HealthProductsRegulatoryAuthority IPAR Publicly Available Assessment Report for a Veterinary Medicinal Product FasimecDuo50mg/ml+1mg/mloralsuspensionforsheep 08March2019 CRN000XGK Page1of10 HealthProductsRegulatoryAuthority PRODUCT SUMMARY EU Procedure Number IE/V/0493/001(formerlyUK/V/0428/001) Name, Strength, Pharmaceutical Form FasimecDuo50mg/ml+1mg/mloralsuspensionforsheep Active Substances(s) Triclabendazole,Ivermectin ElancoGmbH,Heinz-Lohmann-Strasse4,27472Cuxhaven, Applicant Germany Fixedcombinationapplication(Article13bofDirectiveNo Legal Basis of Application 2001/82/EC) Target Species Sheep Treatmentofmixedtrematode(fluke)andnematodeor arthropodinfectionsduetogastrointestinalroundworms, lungworms,liverflukeandnasalbots. Gastrointestinalnematodes(adultandimmature): Haemonchus contortus, Teladorsagia (Ostertagia) circumcincta, Trichostrongylusspp,Cooperiaspp,Nematodirussppincluding N. battus, Strongyloides papillosus,Oesophagostomumspp,and adultChabertia ovina. Inhibitedlarvalstagesandbenzimidazoleresistantstrainsof Indication For Use Haemonchus contortusandTeladorsagia (Ostertagia) circumcinctaarealsocontrolled. Liverfluke(mature,immatureandearlyimmaturestagesdown tolessthan1weekofage): Fasciola hepatica Lungworms(adultandimmature): Dictyocaulus filaria Nasalbots(allstages): Oestrus ovis ATC Code QP54AA51 ​Date of completion of the original mutual recognition ​20April2012 ​Date product first authorised in the Reference Member 20November2007(UK)​ State (MRP only) 19October2012(IE) ​France,Ireland(nowRMS),Italy,Spain Concerned Member States for original procedure​ UKaddedviaRMSchange PUBLIC ASSESSMENT REPORT ThepublicassessmentreportreflectsthescientificconclusionreachedbytheHPRAattheendoftheevaluationprocessand providesasummaryofthegroundsforapprovalofthemarketingauthorisationforthespecificveterinarymedicinalproduct.It ismadeavailablebytheHPRAforinformationtothepublic,afterthedeletionofcommerciallyconfidentialinformation.The legalbasisforitscreationandavailabilityiscontainedinArticle25.4ofECDirective2001/82/ECasamendedbyDirective 2004/28/ECforveterinarymedicinalproducts.Itisaconcisedocumentwhichhighlightsthemainpartsofthedocumentation submittedbytheapplicantandthescientificevaluationcarriedoutbytheHPRAleadingtotheapprovaloftheproductfor marketinginIreland. TheSummaryofProductCharacteristics(SPC)forthisproductisavailableontheHPRA'swebsite. I. SCIENTIFIC OVERVIEW FasimecDuo50mg/ml+1mg/mlOralSuspensionforSheepisanoralsuspensioncontainingtriclabendazole 50 mg/mland ivermectin 1 mg/mlforuseinthetreatmentandcontrolofgastrointestinalnematodes,liverfluke,lungwormsandnasalbotsin sheep. TheproductmayalsobeusedtotreatbendimidazoleresistantHaemonchus contortus andTeladorsagia circumcinta . Therecommendeddoserateis1 mlper5 kgbodyweight.TheproductwasauthorisedNationallyintheUnitedKingdomin November2007. 08March2019 CRN000XGK Page2of10 HealthProductsRegulatoryAuthority The product is produced and controlled using validated methods and tests which ensure the consistency of the product releasedonthemarket. Ithasbeenshownthattheproductcanbesafelyusedinthetargetspecies. Theproductissafefor theuser,theconsumeroffoodstuffsfromtreatedanimalsandfortheenvironment,whenusedasrecommended. Suitable warningsandprecautionsareindicatedintheSPC.[1] Theefficacyoftheproductwasdemonstratedaccordingtotheclaims madeintheSPC. Theoverallbenefit/riskanalysisisinfavourofgrantingamarketingauthorisation. II. QUALITY ASPECTS A. Composition Theproductcontainsivermectin1mg/mlandtriclabendazole50mg/ml,andexcipientsmethylparahydroxybenzoate(E218), propylparahydroxybenzoate(E216),benzylalcohol,microcrystallinecelluloseandcarmellosesodium,povidoneK30,propylene glycol,disodiumphosphatedodecahydrateandpurifiedwater.Thechoiceoftheformulationandpresenceofpreservativeare justified. Theproductispresentedinwhitehighdensitypolyethylene(HDPE)bottlesofnominalcapacity0.8,2.2,5.0litres,anda12.0 litreHDPEcontainer.Bluepolypropylenescrewcapswithaflip-topareusedasclosuresforthesmallerpacksizes;ablueHDPE screwcapisusedonthe12 litrepack. Theproductisanestablishedpharmaceuticalformanditsdevelopmentisadequatelydescribedinaccordancewiththe relevantEuropeanguidelines. B. Method of Preparation of the Product Theproductismanufacturedfullyinaccordancewiththeprinciplesofgoodmanufacturingpracticefromalicensed manufacturingsite. Themanufactureofabatchoftheproducthasbeendescribed. In-processchecksareconductedfor completenessofdissolutionofsolublesubstances,forabsenceoffoamingthatmightselectivelyremovesuspendedmaterials fromthebulk,andforhomogeneity,freedomfromaggregatesandviscosityincreaseinthefinalstages. Filledcontainersare check-weighed,withlimitsreflecting100 - 103 %oftheclaimedcontent. Processvalidationdataontheproducthavebeen presentedinaccordancewiththerelevantEuropeanguidelines. C. Control of Starting Materials TheactivesubstanceivermectinisanestablishedactivesubstancedescribedintheEuropeanPharmacopoeia(Ph. Eur.) Acopy ofthecurrentEDQMcertificateofsuitabilityhasbeenprovided. Notestingadditionaltothatspecifiedinthemonographof theEuropeanPharmacopoeiaiscarriedout. Nopharmacopoeialspecificationisavailablefortriclabendazole,forwhichanin-housespecificationhasbeendeveloped. The agreedspecificationhasbeenprovided. Dispersiblecellulose,anintimatemixtureofmicrocrystallinecelluloseandcarmellosesodium,isthesubjectofamonographin theBritishPharmacopoeia. AllothersubstancesaredescribedintheEuropeanPharmacopoeia. Thespecificationsappliedare appropriatelythoseoftherelevantmonograph. Thedossierincludesacertificateofanalysisforonebatchofeachingredient, showingcompliance. D. Specific Measures concerning the Prevention of the Transmission of Animal Spongiform Encephalopathies TherearenosubstanceswithinthescopeoftheTSEGuidelinepresentorusedinthemanufactureofthisproduct. E. Control on intermediate products Therearenointermediateproducts.Thesuspensionisnotstoredortransportedinbulk. F. Control Tests on the Finished Product Thefinishedproductspecificationcontrolstherelevantparametersforthepharmaceuticalform. Thetestsinthespecification, andtheirlimits,havebeenjustifiedandareconsideredappropriatetoadequatelycontrolthequalityoftheproduct. Satisfactoryvalidationdatafortheanalyticalmethodshavebeenprovided. Batchanalyticaldatafromtheproposed productionsitehavebeenprovideddemonstratingcompliancewiththespecification.Testsincludethoseforappearance,pH, density,andresuspendability. G. Stability The Certificate of Suitability for ivermectin specifies a 3 year retest interval for material stored in the commercial container, double-linedpolyethylenebagswithinanaluminiumdrum. 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 monthsunderbothlong-termconditions,25°C/60%RH,andrefrigeration,5°C. Samplesweretestedandonthebasisofthe evidence,theproposedretestintervalof5 yearsisjustified. Nospecialconditionsofstoragearerequired. 08March2019 CRN000XGK Page3of10 HealthProductsRegulatoryAuthority StabilitydataonthreebatchesthefinishedproducthasbeenprovidedinaccordancewithapplicableEuropeanguidelines, demonstratingthestabilityoftheactivesubstancewhenstoredundertheapprovedconditions.Testsincludethosefor appearance,density,resuspendability,pHandmicrobialpurity. J. Other Information Theshelflifeoftheveterinarymedicinalproductaspackagedforsaleis18months.Afterfirstopeningtheimmediate packaging,theshelf-lifeis12months.Theproductshouldbestoredintheclosedoriginalcontainer. III SAFETY AND RESIDUES ASSESSMENT (PHARMACO-TOXICOLOGICAL) Bothactivesubstances,triclabendazoleandivermectin,arewellknownandwellestablishedsubstancesthathavebeenusedin veterinary medicine for a number of years. This is a full stand alone fixed combination product for sheep which is an oral flukicideandbroadspectrumantiparasiticdrench. Fasimec Duo S 0.1%/5% Oral Suspension for Sheep is a white to cream-coloured oral suspension containing 5% triclabendazoleand0.1%ivermectin. Itisadministeredorallyatadoserateof2 ml/10 kg bodyweight(bw)whichisequivalent to 0.2 mg ivermectin and 10 mg triclabendazole per kg bw. The administration may be repeated depending on the epidemiologicalsituation. III.A Safety Testing Pharmacological Studies Pharmacology: Triclabendazole: Triclabendazoleisamemberofthesulphidebenzimidazolegroupofanthelmintics. Itismetabolisedinhostanimalsbyafirst passprocesstoasulphoxidewhichisthoughttohaveanthelminticactivityandissubsequentlymetabolisedtoasulphone, whichisthoughttobeanthelminticallyactiveaswell. Ivermectin: Ivermectinisanavermectin. Ithasabroadspectrumofactivityagainstnematodeandarthropodspeciesinmanydomestic animalsandisusedinmanforthetreatmentofOnchocerca volvulus. Pharmacodynamics: Triclabendazole: Thetriclabendazolemodeofactionisnotfullyclearbutisthoughttointerferewithintracellulartransportmechanismsand inhibitproteinsynthesis. ItisactiveagainsttheliverflukeFasciola 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 permeabilityofthecellmembranetochlorideionswithhyperpolarisationofthenerveormusclecell,resultinginparalysisand deathoftheparasite. Mammalsdonothaveglutamate-gatedchloridechannels;themacrocycliclactoneshavealowaffinity forothermammalianligand-gatedchannelsanddonotreadilycrosstheblood-brainbarrier. Pharmacokinetics: Ivermectin: