,suchasthosegatedbytheneurotransmitter

gamma-aminobutyricacid(GABA).Themarginofsafetyforcompoundsofthis

classisattributabletothefactthatmammalsdonothaveglutamate-gatedchloride

channels.Themacrocycliclactoneshavealowaffinityforothermammalian

ligand-gatedchloridechannelsandtheydonotreadilycrosstheblood-brain

barrier.

ResistancetomacrocycliclactoneshasbeenreportedinTeladorsagiaand

Trichostrongylusinsheepinanumberofcountries.Incattleresistanceto

macrocycliclactones(MLs)hasbeenreportedmainlywithCooperiaoncophorain

someEuropeancountries.Thereforetheuseofthismedicinalproductshouldbe

basedonlocal(regional,farm)epidemiologicalinformationaboutsusceptibilityof

parasites,localhistoryoftreatmentsandrecommendationsonhowtousethe

medicinalproductundersustainableconditionstolimitfurtherselectionfor

anthelminticresistance.

P-glycoproteins(Pgps)havebeenfrequentlyimplicatedinivermectinresistance

andareamajorcauseofmulti-drugresistanceinprotozoaandhelminths.

Closantelisamemberofthesalicylanilideclassofanthelmintics.Salicylanilides

arehydrogen(proton)ionophores(referredtoasoxidativephosphorylase

uncouplers.)

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Thechemicalstructureofsalicylanilidesillustratethepossessionofadetachable

proton.Thistypeofmoleculeislipophilicandisknowntoshuttleprotonsacross

membranes,inparticulartheinnermitochondrialmembrane.Closantelactsby

uncouplingoxidativephosphorylation..

Closantelisaparasiticidewithflukicideactivityandefficacyagainstcertainother

helminthsandarthropods.Treatmentwiththeveterinarymedicinalproductwhen

flukearefiveweeksandgreaterhasbeenshowntoreducesubsequent

reproductivecapacityandeggshedding.

5.2 PharmacokineticProperties

Cattle:

Aftersubcutaneousadministrationoftheveterinarymedicinalproducttocattleata

doserateof200ugivermectinperkgand5mgclosantelperkgthefollowing

parameterswereobserved:IvermectinCmaxof57.3ng/mlandAUCof

7106ng.hr/ml;ClosantelCmaxof63.4ug/mlandAUCof21996ug.hr/ml.Ivermectin

isonlypartiallymetabolised.Incattle,onlyabout1-2%isexcretedintheurinethe

remainderisexcretedinthefaeces,approximately60%ofwhichisexcretedas

unaltereddrug.Theremainderisexcretedasmetabolitesordegradation

products.Salicylanilidesarepoorlymetabolisedandareexcretedmainly

unchanged.Closantelisextensivelyboundtoplasmaprotein.About90%of

closantelisexcretedunchangedinthefaecesandurineincattle.

Sheep:

Aftersubcutaneousadministrationoftheveterinarymedicinalproductatadose

rateof200

givermectinperkgand5mgclosantelperkgthefollowingparameters

wereobserved:IvermectinCmaxof24.52ng/mlandAUCof2082.93ng.h/ml;

ClosantelCmaxof70.4

g/mlandAUCof41043

g.h/ml.

Ivermectinbindsextensivelytoplasmaproteins.Duetoitshighlipophilicnature,

ivermectinisextensivelydistributed.Ittendstoaccumulateinfattissue,which

actsasadrugreservoirandthehighestlevelsofivermectinarefoundinliverand

fat.Ivermectinisonlypartiallymetabolised.Ivermectinismainlyeliminatedinthe

faecesasunaltereddrugandfaecalexcretionaccountsfor90%ofthedose

administeredwith<2%ofthedoseexcretedinurine.Ivermectinisalsoexcreted

bythemammarygland.

Salicylanilidesarepoorlymetabolisedandareexcretedmainlyunchanged.The

mainexcretionrouteisthefaecesviathebile.Closantelisextensivelyboundto

plasmaproteins,almostexclusivelytoalbumin.Thedistributiontotissuesispoor.

Closantelhasalongeliminationhalf-life.

5.3 EnvironmentalProperties

Thelongtermeffectofivermectinandclosantelonthepopulationdynamicsofthe

dungbeetlehasnotbeeninvestigated

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6. PHARMACEUTICALPARTICULARS

6.1 ListofExcipients

SodiumFormaldehydeSulphoxylate

PovidoneK12

Macrogol200

GlycerolFormal

6.2 MajorIncompatibilities

Intheabsenceofcompatibilitystudies,thisveterinarymedicinalproductmustnot

bemixedwithotherveterinarymedicinalproducts.

6.3 Shelf-Life

Shelf-lifeoftheveterinaryproductaspackagedforsales:18months.

Shelf-lifeafterfirstopeningofimmediatepackaging:28days.

6.4 SpecialPrecautionsforStorage

Donotstoreabove25°C.

Protectfromlight.

6.5 NatureandCompositionofImmediatePackaging

100ml,250mland500mlType1glassmultidosevialsandaluminiumcaps

completewithbromobutylbungsandaluminiumseals.

Notallpacksizesmaybemarketed.

6.6 SpecialPrecautionsfortheDisposalofUnusedVeterinaryMedicinalProduct

orWasteMaterialsDerivedfromtheUseofSuchProducts,ifappropriate

EXTREMELYDANGEROUSTOFISHANDAQUATICLIFE.Donotcontaminate

surfacewatersorditcheswiththeproductorusedcontainer.Anyunused

veterinarymedicinalproductorwastematerialsderivedfromsuchveterinary

medicinalproductshouldbedisposedofinaccordancewithlocalrequirements.

7. MARKETINGAUTHORISATIONHOLDER

NorbrookLaboratoriesLimited

StationWorks

CamloughRoad

Newry

CoDown

BT356JP

NorthernIreland

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8. MARKETINGAUTHORISATIONNUMBER

Vm 02000/4262

9. DATEOFFIRSTAUTHORISATION

Date:06February2007

10. DATEOFREVISIONOFTHETEXT

Date:July2013

APPROVED 05/08/13

15-6-2018

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