HealthProductsRegulatoryAuthority

IPAR

Publicly Available Assessment Report for a Veterinary Medicinal Product

FasimecDuo50mg/ml+1mg/mloralsuspensionforsheep

08March2019 CRN000XGK Page1of10 HealthProductsRegulatoryAuthority

PRODUCT SUMMARY

EU Procedure Number IE/V/0493/001(formerlyUK/V/0428/001) Name, Strength, Pharmaceutical Form FasimecDuo50mg/ml+1mg/mloralsuspensionforsheep Active Substances(s) Triclabendazole,Ivermectin ElancoGmbH,Heinz-Lohmann-Strasse4,27472Cuxhaven, Applicant Germany Fixedcombinationapplication(Article13bofDirectiveNo Legal Basis of Application 2001/82/EC) Target Species Sheep Treatmentofmixedtrematode(fluke)andnematodeor arthropodinfectionsduetogastrointestinalroundworms, lungworms,liverflukeandnasalbots. Gastrointestinalnematodes(adultandimmature): Haemonchus contortus, Teladorsagia (Ostertagia) circumcincta, Trichostrongylusspp,Cooperiaspp,Nematodirussppincluding N. battus, Strongyloides papillosus,Oesophagostomumspp,and adultChabertia ovina. Inhibitedlarvalstagesandbenzimidazoleresistantstrainsof Indication For Use Haemonchus contortusandTeladorsagia (Ostertagia) circumcinctaarealsocontrolled. Liverfluke(mature,immatureandearlyimmaturestagesdown tolessthan1weekofage): Fasciola hepatica Lungworms(adultandimmature): Dictyocaulus filaria Nasalbots(allstages): Oestrus ovis ATC Code QP54AA51 ​Date of completion of the original mutual recognition ​20April2012 ​Date product first authorised in the Reference Member 20November2007(UK)​ State (MRP only) 19October2012(IE) ​France,Ireland(nowRMS),Italy,Spain Concerned Member States for original procedure​ UKaddedviaRMSchange

PUBLIC ASSESSMENT REPORT

ThepublicassessmentreportreflectsthescientificconclusionreachedbytheHPRAattheendoftheevaluationprocessand providesasummaryofthegroundsforapprovalofthemarketingauthorisationforthespecificveterinarymedicinalproduct.It ismadeavailablebytheHPRAforinformationtothepublic,afterthedeletionofcommerciallyconfidentialinformation.The legalbasisforitscreationandavailabilityiscontainedinArticle25.4ofECDirective2001/82/ECasamendedbyDirective 2004/28/ECforveterinarymedicinalproducts.Itisaconcisedocumentwhichhighlightsthemainpartsofthedocumentation submittedbytheapplicantandthescientificevaluationcarriedoutbytheHPRAleadingtotheapprovaloftheproductfor marketinginIreland. TheSummaryofProductCharacteristics(SPC)forthisproductisavailableontheHPRA'swebsite.

I. SCIENTIFIC OVERVIEW

FasimecDuo50mg/ml+1mg/mlOralSuspensionforSheepisanoralsuspensioncontainingtriclabendazole 50 mg/mland ivermectin 1 mg/mlforuseinthetreatmentandcontrolofgastrointestinalnematodes,liverfluke,lungwormsandnasalbotsin sheep. TheproductmayalsobeusedtotreatbendimidazoleresistantHaemonchus contortus andTeladorsagia circumcinta.  Therecommendeddoserateis1 mlper5 kgbodyweight.TheproductwasauthorisedNationallyintheUnitedKingdomin November2007.

08March2019 CRN000XGK Page2of10 HealthProductsRegulatoryAuthority The product is produced and controlled using validated methods and tests which ensure the consistency of the product releasedonthemarket. Ithasbeenshownthattheproductcanbesafelyusedinthetargetspecies. Theproductissafefor theuser,theconsumeroffoodstuffsfromtreatedanimalsandfortheenvironment,whenusedasrecommended. Suitable warningsandprecautionsareindicatedintheSPC.[1] Theefficacyoftheproductwasdemonstratedaccordingtotheclaims madeintheSPC. Theoverallbenefit/riskanalysisisinfavourofgrantingamarketingauthorisation.

II. QUALITY ASPECTS

A. Composition Theproductcontainsivermectin1mg/mlandtriclabendazole50mg/ml,andexcipientsmethylparahydroxybenzoate(E218), propylparahydroxybenzoate(E216),benzylalcohol,microcrystallinecelluloseandcarmellosesodium,povidoneK30,propylene glycol,disodiumphosphatedodecahydrateandpurifiedwater.Thechoiceoftheformulationandpresenceofpreservativeare justified. Theproductispresentedinwhitehighdensitypolyethylene(HDPE)bottlesofnominalcapacity0.8,2.2,5.0litres,anda12.0 litreHDPEcontainer.Bluepolypropylenescrewcapswithaflip-topareusedasclosuresforthesmallerpacksizes;ablueHDPE screwcapisusedonthe12 litrepack.  Theproductisanestablishedpharmaceuticalformanditsdevelopmentisadequatelydescribedinaccordancewiththe relevantEuropeanguidelines.

B. Method of Preparation of the Product Theproductismanufacturedfullyinaccordancewiththeprinciplesofgoodmanufacturingpracticefromalicensed manufacturingsite. Themanufactureofabatchoftheproducthasbeendescribed. In-processchecksareconductedfor completenessofdissolutionofsolublesubstances,forabsenceoffoamingthatmightselectivelyremovesuspendedmaterials fromthebulk,andforhomogeneity,freedomfromaggregatesandviscosityincreaseinthefinalstages. Filledcontainersare check-weighed,withlimitsreflecting100 - 103 %oftheclaimedcontent. Processvalidationdataontheproducthavebeen presentedinaccordancewiththerelevantEuropeanguidelines.

C. Control of Starting Materials TheactivesubstanceivermectinisanestablishedactivesubstancedescribedintheEuropeanPharmacopoeia(Ph. Eur.) Acopy ofthecurrentEDQMcertificateofsuitabilityhasbeenprovided. Notestingadditionaltothatspecifiedinthemonographof theEuropeanPharmacopoeiaiscarriedout. Nopharmacopoeialspecificationisavailablefortriclabendazole,forwhichanin-housespecificationhasbeendeveloped. The agreedspecificationhasbeenprovided. Dispersiblecellulose,anintimatemixtureofmicrocrystallinecelluloseandcarmellosesodium,isthesubjectofamonographin theBritishPharmacopoeia. AllothersubstancesaredescribedintheEuropeanPharmacopoeia. Thespecificationsappliedare appropriatelythoseoftherelevantmonograph. Thedossierincludesacertificateofanalysisforonebatchofeachingredient, showingcompliance.

D. Specific Measures concerning the Prevention of the Transmission of Animal Spongiform Encephalopathies TherearenosubstanceswithinthescopeoftheTSEGuidelinepresentorusedinthemanufactureofthisproduct.

E. Control on intermediate products Therearenointermediateproducts.Thesuspensionisnotstoredortransportedinbulk.

F. Control Tests on the Finished Product Thefinishedproductspecificationcontrolstherelevantparametersforthepharmaceuticalform. Thetestsinthespecification, andtheirlimits,havebeenjustifiedandareconsideredappropriatetoadequatelycontrolthequalityoftheproduct.  Satisfactoryvalidationdatafortheanalyticalmethodshavebeenprovided. Batchanalyticaldatafromtheproposed productionsitehavebeenprovideddemonstratingcompliancewiththespecification.Testsincludethoseforappearance,pH, density,andresuspendability.

G. Stability The Certificate of Suitability for ivermectin specifies a 3 year retest interval for material stored in the commercial container, double-linedpolyethylenebagswithinanaluminiumdrum. The dossier includes a report on stability tests carried out on three batches of triclabendazole.  These have been stored in containers representative of commercial packaging for 12 months under VICH accelerated conditions, 40°C/75%RH, and for 36 monthsunderbothlong-termconditions,25°C/60%RH,andrefrigeration,5°C. Samplesweretestedandonthebasisofthe evidence,theproposedretestintervalof5 yearsisjustified. Nospecialconditionsofstoragearerequired.

08March2019 CRN000XGK Page3of10 HealthProductsRegulatoryAuthority StabilitydataonthreebatchesthefinishedproducthasbeenprovidedinaccordancewithapplicableEuropeanguidelines, demonstratingthestabilityoftheactivesubstancewhenstoredundertheapprovedconditions.Testsincludethosefor appearance,density,resuspendability,pHandmicrobialpurity.

J. Other Information Theshelflifeoftheveterinarymedicinalproductaspackagedforsaleis18months.Afterfirstopeningtheimmediate packaging,theshelf-lifeis12months.Theproductshouldbestoredintheclosedoriginalcontainer.

III SAFETY AND RESIDUES ASSESSMENT (PHARMACO-TOXICOLOGICAL)

Bothactivesubstances,triclabendazoleandivermectin,arewellknownandwellestablishedsubstancesthathavebeenusedin veterinary medicine for a number of years.  This is a full stand alone fixed combination product for sheep which is an oral flukicideandbroadspectrumantiparasiticdrench. Fasimec Duo S 0.1%/5% Oral Suspension for Sheep is a white to cream-coloured oral suspension containing 5% triclabendazoleand0.1%ivermectin. Itisadministeredorallyatadoserateof2 ml/10 kg bodyweight(bw)whichisequivalent to 0.2 mg ivermectin and 10 mg triclabendazole per kg bw.  The administration may be repeated depending on the epidemiologicalsituation.

III.A Safety Testing Pharmacological Studies Pharmacology: Triclabendazole: Triclabendazoleisamemberofthesulphidebenzimidazolegroupofanthelmintics. Itismetabolisedinhostanimalsbyafirst passprocesstoasulphoxidewhichisthoughttohaveanthelminticactivityandissubsequentlymetabolisedtoasulphone, whichisthoughttobeanthelminticallyactiveaswell.

Ivermectin: Ivermectinisanavermectin. Ithasabroadspectrumofactivityagainstnematodeandarthropodspeciesinmanydomestic animalsandisusedinmanforthetreatmentofOnchocerca volvulus.

Pharmacodynamics: Triclabendazole: Thetriclabendazolemodeofactionisnotfullyclearbutisthoughttointerferewithintracellulartransportmechanismsand inhibitproteinsynthesis. ItisactiveagainsttheliverflukeFasciola hepatica.

Ivermectin: Ivermectin is a member of the macrocyclic lactone class.  These substances bind selectively and with high affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells.  This leads to an increase in the permeabilityofthecellmembranetochlorideionswithhyperpolarisationofthenerveormusclecell,resultinginparalysisand deathoftheparasite. Mammalsdonothaveglutamate-gatedchloridechannels;themacrocycliclactoneshavealowaffinity forothermammalianligand-gatedchannelsanddonotreadilycrosstheblood-brainbarrier.

Pharmacokinetics:

Ivermectin: Ivermectin is readily absorbed and reaches peak plasma concentration within 1 day. Afterwards plasma concentrations decrease with a half life of 2 to 5 days.

Triclabendazole: Triclabendazole is readily absorbed, oxidised to triclabendazole sulphoxide and to triclabendazole sulphone. Peak plasma concentrationsarereachedwithin1.5days. Afterwardsplasmaconcentrationsdecreasewithahalflifeofabout1day. Both metabolitesbindstronglytoplasmaproteins,particularlyalbumin. Morethan90%ofthedoseisexcretedinthefaeces,about 2%intheurineandlessthan1%inthemilkwithin10days.

Astheapplicantdescribed,thetwoactivesarewellcharacterisedandhavebeenusedinveterinarymedicineforanumberof years. Themodeofactionofbothactivesisdifferentanditisunlikelythattherecouldbeinterferencebetweenthesetwo mechanisms.  In order to investigate the likelihood of any interference in the absorption, distribution, metabolism and

08March2019 CRN000XGK Page4of10 HealthProductsRegulatoryAuthority excretion, the applicant conducted a bioequivalence study comparing the profiles of the single actives to that of the combination.  There is no indication from the pharmacokinetic studies of any interference between triclabendazole and ivermectin. 

Toxicological Studies

Single dose toxicity:

Triclabendazole: Studies indicated that triclabendazole is of low acute toxicity when administered by the oral, intraperitoneal, dermal and inhalation routes in rats and mice.  The sulphoxide and sulphone metabolites of triclabendazole also had low acute oral toxicity. Triclabendazoleproducedminimalskinirritationandnoeyeirritationintherabbit. Anoptimisationtestintheguinea pigproducedsensitisationonintradermalchallengebutnotonepidermalexposure.

Ivermectin: Acutestudieswereconductedinmice,rats,rabbits,dogsandmonkeys. Thetypicalsignsofacuteivermectintoxicitywereall attributedtoeffectsonthecentralnervoussystem. TheseweremostsevereinCF-1[1]mice. Approximately30%ofcolliedogs were highly sensitive to ivermectin.  In immature rhesus monkeys no tremors or convulsions occurred.  The steep dose responsecurveinrodentswasnotreproducedinmonkeys.

Acute oral toxicity Atesttodeterminetheacuteoraltoxicityofthecombinationwasconductedinrats. Ratswereadministeredasingleoraldose of 3000 mg/kg (Limit test) followed by a 14-day post treatment observation period.  The study was conducted to GLP and therewasnomortalityorothertreatmentrelatedabnormalities. Bodyweightsandbodyweightchangeswerenotaffectedby treatmentandnecropsyexaminationsdidnotrevealanytreatmentrelatedeffects. LD50>3000mg/kg.

Acute dermal toxicity Atesttodeterminetheacutedermaltoxicityofthecombinationwasconductedalsoinrats. Thesewereadministeredasingle dermal dose of 4000 mg/kg (Limit test) for 24 hours under semiocclusive conditions followed by a 14-day post treatment observation period.  The study was conducted to GLP and there was no mortality or other treatment related abnormalities. Bodyweightsandbodyweightchangeswerenotaffectedbytreatmentexceptforoneratwhereaslightlossofbodyweight wasrecorded. Necropsyexaminationsdidnotrevealanytreatmentrelatedeffects. LD50>4000mg/kg.

Repeated dose toxicity:

Triclabendazole: Repeated-dosetoxicitystudiesinratsfeddietscontaining10,100or1000 mg/kgfeedtriclabendazolerevealedminortransient haematologicaleffectsandsomeeffectsonclinicalchemistrywereseenathighdoses(equalorgreaterthan100 mg/kgfeed). Decreasedfoodintakeandgrowthretardationwereobservedat1000 mg/kgfeed. Noeffectswereseenat10 mg/kgfeed (NOEL[2]=0.7 mg/kgbw). A13-weekfeedingstudyindogs(10,100or1000 mg/kgfeedtriclabendazole)gaverisetoaNOEL of10mg/kgfeed(0.35 mg/kgbw).

Ivermectin: Short-termstudieswereconductedinrats,dogsandmonkeys. Ina14-weekstudyinratsivermectinwasadministeredorally topregnantdams,theNOELwas0.4 mg/kgbw. Ina14-weekoralstudyinbeagledogstheNOELwas0.5 mg/kgbw. In a two-week oral study, ivermectin was administered to neonatal monkeys at 0.04 and 0.1 mg/kg bw and to immature monkeysat0.3,0.6and1.2 mg/kgbw. Notreatment-relatedeffectswereobserved. Inashort-termescalatingdosestudyin monkeys,anNOELof1mg/kgwasidentified.

Tolerance in the target species:

Triclabendazole: Insheep,singleoraldosesof100 mg/kgand125 mg/kgbwweretoleratedwithminoradverseeffects. 

Ivermectin: 08March2019 CRN000XGK Page5of10 HealthProductsRegulatoryAuthority Ivermectin is generally well tolerated in the intended target species, with occasional coughing in sheep after oral administration.Neurotoxiceffectssimilartothoseseeninlaboratoryspeciesmayoccurinoverdosage. Astudywasperformedongroupsofsheepreceivingone,fiveortentimestherecommendeddose. Nosignificantdeviations fromnormalhealthstateandnormalvaluesofmeasuredparametersweredetectedinanimalstreatedatoneorfivetimesthe recommendeddose. Increasedliverweightandslightlyincreasedclinicallaboratoryparameterswereobservedinthegroup thatreceived10timestherecommendeddose. Therefore,itcanbeconcludedthattheproductiswelltoleratedinsheep.

Reproductive toxicity (inc. teratogenicity):

Triclabendazole: Inatwo-generationstudyinrats,animalswereexposedtodietarylevelsof3,15and75 mg/kgfeedtriclabendazole. Neonatal survivalandbodyweightweredecreasedat15and75 mg/kgfeedintheF2generationbutnotintheF1generation. ANOEL wasdeterminedat3 mg/kgfeed(0.15 mg/kgbw/day).

There was no evidence of teratogenicity in rats following oral administration with daily doses of 10, 30 or 100 mg triclabendazole/kg bw on gestation days 6-16.  Foetal development was retarded at 100 mg/kg associated with maternal toxicity. Inratsexposedto10,25,50or100 mg/kgongestationdays8-15,decreasedmaternalandfoetalbodyweightgains wereobservedat100and200 mg/kg. TheoverallNOELforthesestudieswas50 mg/kgbw. Rabbitswereexposedtodosesof 3, 10 and 20 mg/kg on gestation days 6-18.  Maternal toxicity and retarded foetal development was observed at 10 and 20 mg/kg. TheNOELwas3 mg/kgbw. Oraladministrationtosheepofsingleormultipledosesof10-50 mg/kgbwhadno adverseeffectsonreproductiveparametersoroffspring. Incattle,dosesof15-30 mg/kgbwduringthefirstor2-7monthsof pregnancy caused no adverse effects.  Single or four weekly oral doses of 50 mg/kg bw had no effect on testis weights or spermconcentrationorqualityinmalesheep.

Ivermectin: Inathree-generationstudy,neonataltoxicitywasobservedat0.4 mg/kgbwwithincreasedneonatalmortalityuptoabout10 dayspost-partumanddecreasedbodyweightinthesurvivors.Across-fosteringstudyindicatedthattheneonataltoxicitywas not related to in-utero  exposure but post natal exposure via maternal milk.  There is evidence that neonatal rats are hypersusceptibletoavermectintoxicity.

The developmental toxicity of ivermectin was investigated in mice, rats, rabbits and dogs. The results demonstrated that teratogeniceffectswereproducedonlyatdosessimilartothosecausingseverematernaltoxicity.TheNOELforteratogenicity in the most sensitive species and strain, the CF-1 mouse was 0.2 mg/kg bw, while the NOEL for maternal toxicity was 0.1 mg/kg bw. TheCF-1mousehasageneticpredispositiontoavermectintoxicity. Noteratogenicormaternotoxiceffects wereobservedindogsgivenoraldosesof0.5 mg/kgbweveryfiveortendaysfromdays5to40ofgestation.

Mutagenicity:

Triclabendazole: Triclabendazolewasclearlynegativeinnumerousin-vitroandin-vivomutagenicitytests,includingtheAmestest.

Ivermectin: Ivermectin was negative for mutagenic effects in a bacterial gene mutation study, a mouse lymphoma assay, and an UnscheduledDNA(deoxyribonucleicacid)Synthesis(UDS)studyinhumanfibroblasts(to1000 μg/ml).Thetwocomponents werenegativeinabacterialgenemutationstudy.

Carcinogenicity:

Triclabendazole: Acarcinogenicitystudywasconductedinmicewheretheonlypathologicalfindingswereincreasedserumlevelsofhepatic enzymes,increasedliver-weightandbenignhepatomasinfemalesinthetopdosegrouponly(300 mg/kginthediet).

A chronic toxicity/carcinogenicity study was conducted in mice (3, 15, 60 or 300 mg/kg feed triclabendazole in the diet for 737-752days.TheNOELforthisstudywas60 mg/kgfeed(5.35 mg/kgbw).

08March2019 CRN000XGK Page6of10 HealthProductsRegulatoryAuthority Achronictoxicity/carcinogenicitystudyinrats(3,13,30or100 mg/kginthedietfor2years)demonstratednostatisticallyor biologically significant effects on survival, clinical findings, food or water intake, haematology, biochemistry, urinalysis or tumour incidences at any dose.  Bodyweight gain was significantly depressed in the high dose females and kidney weights werelowerinthehighdosemalesat52weeks. TheNOELwas30 mg/kgfeed(equivalenttoabout1.5 mg/kgbw/day).

Ivermectin: Nocarcinogenicitystudieswereperformed. However,suchdatawerenotconsiderednecessaryonthebasisoftheabsenceof structuralalertsandtheresultsofthemutagenicitystudies.

Other Studies Nospecificstudieswereprovidedconcerningpotentialimmunotoxicity.Theresultsoflaboratoryanimalstudiesandclinical useinhumansgavenoindicationsofanyeffectontheimmunesystem.

Observations in Humans Triclabendazole: Triclabendazolehasbeenusedinclinicaltrialsforthetreatmentofparasiticinfestationsinhumans. Singleanddoubledoses of10 mg/kgbwwerewelltolerated. TransientepigastricpainwasattributedtothedeathoftheFasciolaparasites. Preliminary studies in humans indicate that triclabendazole is well absorbed from the gut.  In fasted patients, peak plasma levels occurred 2 hours after a single oral dose of 10 mg/kg bw.  Administration after a meal resulted in plasma levels approximately3timeshigherthoseinfastedsubjects. Thesulphoxideandsulphonemetaboliteswereidentifiedinplasma, with the sulphoxide predominating.  Parent compound was undetectable after 8 hours, peak levels of the sulphoxide and sulphonewerefoundatabout4hoursandwerestillpresentatlowlevelsat24hours. Ivermectin: Ivermectiniswidelyusedinhumansfortreatmentofonchocerciasisandotherparasiticdiseasesatsingleorrepeateddosesof 0.15to800 mg/kgbw. Tolerancetothecompoundhasbeenassessedinhealthyvolunteersandinpatients;adverseeffects areusuallymildandtransient. Inparticular,noeffectsonthecentralnervoussystemwereobserved. Themaineffectsnotedin fieldandcommunitybasedtrialshavebeenthosearisingfromthedeathoftheparasiteswhichischaracterisedbyarthralgia, fever, hypertension, tachycardia, headache and ocular changes.  Neither in these studies nor during treatment for other parasiticdiseaseshasasubsetofatypicallysensitiveindividualsbeendetected. Also,theadverseeffectsexperiencedbythe smallnumberofpersonsaccidentallyexposedtodoses(oftenofveterinarypreparations)higherthancustomaryhumandoses areinkeepingwiththosenotedintestanimals.

A double blind, randomised, placebo controlled clinical trial was conducted to assess the safety and tolerability of oral subacuterepeatdosesofupto1.2 mg/kg bwandanacutedoseof2.0 mg/kgbwin68healthyadultmaleandfemalehuman subjects as a treatment for headlice. No treatment related signs of toxicity were observed. A NOEL of 420 μg/kg bw was identified.

Microbiological Studies Triclabendazole: Triclabendazolehasnosignificantantimicrobialactivity.

Ivermectin: No data on the effects of ivermectin of the human gut flora or micro-organisms used in food processing were available. However,suchdatawerenotconsiderednecessaryforthisclassofcompound.

Studies on metabolites impurities, other substances and formulation:

Inastudyonacuteeyeirritation/corrosionintherabbit0.1 mloftheproductwasinstilledintotheconjuctivalsacoftheleft eyeofeachanimalwhiletherighteyeremaineduntreatedandservedascontrol. Theeyeswereexaminedforirritationat1,24, 48and72hoursaftertreatment. Hyperaemicconjuctivalbloodvesselswereseeninallanimalsatthe1-hourreadingonly. All eyereactionswereclearbyday1. Therewasnomortalityandnoothersignificantclinicalorbodyweightchanges. Therefore, itwasconcludedthatitisnotclassifiedasirritanttotheeyeaccordingtoCommissionDirective93/21/EEC. Inastudyonskinsensitisation,guineapigsweresplitintotwogroups,avehiclecontrolgroupandatestgroup. Therewere no positive skin reactions among either the vehicle control or test group animals.  There was no mortality and no other significantclinicalorbodyweightchanges. Therefore,itwasconcludedthatitisnotclassifiedasskinsensitizeraccordingto CommissionDirective93/21/EEC.

User Safety

08March2019 CRN000XGK Page7of10 HealthProductsRegulatoryAuthority Theapplicanthasprovidedausersafetyassessmentincompliancewiththerelevantguidelinewhichshowsthattheproductis safefortheuserwhenusedasrecommended.Warningsandprecautionsaslistedontheproductliteratureareadequateto ensuresafetytousersoftheproduct:

 Peoplewithknownhypersensitivitytotheactivesubstancesshouldavoidcontactwiththeproduct.Protective glovesshouldbewornwhenhandlingtheveterinarymedicinalproduct.  Incaseofaccidentalspillageontoskinorintotheeyeswashimmediatelywithwater.Takeoffanycontaminated clothes.  Donoteat,drinkorsmokewhilsthandlingtheproduct.Washhandsandexposedskinbeforemealsandafterwork.

Ecotoxicity Theapplicantprovidedanenvironmentalriskassessmentincompliancewiththerelevantguideline. Animalsaretreatedorallyandresiduesoftheactivesubstanceswillenterthesoilenvironmentdirectlythroughexcretionof urineandfaeces. Metabolismandexcretionstudiesinsheephaveshownthattriclabendazoleisexcretedalmostallinfaeces. Parentcompound isthemajorcomponentoffaecalresidue(16%ofthedose).Themainrouteofexcretionofivermectinisalsothefaeceswith 61-69%ofthedoseexcretedinfaecesasivermectin.Forbothactivesthegreatestexposureistodungfauna. Information has been provided which demonstrates that there will not be any additional toxicity due the presence of two activesintheproduct. Theriskassessmentwascarriedoutoneachactiveindividuallyonthebasisthateachwasexcretedonly asparentcompound. Triclabendazolehasbeenshowntobenon-mobileinsoilandslightlypersistent. Ivermectinisalsonon-mobileinsoilbutis considered persistent in soil.  Based on these properties leaching to groundwater and surface waters is negligible for both compounds. ThePECsoil[3]forivermectinisverylow<1 mg/kgandaccumulationofresidueisnotconsideredtobearisk. Information was provided that demonstrated that triclabendazole will not bioaccumulate.  The PEC of ivermectin was calculatedforsoil,groundwaterandsurfacewater. ComparisonofthesePECvalueswiththeresultsofeffectsstudiesinsoil andaquaticorganismsdemonstratedthattherisktothesoilandaquaticenvironmentsisacceptable. Environmental safety of Fasimec Duo 50 mg/ml + 1 mg/ml Oral Suspension for Sheep is considered acceptable and the followingwarningshavebeenincludedontheSPC:

 Ivermectinisverytoxictoaquaticorganismsanddunginsects.

 Anyunusedveterinarymedicinalproductorwastematerialsderivedfromsuchveterinarymedicinalproducts shouldbedisposedofinaccordancewithlocalrequirements.Dangeroustofishandotheraquaticlife.Donot contaminateponds,waterwaysorditcheswiththeproductorusedcontainer.

III.B Residues documentation Theapplicantsubmittedanumberofpublishedreferencesandin-housestudiestoaddresstheissueofresidues. Someof thesestudieswereontheindividualactives. Thebioequivalencestudywasalsosubmittedtoshowbioequivalenceofthelevels of the active substances when used alone and in combination.  A residue depletion study using the product has also been submitted. Theresiduedepletionstudyusingthefinalformulationwasconductedinyoungsheep. Samplesofmuscle,kidney,fatand liverweretakenfromanimalsatseveraltimepoints. IvermectinlevelswerebelowtheLOQ[4]fromthefirsttimepointexcept inrenalfatwheredetectableresidueswerereported. Thedeterminantfactorwastriclabendazoleresiduelevels Theanalyticalmethodsemployedforthedeterminationofbothtriclabendazoleandivermectinresidueswerealsoacceptable.  Themethodwasfullyvalidated. Basedonthemaximumresidueslimitedawithdrawalperiodof27daysformeatinsheepis justified. Theproductisnotpermittedforuseinanimalsproducingmilkforhumanconsumption,includingpregnantanimalsintended toproducemilkforhumanconsumption.

[1]Astrainofmouseusedintoxicological [2]NOEL=NoObservedEffectLevel

[3]PECsoil=PredictedEnvironmentalConcentrationofasubstanceinsoil [4]LOQ=LimitofQuantification

IV. CLINICAL ASSESSMENT

08March2019 CRN000XGK Page8of10 HealthProductsRegulatoryAuthority Clinical Pharmacology Pharmacodynamics Theapplicanthaspresentedreferencesdetailingtheactionofavermectins,includingivermectin,whichpotentiateorgate,the openingofglutamate-gatedchloridechannels,foundonlyininvertebrates,resultinginparalysisanddeath. Thereferences supportthefactthattriclabendazolehasactivityagainstearlyimmature,immatureandadultFasciola hepatica andFasciola gigantica , but no nematodicidal activity and that ivermectin has a broad spectrum of activity against a range of gastro-intestinalnematodesandofarthropods.

Pharmacokinetics Literature references have been provided by the applicant that demonstrate the expected pharmacokinetic profiles of ivermectin and triclabendazole.  These are acceptable as stand alone supportive evidence, although the data they provide cannot be used to assess bioequivalence to the final formulation, as different formulations were used, than that of the proposedproduct.

The applicant was unable to show bioequivalence for ivermectin in any pharmacokinetic study, due to individual animal variations. However,thisisnotuncommonwithivermectin.Theapplicantlaterdemonstratedbioequivalenceofivermectin,via pharmaceuticalendpointsinclinicaltrials

Thebioequivalenceoftriclabendazolewasaddressedintermsofitstwoactivemetabolites.However,theapplicantwasonly abletoshowbioequivalenceofoneoftheactives)insidethenormal80-125%range. Theothermetabolite)wasshowntobe equivalentifthewiderlimitsof70-143%wereapplied. Thesewiderlimitswerefullyjustifiedbytheapplicant.

Tolerance in the Target Species

Theapplicantprovidedreferencetoatoleranceinthetargetspeciesstudy. Therewasincreasedliverweightseeninallofthe super-clinicaldoserategroups. Itislikelythatthisisofnoclinicalsignificanceastherewerenoothersignificantchangesin haematology,biochemistry,clinicalexamination,orpathology,andincreasedliverweightisacommonoccurrenceafterdosing with triclabendazole.  This reference is supported by extensive PSUR[1], with an overall incidence on 0.00008% adverse reactionsrecorded. Theapplicanthasprovidednospecificlocaltolerancedataforthisproposedproduct. Theapplicanthas statedthattherewasonlyonePSURreportlinkedtooralproblems,andthiswasthoughttoberelatedtoincorrectdosingand subsequentpneumonia. Therewerenoreportedinstancesoflocalintoleranceinanyofthefieldtrials. Thisisacceptableas supportiveoflocaltoleranceoftheproposedproduct.

Resistance

TheapplicanthasaddressedtheissueofresistanceandadequatewarningsandprecautionsappearontheSPC:

 Careshouldbetakentoavoidthefollowingpracticesbecausetheyincreasetheriskofdevelopmentofresistance andcouldultimatelyresultinineffectivetherapy:

-Toofrequentandrepeateduseofanthelminticsfromthesameclass,overanextendedperiodoftime. -Underdosingwhichmaybeduetounderestimationofbodyweight,misadministrationoftheproductorlackofcalibrationof thedosingdevice(ifany).

Suspectedclinicalcasesofresistancetoanthelminticsshouldbefurtherinvestigatedusingappropriatetests(e.g.FaecalEgg CountreductionTest).Wheretheresultsofthetest(s)stronglysuggestresistancetoaparticularanthelmintic,ananthelmintic belongingtoanotherpharmacologicalclassandhavingadifferentmodeofactionshouldbeused. ResistancetoivermectinhasbeenreportedinTeladorsagia (Ostertagia) circumcinctainsheepandresistancetotriclabendazole hasbeenreportedinFasciolaspeciesinsmallruminantsinanumberofcountriesincludingtheEU.Thereforetheuseofthis productshouldbebaseduponlocal(regional,farm)epidemiologicalinformationaboutsusceptibilityoftheTeladorsagia (Ostertagia) circumcinctaandrecommendationsonhowtolimitfurtherselectionforresistancetoanthelmintics

Clinical Efficacy

Clinicaltrialsprovideevidenceofthebioequivalenceoftheivermectincomponentoftheformulationaspreviouslystated. The referenceproductusedwasequivalenttooneauthorisedwithintheUKandconsequentlyextrapolationoftreatmentclaims maybemadeonthisbasis.TheriskbenefitassessmentforFasimecDuo50mg/ml+1mg/mlOralSuspensionforSheepis favourable. Referencestotrialsalsosupporttheproposedtreatmentclaimsoftheproduct. 08March2019 CRN000XGK Page9of10 HealthProductsRegulatoryAuthority [1]PSUR=PeriodicSafetyUpdateReport

V. OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT

ThedatasubmittedinthedossierdemonstratethatwhentheproductisusedinaccordancewiththeSummaryofProduct Characteristics,thebenefit/riskprofileforthetargetspeciesisfavourableandthequalityandsafetyoftheproductforhumans andtheenvironmentisacceptable.

08March2019 CRN000XGK Page10of10