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Continued

WHO Drug InformationContents

WHO Prequalification425 Building quality-assured manufacturing

capacity in Nigeria

Pharmacopoeial standards431 Globalspecifications:theexampleof

capreomycin

Medicines quality assurance434 Aharmonizedself-assessmenttoolfor

procurement agencies

Safety news448 Unchanged recommendations

Testosterone :cardiacrisknotconfirmed;Agomelatine :strengthenedadvicetomonitorliverfunction;

449 Restricted useIntravenousnicardipine:onlytocontrolhighbloodpressureinspecialistsettings;Bromocriptine : not for pre menstrual syndrome or benign breast

disease;Colistimethatesodium:reserveforseriousinfectionsresistanttostandardantibiotics;Valproate : not to be used in pregnancy;Sulfur hexafluoride:nottobeusedwithdobutamineincertainpatients;

451 Safety warningsIvabradine:heartproblems;Carvedilol:Raresevereskinreactions;Voriconazole:phototoxicityandsquamousskin

cancer; Immunoglobulins : rare but serious risk of blood clots;Simeprevir: increased bilirubin may cause serious outcomes;Basiliximab:

cardiacadverseeventswhenusedoff-labelinhearttransplants;Ustekinumab : serious skin conditions;Ponatinib :bloodvesselblockage;Diclofenac and otherNSAIDs:cardiovascularrisksandliverdamage;Denosumab :osteonecrosisofthejawandhypocalcaemia;Pregabalin :

liverdamage; Zopiclone :next-dayimpairment;Bupropion :seriouscardiovascularevents;Galantamine hydrobromide: serious skin reactions;Dimethylfumarate: rare brain

infection;Omalizumab:slightlyincreasedriskofheartandbrainadverseevents;

457 Risk minimization measuresMethylphenidate: web-based prescribing guide;

457 Medicines review started458 Manufacturing quality issues

HealthCanadarestrictsimportsfromvariousIndian sites

458 Site review started

Regulatory news459 Ebola

Updateontreatmentsandvaccines460 Clinical trials transparency

EMA adopts policy on publication of clinical reports

461 Pre-market assessmentEMArevisesguidanceonbiosimilars;EMAproposesharmonizedclinicaltrialsplanforvaccineinchildren;EMA pilot to seekpatientviewsonmedicinesrisksandbenefits;AustraliatorecognizeEUconformityassessmentformedicaldevices

462 PharmacovigilanceCanada passes Vanessa’s Law; EUprojectonusingsmartphonesfordrugsafetyinformation;EMAexpandspublicwebaccess to reports on suspected side effects ;Australia,Switzerlandcreatewebportalstoreportadversereactions;New MHRA guidanceonreportingadversedrugreactionsinchildren

464 OrganizationsAustralia and New Zealand to keep separate regulatoryauthorities

464 Veterinary medicinesEUproposesveterinarymedicineslegislationrevisions;SalesofveterinaryantibioticsinEurope decrease

465 ApprovedNetupitant and palonosetron:forchemotherapy-inducednausea; Naloxegol:

for opioid-induced constipation ; Dulaglutide : for type 2 diabetes; Antihaemophilicfactor(recombinant), porcine sequence :inacquiredhaemophiliaA

; Nonacog gamma :inhaemophiliaB; Afamelanotide :forerythropoietic

protoporphyria; Darunavir&cobicistat: for HIV infection; Ledipasvir&sofosbuvir:forhepatitisCinfection; Dasabuvir:forhepatitisCinfection; Ombitasvir&paritaprevir&ritonavir:forhepatitisCinfection; Meningococcus B vaccine; Pembrolizumab:foradvancedmelanoma; Ramucirumab : for gastric

cancer; Secukinumab : for plaque psoriasis; Pirfenidone :foridiopathicpulmonaryfibrosis; Nintedanib :fornon-smallcelllungcancer/idiopathicpulmonaryfibrosis;

Olaparib :forasubtypeofovariancancer; Blinatumomab :forarareformofacutelymphoblasticleukaemia; Abuse-deterrent hydrocodone:single-entity,extendedreleaseproduct;

469 Labelling changes approvedKetoconazole:forCushing’ssyndrome; Ulipristal :emergencycontraceptivewithoutprescription;

Publications and events471 Access to treatment

2014AccesstoMedicinesIndexlaunched;New Lancet Commission on Essential Medicines Policies;WHO inviteshepatitismedicinesforprequalification;Antiviral Therapy special issue on access to HIV treatment


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472 Intellectual propertyInteragency symposium on access to medical technologies;WHO report on patent status ofhepatitismedicines;NIH and FDA win top awardformeningitisvaccinelicensingdeal

473 Medicines for childrenImprovingmedicinesforchildreninCanada

473 Medicines useStudyshowsbetterdrugandantibioticusewherethereispolicyimplementation

474 WHO mattersTwoWHOExpertCommitteemeetingsheld;WHOprequalificationofmedicines2013annual report

Consultation documents476 The International Pharmacopoeia476 Flucytosine480 Flucytosineintravenousinfusion

ATC/DDD Classification482 ATC/DDDClassification(Temporary)484 ATC/DDDClassification(Final)

International Nonproprietary Names485 Proposed List No. 112

Continued

Abbreviations and web sites

CHMP Committee for Medicinal Products for Human Use (EMA)EMA European Medicines Agency (www.ema.europa.eu)EU European UnionFDA U.S. Food and Drug Administration (www.fda.gov)HealthCanadaFederaldepartmentresponsibleforhealthproductregulationinCanada(www.hc-sc.gc.ca)MHRA MedicinesandHealthcareProductsRegulatoryAgency,UnitedKingdom

(www.mhra.gov.uk)Medsafe NewZealandMedicinesandMedicalDevicesSafetyAuthority(www.medsafe.govt.nz)PRAC PharmacovigilanceRiskAssessmentCommittee(EMA)PMDA PharmaceuticalandMedicalDevicesAgency,Japan

(www.pmda.go.jp/english/index.htm)lSwissmedic SwissAgencyforTherapeuticProducts(www.swissmedic.ch)TGA TherapeuticGoodsAdministration,Australia(www.tga.gov.au)U.S. United States of America

Note:Theonlineversionofthisissue(availableatwww.who.int/medicines/publications/druginformation)hasdirectclickablehyperlinkstothedocumentsandwebpagesreferenced.

http://www.ema.europa.eu

http://www.fda.gov

http://www.hc-sc.gc.ca

http://www.mhra.gov.uk

http://www.medsafe.govt.nz

http://www.pmda.go.jp/english/index.htm

http://www.swissmedic.ch

http://www.tga.gov.au

http://www.who.int/medicines/publications/druginformation

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WHO PrequalificationBuilding quality-assured manufacturing capacity in Nigeria

As a fast growing economy and large provider of goods and services to countries in the region, Nigeria is poised to expand its pharmaceutical production to achieve self-sufficiency in essential medicines and compete on regional and global markets. To this end, government health authorities and local manufacturers requested WHO support and technical assistance to prequalify several locally produced medicines, as a way to fast-track the building of local capacity to manufacture medicines according to international quality standards. An integral part of the process is the strengthening of national regulatory capacity to enforce these standards on an ongoing basis.

The Nigerian questWhilenomedicinesmanufacturerinWestAfricahassofarachievedprequalificationofapharmaceuticalproductbytheWorldHealthOrganization(WHO),Nigeriaisattemptingtochangethestatusquo.AnumberofcompaniesbelongingtothePharmaceuticalManufacturersGroupoftheManufacturersAssociationofNigeria(PMG-MAN)areworkingtoreachamanufacturingqualitystandardthatwillenablethemtohavesomeoftheirproductsWHO-prequalifiedandapplyforinternational medicines tenders. Theprojecthasbeensupportedbythe

NigeriangovernmentandbytheNationalAgency for Food and Drug Administration (NAFDAC).WHOwasapproachedtoprovidetechnicalassistancetobothmanufacturers and regulators especially in theareasofgoodmanufacturingpracticeanddossiersubmissionsinlinewithWHOand international standards.

Role of WHOTheWHOprequalificationprogrammeaimstoensurethatmedicinesfor

priority diseases meet global standards ofquality,safetyandefficacy.Byevaluatingneededpharmaceuticalproducts–includingthoseproducedincountrieswithlimitedregulatorycapacity–theWHOprequalificationteam(WHO/PQT)providesabasisfornationalandinternational procurers to make cost-effectivechoicesamongfinishedproductsof assured quality. WHO/PQThasincreasinglyengaged

inactivitiesthatgobeyonddossierassessmentandsiteinspections.Theteam is training national regulators, providingguidancetomanufacturers,facilitating registration in countries and supporting post-procurement qualitycontrol.Theexpertswhoadvisemanufacturersinpreparingprequalificationsubmissionsworkindependentlyoftheprequalificationdossier assessment and inspection groups.Themainobjectiveoftheseactivitiesistodisseminatesoundknowledge and practices and to ensure thatalltheactorsworktogetheraccording

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tothesameinternationalqualitystandards. FromtheWHOperspective,the

Nigerianprojectisinlinewiththeseaims.GiventheimportanceofNigeriainitsgeo-economicregion,itishopedthatincreased production of quality medicines inthecountrywillalsoleadtobetterquality medicines in West Africa as a whole.

Snapshot of Nigeria’s pharmaceutical landscape

NigeriaisanaturalcandidateforthelocalcapacitystrengtheningofferedbyWHO/PQT.Thecountry’spharmaceuticalindustryisvibrantandexpanding,withover100pharmaceuticalmanufacturersandamostlylocalownershiporganizedundertheumbrellaofthePharmaceuticalManufacturersGroupoftheManufacturersAssociationofNigeria (PMG-MAN). Nigeria accounts for approximately60%ofthepharmaceuticalproductionintheEconomicCommunityof West African States (ECOWAS) by volume(1). Production is geared mostly towards essential medicines, including antimalarials and HIV medicines. Ontheotherhand,drugmanufacturers

in Nigeria face a number of constraints. Theseincludeaweakfinancialbase,highproductioncostsasaresultofthehighcostofimportedpharmaceuticalingredientsandmachinery,infrastructuralproblems,outdatedtechnologyandweakdistributionsystems.Inaddition,astherearenocontractresearchorganizationsinWestAfricaproventoworkinlinewithinternational standards, manufacturers needtorelyonexpertisefromEuropeandAsiawhentheyrequirebioequivalencestudiesorspecificlaboratorytesting.Duetothesefactors,thecountryimportsabout

70%ofitsmedicines,mainlyfromAsia,EuropeandtheAmericas.Intermsoftheregulatoryenvironment,

theNationalAgencyforFoodandDrugAdministration and Control (NAFDAC) hasinrecentyearsenactednumerousenforcementactivitiestocombatsubstandard and counterfeit medicines. It hasalsoconsistentlyworkedwithWHOtostrengthenitsqualitycontrolandpost-marketingmonitoringofpharmaceuticals.Butchallengespersist,whicharelargelyrelatedtoinsufficientcapacitytoensurefullregulatoryfunctionsinlinewithinternational standards, including speedy registration of medicines. Despitethesechallenges,thecountry’s

pharmaceuticalsectorisoneofthestrongestinAfricaintermsofsize,rangeof products manufactured and potential to meet and sustain international pharmaceuticalqualitystandards.

The projectSelection of manufacturersIn 2011 NAFDAC and WHO/PQT came toanagreementontheprinciplesoftheprojectand,incollaborationwithPMG-MAN,selectedeightmanufacturersthathadexpressedcommitmenttoinvestinqualityimprovementsandthatweredeemedtechnicallyreadytoembarkonaprogrammetoaligntheirmanufacturingoperationswithinternationalqualitystandards. WHO/PQT arranged for externalexpertstoverifytheproductionstandardsatthemanufacturingsitesand to assess product data and documentation.

Capacity-buildingBasedontheresultsoftheassessmentsbytheexternalexperts,WHO/PQTinitiatedanintensivecapacity-buildingprogramme for Nigerian manufacturers

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andregulators.Since2012,severaltraining sessions on good manufacturing practices,combinedwithsitevisitsatparticipatingcompanies,havebeenco-organizedbyWHO/PQTandNAFDAC.Inparallel,WHO-appointedexpertshaveadvisedthecompaniesonspecificqualityissuesrelatedtovariousmedicines.Inresponsetoobservationsraised

duringtheauditsanddocumentreviews,thecompaniesimplementedaseriesofcorrectiveactions.Theyupgradedtheirequipment,improvedmanufacturingprocesses,andestablishedprofessionalprocedures to build documentation for pharmaceuticalingredientsandfinishedproducts.Thesecorrectiveactionsexceedcurrentlyapplicableregulatoryrequirements in Nigeria. Implementation is monitoredbyNAFDACprofessionals,whoreportonprogresstoWHO.Theprocessisongoing,withacurrentfocusonthedevelopmentoftechnicallysoundproductdossiers. WHO/PQTalsoworkswiththe

participating manufacturers to identify alltheirmedicinalproductseligibleforprequalification.Thiswillfacilitateprogress towards GMP-compliant production of additional medicines of interestforinternationalorganizations.Forexample,interestmaycomefromUNCommissionforLifesavingCommoditiesforWomenandChildren(UNCoLSC),giventhatalargeportionofthemedicinesneededintheWestAfricanregionarereproductivehealthandpaediatricproducts.

Regulatory and in-country supportOntheregulatoryside,NAFDAChasprovedtobeastrongpartnerincapacity-buildingefforts.Theauthorityhasupgraded its laboratories, recruited more specializedstaffandhasestablishednew

departments,suchastheClinicalTrial/PharmacovigilanceandPostMarketingSurveillanceandDrugEvaluationandResearchDirectorates.NAFDACprofessionalsalsoparticipateactivelyintrainingsorganizedforlocalindustry.TheclosesupportbytheWHOCountry

Officehasalsobeenanassettotheproject.TheprocesshasopeneddoorsforNigerianstakeholdersandinternationalorganizationstoworktogethermoreclosely.

Pre-submission auditsTheWHOprequalificationteamnormallyplans its inspections on a risk-basis oncecompanieshavesubmittedaprequalificationdossiers.Toenableapplicants to work on product dossiers and good manufacturing practice (GMP) inparallel,thenewconceptofpre-submission GMP audits was piloted in Nigeria.Aninspectioncanbescheduledbeforeadossierhasbeensubmitted,providedthattheexpertadvisorsandNAFDACnotifyWHO/PQTthatthemanufacturerhasachieved–inprinciple–compliancewithWHOGMP.PrequalificationinspectorsthenverifythestatusofgeneralGMPcompliancewhilecompletionofaprequalificationdossierisstill ongoing.

Successful audits represent a milestone intheprogresstowardsprequalification,andtheoutcomesareconsideredbyorganizationslookingforcompaniesthatmanufactureneededhealthproductsinlinewithinternationalGMP.Aseriesofpre-auditswasorganizedin

2013and2014atNigerianmanufacturingsitesincloseco-operationwithNAFDAC,whoseregulatoryinspectorsplayedanactiveroleinverifyingthecorrectiveactionsadoptedaftertheauditanddraftingpartsoftheinspectionreports.


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FundingTheNigerianMinistryofHealthhasinvestedconsiderablyintotheproject.Inaddition,advocacyison-goingforaspecialinterventionfundfromthedevelopmentbanksinNigeria,ECOWASandtheAfricanDevelopmentBank(AfDB). WHO’sparticipationintheprojecthas

largelydependedonfinancialbackingfromUNITAID,whichwasusedtosupporttechnicalassistance,transferofknowledge, capacity building, audits and inspectionsandhumanresources.Fromthemanufacturers’side,

informationfromPMG-MANindicatesthatthecompaniesparticipatingintheprojecthaveinvestedacumulativeamountexceedingUSD400millionoverthelastfour years.

AchievementsGMP complianceThepre-submissionauditsledtoalandmarksuccessbeingachievedinApril2014,whenSwissPharmaNigeriaLimited(Swipha)wasconfirmedtobeoperatingatanacceptablelevelofcompliancewithWHOGMPguidelinesforthemanufactureof oral solid dosage forms (2).SwiphawasthefirstpharmaceuticalmanufacturerinSub-SaharanWestAfricatopassa GMP inspection by WHO/PQT after implementingsuccessfulcorrectiveandpreventativeaction(CAPA).Threeothercompaniesparticipatingintheproject-EvansMedicalPlc,May&BakerNigeriaPlcandCHIPharmaceuticalsLtd–reachedthisstandardinNovember2014,aftersuccessfullyimplementingcorrectiveandpreventiveaction(CAPA)identifiedduring WHO pre-submission audits in May 2014 (3).

Prequalification dossiers OneNigeriancompanyhassubmittedaprequalificationdossiertoWHOandthishasbeenacceptedforscreening.Anothersubmissionisexpectedbeforetheendoftheyear,withmoretofollowinthenearfuture.Thechoiceofmedicinesincludesantimalarials,antiretrovirals,zincsulphateand antibiotics.

Outlook and impactTendersTheachievementsmadebyparticipatingmanufacturers open up opportunities for internationaltenders,wherecompliancewithstringentGMPisaminimumrequirementforanypharmaceuticalproduct. Additional requirements apply tokeycategoriessuchasantiretrovirals,anti-TB products and antimalarials. Inthesecategories,compliancewithstringent GMP enables manufacturers to applyforreviewofrelevantproductsbytheExpertReviewPanel(ERP).ProductsthathavereceivedapositiveERPopinioncanthencompeteininternationaltendersinsituationswherenooronlyoneWHO-prequalifiedorstringentlyauthorizedcompetitorproductisavailableonthemarket (4). ItishopedthatAfricanministries

ofhealth,regionalinitiativesandinternational procurers will consider WHO GMP-compliant African manufacturers intendersforpurchaseofmedicinesintheregion.Thiswouldsupportquality-assured local production, and would signalrecognitionofthecostthatqualityassurance entails for manufacturers.

Raising the bar for medicines qualityFeedback from PMG-MAN suggests thattheprojectisbeginningtoyieldwiderbenefits.Theunderstandingofworld class manufacturing practices in

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Nigeriahasimproved.Asaresult,theperceptionoftheimportanceofqualityinpharmaceuticalmanufacturingisgraduallyshifting.OtherNigeriancompaniesdonotwanttobeleftbehindandarealsobecominginterestedinupgradingtheirproduction,withsupportfromPMG-MAN,toachieveWHOprequalificationoftheirproducts.NAFDAChasbenefittedthrough

hands-onparticipationinprequalificationinspections, assessments, training workshopsandothercapacity-buildingactivities,withaccesstoprequalificationinspection and assessment reports.

Local regulatory oversightMedicines regulation is essentially a publicfunctionthatshouldbeassuredbythegovernmentsofcountrieswheremedicines are produced and used. NAFDAC’sactivefollow-upofindividualmanufacturers’progressandverificationofcorrectiveactionshasprovedextremelyvaluableinworkingtowardsthisgoal.Theprocesshasstrengthenedcommunicationbetweenindustryandregulators,withacommonunderstandingofthequalityissues at stake. ThecooperationwithNAFDACunder

thisprojectmarksthestartofanewmodelwherebythelocalregulatoryauthorityassumes responsibility for ensuring thatWHOprequalificationrequirementscontinuetobemet.Thisapproachisofcoursedependentonobjectiveevidencethatthelocalregulatoryauthoritycanin fact conduct routine monitoring and maintenancetotherequiredstandards.Theactivitieswillthereforebecoordinatedwith,andreportedto,WHO/PQT.Inaddition, NAFDAC assessors will work closelywiththeWHOprequalificationassessorstoreviewproductdossiers

submitted by Nigerian companies in line withinternationalstandards.

ChallengesFurtherchallengeslieaheadbeforetheNigerianpharmaceuticalsectorwillbeabletoreachthelevelofqualityproductionandautonomytowhichitaspires.Mostchallengesarerelatedtotheneedforfurtherguidanceinmanufacturing practices, dossier development,bio-equivalenceandsupplychainmanagement.Toaddresstheseneeds,theinitialtimelinefortheprojectwasextended.Importantalsoisthechoiceofproducts

forprequalification,whichmustbewellconsideredtoensurethatitservesbothqualityandcommercialobjectives.Otherchallengesarerelatedto

financing.GiventhefactthatWHOprequalificationwillnotoccurimmediately,financialincentivesmaywellbeneededforthecompaniestocontinuetoprogress.AndwhileWHOprequalificationofanumber of Nigerian-made products in thenearfutureseemsfeasibleandcanenable companies to win international procurementtenders,furtherchangeisneeded to ensure a sustainable supply ofqualitymedicinesintheregionandtoresolvesupplymanagementproblems.

ConclusionTheclosecooperationbetweenNigerianmanufacturers, regulators and WHO startstoproduceresults.Thegeneralunderstanding of international regulatory standardshasimproved,andseveralcompaniesarewellontheirwaytowardsprequalificationoftheirproducts.Ascorrectivemeasuresandupgrades

continue,Nigerianauthoritiesandmanufacturerswillneedtofindwaystoraisesufficientfundstoputintoplace


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sustainable structures and processes for production of quality-assured pharmaceuticals.

Spokespersons of NAFDAC and PMG-MANhaveexpressedsatisfactionwithprogressmadetodateandremainfirmlycommittedtoenhancingthepharmaceuticalsectortomakeitworkbothforpublichealthandthepharmaceuticalindustry.WHOwillcontinuetoadvocatefor

greatersupportofthiskindofcross-sectoralcapacity-building.Ensuringthataffordable, quality-assured medicines are withinreachofallthosewhoneedthemisapillarofaneffectivehealthsystemandan area requiring greater attention from theinternationalcommunity.

References 1 Nigeriapharmaceuticalcountryprofile.

PublishedbyFederalMinistryofHealthincollaborationwiththeWorldHealthOrganization.June2011.

2 WHO/PQT. First Nigerian manufacturer consideredcompliantwithWHOGMP.PrequalificationUpdate,4April2014.

3 WHO/PQT.ThreemoreNigeriancompaniesmeetinternationalpharmaceuticalmanufacturing standards. Informationnote,21November2014.

4 WHO/PQT. ExpertReviewPanel.Arapidqualityriskassessmentmechanismforassessingneededpharmaceuticalproductsthathavenotcompletedastringentassessment.Briefingpaper:27April2012.

http://apps.who.int/medicinedocs/documents/s19090en/s19090en.pdf

http://apps.who.int/prequal/info_press/pq_news_04April2014_WHOPIR.htm

http://apps.who.int/prequal/info_press/documents/GMP_Nigerian_companiesNov2014.pdf

http://apps.who.int/prequal/info_press/documents/ERP_article.pdf





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Pharmacopoeial standardsGlobalspecifications:theexampleofcapreomycin

Capreomycin is used to treat multi-drug-resistant tuberculosis, an increasing public health problem. The example of the new capreomycin monographs in The International Pharmacopoeia shows how international specifications can provide added value for WHO Member States, including countries with resource limitations.

Public quality control standardsPharmacopoeialmonographscanbeusedbymanufacturers,regulatorsandotherstakeholdersforqualitycontrolofactivepharmaceuticalingredients(APIs)andfinishedproductsagainstinternationallyrecommendedspecifications.Pharmaco-poeial requirements in countries form partofnationallegislation,definingthespecificationswhichpharmaceuticalproductscirculatingontheirmarketmustfulfil.

The International Pharmacopoeia (1) wascreatedtohelppromoteharmonizedand suitable quality control testing standards among WHO Member States. Itaimstoprovideanalyticalteststhatcanbeperformedwiththerecommendedequipmentforfirst-stageandmedium-sizedpharmaceuticalqualitycontrollaboratories (2)inallregionsoftheworld,including remote areas.

Focus on ‘neglected monographs’The International Pharmacopoeia focuses onessentialmedicinesthatareofpublichealthimportanceinWHOMemberStates,andforwhichmonographsarenotavailableinotherpharmacopoeias.Anexampleofsuchamedicineiscapreomycin, an aminoglycoside antibioticdiscoveredin1960andfirstregisteredin1971.Todayitispartof

WHO-recommended regimens to treat multi-drug-resistant tuberculosis, an increasingpublichealththreatinmanypartsoftheworld.Capreomycinwasremovedfromthe

BritishPharmacopoeiain2003becauseofitslowuseintheUK.AlthoughmonographsforcapreomycinareincludedintheUnitedStatesPharmacopeia(USP)aswellastheChineseandIndianPharmacopoeias,WHOdecidedtodevelopafurtherpublicstandardbecauseitwasfeltthattheavailablemethodsandspecificationswerenotsufficienttofullycharacterizeandstandardizethequalityofthesubstance.

Input from world expertsExpertsfromuniversities,WHOCollaborating Centres and national regulatoryauthoritiescollaboratedtodevelopthemonographsforcapreomycinsulfateactivesubstanceandcapreomycininjectionthroughWHO’sdefinedstep-wiseprocess (3).Theinitialdraftsunderwenttwopublicconsultations,duringwhichmanyvaluablecommentswerereceived.Thenewmonographswerepublishedin

theThirdandFourthSupplementofThe International Pharmacopoeia respectively.Theiradvantagesforusersareoutlinedonthenextpage.

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Capreomycinmonographs:AddedvalueforWHOMemberStatesComprehensive descriptionProduced by fermentation, capreomycin isamixtureofseveralstructurallyrelatedcomponentsandthusdifficulttocharacterize.The International Pharmacopoeia is currently theonlypharmacopoeiatogivecomprehensiveinformationonstructures,formulas,relativemolecularweightsandchemicalnamesforallfourmajorcomponents(capreomycinIA,IB,IIAandIIB).Thisinformationfacilitatestheproduction and registration of products containing capreomycin.

Alternative options for identity testTwoalternativecombinationsofidentitytestsareprovided,foruserstochoosetheoptionthatcanbeperformedusingtheequipmentthatisavailableinthelaboratory(seeTable 1).

Table 1. Options for identity testTest Option 1 Option 2

A IRSpectrophotometry ■B Thin-layerchromatography ■C Absorption spectrum of

solutioninhydrochloricacid ■D Absorption spectrum of

solutioninsodiumhydroxide ■E Generalidentificationtest

for sulfates ■ ■

First-ever pharmacopoeial test for related substancesTheimpuritiesofcapreomycinaffectthesafetyofthefinishedproduct.The International Pharmacopoeia describesthefirst-everpharmacopoeialrelatedsubstancestestforcapreomycinanddefinesacceptablelimitsfor

impurities–notaneasytask,astoxicitydatafor old medicines like capreomycin can be challengingtoputtogether.Thetestusesahighperformanceliquidchromatography(HPLC)method,awidelyusedanalyticaltechnique(seeFigure 1).

Quantification of content Otherpharmacopoeiasproposeamicrobiologicalassay,wherethecontentofcapreomycinismeasuredthroughitsinhibitoryeffectonsusceptiblemicroorganisms.TheassayinThe International Pharmacopoeia isbasedonthesameHPLCmethodastherelatedsubstancestest (Figure 1),enablingadirectcalculationofthecontentintermsofmass.Thissavestimeandresourcesasthelaboratorycanperformtwotestswiththesameanalyticalsystem.

Easy-to-use reference standardAsolutionofthereferencesubstancewithadefinedconcentrationisneededtoquantifycapreomycin. Capreomycin absorbs water from theatmosphere.Itmaythereforebedifficulttoweighthesubstanceaccuratelyonananalyticalbalance. TheEuropeanDirectoratefortheQualityof

MedicinesandHealthcare(EDQM)isresponsiblefortheestablishmentanddistributionofWHO’sInternationalChemicalReferenceSubstances.Giventheimportanceofthisprojectandtheobjectivedifficultyofweighingcapreomycininalaboratory,theEDQMiscurrentlyassessingthefeasibilityoflyophilizingthereferencestandard.Ifthisisfeasible,theuseoftheICRSwillbecomefairlysimplei.e.justaddingtothevialapredefinedvolumeofsolvent.

Quantification of capreomycin components and related substances by HPLC

TheHPLCmethodseparatesthedifferentrelatedcompoundsincapreomycinsulfateaccordingtotheiraffinitytoalipophilicstationaryphase.Intheresultingchromatogramthecontentofeachcompoundisproportionatetotheareaofthecorrespondingpeak.

Figure 1.Typicalchromatogramshowingtheseparationofthefourmaincomponentsofcapreomycinsulfate(7,9,12and13)andrelatedsubstances.Source:Reference(5).

Related substances: ThepeakresponseareasfortheimpuritiesarecomparedwiththoseofthemajorpeaksforcapreomycinIA,IB,IIAandIIB;Acceptancelimitsare:• Allimpurities≤2%• Onlyoneimpuritybetween1and2%• Sumofallimpurities:≤7%

Assay:Thecontentiscalculatedfromcomparingthefourmajorpeakareasofthetestsubstancewiththoseofthereferencesubstance,whichhasadeclaredcontentofcapreomycin IA, IB, IIA and IIB.

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Supporting market entry of quality-assured productsThe International Pharmacopoeia is alignedwiththeneedsoftheWHOprequalificationprogramme,whichassessesthequalityofmedicinesforprocurementbyUNagenciesandotherbuyersthathaverecognizedthecentralimportance of medicines quality not only intreatingindividualpatients,butalsoinreducingtheriskofresistancethatcouldmakeamedicineineffectiveforentirepopulations.CapreomycinisinvitedforWHO

prequalification.AttheendofSeptember2014thefirstAPIwasprequalified,anotherwasunderassessment.ThefirstcapreomycininjectionwasprequalifiedinOctober2014,withfourothersubmissionsunder assessment (4). Appropriate specificationsandsuitabletestmethodswillsupportmanufacturersinachievingWHOprequalificationfortheirproducts,resulting in additional quality-assured productsontheglobalmarket.

FundingInthepast,theworkonThe International Pharmacopoeia used to be funded from WHO’sregularbudget.Thisfundingsourcehasdecreasedtovirtuallyzeroinrecentyears.TheactivitiesarecurrentlyfundedforthemostpartbyUNITAID,whosefinancialcontributionisgratefullyacknowledged. In addition, WHO Member Statesprovidein-kindcontributionsandsupportvaluedatamultipleoftheprogramme’soperationalbudget.Thesecontributionsincludeactivitiesbynationalquality control laboratories, national support to WHO collaborating centres, and–veryimportantly–timegivenbyindividualexperts.

ConclusionQuality control testing is a mainstay of pharmaceuticalqualityassuranceinproductionandregulation.Inprovidingwell-designed, globally applicable specificationsandtestmethodsforwidelyusedmedicinesfreeofcharge,WHOfillsaneed in Member States. The International Pharmacopoeiaisusefulindevelopment,production, registration and post-market surveillanceincountriesaroundtheworld,andthushelpstoensurethatessentialmedicines used in WHO Member States meettheinternationallyacceptedqualityrequirementsthatmakethemsafeandeffective.

References1 WHO. The International Pharmacopoeia.

FourthEdition,2014(includingFirst,Second,ThirdandFourthSupplements).Geneva,Switzerland:2014.Availablefreeofchargeat:http://apps.who.int/phint/en/p/about/

2 WHO. Goodpracticesforpharmaceuticalquality control laboratories.Annex1.In:WHOTechnicalReportSeries,No.957.Geneva,Switzerland:2010.

3 WHO. DevelopmentofmonographsforTheInternationalPharmacopoeia.Annex1.In:WHOTechnicalReportSeries,No.970.Geneva,Switzerland:2012.

4 WHO. ListofallAPIsandFPPsinvitedforprequalification,andnumberprequalifiedorcurrently under assessment per product.(25September2014).Availablefromapps.who.int/prequal - Information for applicants.

5 MallampatiS,HuangS,AshenafiD,VanHemelrijckE,HoogmartensJ,AdamsE.Developmentandvalidationofaliquidchromatographicmethodfortheanalysisofcapreomycinsulfateanditsrelatedsubstances.JChromatogrA.2009;1216(12):2449-55.doi:10.1016/j.chroma.2009.01.031.

æ

http://apps.who.int/phint/en/p/about/

http://apps.who.int/phint/en/p/about/

http://www.who.int/entity/medicines/areas/quality_safety/quality_assurance/GoodpracticesPharmaceuticalQualityControlLaboratoriesTRS957Annex1.pdf?ua=1

http://www.who.int/entity/medicines/areas/quality_safety/quality_assurance/GoodpracticesPharmaceuticalQualityControlLaboratoriesTRS957Annex1.pdf?ua=1

http://www.who.int/entity/medicines/areas/quality_safety/quality_assurance/Annex1TRS-970.pdf?ua=1

http://www.who.int/entity/medicines/areas/quality_safety/quality_assurance/Annex1TRS-970.pdf?ua=1

http://apps.who.int/prequal/info_applicants/eoi/FPPs_APIs_invited.xlsx



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Medicines quality assuranceAharmonizedself-assessmenttoolforprocurementagencies

In the absence of stringent regulatory systems for medicines in many parts of the world, procurement agencies have an important role in ensuring the quality of pharmaceutical products that they buy for use in treatment programmes. During the recent update of WHO’s quality assurance guidance for procurement agencies, a harmonized tool was developed enabling procurement agencies to assess their compliance with the principles of this guidance.

BackgroundTheWHOModelQualityAssuranceSystem for Procurement Agencies (MQAS) (1) is a WHO guidance document developedattherequestoftheGlobalFundtoFightAIDS,TuberculosisandMalariaandadoptedbytheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparationsin2006.Intheyearsthatfollowed,internationalorganizationsinvolvedinmedicinesprocurementincorporatedtheMQASrequirementsintotheirqualityassurancepoliciesandphasedinstringent,harmonizedqualitycriteriaforkeyproductcategories procured in large quantities andconsideredcrucialforthesuccessoftreatment programmes. Inintroducingharmonizedquality

requirements for priority medicines, an importantelementoftheMQASwasitsAppendix6,theinteragencyproductquestionnaire.Itwasadoptedasthe

common format for suppliers to submit dataforneededmedicinesthatwerenotyetavailableasstringentlyapprovedorWHO-prequalifiedproducts.

Beyond priority medicinesInAugust2011internationalorganizationscametogetheratameetingconvenedbyWHOandtheGlobalFundtodiscusswaystoassurethequalityofallessentialmedicinesbeingprocured,includingthosenotbelongingtothekeycategories.Itwasfoundthatforthesediverse

productsoftenpurchasedinsmallquantities,theMQASdidprovidevalidapproachesforqualityassuranceinprocurement.Thedifferentagencieshadstrongqualityassurancecapacities,andseveralofthemhaddevelopedtheirownsystemstoimplementtheMQASprinciples.Howeverthisresultedindivergingpracticesandrequirements,withduplicationofefforts.Theneedwas

Theassessmenttoolpresentedinthisarticlewasdevelopedbyaninteragencyworkinggroupcomprisedoffollowingmembers:A.J.vanZyl(Consultant)–coordinator;S.Arsac-Janvier,InternationalCommitteeoftheRedCross(ICRC);J.-M.Caudron,QualityMedicinesforAll(QUAMED);L.Chacksfield,CrownAgents;J.Daviaud,GlobalFundtoFightAIDS,TuberculosisandMalaria(GlobalFund);M.deGoeje,InternationalDispensaryAssociation(IDA)Foundation;S.Hamel,UnitedStatesAgencyforInternationalDevelopment(USAID);N.Heltzer,ManagementSciencesforHealth(MSH);S.IJland,IDAFoundation;P.SvarrerJakobsen,UnitedNationsChildren’sFund(UNICEF);E.Jambert,MédecinsSansFrontières(MSF);S.Logez,GlobalFund;C.Macé,WHOPolicyAccessandUse(WHO/PAU);P.MarroquinLerga,GlobalDrugFacility(GDF);C.Perrin,InternationalUnionAgainstTuberculosisandLungDisease(TheUnion);B.Runbeck,PartnershipforSupplyChainManagement(PFSCM);E.Seaver,USAID;M.Sesay,UnitedNationsOfficeforProjectServices(UNOPS);A.Seiter,WorldBank;C.Werder,GlobalFund.

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WHO Drug Information Vol. 28, No. 4, 2014 Medicines quality assurance

Table 1. Standardized assessment of compliance with the six MQAS modules

Module IGeneral

requirements(33items)

Module IIPre-

qualification (21 items)

Module IIIPurchasing

(12 items)

Module IVReceipt and

storage (35items)

Module VDistribution

(23items)

Module VIReassess-

ment (13items)

Organizationand manage-ment (2 items)Personnel(3)

Quality systems (10, including

2 critical)Documentation

(9)Counterfeit products

(3,including 2 critical)

Self-inspection (2)

Complaints (2)Recalls

(2 critical)

Prequalificationprocedure

(4, including 1 critical)

Expressionofinterest

(2)Product

information, screening and evaluation

(5)Inspections

(7)Prequalification

outcome (3)

Purchasing (10)

Monitoring of performance ofprequalifiedmanufacturers

(2)

Receiving– sampling

and testing – storage

(7, including 1 critical)

Quality control (6)

Storage (9,including

1 critical)Stock control

(13)

Containers and labelling

(6,including 1 critical)Dispatch

(10)Transport and

transit (7)

Reassess ment (1)

Reassess ment of manu-facturers

(3)Reevaluationof products

(5)Monitoring of

contracted-out services

(4)

How it works: Atotalof137itemsareratedonascaleof0–100%.Complianceistakenasanoverallratingofatleast60%(“Mediumlevelofimplementation,e.g.procedureshavebeendeveloped,butlackscopeanddepth”)acrossthe137items.Dependingonthecontext,aratingoflessthan60%foracriticalitemcanleadtotheentiremodulebeingconsiderednon-compliant.

identifiedforaharmonizedtooltoassesscompliancewiththeMQAS.

Measuring compliance with WHO guidance principlesAninformal,voluntaryworkinggroupwasestablishedatthe2011meetingandworkedtogetheroverthenexttwoyearstoproposeaharmonizedMQAScomplianceself-assessmenttool.ThetoolisbasedonthesixmodulesoftheMQAS,withpercentage ratings allocated to a total of137items,includingtencriticalitems(Table 1).Atthesametime,thegroupupdatedtheMQASguidanceitselfandcomplementeditwithanaide-memoireforinspection of procurement agencies (2). Thefullself-assessmenttooldeveloped

bytheworkinggroup,togetherwithinstructions and a model report format, is

reproduced in Annex 1.ItsupplementstheformalWHOguidancetextsbyprovidingaconsistentyetflexiblewaytomeasuretheimplementationoftheprinciplesdefinedintheguidance.Thistoolwillenableprocurement

agenciestoassessthemselves,tocommunicatetheoutcomesinastandardizedway,andtotaketargettedmeasuresforimprovement.

References1 WHO. Model quality assurance system for

procurement agencies.Annex3.In:WHOTechnicalReportSeries,No.986.Geneva,Switzerland:2014.

2 WHO. Assessmenttoolbasedonthemodelquality assurance system for procurement agencies:aide-memoireforinspection. Annex4.In:WHOTechnicalReportSeries986,2014.

http://www.who.int/medicines/areas/quality_safety/quality_assurance/TRS986annex3.pdf?ua=1





Medicines quality assurance WHO Drug Information Vol. 28, No. 4, 2014

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Annex 1: Self-assessment tool based on the WHO Model Quality Assurance system

for procurement agencies (MQAS)

a) InstructionsFor whom is this tool intended, and who can use it? ThetoolcanbeusedbytheQualityManagerina

procurementagencyforself-assessmentoftheagencyandtoidentifyitslevelofcompliancewiththestandardsasrecommendedbyWHOintheMQAS.

What does the tool contain? Thetoolcontainsstatementsrelatingtosystemsandproceduresthatshouldbeinplaceinaprocurementorganizationasameanstoassessthequalityofsystemsandmedicines.

Level of implementation of a system: 0% Nocompliance,orthesystem/proceduredoesnotexist 20% Verylowlevelofcomplianceorimplementation 40% Lowlevelofcomplianceorimplementation 60% Mediumlevelofimplementation(e.g.procedureshavebeendeveloped,butlackscope

anddepth) 80% Agoodlevelofcompliance 100% FullyimplementedandconsistentlycomplieswithMQASexpectation

Steps in the procedure for assessment:1. InspecttheindividualrequirementsineachsystemofeachModule.2. Allocatethepercentagetoindicatethelevelofcompliance(0–100%.Incasethe

activityisnotapplicabletothePA,stateN/Aanddonotallocate“0”).3. Makeadditionalnotesondeficienciesinthespaceprovided(ifneeded)ineach

section.4. CalculatethepercentagecomplianceineachModule(I–VI)5. Reachaconclusiononthelevelofcomplianceofthesiteineacharea.6. Forcriticalissues(markedas!),ascorebelow60%indicatesfailureofcompliance

withstandardsandmayresultinanoutcomeof“non-compliant”.7. Prepareareportbasedonthefindingsandpresentitintheagreedformat.

Foreachmodulethecalculatedlevelofcompliancewillfallwithinoneofthethreelevelsbelow:

• LevelI:<60%(Notincompliance–unacceptable)• LevelII:60%(Acceptablelevelofcompliance)• LevelIII:>80%(Highlevelofcompliance)

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b) Self-assessment toolAn Excel version of this tool is available on request from: [email protected].

Number System/procedure (“!” = critical) Rating

MODULE I: Organization and management1 Anauthorizedorganizationchartindicatespositions,namesofresponsible

personsandreportinglinesandisinlinewiththejobdescriptions.2 Therearewrittenjobdescriptionsdefiningresponsibilities,forallpersonnel–

signedbyeachemployee.Thepersonresponsibleforprequalificationandthepersonresponsibleforpurchasingisindependentofoneanother.

Personnel3 Thereisasufficientnumberofqualified,trainedstaffwiththenecessary

experienceandauthoritytocarryouttheirdutiesforkeyactivities(includingprequalification,purchasing,storage,distribution).

4 Relevantpersonnelhavesignedandfollowanauthorizedwrittencodeofconduct,confidentialityagreementsanddeclarationofinterest.Thesearearchivedandaccessibleforverificationtoensurethatthereisnoadverseeffectonthequalityofserviceprovidedorontheintegrityofpharmaceuticalproducts.

5 Personnelaretrainedinaccordancewithastandardoperatingprocedure(SOP) and training programme, and assessment records are maintained.

Quality system6 ! ThePAisauthorized/licensedtoperformtheactivities(e.g.distributionof

pharmaceuticalproducts)inaccordancewithnationallegislation.7 ! Authorizedprocurementandreleaseproceduresforalladministrative

andtechnicaloperationsperformedareinplacetoensurethatapprovedpharmaceuticalproductsaresourcedonlyfromapprovedsuppliersanddistributedbyapprovedentitiestopersonsorentitiesauthorizedtoacquiresuchproducts.

8 Anydelegatedandcontractedactivitiesaredocumentedinagreementsorcontracts,andarewithinthelegalframeworkofthecountry.ThereisevidencethatthecontractacceptercomplieswiththelegalrequirementsandGDP.

9 Thecontractsclearlydefineresponsibilitiesoftheparties.Contractsaresigned and dated.

10 Contractacceptersareauditedperiodicallyandreportsshowevidenceoffindingsandcorrectiveactionsbeingtaken.

11 Definedproceduresareimplementedwherethedistributorisusingelectronicsystems.Thesesystemsandproceduresareproventobereliableandensuretraceability.Transactionsareperformedonlybyauthorizedpersonsorentities.

12 Safetyproceduresareinplaceandcoverpersonnel,property,environmentalprotection and product integrity.

13 Thereisaqualitymanualinplace.Thequalitypolicyisimplemented.14 Thereissufficientofficespace,andotherstoragespaceforretentionof

commodities,documentation,samples,stock,reports,filesandotherrecords.15 Computersystemapplicationsareappropriatefortheirintendeduse.

(Includingappropriatehardwareandsoftwarewithsecuritysystemsaccess;virusprotection;firewall;technicalsupport;capacityandmemory;maintenanceandupgradingplan,andbatchtraceability).Aback-upofelectronicrecordsismadeandmaintainedtopreventanyaccidentaldataloss.

Continued


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ContinuedNumber System/procedure (“!” = critical) Rating

Documentation16 Acomprehensivedocumentedsystemexistscoveringpolicies,organizational

structure(s), procedures, guidelines, norms, standards, manuals, records and related documents.

17 ActivitiesaredocumentedinauthorizedSOPs(signedanddated).SOPsforallactivitiesareinanappropriateformatandcoveratleastbutarenotlimitedto. -HowtowriteanSOP: -Productdossierevaluation; - Inspections; - Decision making process for products; -Purchasing; -Receiving; -Issuinganddispatch; -Deviations; -Changecontrol; -Evaluatingoffersreceived; - Handling of complaints; - Handling recalls; - Regular reinspection; - Quality control - Handling counterfeit/substandard products; -Handlingvariations; -Evaluatingoffersreceived.

18 Documentsaredesigned,completed,reviewed,amendedanddistributedwithcare.Documentsarereviewedregularlyandkeptuptodate.Supersededdocumentsareremovedfromuse.

19 Thereisevidencethatriskassessmentisdonetoassesspotentialriskstothequality and integrity of products.

20 AnSOPisfollowedtomanagechangessuchaschangestoSOPsandotherdocuments, facilities etc.

21 Procedurescoverhealthandhygieneofpersonnel.Theseareimplementedand followed.

22 Records(electronicorhardcopies,alsoformanualsystems)aremaintainedforadefinedperiodandensureproducttraceabilitythroughoutthesupplychainwhichcoverproductsreceivedanddistributed.(Fromthemanufacturer/importertotheentityresponsibleforsellingorsupplyingtheproducttothepatient.)Thesearereadilyretrievablewithnounauthorizedchanges,damage,deteriorationand/orlossthereof.

23 Recordsforreceivingofproductscontainatleastthedate;nameoftheproduct;batchnumbersandexpirydates,quantityreceived,orsupplied;andnameandaddressofthesupplier.

24 Aprocedureisfollowedforidentification,collection,indexing,retrieval,storage, maintenance, disposal of and access to all applicable documents and records.

Counterfeit products25 Thereisaproceduretohandlecounterfeitandsuspectedcounterfeit

products.Itensuresthatregulatorybodiesandotherrelevantcompetentauthoritiesandtheholderofthemarketingauthorizationfortheoriginalproductareinformedimmediatelyinacaseofconfirmedorsuspectedcounterfeitingofapharmaceuticalproduct.

26 ! Counterfeit and suspected counterfeit products are kept secured, separately, clearly labelled and are not sold.

Continued

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27 ! Aformaldecisiononthedisposalofeachcounterfeitorsuspectedcounterfeitproduct,ensuringthatitdoesnotreenterthemarket,isrecorded.

Self-inspection 28 AnSOP,calendarandreportsshowevidenceofself-inspectionsbeing

conducted by independent, designated, competent persons.29 Thereisevidenceofmanagementinvolvementandeffectivefollow-upof

correctiveactionstaken. Complaints

30 AnSOPisfollowedforthehandlingofcomplaintsdistinguishingbetweendifferent types of complaints, e.g. complaints about a product or its packaging, or complaints relating to distribution.

31 Allcomplaintsarethoroughlyinvestigated,riskassessmentisdoneandtherootcauseisidentified.Appropriateactionistaken.Recordsaremaintained.

Recalls32 ! AnSOPisinplacetoeffectivelyandpromptlyrecallproducts.Aprogress

reportandafinalreportontherecallisissued,whichincludesreconciliationbetweendeliveredandrecoveredquantitiesofproducts.Thisprocedureischeckedregularlyandupdatedasrequired.Theeffectivenessofthearrangementsforrecallsisevaluatedatregularintervals(e.g.mockrecall).

33 ! Recalledpharmaceuticalproductsaresegregatedduringtransitandstorageandareclearlylabelledassuch.Theyarekeptunderappropriatestorageconditions.

Comments: Total calculated for Module I

(e.g.totalpercentagedividedby33ifall33questionswererated):

MODULE II: Prequalification procedure34 TheprequalificationprocedureandstandardsusedarebasedontheWHO-

recommendedproceduresandguidelines.KeystepsinprequalificationhavebeendefinedandarefollowedmeetingtherecommendationsintheMQAS.

35 ! ThePAhasaqualitypolicytoensurethatprequalifiedproductswillbesourced–eitherthroughitsownprequalificationprocedure,WHOprequalification,orproductsapprovedbystringentregulatoryauthorities(SRA).(Specialnote:VerifypolicyregardingproductsapprovedbySRAsforexportonly,asthismaynotalwaysbeappropriatelycontrolledbytheSRA).

36 ProceduresandrecordsshowthatmanufacturingsitescomplywithWHOgoodmanufacturingpractices(GMP)(orotherinternationallyrecognizedGMP).

37 Thepersonsresponsibleforprequalificationandthoseresponsibleforpurchasingareindependentfromanother.

Expression of interest (EOI) – public sector/non-commercial38 Proceduresandclearpoliciesarefollowedforinviting,receivingand

reviewingEOIs.Recordsaremaintained.39 Detailedguidelinesforthecompilationandsubmissionofinformationon

productsandmanufacturingsitesarepubliclyavailable. Product information, screening and evaluation

40 Productinformationisreceivedinasuitableformatwithnecessarycontentssuchasaproductdossier(detailasdescribedbyWHO,e.g.seeAppendix6oftheModel quality assurance system for procurement agencies.

Continued



440


41 Normally,aWHO-typecertificateofapharmaceuticalproduct(CPP)isreceivedwiththeproductinformation.(Iftheformulation,strengthorotherspecificationsaredifferentfromtheproductforwhichtheWHO-typeproductcertificate(CPP)wasissued,argumentsand/ordatatosupporttheapplicabilityofthecertificatedespitethedifferencesarerequested).

42 Thereisanappropriatesystemandinfrastructureforthereceivingandprocessingofproductinformation.Thescreeningofproductinformationsubmitted is done according to an SOP and records are maintained. Written proceduresarefollowedforevaluation.Evaluationreportsarepreparedforeachproductwhichincludesarecommendationforacceptanceorrejection.Theevaluationandthereportaredonewithinappropriatetimeframes.

43 Evaluatorswithsuitablequalifications(e.g.inthepharmaceuticalfield)andexperience(e.g.regulatoryaffairs)evaluateproductdata.

44 Whereappropriate(basedonriskassessment)samplessubmittedtogetherwithproductinformationpackagesaretestedatlaboratoriesmeetingdefinedstandards recommended by WHO.

Inspections45 Thereisappropriateevidencethatactivepharmaceuticalingredients(API)

manufacturersareassessedforcompliancewithGMP(e.g.byfinishedpharmaceuticalproduct(FPP)manufacturers).

46 Inspections are planned and performed according to an SOP and plan, for FPP manufacturers.

47 Auditsareperformedbysuitablyqualified,experiencedauditorswithrelevantqualifications,trainingandexperience.

48 Waivingofauditsisonlydoneunderappropriate,definedconditions.Incaseoutcomesofinspectionsdonebyotherauthoritiesarerecognized,suchprocedureiswrittenandappropriatetoensurethatGMPoutcomesarereliable.

49 AuditscoverallaspectsofGMPaswellasverificationofdataandinformationprovided(e.g.inproductdataandsitemasterfile).

50 Anauditreportispreparedaftereachaudit,containingdetailedinformationandlistsofdeficiencieswhererelevant.Auditreportsarecommunicatedtomanufacturersandacopyiskeptasarecordforadefinedperiodoftime.

51 Correctiveactionstoauditfindings,andtimelinesforcompletingthemarereceived,reviewed,andverifiedonsitewhennecessary.

Prequalification outcome52 Awrittenprocedureisfollowedtofinalizeoutcomesoftheproductevaluation

andinspection(resultinginprequalification).Recordsaremaintainedontheprocessanddecisiontaken.Manufacturersareinformedoftheoutcome.

53 Alistofprequalifiedproductsandmanufacturers,basedontheoutcomeoftheevaluationofproductdataandinformationandmanufacturingsiteinspections,ismaintained.Thelistisproduct-andmanufacturingsite-specificandisreviewedregularly.

54 Incasecostsarerecoveredforprequalification,thenthesearedefinedintransparentproceduresandarebasedonafee-for-servicesstructure.Manufacturersarenotifiedoftheseinadvance.

Comments: Total calculated for Module II


Continued

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MODULE III: Purchasing55 Importedproductsenterthroughdesignatedportsofentryasstipulatedby

national legislation.56 TransparentSOPsarefollowedforprocurementandpurchasing,awarding

contracts.57 Suppliersareselectedandmonitoredthroughaprocessthattakesinto

accountproductquality,servicereliability,deliverytimeandfinancialviability.58 Awrittenprocedureisfollowedtohandledonatedproducts–anditensures

thatproductsofknown,appropriatequalityareacceptedanddonated.59 Adocumentedprocurementqualitysystemisinplacecoveringpurchaseand

procurement.Proceduresareinplacefor: -theestablishmentoftechnicalspecifications; -quantificationofrequirements; - issuing of a tender (as appropriate); - selection of product(s) and manufacturer(s)

60 Responsestotendersasappropriateareexaminedbytherelevantresponsiblepersonstoevaluatecompliancewithtendertermsandconditions.Thereisevidencethatawardsaremadetothemakerofthelowestacceptablebidthatmeetstheseconditions.

61 Keyactivitiesinpurchasingproceduresaredefinedandincludeproductselectionandspecification,productquantification,selectionofsuppliersandadjudicationoftenders.

62 AnSOPisfollowedfortheselectionofproducts,andisbased,wherepossible,onanationalformularyorontheessentialmedicineslist.

63 ProcurementandtenderdocumentslistpharmaceuticalproductsbytheirINNor national generic names.

64 Requestsforproductsincludequantitiesandrequireddeliverydates. Monitoring of performance of prequalified manufacturers

65 Proceduresandrecordsshowthatthereistrackingandmonitoringof: -thevalueofcontractsawarded; -purchaseandsupplyofprequalifiedproducts; - supplier performance; - product compliance.

66 Monitoringincludesatleast: -compliancewithallofthecontracttermsandconditions; - sampling and testing; -suppliedbatchesmeetagreedspecifications; -pharmacovigilanceasrequiredinthecountry; - complaints; - reinspection of manufacturing sites and reassessment of product information; -deliveryschedules.

Comments: Total calculated for Module III

(e.g.totalpercentagedividedby12ifall12questionswererated).

Continued


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MODULE IV: Receiving – sampling and testing – storage67 Thereisevidencethattheproductsarestoredatportsofentryunder

appropriateconditions;andasshortaspossiblebeforebeingtakenintostock.68 ! SOPsarefollowedandrecordsarekeptforreceiving,sampling,storage

andhandlingofproducts(includingquarantined,rejected,expired,recalled,returnedproductsandsuspectedcounterfeitsexpiredstock).

69 Thereissufficientspaceforthereceivinganddispatchofproducts.Receivinganddispatchbaysareseparatedandprotectproductsfromtheweather.

70 Product containers are cleaned, if necessary, before taken into storage areas.71 Allincomingmaterialsandproductsarereceivedandcheckedinaccordance

withtheirSOPandquarantineduntilreleased(e.g.meetingspecificationsasperprequalifieddossier,purchaseorder,certificateofanalysis(CoA).

72 Recordsforeachdeliveryshowdescriptionofthegoods,quality,quantity,supplier,supplier’sbatchnumber,thedateofreceipt,assignedbatchnumberandtheexpirydate.

73 Otherproceduresimplementedincludecleaning,pestcontrol,containmentandcleaningofspillages,preventionofcontaminationandcross-contamination;andwasteremoval.Programsandrecordsareinplacewhereappropriate.

Quality control74 Thereisasysteminplaceforqualitycontroloffinishedproductsprocured

(e.g.preshipmentsampling,testing,andreleaseorsampling,checksonshelf-lifeandlabelling,testingwhenconsignmentsarereceived).

75 Samplingplanswhichensurethatrepresentativesamplesaretakenfortesting(usedduringreceivingofconsignments)aredetailedinSOPsandarebasedonriskassessment.QualifiedandexperiencedpersonnelreviewCoAsaccompanyingbatchesreceived.

76 Adequatelaboratoryservicesareusedtotestproductsindependentlyaccordingtoapprovedspecificationsandstandards.Thelaboratorymeetsgeneralrequirementsforgoodpracticescovering,e.g.facilities,policiesandprocedures, personnel, equipment, etc.

77 AnSOPclearlydescribestheprocessandensuresthatmaterialsorproductsarenotreleasedforuseuntiltheirqualityhasbeenjudgedsatisfactory.

78 Out-of-specificationresultsarehandledinaccordancewithanSOPforOOSinvestigation.

79 ProductsfailingtomeettheirspecificationsarerejectedinaccordancewithanSOPanddocumentedevidenceexistsforthedispositionofsuchproducts.

Storage80 Accesstostorageareasiscontrolledtoensurethatnounauthorizedperson

hasaccess(24hoursaday,7daysaweek).81 Separatedareasareusedforthestorageofquarantined,rejected,expired,

recalled, returned products and suspected counterfeits.82 Storageareashavesufficientspaceandventilationandfirecontrolmeasures.83 Temperaturemappingofthestorageareaswasdoneinanappropriate

manner.84 Systemsareinplacetoprovide,control,monitorandrecordtemperature(and

relativehumiditywhererequired).Recordsofmonitoringarekeptforsuitableperiodsoftime.Appropriatelycalibrateddevices(i.e.range,traceabletonationalstandard)areusedtomonitorthetemperatureandrelativehumidity.

Continued

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85 Allproductsarestoredinsuitablyprotective,labelledcontainers;underappropriatestorageconditionsasspecifiedonthelabels.

86 Productsthatshouldbestoredunderspecifiedcoldconditions(requiringcold-chain)arehandledappropriatelyduringtransport,delivery,receivingandstorage. Temperature mapping studies were done for cold rooms; and power generatorsareavailableincaseofpowerfailure.Proceduresarefollowedtoensurethaticepacksareusedinthecorrectmannerincold-chainboxes.Containersusedforthetransportarevalidatedtoensurethatcoolproductsremainattherequiredtemperatureduringtransport.

87 ! Narcoticandpsychotropicsubstances/productsarehandledinaccordancewithnationallegislationandwrittenprocedures.Theseproductsarestoredseparately,whereaccessiscontrolledandreconciliationisdonemonthlyaswellaseachtimestockisissued.

88 Miscellaneousandhazardousmaterialsarehandledinaccordancewithwritten procedures.

Stock control89 Stockrotationandcontrolismaintainedensuringbatchnumbercontroland

expirydating.90 Periodicstockreconciliationisdone(actualstockvsrecordedstock).

Significantstockdiscrepanciesareinvestigatedandresultsaredocumentedinaccordancewithwritteninstructions

91 Damagedcontainersarehandledinaccordancewithwrittenprocedures.Anyaction taken is documented.

92 RegularchecksareperformedaccordingtoanSOP–toidentifyobsoleteandoutdatedproducts.Thesearenotissued/distributed.

93 Recalledmaterialsarehandledinaccordancewithawrittenprocedure.94 Returnedgoodsarehandledinaccordancewithawrittenprocedure

ensuringphysicalsegregationandappropriatestorageconditions.Thereisnopossibilityofentryofcounterfeitproducts,orthattheproductqualityiscompromised.

95 Productreturnsandexchangesaredoneinaccordancewithtermsandconditionsofanagreementbetweenthedistributorandtherecipient.

96 Returnedproductsaretransportedinaccordancewiththerelevantstorageandotherrequirements.

97 Anauthorizedpersonisidentifiedtodecideonthedispositionofreturnedgoods.Thedecisionisbasedon,e.g.thenatureoftheproductreturned,specialstorageconditionsrequired,itsconditionandhistory;andthetimeelapsed since it was issued.

98 Thereisaprocedurefortheappropriatedestructionofproducts(complyingwithinternational,nationalandlocalrequirements).

99 Recordsaremaintainedofallreturned,rejectedand/ordestroyedproducts100 RejectedgoodsarehandledinaccordancewithanSOP,arestored

separately (locked) and are marked accordingly. Access is controlled.101 Wastematerialsarehandledinaccordancewithawrittenprocedureandare

notallowedtoaccumulate.Thesearecollectedinsuitablereceptaclesanddisposed of safely and in a sanitary manner.

Comments: Total calculated for Module IV


Continued


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MODULE V: Distribution of purchased products (Packaging – transport) Containers and labelling

102 ! Norepackagingorrelabellingisdone,unlesslicensedtodoso,andtheactivitiesarefoundtomeetinternationalstandardssuchasWHOGMP.(Insuchacase,repackagingandrelabellingofproductsdonotresultinlossofidentificationandauthenticationoftheproducts;andproceduresareinplaceforthesecuredisposaloforiginalpackaging.)

103 Productsareissuedonafirst-expiry-first-out(FEFO)basis.104 Suitablepackagingmaterialsandcontainersareusedthatgiveprotectionand

preventdamageofproducts.Damageisrecorded,reportedandinvestigated.105 Containersbearlabels(indicatinghandling,storageconditions,precautions,

identificationofcontentsandsource).Wherespecialtransportand/orstorageconditionsarerequired,thesearestatedincludinganyspeciallegalrequirements, safety symbols, etc.

106 Specialcareistakenwhenusingdryiceinshipmentcontainers.107 Damagedand/orbrokencontainersarehandledaccordingtoprocedures,

alsoconsideringthosethatcontainedpotentiallytoxicandhazardousproducts.

Dispatch108 Dispatchandtransportationisdoneafterthereceiptofawritten,validdelivery

order.109 Writtenproceduresforthedispatchareimplemented,andcover,e.g.the

natureoftheproductandspecialprecautions.110 Detailedrecordsfordispatcharemaintainedwhichprovidefortraceabilityand

facilitaterecallsandinvestigationofcounterfeits.111 Writtenagreementswiththird-partycarriersareinplaceiftheseareused.112 Deliveryschedulesarepreparedandsuitablevehiclesareselected.113 Vehiclesandequipmentusedtodistribute,storeorhandlepharmaceutical

productsaresuitablefortheirpurposeandappropriatelyequipped.114 Non-dedicatedvehiclesandequipmentusedaresubjectedtoprocedures

whichensurethatthequalityofthepharmaceuticalproductisnotcompromised.

115 Vehiclesandcontainersareloadedcarefullyandsystematically.Wherenecessary,storageconditionsaremonitored,recordedandcheckedduringtransport.Devices/equipmentusedareappropriatelycalibrated.

116 Productswithdifferentstatusarekeptseparatelyduringtransport,e.g.rejected,recalledandreturnedproductsandaresecurelypackaged,clearlylabelled.

117 Proceduresensurethatnounauthorizedpersonscanenter/tamperwithvehiclesand/orequipment.

Transport and transit118 Productsandcontainersaresecuredtopreventunauthorizedaccess,theft

andothermisappropriationofproductsduringtransportation.119 Appropriate documentation accompanies products in transit.120 Proceduresareinplacetoensurethatduringtransport:

-theidentityoftheproductismaintained; -thecorrectstorageconditionsaremaintained; -thereisnocontaminationofproducts; -precautionsaretakenagainstspillage,breakage,misappropriationandtheft.

Continued

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121 Deviationsinstorageconditionsduringtransportareaddressed,investigatedandreportedinaccordancewithanSOP.

122 Hazardoussubstancesandotherdangerousproductsaretransportedinsafe,dedicatedandsecurecontainersandvehicles,andaccordingtoagreementsand legislation.

123 Narcoticsandotherdependence-producingsubstancesaretransportedinsafeandsecurecontainersandvehiclesandincompliancewithagreementsand legislation.

124 Procedures are followed for cleaning spillages.Comments:

Total calculated for Module V (e.g.totalpercentagedividedby23ifall23questionswererated):

MODULE VI: Reassessment125 Proceduresandrecordsshowthatrequalificationisdoneatregularintervals.

Thisincludesreinspectionofmanufacturersandreevaluationofproductinformation or data.

Reassessment of manufacturers126 Thereisaprocedure,programme(plan)andrecordsthatshowreassessment

ofmanufacturerstakingplaceatleasteverythreetofiveyears.(Thiscoversroutine and non-routine assessment.)

127 Asystemisinplace(e.g.agreementorSOP)ensuringthatmanufacturersinformthePAimmediatelyofanychangestothemanufacturingsiteorequipmentthatmayhaveanimpactonitsprequalification.

128 Aprocedureisfollowedprovidingforsuspensionandwithdrawalofaprequalifiedfacility.

Reevaluation of products129 Productinformationisreviewedroutinelyeverythreeyearsorsoonerifmajor

changesoccur.130 Thereisasysteminplace(agreement/procedure)thatensuresthat

manufacturersinformtheprocurementagencyofanycontemplatedchangestotheproductthatmayaffectitssafety,performance,efficacyorquality.

131 Asystemisinplacetoreviewtherequestedchanges(seeabove)andcommunicatingapprovedchangestotheprocurementagency.

132 Non-routinereevaluationofproductsisdoneaccordingtoaprocedure.133 AnSOPisusedtomanagevariationstoproductinformation.

Monitoring of contracted-out services134 Agreementsareinplaceforactivitiescontractedoutsuchasstorage,

distribution,qualitycontrol,andarereviewedperiodically.135 Thereisevidenceofcompliancewithaprocedureforthemonitoringofthe

performance of contractors and follow-up of non-compliance.136 Managementinformationshowscontinuousmonitoringofperformanceof

contractorswhichincludetrackingofcost,orderanddeliverystatus,lead-timeandcompliancewithcontracttermsandconditions.Problemsarereportedandinvestigatedwithactiontaken.

137 On-siteauditsaredoneatintervalstoverifycompliancewithstandards,agreementsandtoverifysourcedatawhereappropriate.

Comments: Total calculated for Module VI



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c) Model report format

Section 1: General informationNameoforganization:Websitereference:Physicaladdress:Postaladdress:Tel.:Fax:Contactperson:Emailaddress:Activities(tickallthatapply): Prequalification

PurchasingReceivingandstorageDistribution

Dateofinspection:Productsand/orservices:Inspector:

Section 2: SummaryGeneralinformationabouttheprocurementagentandsite

History of inspections

Focusoftheinspectionandinspectedareas

SummaryoffindingsGeneralrequirementsforprocurementagencies:

Prequalification:

Purchasing:

Receivingandstorage:

Distribution (includingtheabilitytosupplytheneededproductsinquantitiesrequired):

Reassessment:

Continued

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Model report format, continuedOutcome and conclusion

ModuleI:GeneralrequirementsModuleII:PrequalificationModuleIII:PurchasingModuleIV:ReceivingandStorageModuleV:DistributionModuleVI:Reassessment

LevelI:<60%(Notincompliance–unacceptable)LevelII:60%(Acceptablelevelofcompliance)LevelIII:>80%(Highlevelofcompliance)

Comments:

Conclusion(Selectandcompleteasappropriate):Basedontheareasinspected,thepeoplemetandthedocumentsreviewed,andconsideringthefindingsoftheself-assessment,includingtheobservationslistedabove–theagencywasconsideredtobeoperatingatahighlevelofcompliancewiththeMQASforthefollowingmodules:……………...And/orBasedontheareasinspected,thepeoplemetandthedocumentsreviewed,andconsideringthefindingsoftheself-assessment,includingtheobservationslistedabove–theagencywasconsideredtobeoperatingatanacceptablelevelofcompliancewiththeMQASforthefollowingmodules:……………...And/orBasedontheareasinspected,thepeoplemetandthedocumentsreviewed,andconsideringthefindingsoftheself-assessment,includingtheobservationslistedabove–theagencywasconsideredtobeoperatingatanunacceptablelevelofcompliancewiththeMQASforthefollowingmodules:……………...

Signature: _________________________ Date: _________________________________

Name: ____________________________

æ

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Safety news

Unchanged recommendations

Testosterone: cardiac risk not confirmedE u r o p e a n U n i o n –TheEuropeanMedicinesAgency(EMA)hasreviewedavailabledatafromstudieson testosterone-containing medicines, followingconcernsoverserioussideeffectsontheheartandbloodvessels.Testosteroneisusedtotreathypo-gonadism (lack of testosterone produced bythebody)inmen.Availabledatadonotprovideconsistentevidencethattheuseoftestosteroneincreasestheriskofheartproblemsinthesepatients,andhypogonadismitselfmayincreasethisrisk. TheEMArecommendedthat

testosterone-containing medicines shouldonlybeusedwherelackoftestosteronehasbeenconfirmedbysigns and symptoms as well as laboratory tests.Theproductinformationforthesemedicineswillbeupdatedtoincludethisrecommendation,togetherwithwarningsagainstuseinmenwithsevereheart,liverorkidneyproblems,andinformationthatdataonsafetyandeffectivenessinpatientsover65yearsofagearelimitedandthatage-specifictestosteronereferencevaluesdonotexist.Clinicalstudiesonthesafetyof

testosteronearestillongoing,andtheirresults will be considered in future regular benefit-riskassessmentsforthesemedicines. (1)

N e w Z e a l a n d – Medsafe’s Medicines AdverseReactionsCommittee(MARC)

hasreviewedtheavailableinformationaboutcardiovascularrisksassociatedwithtestosteronetherapy,andhasfoundthattheevidenceofincreasedcardiovascularriskwasnotconclusive.TheCommitteerecommendedthatmarketingauthorizationholdersshouldberequestedtoupdatethewarningsandprecautionssectionintheproductinformation,andthatgeneralarticlesshouldbepublishedtoraiseawarenessofthisrisk.(2)

► (1) EMA Press release, 21November2014.(2)Medsafe.Minutesofthe159thMedicinesAdverseReactionsCommitteeMeeting-11 September 2014.

Agomelatine: strengthened advice to monitor liver function;

E u r o p e a n U n i o n –TheEMAhasconcludeditsregularbenefit-risk assessment of agomelatine (Valdoxan®,Thymanax®),usedtotreatmajordepressioninadults,andhasrecommended measures to reiterate theimportanceoflivermonitoring,thecornerstoneforthesafeuseofagomelatine.Agomelatinehasariskofsevere

sideeffectsontheliver,especiallyinvulnerablepatients.Neverthelessitremainsavaluabletreatmentoptionincertainsituations.Strengthenedadviceonliverfunctionmonitoringwillbeincludedintheproductinformation,andapatientbooklet will be distributed.Thecurrentproductinformationincludes

awarningthatthemedicineshouldnotbeusedinpatientsaged75yearsormore.TheEMAconsideredthatavailabledata

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/11/news_detail_002218.jsp&mid=WC0b01ac058004d5c1

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WHO Drug Information Vol. 28, No. 4, 2014 Safety news

doesnotjustifyupgradingofthiswarningto a contraindication.

►EMANews,26September2014.

Restricted use

Intravenous nicardipine: only to control high blood pressure in specialist settingsU n i t e d K i n g d o m – In agreement withtheMedicinesandHealthcareProducts Regulatory Agency (MHRA), themarketingauthorizationholderofanintravenousnicardipinemedicinehasinformedhealthprofessionalsoftheoutcomesofaEuropeanregulatoryreviewofintravenousnicardipine,initiatedin2012attherequestoftheMHRA.TheEMAhadadvisedthatthesemedicinesshouldonlybeusedtotreatacutelife-threateninghypertensionandpost-operativehypertension.Treatmentshouldbe administered by a specialist and in a well-controlledenvironment.Otherusesare not recommended.Inadults,continuousinfusionshould

bestartedatarateof3–5mg/h.Theratecanthenbeincreasedbutshouldnotexceed15mg/h,itshouldgraduallybereducedwhenthetargetbloodpressureisreached.Bloodpressureshouldbemonitored continuously during infusion andforatleast12hoursthereafter.

► MHRA Safety Communication, 12 September 2014. Seealso:EMAPressrelease,25October2013.

Bromocriptine: not for pre-menstrual syndrome or benign breast diseaseN e w Z e a l a n d – Medsafehasrevieweddataontheefficacyandsafetyof

bromocriptinewhenusedtotreatpremenstrual symptoms and mastalgia. Availabledataprovideinsufficientevidencetorecommendbromocriptineusefortheseindications,andinformationfromitsuseofsimilardosesforotherindicationssuggestthatbromocriptinemaycausefibrosisandimpulsecontroldisorders.Medsafewillthereforerequestthemarketingauthorizationholderofbromocriptinetoremovetheaboveindicationsfromthedatasheet.(1)Earlier,Medsafehadmade

recommendationsonthesafetyandefficacyofbromocriptineforlactationsuppression (2) in response to an EMA reviewstartedonthesubject,and–asmentionedinthepreviousissueofWHODrugInformation–theEMAhadrecommendedagainsttheroutineuseof bromocriptine to stop lactation or to relievepainorswellingofthebreastsafterchildbirth(3).

► (1) Medsafe.Minutesofthe159thMedicinesAdverseReactionsCommitteeMeeting-11 September 2014. ► (2) Minutesofthe156thMedicinesAdverseReactionsCommitteeMeeting-5December2013.(3) EMA Press release, 21 August 2014.

Colistimethate sodium: reserve for serious infections resistant to standard antibioticsE u r o p e a n U n i o n – Colistinin and colistimethatesodium(knownaspolymyxins)havebeenavailablesincethe1960s,buthavebeeninlittleuseuntiltheywerebroughtbackinrecentyearsas an option to treat infections resistant tostandardantibiotics.TheEMAhasreviewedthesafetyandeffectivenessofinjectableandliquidinhaledproductscontainingcolistimethatesodium.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/09/news_detail_002173.jsp&mid=WC0b01ac058001d126

http://www.mhra.gov.uk/home/groups/comms-ic/documents/drugsafetymessage/con465932.pdf


http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Intravenous_nicardipine_medicines/human_referral_000354.jsp&mid=WC0b01ac05805c516f

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Intravenous_nicardipine_medicines/human_referral_000354.jsp&mid=WC0b01ac05805c516f

http://www.medsafe.govt.nz/profs/adverse/Minutes159.htm#3.2.3







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Thereviewconcludedthatinjectionorinfusionofcolistimethatesodiumshouldbereservedforthetreatmentofserious infections caused by susceptible (i.e.aerobicGram-negative)bacteriainpatientswhoseothertreatmentoptionsarelimited.Themedicineshouldbegivenwithanothersuitableantibioticwherepossible. Greatcautionisadvisedwhenusingintravenouscolistimethatesodiumtogetherwithothermedicationsthatarepotentiallynephrotoxicorneurotoxic. TheCommitteerecommendedthat

dosesshouldalwaysbeexpressedininternationalunits(IU)toavoidmedicationerrors,andproposedaconversiontableforinclusionintheproductinformation.DespitelimiteddatatheCommitteerecommended doses for use in patients withkidneyproblemsandinchildren,andprovidedguidanceondosageforintraventricularorintrathecalorinjectioninadults,i.e.whenthemedicineisgivendirectlyintofluidsurroundingthebrainorspinal cord.

► EMA Press release, 24 October 2014.

Valproate: not to be used in pregnancyE u r o p e a n U n i o n –TheEMAhasrecommendedstrengtheningtherestrictionsontheuseofvalproatemedicinesduetotheriskofmalformationsanddevelopmentalproblemsinchildrenexposedtovalproateinthewomb.Valproateshouldnotbeusedtotreat

epilepsy or bipolar disorder in girls and inwomenwhoarepregnantorwhocanbecomepregnantunlessothertreatmentsareineffectiveornottolerated.Wherevalproateistheonlyoption,womenshoulduseeffectivecontraceptionandtreatmentshouldbestartedandsupervisedby

adoctorexperiencedintreatingtheseconditions. Insomecountriesvalproateis

authorizedforthepreventionofmigraine.Pregnancyshouldbeexcludedbeforestartingvalproatetreatmentformigraine,andwomenshoulduseeffectivecontraception.TheEMAfurtherrecommendedthat

educationalmaterialsshouldbeprovidedtoallhealthcareprofessionalsintheEUandtowomenwhoareprescribedvalproatetoinformthemoftheserisks.Thesestrengthenedrestrictionsare

basedonareviewofavailabledataaswellasconsultationswithpatients,affectedfamiliesandexperts.

► EMA Press release, 21November2014.

Sulfur hexafluoride: not to be used with dobutamine in certain patients;

U n i t e d K i n g d o m –Themarketingautorizationholder,inagreementwiththeEMAandtheMHRA,haveinformedhealthprofessionalsthatrarebutsevereandsometimesfatalarrhythmiashavebeenreportedinpatientswithcardiovascularinstabilityundergoingstressechocardiographywithsulfurhexafluoride(SonoVue®)incombinationwithdobutamine.Sulfurhexafluorideistherefore

contraindicatedincombinationwithdobutamineinpatientswithconditionssuggestingcardiovascularinstability,e.g. recent acute coronary syndrome or clinicallyunstableischaemia.Whenadministeredalone,sulfur

hexafluorideshouldbeusedinsuchat-riskpatientsonlywithextremecautionandafteracarefulrisk/benefitassessment.Vitalsignsshouldbecloselymonitored during and after administration, becauseinthesepatientsallergy-likeand/



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orvasodilatoryreactionsmayleadtolife-threateningconditions.Sulfurhexafluorideisacontrast

agent used in diagnostic procedures involvingechocardiographyandDopplersonography.

► MHRA Safety Information, 1 October 2014.

Safety warnings

Ivabradine: heart problemsE u r o p e a n U n i o n –TheEMAhascompleteditsreviewofivabradine–usedtotreatheartfailureandsymptomsofangina–andhasmaderecommendationsaimedatreducingtheriskofheartattackand bradycardia. Whenusedforangina,ivabradine

shouldonlybestartedifthepatient’srestingheartrateisatleast70beatsperminute.Doctorsshouldconsiderstoppingtreatmentifthereisnooronlylimitedimprovementinanginasymptomsafterthreemonths.Ivabradineshouldnotbeprescribed

togetherwithverapamilordiltiazemthatreducetheheartrate,andpatientsshouldbemonitoredforatrialfibrillation.Ifatrialfibrillationdevelopsduringtreatment,thebalanceofbenefitsandrisksofcontinuedivabradinetreatmentshouldbecarefullyreconsidered.

►EMAPressrelease,21November2014.

Carvedilol: Rare severe skin reactionsN e w Z e a l a n d –Themarketingauthorizationholderofcarvedilol(Dilatrend®)hasinformedhealthprofessionalsthatveryrarecasesofseverecutaneousadversereactions

suchastoxicepidermalnecrolysisandStevens-Johnsonsyndromehavebeenreportedduringtreatmentwiththeproduct,andthattreatmentshouldbepermanentlydiscontinuedinpatientswhoexperienceseverecutaneousadversereactionspossiblyattributabletothismedicine.Theproductinformationhasbeenupdatedaccordingly.

► Medsafe Safety information, sent 26November2014.

Voriconazole: phototoxicity and squamous skin cancerU n i t e d K i n g d o m –Themarketingauthorizationholder,inconsultationwiththeMHRA,hasremindedhealthprofessionalsthatvoriconazole(Vfend®)isassociatedwithariskofphototoxicityand skin squamous cell carcinoma. Voriconazoleisusedforthetreatmentofworsening,possiblylife-threateningfungalinfectionsandprophylaxisofinvasivefungal infections in certain transplant recipients. Healthprofessionalsareremindedto

adheretotheadvicegivenintheproductinformation.Ifphototoxicreactionsoccur,theyshouldreferthepatienttoadermatologistandshouldconsiderstoppingvoriconazoletreatment.Iftreatmentiscontinued,theskinshouldbecheckedfrequentlyandthoroughly,andvoriconazoletreatmentshouldbestoppedif precancerous skin lesions or squamous cellcarcinomaareidentified.Voriconazoleisalsoassociatedwith

ariskoflivertoxicity.TheUKproductinformation(availableatwww.medicines.org.uk)hasbeenupdatedwithrevisedadviceonmonitoringliverfunction.

► MHRA Drug safety message, 10 October 2014.


http://www.medsafe.govt.nz/safety/DHCPLetters/DilatrendNovember2014.pdf

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Immunoglobulins: rare but serious risk of blood clotsC a n a d a –HealthCanada,incollaborationwithmarketingauthorizationholders,hasinformedhealthprofessionalsoftheriskofthromboemboliceventsinpatientsusingnon-hyperimmuneimmunoglobulins.Sucheventscanoccurregardlessofdoseorrouteofadministrationandintheabsenceof known risk factors. Canadian product monographsforallnon-hyperimmuneimmunoglobulins(GamaSTAN®S/D,Gammagard Liquid, Gammagard S/D, Gamunex®,Hizentra®,IGIVnex®,Immune Serum Globulin (Human), Octagam®5%,Octagam®10%,andPrivigen®)wereupdatedtoincludethromboemboliceventsintheSeriousWarnings and Precautions section.

►HealthCanadaAdvisory,9October2014.

Simeprevir: increased bilirubin may cause serious outcomesJ a p a n –ThePharmaceuticalandMedicalDevicesAgency(PMDA)hasinformedhealthcareprofessionalsthateightcases,includingthreefatalones,of remarkably increased blood bilirubin inpatientstreatedwithsimeprevirhavebeenreportedinJapanwithin10monthsfollowingmarketauthorization.SimeprevirisarecentlyapprovedmedicineusedincombinationwithothermedicinalproductsforthetreatmentofchronichepatitisC.Whiletheriskofincreasedblood

bilirubinlevelswithsimeprevirisknown,thethreedeathsoccurredafterhepaticdysfunction and renal impairment towhichthePMDAconsidersthathyperbilirubinaemiamayhavecontributed.ThePMDAhasrequestedthatthe

productinformationshouldbeupdatedtoadvisehealthprofessionalstotestbloodbilirubinregularlyduringsimeprevir

treatment and to monitor patients carefully evenaftersimeprevirisstopped.Promptactionisimportant,asmeasurestoavoidseriousoutcomesmaybelesseffectiveoncejaundice,generalmalaiseand/orothersymptomsoccur.

►PMDAInvestigationresults,24October2014.

Basiliximab: cardiac adverse events when used off-label in heart transplantsU n i t e d K i n g d o m –InagreementwiththeEMAandtheMHRA,themarketingauthorizationholderhasremindedhealthprofessionalsthatbasiliximab(Simulect®)isindicatedonlyfortheprophylaxisofacuteorganrejectionindenovoallogeneicrenaltransplantation.Itsefficacyandsafetyinothertransplantindicationshavenotbeendemonstrated.Inseveralsmallclinicaltrialsinheart

transplantrecipients,seriousadverseeventssuchascardiacarrest,atrialflutterandpalpitationshavebeenreportedmorefrequentlywithbasiliximabthanwithotherinductionagents.ThewarningssectionoftheSummaryofProductCharacteristicswill be updated accordingly.Thecommunicationfollowsareview

by European drug regulatory agencies regardingtheoff-labeluseofbasiliximabinhearttransplants.

► MHRA Drug safety message, 10 October 2014.

Ustekinumab: serious skin conditionsC a n a d a –Themarketingauthorizationholder,inconsultationwithHealthCanada,hasinformedhealthprofessionals about rare reports of exfoliativedermatitisanderythrodermic

http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/41749a-eng.php

http://www.pmda.go.jp/english/service/pdf/revision/20141024-simeprevir.pdf

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psoriasisinpsoriasispatientsreceivingustekinumab(Stelara®).Theseskinconditionscanoccurwithinafewdaysofstartingtreatment,canbesevereandcanleadtohospitalization.Treatmentwithustekinumabshouldbediscontinuedifadrugreactionissuspected,andthesymptomsshouldbetreated.Exfoliativedermatitiscanappear

asrednessandsheddingoftheskinoveralmosttheentireareaofthebody,whichmaybeitchyorpainful.Patientswithplaquepsoriasismaydeveloperythrodermicpsoriasis,withsymptomsthatmaybeclinicallyindistinguishablefromexfoliativedermatitisaspartofthenaturalcourseoftheirdisease.Theproductmonographwillbeupdated

toreflectthisinformation.(1)

E u r o p e a n U n i o n – At its October meeting,theEMA’sCommitteeforMedicinal Products for Human Use (CHMP)adoptedasafetyvariationtoaddtheriskofseriousskinconditionswithustekinumabtotheSummaryofProductCharacteristics.HealthprofessionalsintheEUwillbeinformedandtheproductinformation will be updated. (2)

► (1) HealthCanadaAdvisory,21November2014.(2) EMA/CHMP. Opinions on safety variations/PSURsadoptedattheCHMPmeetingof20-23October2014.

Ponatinib: blood vessel blockageE u r o p e a n U n i o n –TheEMAhasreviewedthebenefitsandrisksofponatinib(Iclusig®)andhasrecommendedtoincludestrengthenedwarningsabouttheriskofbloodclotsorbloodvesselblockageintheproductinformation.Theriskislikelytobedose-related,althoughavailabledata

arenotsufficienttomakeaformalrecommendation on dose reduction. Ponatinibisauthorizedforusein

patientswithchronicmyeloidleukaemia(CML)andacutelymphoblasticleukaemiawhocannottakeortolerateseveralothermedicinesofthesameclass.Therecommendedstartingdoseshould

remain45mgofponatinibonceaday.Thecardiovascularstatusofthepatientshouldbeassessedbeforestartingtherapyandregularly monitored during treatment. Healthcareprofessionalsshould

consider a dose reduction in patients with‘chronicphase’CMLwhoarerespondingwelltotreatment,andwhomightbeatparticularriskofbloodvesselblockage.Dosemodificationsortreatmentinterruptionshouldbeconsideredtomanagetreatmenttoxicity;ifareduceddoseisused,patientsshouldbemonitoredformaintenanceoftherapeuticresponse.Ponatinibshouldbestoppediftherehasbeennoresponseafterthreemonthsoftreatment.Patientsshouldbemonitoredforhighbloodpressureorsignsofheartproblems.Educationalmaterialwillbeprovidedto

healthcareprofessionals,andanewstudyonthesafetyandbenefitsatlowerdosesofthemedicineisplanned.


Diclofenac and other NSAIDs: cardiovascular risks and liver damageA u s t r a l i a – TheTherapeuticGoodsAdministration(TGA)hasreviewedarangeofnon-steroidalanti-inflammatorydrugs(NSAIDs)andhasfoundthattheknown risks at prescription-only dosages –highbloodpressure,heartfailure,heartattackandstroke,aswellasliverdamageinthecaseofdiclofenac–also



http://www.ema.europa.eu/docs/en_GB/document_library/Annex_to_CHMP_highlights/2014/10/WC500176773.pdf





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applytoover-the-counter(OTC)formsofdiclofenac,naproxenandibuprofen.WhiletheOTCproductsaresafeat

therecommendeddosesandforshortdurations,inappropriateuseoroverusecanposeasignificanthealthrisk.TheTGAhasremindedhealthprofessionalsofprescribing recommendations for NSAIDs, andhasencouragedthemtoeducatepatientsonthesignsandsymptomsofseriouscardiovasculartoxicityandtheneedtoseekmedicalattentionimmediatelyiftheyoccur.Therecommendationsarebasedona

reviewofcardiovascularrisksassociatedwithdiclofenac,naproxen,ibuprofen,celecoxib,etoricoxib,indomethacin,meloxicamandpiroxicam,aswellasafullsafetyreviewofdiclofenac.TheTGAisexploringoptionstoreducetherisks.(1)

C a n a d a – Themarketingauthorizationholdersofsystemicdiclofenacproducts(Voltaren®,Arthrotec®),inconsultationwithHealthCanada,haveinformedhealthprofessionalsthatatdosesfrom150mgperdaytheseproductshaveariskofheartproblemsandstrokethatiscomparabletothatofCOX-2inhibitors(coxibs).Theriskmayincreasewiththedose and duration of use. Themaximumrecommendeddaily

doseforallindicationshasbeenreducedto 100 mg in product information and labelling of diclofenac-containing tablets andsuppositories,exceptforVoltarenRapide®whichallowsfora200mgdoseonlyonthefirstdayoftreatmentfordysmenorrhea.Thelowesteffectivedoseshouldbeusedfortheshortestpossibleduration.COX-2inhibitorsanddiclofenacarenotrecommendedinpatientswithpre-existingcardiovasculardisease(CVD)orcerebrovasculardisease,orpresentingrisk factors for CVD. Treatment options

otherthanNSAIDs,particularlyCOX-2inhibitorsanddiclofenac,shouldbeconsideredfirstinthesepatients.(2)

► (1) TGASafetyadvisory,7October2014.(2) HealthCanadaAdvisory,October6,2014.

Denosumab: osteonecrosis of the jaw and hypocalcaemiaU n i t e d K i n g d o m – Themanufacturer,inconsultationwithregulatoryauthorities,haswarnedthatdenosumab(Prolia®,Xgeva®)isassociatedwithariskofosteonecrosisofthejawandhypocalcaemia.Denosumabisusedtopreventbonecomplicationsinosteoporosis and certain types of cancer.Treatmentshouldnotbestartedin

patientsduetoundergo,orrecoveringfrom,oralsurgery.Appropriatepreventivedentistry is recommended before patients withriskfactorsforosteonecrosisofthejawaregivendenosumab.Duringtreatment,goodoralhygieneanddentalcheck-upsareencouraged.Theriskofhypocalcaemiaincreases

withthedegreeofrenalimpairment.Beforetreatmentexistinghypocalcaemiamust be corrected. Adequate calcium and vitaminDintakeisimportantespeciallyinpatientswithrenalimpairment.Patientsshouldimmediatelyreport

anypainorswellinginthemouth,looseteeth,aswellasanysymptomsofhypocalcaemia.

►MHRA.InformationsenttohealthcareprofessionalsinAugustaboutthesafetyofmedicines. 2014.

Pregabalin: liver damageJ a p a n – ThePMDAhasinformedhealthprofessionalsthatcasesoffulminanthepatitisandhepaticdysfunctionhave

http://www.tga.gov.au/safety/alerts-medicine-nsaid-diclofenac-141007.htm#.VDQUT_mSzt4



http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/Monthlylistsofinformationforhealthcareprofessionalsonthesafetyofmedicines/CON454357



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beenreportedinpatientstreatedwithpregabalininJapan,includingcaseswherecausalitycouldnotberuledout.Pregabalinisusedforthetreatmentofneuropathicpainandfibromyalgia.TheAgencyrecommendedtorevisethepackageinserttoincludetheseadverseeventsinthesectiononclinicallysignificantadversereactions.Whilehepaticeffectsinpatientstaking

pregabalinhavealsobeenreportedtoEUandWHOpharmacovigilancedatabases,thedatadonotsupporttheconclusionthattheseadverseeffectsareassociatedwiththeuseofpregabalinspecifically.

►PMDA.Summaryofinvestigationresults.Pregabalin.16September2014.

Zopiclone: next-day impairmentC a n a d a –Themanufacturer,inconsultationwithHealthCanada,hasinformedhealthprofessionalsofnewdosagerecommendationsforthesleepingmedicationzopiclone(Imovane®)tominimizetheriskofnext-dayimpairment.ThisfollowsrecommendationsprovidedbytheEMAforzolpidemandbytheFDAforeszopiclone(seeWHO Drug Information Vol. 28, No. 2, 2014). Therecommendedstartingdoseof

zopiclonehasbeenreducedto3.75mg(one-halfofthe7.5mgtablet)atbedtime;thelowesteffectivedoseforeachpatientshouldbeused.Theprescribeddoseshouldnotexceed5mginelderlypatients,inthosewithhepaticorrenalimpairmentorinthosebeingtreatedwithpotentCYP3A4inhibitors.DoseadjustmentmaybeneededifotherCNS-depressantdrugsareusedatthesametime.Patientsshouldbeinformedoftherisksandshouldwaitatleast12

hoursbeforedrivingorengaginginotheractivitiesrequiringfullmentalalertness.

►HealthCanadaAdvisory,19November2014.

Bupropion: serious cardiovascular eventsA u s t r a l i a –TheTGAisaddingstrengthenedwarningstoproductinformationforbupropion(Zyban®andotherbrandnames)asseriouscardiovascularadverseeventshavebeenreportedwiththismedicineinAustralia.Theeventsincludedmyocardialinfarction,cerebrovascularaccidents,andseverehypertensionrequiringacutetreatment.Ahigherrateofhypertensionwasobservedwhenbupropionwascombinedwithnicotinetransdermalpatches.BupropionisregisteredforuseinAustraliaasashort-termadjunctivetherapy,inconjunctionwithcounsellingandabstinence,toassistin smoking cessation.TheTGAadvisesthatcareshouldbe

takenwhenusingbupropion,especiallyinpatientswitharecenthistoryofmyocardialinfarctionorunstableheartdiseaseasthereislimitedinformationaboutthesafetyofbuproprioninthesepatients.Bloodpressureshouldbemonitored during treatment, especially in patientswithpre-existinghypertension,andconsiderationbegiventostoppingtreatmentifaclinicallysignificantincreaseisobserved.

►MedicinesSafetyUpdate,Volume5,Number5,October2014.

Galantamine hydrobromide: serious skin reactionsC a n a d a –Themanufacturer,inconsultationwithHealthCanada,hasprovidednewsafetyinformation

http://www.pmda.go.jp/english/service/pdf/revision/20140916-pregabalin.pdf

http://www.pmda.go.jp/english/service/pdf/revision/20140916-pregabalin.pdf

http://www.who.int/entity/medicines/publications/druginformation/DI_28-2_SafetyEfficacy.pdf

http://www.who.int/entity/medicines/publications/druginformation/DI_28-2_SafetyEfficacy.pdf



http://www.tga.gov.au/publication-issue/medicines-safety-update-volume-5-number-5-october-2014-0#bupropion

http://www.tga.gov.au/publication-issue/medicines-safety-update-volume-5-number-5-october-2014-0#bupropion


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abouttheriskofseriousskinreactionsassociatedwiththeuseofgalantaminehydrobromide(ReminylER®),usedforthesymptomatictreatmentofpatientswithmildtomoderatedementiaoftheAlzheimer’stype.Veryrarecasesofserious skin reactions including cases ofStevens-Johnsonsyndrome,acutegeneralizedexanthematouspustulosis,anderythemamultiformehavebeenreportedwiththismedicine.Healthcareprofessionalsshouldinformpatientsandcaregiversaboutthesignsoftheseseriousskinreactions,anddiscontinuethemedicineatthefirstappearanceofskinrash. (1)J a p a n –ThePMDAhasrequestedarevisionofthepackageinsertforgalantaminehydrobromide(Reminyl®),toincludeacutegeneralizedexanthematouspustulosisinthesectiononclinicallysignificantadversereactionsofthepackageinsert.Thechangewasbasedonexpertopinionsandavailableevidencefromreportsofthisadverseeventinothercountries. (2)A u s t r a l i a –themarketingauthorizationholderhasupdatedtheproductinformationforReminyl®andothergalantamine-containingproductstoreflecttheriskofseriousskinreactions.(3)

► (1) HealthCanadaAdvisory,18November2014.(2) PMDASummaryofinvestigationresults:galantaminehydrobromide,20November2014.(3) TGASafetyadvisory,8December2014.

Dimethyl fumarate: rare brain infectionU n i t e d S t a t e s –TheU.S.FoodandDrugAdministration(FDA)hasalertedhealthprofessionalsandthepublicthatapatientwithmultiplesclerosiswhowas

beingtreatedwithdimethylfumarate(Tecfidera®)developedprogressivemultifocalleukoencephalopathy(PML),a rare and serious brain infection, and laterdied.Thepatienthadtakendimethylfumarateformorethanfouryearsbeforetheadverseeventoccurred.TheFDAdecidedtoaddinformation

describingthiscaseonthedruglabelandhasadvisedthatpatientstakingdimethylfumarateshouldcontacttheirhealthcareprofessionalsrightawayiftheyexperiencesymptomssuchasneworworseningweakness;troubleusingtheirarmsorlegs;orchangestotheirthinking,eyesight,strengthorbalance.Healthcareprofessionalsshouldstopdimethylfumarate if PML is suspected.

►FDASafetyannouncement,25November2014.

Omalizumab: slightly increased risk of heart and brain adverse events ;

U n i t e d S t a t e s o f A m e r i c a – An FDA reviewofsafetystudiessuggestsaslightlyhigherriskofproblemsinvolvingtheheartandbloodvesselssupplyingthebrainamongpatientsbeingtreatedwiththeinjectableasthmadrugomalizumab(Xolair®)thaninthosewhowerenottreatedwiththemedicine.Informationaboutthesepotentialriskshavebeenaddedtothedruglabel.Also,informationaboutuncertainfindingsregardingapotentialriskofcancerwasaddedtothedrug label.Omalizumabisusedtotreatpatients

12yearsandolderwithmoderatetoseverepersistentasthmaandelevatedimmunoglobulinElevels,andthosewithchronichiveswithoutaknowncause,iftheseconditionscannotbecontrolledbyothertreatments.Healthcareprofessionalsshouldperiodicallyreassess



http://www.pmda.go.jp/english/service/pdf/revision/20141120-galantamine.pdf



http://www.tga.gov.au/alert/galantamine

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Medicinesreviewstarted

Medicine Use Concerns Reviewing authority, date of communication

Dual anti-platelet therapy

Preventionof stent thrombosisandheartattacks

Preliminary clinical trialdatahaveshownahigheroverallriskofdeathwithdualanti-platelettherapyfor30monthscomparedto12months.Thisriskwasnotobservedinpreviouslargetrials.

►FDA,16November2014. ►HealthCanadaAdvisory,18November2014.

MauriL,KereiakesDJ,YehRW,etal.Twelveor30MonthsofDualAntiplateletTherapyAfterDrug-elutingStents.NewEnglandJournalofMedicine.OnlineaheadofprintNovember16,2014.

theneedforcontinuedtherapywithomalizumab.

► FDA Drug safety communication, 26September2014.

Risk minimization measures

Methylphenidate: web-based prescribing guide;

E u r o p e a n U n i o n – Following an EMAreviewofRitalin®andothermethylphenidate-containingmedicineswhichcalledfortheriskminimizationmeasures (1),sixMPHMarketingAuthorisationHolders(MAHs)intheEUhavecollaboratedinordertoproduceaweb-basedphysician’sguidetomethylphenidateprescribing(2).

Methylphenidateispartofamulti-modaltreatmentapproachforattentiondeficithyperactivitydisorder(ADHD).Thewebsiteproposeschecklistsaiming

tominimizetheriskofcardiovascular,cerebrovascular,neuropsychiatricandgrowthdisorders.Healthprofessionalsshouldrevieworcompletethesechecklistsbeforetreatmentstartsandduringtherapy.Thematerialsprovidedonthewebsiteshouldbeusedtogetherwiththefullprescribinginformationforeachindividualproduct.

► (1)EMAPressRelease,21January2009.

(2)Methylphenidate(MPH):physician’sguidetoprescribing[website].Availableat:http://www.methylphenidate-guide.eu/







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Facility Activities Concerns Reviewing authority, date of communication

GVK Biosciences, Hyderabad, India

Contract researchorganization

Findingsofnon-compliancewithgood clinical practice. An inspection bytheFrenchmedicinesagencyANSMhadraisedconcernsaboutstudydatausedtosupportthemarketingauthorizationapplicationsof generic medicines.

►EMA,26September2014

WHOprequalificationupdate, 7 August 2014..

SomeEUMemberStateshavedecided to suspend medicines marketingauthorizationsissuedonthebasisofstudiesconductedattheGVKBiosciencessite.

EMA Press release, 5December2014.

Manufacturing quality issues

Health Canada restricts imports from various Indian sitesC a n a d a –HealthCanadahastakenactiontorestrictimportsoffinishedpharmaceuticalproductsfromApotexResearchPrivateLimited,activepharmaceuticalingredients(APIs)fromApotexPharmachemIndiaPvtLtdandfrom IPCA Laboratories, as well as productsmadewithAPIsfromthesesites(1). HealthCanadahasalsorestrictedthe

importofhealthproductsfromthreeMicroLabsfacilitiesinIndia:Bangalore,Goaand Hosur (2).Onlyproductsthatareonauthority’s“medicallynecessary”listwillbeallowedonthemarket,subjecttopriortestingbyanindependentthirdparty.Inbothcases,theregulatory

action was triggered by data integrity concernsidentifiedininspectionsbyinternationalpartners.Theimportbanisaprecautionarymeasure.Nospecificsafety

issueshavebeenidentifiedwithproductsalreadyonthemarket,andneitherHealthCanadanoritsregulatorypartnershaverequestedarecalloftheseproducts.HealthCanadacontinuestoworkwithregulatory partners to monitor compliance withgoodmanufacturingpracticesatthesites.

W o r l d H e a l t h O r g a n i z a t i o n –InJune2014theWHOPrequalificationTeamhadpublishedonitswebsiteanoticeofconcern addressed to Micro Labs Ltd (3). Todatethenoticeofconcernhasnotbeenlifted.InAugust2014theprequalificationteampublishedinformationaboutWHOactiontakenregardingthedeficienciesnotedattheIPCAsite(4).(1) HealthCanadaAdvisory,30September2014.(2) HealthCanadaAdvisory,27October2014.(3) WHOPrequalificationupdate,6June2014.(4) WHOPrequalificationupdate,14August2014.

http://apps.who.int/prequal/info_press/documents/GVK-Bio_07August2014.pdf







(2)http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/41963a-eng.php

http://apps.who.int/prequal/info_press/pq_news_06June2014_NOC.htm

http://apps.who.int/prequal/info_press/documents/Ipca_Ratlam_Note14August2014.pdf

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Regulatory news

Ebola

Update on treatments and vaccines

TheEbolacrisishaspromptedanunprecedented cooperation between regulators tosupportWHOandtoadviseonpossiblepathwaysforthedevelopment,evaluationandapprovalofmedicinestofightEbola.Progresstowardsprovisionoftreatmentsandvaccinesissummarizedbelow.

InAugust2014,aWHO-convenedpanelhadagreedunanimouslythatisethicallyacceptabletouseofexperimentalmedicinesandvaccinesundertheexceptionalcircumstancesoftheEbolaepidemic (1). In early September, WHO convenedaconsultationonpotentialEbolatherapiesandvaccines(2).Theimportanceofsupportivecareandcommunityresponsewasstressedinthisand subsequent discussions.

TreatmentsInSeptember,morethan200expertsfromaroundtheworldmetatWHOandagreedtoprioritizeconvalescentbloodandplasmatherapiesforfurtherinvestigation.Manyquestionsremaintobeansweredaboutthesafetyandefficacyofconvalescenttherapies,thefeasibilityofimplementationincountrieswithshatteredhealthsystems,andtheprospectsofscalinguptherapytocurbthefatalityrate(2).Tosupportimplementation,WHOhasissuednewinterimguidanceontheuseofconvalescenttherapiesfornationalhealthauthoritiesandbloodtransfusionservices(3).Thefirstclinicaltrialsof–possibly

curative–transfusionsofwholebloodorbloodplasmafromrecoveredpatientshavebeenscheduledtobeconductedinLiberia,inlinewithWHOtechnicalguidelines (4).InSeptembertheEuropeanMedicines

Agency(EMA)establishedanexpertgrouptoreviewavailableinformationonEbolaexperimentaltreatments–excludingconvalescenttherapies–andinviteddeveloperstosubmittheirdata(5).

VaccinesOn29–30September,70expertsattendedaWHO-convenedconsultationonEbolavaccines.TheytookstockofthemanyongoingeffortstorapidlyevaluatethesafetyandefficacyofEbolavaccinesfor deployment as soon as possible to critical frontline workers and ultimately to populationsatriskinmassvaccinationcampaigns.Twocandidatevaccineshaveclinical-gradevialsavailableforsafetytrials. (6)InOctober,WHOconvenedindustry

leaders and key partners to discuss trials andproductionofEbolavaccine(7). ConsensuswasachievedtomakeresultsavailableinDecember2014,tobeginefficacytrialsatthesametime,andtoscaleupproductionin2015.AlsoinOctobertheEMAgaveitsfirst

scientificadviceonadevelopmentplanforanEbolavaccine,usinganew‘rollingreview’procedurefordataassessmentandsharingofoutcomeswithhealthcaredecision-makers in affected countries (8). Atthetimeofwriting,safetytrialsof

vaccineswereunderwayintheU.S.,U.K.,MaliandSwitzerland,andabouttobegin

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inGabon,GermanyandKenya.ThetwoSwiss trials are coordinated by WHO, withtestingdoneonhealthyvolunteers,someofwhomwillbedeployedinthefightagainst Ebola in West Africa (9). AtthemeetingoftheAfricanVaccine

Regulatory Forum (AVAREF) in early November,delegatesdiscussedcollaborativemechanismstofast-trackclinicaltrialapprovalsandregistrationofEbolatreatmentsandvaccinesinaffectedcountries,and–importantly–reaffirmedtheneedtobuildstrongerhealthsystems(10).

Supportive careIndustryleadersandkeypartnershaveemphasizedthatcommunityengagementremainskeytofightEbolaandhavecalled onlocal communities, national governments,NGOsandinternationalorganizationstoscaleupconcertedactivitiesurgently.(7).Meanwhile,aWHO-coordinatedretrospectivestudyhasshownthatsupportivecare,especiallyrehydrationandcorrectionofmetabolicabnormalities, may contribute to patient survival(11).

DiagnosticsQuick and accurate diagnosis is key in fightingEbola.WHOhaslaunchedtwourgentinitiativestoacceleratethedeliveryofrapid,sensitive,safeandsimpleEbola diagnostic tests to West African countries.Thefirstisaclosecollaborationofmanufacturers,researchers,MédecinssansFrontières(MSF)staff,andthenon-profitorganizationFoundationforInnovativeNewDiagnostics(FIND),andaimstosupportthedevelopmentofsuitabletests.Thesecondistheestablishmentofanemergencyrapidreviewmechanismforassessing

a diagnostic’s quality, safety and performance. (12)

► (1) WHO Statement, 12 August 2014.(2) WHO.Ebolasituationassessment-26September 2014.(3) WHO. UseofConvalescentWholeBlood or Plasma Collected from Patients RecoveredfromEbolaVirusDiseaseforTransfusion, as an Empirical Treatment during Outbreaks. Version 1.0, September 2014.(4) WHO.Ebolasituationassessment,6November2014.(5) EMAPressrelease,26September2014.(6) WHO.ExperimentalEbolavaccines.1 October 2014.(7) WHO News release, 24 October 2014.(8) EMAPressrelease,29October2014.(9) WHONewsrelease,6November2014.(10)WHOEssentialMedicinesandHealthProducts. African regulators’ meeting lookingtoexpediteapprovalofvaccinesandtherapiesforEbola [web page].(11)BahEI,LamahM,FletcherT,JacobST,Brett-MajorDM,SallAAetal.Clinical PresentationofPatientswithEbolaVirusDisease in Conakry, Guinea.NEnglJMed.2014;5Nov2014.(12) WHO. Ebola situation assessment - 18 November2014.

Clinical trials transparency

EMA adopts policy on publication of clinical reports E u r o p e a n U n i o n – TheEMA’sManagementBoardhasunanimouslyadoptedanewpolicytopublishtheclinicaltrialreportsthatunderpinthedecision-makingonmedicines.Thepolicywillenterintoforceon1January2015andwill apply to clinical reports supporting allapplicationsforcentralizedmarketingauthorizationssubmittedafterthatdate.Accordingtothepolicy’stermsofuse,

thereportscannotbeusedforcommercialpurposes.Inthelimitedinstances

http://www.who.int/mediacentre/news/statements/2014/ebola-ethical-review-summary/en/

http://www.who.int/mediacentre/news/ebola/26-september-2014/en/

http://www.who.int/mediacentre/news/ebola/26-september-2014/en/

http://apps.who.int/iris/bitstream/10665/135591/1/WHO_HIS_SDS_2014.8_eng.pdf?ua=1





http://www.who.int/mediacentre/news/ebola/06-november-2014/en/

http://www.who.int/mediacentre/news/ebola/06-november-2014/en/


http://www.who.int/entity/mediacentre/news/ebola/01-october-2014/en/index.html

http://www.who.int/entity/mediacentre/news/ebola/01-october-2014/en/index.html

http://www.who.int/mediacentre/news/releases/2014/ebola-vaccines-production/en/


http://www.who.int/entity/mediacentre/news/statements/2014/second-ebola-vaccine/en/index.html

http://www.who.int/medicines/news/AFR_reg_meet/en/



http://www.nejm.org/doi/full/10.1056/NEJMoa1411249?query=featured_home&



http://www.who.int/mediacentre/news/ebola/18-november-2014-diagnostics/en/

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wheretheymaycontaincommerciallyconfidentialinformation,thiswillberedactedinaccordancewiththeprinciplesoutlinedinthepolicy’sannexes.Thenewpolicywillserveasa

complementarytoolaheadoftheimplementationofthenewEUClinicalTrialsRegulationthatwillcomeintoforcenotbeforeMay2016.Publicaccesstoclinical reports will enable academics and researcherstore-assessdatasets,andwillhelptoavoidduplicationofclinicaltrial


Pre-market assessment

EMA revises guidance on biosimilars E u r o p e a n U n i o n –TheEMAhaspublisheditsrevisedguidelineonbiosimilars.ThemainchangeisthatdeveloperscannowuseacomparatorproductauthorizedoutsidetheEuropeanEconomic Area (EEA) in certain clinical studies and in non-clinical studies conductedinvivo.Thisnewconceptaimstoavoidunnecessaryrepetitionofclinicaltrials.ThecomparatormustbeauthorizedbyaregulatoryauthoritywithsimilarrigorousscientificandregulatorystandardstothoseofEMA,andtheapplicantmustestablishthatthecomparatorisrepresentativeofthereferencemedicineauthorizedintheEEA.

A biosimilar is a biological medicine thatissimilartoanalreadyauthorizedreference product (comparator). To obtain amarketingauthorizationthedevelopermustdemonstrateinstudiesthatthebiosimilarisassafeandeffectiveasthereferencemedicine,andmeetstheEMA’squality requirements. Whiletherevisedguidelinewillcome

intoforceasof30April2015,applicants

canapplysomeorallofitsprovisionswithimmediate effect. Two related guidelines and procedural guidance are also being updated.

►EMAPressrelease,29October2014.

EMA proposes harmonized clinical trials plan for vaccine in childrenE u r o p e a n U n i o n –TheEMAhasproposedasingledevelopmentplanfornewtetanus-diphtheria-acellularpertussisvaccinesthatallpharmaceuticalcompaniesacrosstheEUshouldfollow.Theproposalaimstoavoidtheduplication of similar clinical trials and theunnecessaryexposureofchildrentoclinical testing.Astheschedulesofchildvaccinations

varyslightlybetweenEUcountries,alarge number of fairly similar clinical trials arecurrentlyconductedinchildrenwhenanewvaccineisbeingdeveloped.TheEMAcollaboratedwiththeEuropeanCentreforDiseasePreventionandControl(ECDC)todefineasinglescheduleforclinicaltrials.Apanelofpublichealthvaccinologyexpertshaveendorsedtheproposal.Theproposedplanhasbeenreleased

forathree-monthpublicconsultation. ►EMANews,23September2014.

EMA pilot to seek patient views on medicines risks and benefitsE u r o p e a n U n i o n – TheEuropeanMedicinesAgency(EMA)haslaunchedapilotprojecttoinvolvepatientsintheassessmentofthebenefitsandrisksofmedicines in its Committee for Medicinal Products for Human Use (CHMP). PatientswillbeinvitedtopresenttheirviewsonmedicinesforwhichthereisanunmetmedicalneedandwheretheCommitteehasdoubtsonitsregulatory





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decisionsatanystageoftheproductlifecycle.EMAhaspublishedadocumentoutliningtheprinciplesofthisapproach.Thefirstactivesubstanceincludedin

thispilotprojecthasbeenafamelanotide,leadingtotheapprovalofatreatmentforerythropoieticprotoporphyria(EPP),araregeneticblooddisorderwhichcausesanabsoluteintolerancetolight(seealsopage 466). Thepilotprojectstemsfromawider

EMAstrategytoinvolvepatientsintheAgency’sactivities.Itwillrunforatleastone year, leading up to a proposal for full implementation.

►EMAPressrelease,26September2014.

Australia to recognize EU conformity assessment for medical devicesA u s t r a l i a – New regulations will allow Australian manufacturers to obtain market approvalformostmedicaldevicesbasedonconformityassessmentcertificationfromEuropeannotifiedbodies,theaccreditedorganizationsthatcarryoutproductassessmentsintheEU.Thehighestriskdevicessuchasthose

containing medicines or tissues of animal, biological or microbial origin, or Class 4 invitrodiagnostics(IVDs)includingHIV tests, will still need TGA conformity assessment.Therespectiveregulatoryamendmentsareexpectedtobeinplacelaterthisyear.

►AustralianAssistantMinisterforHealth,Mediarelease,15October2014.

Editor’snote:Astheabovemediareleasementions,regulatorscommonlyadaptthelevelofcontrolforIVDstothelevelofriskthatproductdeficiencieswouldposeforpublichealth.IVDs(includingproductsliketuberculosisormalariaIVDs,whichareconsidered‘low-risk’inindustrializedcountries) are crucial in guiding treatment

decisionsforprioritydiseases.Ontheotherhand,regulationofIVDsisstillverylimitedor absent in many countries. Read more in WHODrugInformationVol.28,No.3,2014 onwhatWHOisdoingtobringquality-assured IVDs to its Member States.

Pharmacovigilance

Canada passes Vanessa’s LawC a n a d a –TheGovernmentofCanadahaspassedmodernizedlawsfordrugsandmedicaldevices.TheProtectingCanadians from Unsafe Drugs Act, knownas“Vanessa’sLaw”,willenabletheGovernmenttorecallunsafemedicines,imposetoughpenalties,compelpharmaceuticalcompaniestomakechangestoproductsordofurthertesting,requiremandatoryadverseeventsreportingbyhealthcareinstitutions,and require transparency on regulatory decisions.TheActintroducesthemostprofound

andimportantchangestotheFoodandDrugsActinitsfiftyyearsofexistence.Itis named after an Australian Member of Parliament’sdaughterwhodiedofaheartattackwhileonaprescriptiondrugthatwaslaterdeemedunsafeandremovedfromthemarket.

►GovernmentofCanadaNewsrelease,6November2014.

EU project on using smartphones for drug safety informationE u r o p e a n U n i o n – TheMHRAisleadinga consortium of regulators, academics andthepharmaceuticalindustryinathree-yearproject,knownasWEB-RADR,todevelopnewwaysofgatheringinformationonsuspectedadversedrugreactions(ADRs)usingsmartphonesandsocialmedia.WEB-RADRwillhelpto


http://www.health.gov.au/internet/ministers/publishing.nsf/Content/health-mediarel-yr2014-nash056.htm

http://www.who.int/medicines/publications/druginformation/WHO_DI_28-3_web.pdf

http://news.gc.ca/web/article-en.do?mthd=index&crtr.page=1&nid=900969

http://news.gc.ca/web/article-en.do?mthd=index&crtr.page=1&nid=900969

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developrecommendationsonhowthesenewtoolsshouldbeusedethicallyandscientificallyalongsideexistingdrugsafetymonitoring systems.Theprojectisfundedthoughthe

InnovativeMedicinesInitiative,apublic-privatepartnershipbetweentheEuropeanCommissionandtheEuropeanFederationofPharmaceuticalIndustriesandAssociations (EFPIA).

►MHRAPressrelease,5September2014.

EMA expands public web access to reports on suspected side effects E u r o p e a n U n i o n – TheEMAhasaddedto its website information on suspected adversedrugreactionsforanadditional1700activesubstancescontainedinmedicinesapprovedintheEuropeanUnion(EU)bynationalauthorities.TheinformationcomesdirectlyfromtheEudraVigilancedatabase.Thewebsitewaslaunchedin2012andinitiallyonlycontainedadverseeventsinformationforcentrallyauthorizedmedicines.OverthenextfewyearsitwillbeexpandedtocoverallmedicinesavailableintheEU.SinceJuly2012European

pharmacovigilancelegislationprovidesthepossibilityforpatientstoreportsideeffectsdirectlytotheauthoritiesinallEUMember States. Increasing numbers of patientreportsarebeingreceivedintheEudraVigilance database.


Australia, Switzerland create web portals to report adverse reactionsA u s t r a l i a - TheTGAhaslaunchedanewweb-basedserviceforconsumerstoreportadverseeventsassociatedwithmedicinesandvaccines.

In2013onlyabout3%ofadverseeventsreportsreceivedbytheTGAcamefromconsumers.ThenewwebsiteispartofTGA’sactivitiestakeninlinewithaninternationaltrendforregulatorsto encourage reporting by consumers. TheTGAhasalsopublishedabrochureoutliningwhatandhowtoreport,andisundertakingawarenessactivitiesandconsumerresearch.(1)

S w i t z e r l a n d – Withimmediateeffect,healthcareprofessionalsandpharmaceuticalcompaniescanreportsuspectedadversedrugreactionsdirectlyontheInternetthroughSwissmedic’s“ElViS”(ElectronicVigilanceSystem)onlinereportingportal.UseoftheportalissubjecttoregistrationontheElViSwebsite, and companies are also required to attend a Swissmedic training course. Dataprotectionandsecuritysatisfythemost stringent requirements. SwissmedichopesthatElViSwillresult

inmoreandbetterreportsbeingreceivednearertotheevent,helpingtoimprovedrugandpatientsafetyinSwitzerland.(2)

► (1) TGA News, 24 September 2014.(2) SwissmedicAnnouncement,6October2014.

New MHRA guidance on reporting adverse drug reactions in childrenU n i t e d K i n g d o m – TheMHRAhasannouncednewsimplifiedguidanceonhowhealthcareprofessionalsshouldreportsuspectedadversedrugreactions(ADRs)inchildrentoitsYellowCardScheme(mhra.gov.uk/yellowcard).Recognizingthatitisimpracticalto

reportallsuspectedADRsinchildren,thenewguidanceasksthathealthcareprofessionalsreportthosereactionsthatareserious,medicallysignificantorresult

http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&ssDocName=CON454333


http://www.tga.gov.au/newsroom/media-2014-consumer-reporting.htm#.VCKa65SSySo

https://www.swissmedic.ch/aktuell/00673/02418/index.html?lang=en

https://www.swissmedic.ch/aktuell/00673/02418/index.html?lang=en

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inharm,andthosethatareassociatedwithnewerdrugsandvaccines,identifiedbyablacktrianglesymbolintheYellowCardScheme.TheguidancealsoplacesgreaterimportanceonthereportingofmedicationerrorsinchildrenresultinginsuspectedADRs,andexplainsthemanyreasonswhymonitoringofADRsinchildrenisparticularlyimportant.

►MHRAPressrelease,25September2014.

Organizations

Australia and New Zealand to keep separate regulatory authoritiesTheAustralianandNewZealandGovernmentshaveagreedtoceaseeffortstoestablishajointtherapeuticproductsregulator,theAustraliaNewZealandTherapeuticProductsAgency(ANZTPA).Thedecisionwastakenafterareviewofprogressandanassessmentofthecostsandbenefitsinvolved.Thetwocountries will continue to co-operate on theregulationoftherapeuticproducts.(1)TheNewZealandauthorityhas

announcedthatworkwillnowbeundertakentostrengthenthenationalregulatoryschemefortherapeuticproducts. (2)

► (1) JointMediaRelease,20November2014.(2) MedsafeMediarelease,20November2014.

Veterinary medicines

EU proposes veterinary medicines legislation revisions E u r o p e a n U n i o n – TheEMAhaswelcomedamajorrevisionofthelegalframeworkforveterinarymedicinesintheEUproposedbytheEuropeanCommission.Therevisionincludesmeasurestofightthedevelopmentofantimicrobial resistance, notably by restrictingtheveterinaryuseofcertainantimicrobialsthatarereservedforthetreatmentofinfectionsinpeople.Italso proposes streamlined marketing authorizationprocedures,simplerpharmacovigilancerules,betterincentivesforinnovation,andclearerrulesforinternetretailingofveterinarymedicines.OtherEUinstitutionswillnowconsider

theCommission’sproposalsandwilladopttheirpositions.

► EMA News, 10 September 2014.

Sales of veterinary antibiotics in Europe decreaseE u r o p e a n U n i o n – Salesofveterinaryantibioticshavedecreasedby15%accordingtotheFourthEuropeanSurveillanceofVeterinaryAntimicrobialConsumption (ESVAC) report. Increased awarenessofthethreatofantimicrobialresistance as well as national programmes, campaigns and restrictions havebeencitedamongthereasonsforthedecrease.TheESVACreportisissuedeveryyear

toinformantimicrobialpolicyandtheresponsible use of antimicrobials in EU Member States.


http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON457641

http://www.health.gov.au/internet/ministers/publishing.nsf/Content/health-mediarel-yr2014-dutton100.htm

http://www.health.gov.au/internet/ministers/publishing.nsf/Content/health-mediarel-yr2014-dutton100.htm

http://www.beehive.govt.nz/release/medicine-regulation-upgrade-planned

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Approved

Netupitant and palonosetron: for chemotherapy-induced nausea Product name:Akynzeo®Class:Netupitantandpalonosetronfixed-

dose combination; ATCcode:A04AA55Approval:FDAUse:Treatmentofnauseaandvomitinginpatientsundergoingcancerchemotherapy.

Benefits:Addedeffectivenessinpreventingvomitingepisodesintheacute,delayedandoverallphasesafterthestartofcancerchemotherapy,comparedwithoralpalonosetrone alone. ► FDA News release, 10 October 2014.

Naloxegol: for opioid-induced constipation Product name:Movantik®Class:Peripherallyactingopioidreceptor

antagonist; ATCcode:A06AH03Approval:FDA,EMAUse:Oraltreatmentforopioid-inducedconstipationinadultswithchronicnon-cancer pain.

Benefits:Additionalsupportivecareoptiontodecreasetheconstipatingsideeffectsofopioids.

Safety information:TheFDAisrequiringapostmarketingstudytofurtherevaluatethepotentialriskofcardiovascularadverseevents. ►FDANews,16September2014.EMA /CHMP Summary of opinion, 25September2014.

Dulaglutide: for type 2 diabetesProduct name:Trulicity®Class:Glucagon-likepeptide-1(GLP-1)

receptor agonistApproval:FDA;EMAUse:Once-weeklysubcutaneousinjectiontoimproveglycaemiccontrolinadultswithtype 2 diabetes.

Benefits:Newtreatmentoptionforpatientswithtype2diabeteswhocannotbemanagedwithfirst-lineregimens.Canbeusedaloneoraddedtoexistingtreatmentregimens.

Safety information:Dulaglutideshouldnotbeusedinpatientswithdiabeticketoacidosisorthosewithseverestomachorintestinalproblems.AsthyroidC-celltumourshavebeenobservedinrodentstudies,dulaglutideshouldnotbeusedinpatientswithapersonalorfamilyhistoryofmedullarythyroidcarcinoma(MTC),orinpatientswithmultipleendocrineneoplasiasyndrometype2(whichpredisposesthemto MTC). ► FDA News release, 18 September 2014. ► EMA /CHMP Summary of opinion, 25September2014.

Antihaemophilic factor (recombinant), porcine sequence : in acquired haemophilia A Product name:Obizur®Class:PorcinecoagulationfactorVIIIApproval:FDA(orphandrugdesignation)Use:TreatmentofbleedingepisodesinadultswithacquiredhemophiliaA(acquiredfactorVIIIdeficiency).

Benefits:PorcineFactorVIIIissimilarenoughtohumanFactorVIIItobeeffectiveinbloodclotting,butislesslikelytobeaffectedbytheantibodiesagainsthumanFactorVIIIthatarepresentinpeoplewithacquiredhaemophiliaA. ► FDA News release, 24 October 2014.

Nonacog gamma : in haemophilia BProduct name:Rixubis®Class:Antihaemorrhagic,bloodcoagulationfactorIX;ATCcode: B02BD04

Approval:EMAUse:TreatmentandprophylaxisofbleedinginpatientswithhaemophiliaB(congenitalfactorIXdeficiency)inpatientsofallagegroups.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418375.htm


http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500173691



http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002825/WC500173650.pdf



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Benefits:AbilitytopreventandtreatbleedsinpatientswithhaemophiliaBincludingduring surgery. ►EMA/CHMPSummaryofopinion,23October 2014.

Afamelanotide : for erythropoietic protoporphyriaProduct name:Scenesse®Class:ProtectiveagainstUVradiationfor

systemic use; ATCcode: D02BB02 Approval:EMA(orphandesignation)Use:Preventionofphototoxicityinadultswitherythropoieticprotoporphyria(EPP),a rare genetic disease causing intolerance tolight.

Benefits:Afamelanotidestimulatestheproductionofeumelanin,whichnaturallyprotectstheskinagainstphototoxicreactionscausedbysunlight,therebysignificantlyimprovingpatients’qualityoflife.

Safety information:Thecompanywillimplement a risk management plan and establisharegistryofpatientstocollectsafetyandefficacydata.

Note:Theapprovalwasgrantedunderexceptionalcircumstances,despitealackofrobustefficacydataduetothedifficultiestorecruitpatientsforplacebo-controlled trials. Assessment wassupportedbydatafromtheuseofthemedicineincompassionateuseprogrammesglobally.Inaddition,theEMACommitteeheardfeedbackfrompatientsandhealthcareprofessionalsinvolvedinanexpertgroup.ThiswasthefirsttimethatpatientswereinvolvedinEMAdiscussionsonthebenefitsandrisksofamedicine (see also page 461). ► EMA Press release, 24 October 2014.

Darunavir & cobicistat: for HIV infectionProduct name:Rezolsta®Approval:EMA

Class:Antiretroviralfixed-dosecombination;ATCcode:J05AR14

Use:Treatmentofhumanimmunodeficiencyvirus(HIV)inantiretroviraltherapy(ART)-naïveadultsandART-experiencedadultswithnodarunavir(DRV)resistanceassociated mutations.

Benefits:Abilitytoprovidesustainablevirologicalsuppressionifgivenincombinationwithotherantiretroviralmedicinal products for treatment of HIV-1 infection. ► EMA/CHMP Summary of opinion, 25September2014.

Ledipasvir & sofosbuvir: for hepatitis C infectionProduct name:Harvoni®Class:Fixed-dosecombinationoftwodirect-actingantivirals.SofosbuvirisanNS5Binhibitor;ledipasvir–anewdrug–isanNS5Ainhibitor.ATCCode(temporaryclassification):J05AX65

Approval:EMA(acceleratedassessment),FDA(priorityreview,breakthroughtherapydesignation)

Use:TreatmentofchronichepatitisCvirusinfection in adults.

Benefits:HighcureratesinpatientswithchronicHCVinfectionwithouttheneedfortreatmentsinvolvinginterferons.Thelatterareassociatedwithpoortolerabilityandpotentiallyserioussideeffectsthatruleoutsuchtreatmentinaconsiderableproportion of HCV patients. ►EMANews,26September2014.FDA News release, 10 October 2014.

Dasabuvir : for hepatitis C infectionProduct name:Exviera®Class:Antiviralagent,NS5Binhibitor.ATCcode(temporaryclassification):J05AX16

Approval:EMA(acceleratedassessment)Use:TreatmentofchronichepatitisCinadults,incombinationwithothermedicinalproducts.








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Benefits:Abilitytoinhibitviralreplicationininfectedhostcellswhichcanleadtotheeradicationofthevirus,correlatingtoacureofchronichepatitisCvirus(HCV)infection,inbothnon-cirrhoticandcompensatedcirrhoticpatientswithgenotype 1a/1b HCV infection. ►EMA/CHMPopinion,20November2014.

Ombitasvir & paritaprevir & ritonavir: for hepatitis C infectionProduct name:Viekirax®Class:Fixed-dosecombinationoftwoantiviralagents,inhibitorsofNS5A(ombitasvir)andNS3/4A(paritaprevir),withritonavirasapharmacokineticenhancer.ATCcode(temporaryclassification):J05AX67

Approval:EMA(acceleratedassessment)Use:TreatmentofchronichepatitisCinadults,incombinationwithothermedicinalproducts .

Benefits:Abilitytoinhibitviralreplicationininfectedhostcellswhichcanleadtotheeradicationofthevirus,correlatingtoacureofchronichepatitisCvirus(HCV)infection,inbothnon-cirrhoticandcompensatedcirrhoticpatientswithgenotype 1a/1b and 4 HCV infection. ►EMA/CHMPopinion,20November2014.

Meningococcus B vaccineProduct name:Trumenba®Class:MeningococcalGroupBvaccine;

ATC code:J07AH09Approval:FDA(acceleratedapproval,breakthroughtherapy)

Use:Preventionofinvasivemeningococcaldisease caused by Neisseria meningitidis serogroupBinindividuals10–25yearsofage.

Benefits:FirstlicencedmeningococcalgroupBvaccineintheU.S.;inadditiontolicencedvaccinesforserogroupsA,C,Yand W. ►FDANewsrelease,29October2014.

Pembrolizumab: for advanced melanomaProduct name:Keytruda®Class:Antineoplastic;PD-1pathwayblocker(firstinclass).ATCcode(temporaryclassification):L01XC18

Approval:FDA(acceleratedapproval;breakthroughtherapy,orphanproduct,priorityreview)

Use:Treatmentofadvancedorunresectablemelanomanolongerrespondingtootherdrugs (ipilimumab, or ipilimumab and a BRAFinhibitorinpatientswhosetumorsexpressaBRAFV600mutation)

Benefits:Substantialimprovementoverexistingtherapies;shrinkingtumoursinapproximately24percentofpatients.Improvementonsurvivalremainstobeestablished.

Safety information:Potentialforsevereimmune-mediatedsideeffectsthatcaninvolvehealthyorgans,includingthelung,colon,hormone-producingglandsandliver.Insafetystudies,sucheffectsoccurred uncommonly. ► FDA News release, 4 September 2014.

Ramucirumab : for gastric cancerProduct name:Cyramza®Class:Humanreceptor-targetedantibodythatspecificallybindsVEGFReceptor2and blocks angiogenesis by binding of VEGF-A, VEGF-C, and VEGF-D.

Approval:EMA(orphandesignation)Use:Treatmentofadultpatientswithadvancedgastriccancerorgastro-oesophagealjunctionadenocarcinomawithdiseaseprogressionafterpriorplatinumandfluoropyrimidinechemotherapy.Ramucirumabcanbeusedincombinationwithpaclitaxel,orasmonotherapyinpatientsforwhomtreatmentincombinationwithpaclitaxelisnot appropriate.

Benefits:Abilitytoimprovethesurvivalinpatientscomparedtochemotherapyalone(whenusedincombinationwith

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003837/smops/Positive/human_smop_000757.jsp&mid=WC0b01ac058001d127





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chemotherapy)andcomparedtoplacebo(whenusedalone). ► EMA/CHMP Summary of opinion, 25September2014.

Secukinumab: for plaque psoriasisProduct name:Cosentyx®Class:Immunosuppressant;ATCcode:

L04AC10Approval:EMAUse:Treatmentofmoderatetosevereplaquepsoriasisinadultswhoarecandidatesforsystemictherapy

Benefits:Moreefficaciousthanplacebowithrespect to two co-primary endpoints in clinical studies. ►EMA/CHMPopinion,20November2014.

Pirfenidone: for idiopathic pulmonary fibrosisProduct name:Esbriet®Class:Immunosuppressant;ATCcode: L04AX05

Approval:FDA(fasttrack,priorityreview,orphanproduct,andbreakthroughdesignations).

Use:Treatmentofidiopathicpulmonaryfibrosis

Benefits:Additionaltreatmentoptionforpatientswithidiopathicpulmonaryfibrosis,aserious,chroniccondition.Currenttreatmentsincludeoxygentherapy,pulmonaryrehabilitation,andlungtransplant.

Notes:TheFDAalsoapprovednintedanibforthesameuse,seebelow. PirfenidonewasapprovedbyEMAin2011underorphandesignation.

Safety information:Notrecommendedforpatientswhohavesevereliverproblems,end-stagekidneydisease,orwhorequiredialysis.Patientsshouldminimizeexposuretosunlight,aspirfenidonemaycausethemtosunburnmoreeasily. ► FDA News release, 10 October 2014.

Nintedanib: for non-small cell lung cancer / idiopathic pulmonary fibrosisProduct name:EU:Vargatef®,Ofev®;

U.S.:Ofev®Class:Tyrosinekinaseinhibitoranti-neoplasticagent,angiogenesisinhibitor.ATCcode(temporaryclassification):L01XE31

Approval:EMA(orphandesignationforOfev®),FDA(fasttrack,priorityreview,orphanproduct,andbreakthroughdesignations)

Use:Vargatef®: Incombinationwithdocetaxel,treatmentoflocallyadvanced,metastaticor locally recurrent non-small cell lung cancer of adenocarcinoma tumour histologyafterfirst-linechemotherapy. Ofev®:Treatmentofidiopathicpulmonaryfibrosis.

Benefits:Vargatef®:Improvementinprogression-freesurvivalandoverallsurvivalcomparedtodocetaxelplusplacebo. Ofev®:Additional treatment option for patientswithidiopathicpulmonaryfibrosis.

Safety information:Notrecommendedforpatientswithmoderatetosevereliverproblems.Cancausebirthdefectsordeathtoanunbornbaby;womenwhoareabletogetpregnantshoulduseadequatecontraceptionduringandforatleastthreemonthsafterthelastdoseoftreatment. ► EMA/CHMP Summary of opinion, 25September2014.EMA/CHMPOpinion,20November2014.FDANewsrelease,15October2014.

Olaparib: for a subtype of ovarian cancerProduct name:Lynparza®Class:PolyADPribosepolymerase(PARP)inhibitor(first-in-class)

Approval:EMA(orphandesignation)Use:Monotherapyforthemaintenancetreatmentofadultpatientswithrelapsed,platinum-sensitiveepithelialovarian,









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fallopian tube or primary peritoneal cancer carrying a BRCA gene mutation, and whohaverespondedtoplatinum-basedchemotherapy.

Benefits:Targettedtreatmentofasubtypeofovariancancerforwhichlimitedtreatmentoptionsareavailable. ► EMA Press release, 24 October 2014.

Blinatumomab: for a rare form of acute lymphoblastic leukaemia Product name:Blincyto®Class:Immunotherapeuticmonoclonal

antibody, T-cell engager Approval:FDA(breakthroughtherapydesignation,priorityreviewandorphanproduct designation)

Use:TreatmentofrelapsedorrefractoryPhiladelphiachromosome-negativeprecursorB-cellacutelymphoblasticleukaemia.

Benefits:Potentialforsubstantialimprovementoveravailabletherapies.Themanufacturerisrequiredtoconductastudytoverifythatthedrugimprovessurvival.

Safety information:Boxedwarningabouttherisksoflowbloodpressureanddifficultybreathing(cytokinereleasesyndrome)atthestartofthefirsttreatment,difficultywiththinking(encephalopathy)andothernervoussystemsideeffects.ThemedicinewasapprovedwithaRiskEvaluationandMitigationStrategy,whichconsistsofacommunicationplantoinformhealthcareprovidersabouttheseriousrisksandthepotentialforpreparationandadministration errors. ►FDANewsrelease,3December2014.

Abuse-deterrent hydrocodone: single-entity, extended release product;

Product name:HysinglaER®Class:OpioidanalgesicApproval:FDA(inlinewithguidanceon

abuse-deterrent properties)

Use:Totreatpainsevereenoughtorequiredaily,around-the-clock,long-termopioidtreatmentandforwhichalternativetreatment options are inadequate.

Benefits:Theformulationisexpectedtoreduce abuse by ingestion, snorting or injection.

Safety information:Theproductcanstillbeabusedormisused,andcanthencauseanoverdosethatmayresultindeath.Additional postmarketing studies will be conductedtoassesstheeffectsoftheabuse-deterrentfeaturesontheriskforabuse,andtheconsequencesofthatabuseinthecommunity.

Note:Thisisthefourthextended-releaseopioidanalgesictobeapprovedbytheFDAwithlabellingconsistentwiththeFDA’s2013draftguidanceonevaluationand labelling of abuse-deterrent opioids (afterOxyContin®,Targiniq®andEmbeda®). ►FDANewsrelease,20November2014.Seealso:Guidance for Industry. Abuse-DeterrentOpioids—EvaluationandLabeling.DraftGuidance.FDA;2013.

Labelling changes approved

Ketoconazole: for Cushing’s syndromeProduct name:KetoconazoleHRA®Class:Antimycoticforsystemicuse;ATC code:J02AB02

Approval:EMA(orphandesignation;acceleratedapprovalofnewindication)

Use:TreatmentofCushing’ssyndromeBenefits:Additionaltreatmentoptionwhensurgeryorothermedicinesfailorcannotbe administered.

Note:Ketoconazolehasbeenused“off-label”formorethan30yearstotreatthisrareandpotentiallylife-threateningcondition,althoughithasneverbeenauthorizedforthisindicationintheEU.

Safety information:InJuly2013,EMArecommendedtosuspendthemarketing



http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm423977.htm

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authorizationsoforalketoconazolemedicines to treat fungal infections due totheriskofliverinjury.InthetreatmentofCushing’ssyndromehowever,thebenefitsaregreaterthantherisks,whichcan be managed by close monitoring of thepatients’liverfunction.Theproductistobeprescribedonlybyspecialistsastheposologyneedstobeindividualizedforeachpatient.RelevantinformationwillbesenttohealthcareprofessionalsintheEU. ►EMAPressrelease,26September2014.

Ulipristal: emergency contraceptive without prescription;

Product name:ellaOne®Class:Emergencycontraceptive;ATCcode: G03AD02

Approval:EMA/CHMPrecommendation,tobesenttotheEuropeanCommissionforalegally binding decision.

Use:Topreventunintendedpregnancy.Mustbetakenwithin120hours(fivedays)of

unprotectedintercourseorcontraceptivefailure;worksbestiftakenwithin24hours.

Benefits:MakingthemedicineavailablewithoutprescriptionintheEUshouldspeedupwomen’saccesstothemedicineandthereforeincreaseitseffectiveness.

Safety information:Thesafetyprofileofulipristaliscomparabletothatoflevonorgestrel-containingemergencycontraceptives,whicharealreadyavailablewithoutprescriptioninmostEUcountries and are registered for use up to 72hoursafterunprotectedintercourseorcontraceptivefailure.

Notes:IfgrantedbytheEuropeanCommission,there-classificationtonon-prescription status would in principle need to be implemented by all EU Member States.Anyexceptionregardingthenon-prescriptionstatusofthismedicinewouldfallwithintheresponsibilitiesoftheMember States. ►EMAPressrelease,21November2014.




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Publications and events

Access to treatment

2014 Access to Medicines Index launchedH a a r l e m –The2014AccesstoMedicineIndex,launchedon17November,presentsanupdatedrankingofthetop20pharmaceuticalcompanies.Keyfindingssuggestthatcompaniesdomoretoimproveaccessalthoughprogressisuneven,andthatpricingstrategiesareincreasinglytailored.Ontheotherhand,18ofthe20companieshavebeenthesubjectofsettlementsorjudgementsregardingbreachesinethicalmarketing,bribery or corruption standards or competitionlawsinthelasttwoyears.TheAccesstoMedicinesFoundation,

basedintheNetherlands,isaninternationalnot-for-profitorganisationdedicatedtoaddressingthechallengesofaccesstomedicineworldwide.TheIndexispublishedeverytwoyearsandgivesinsightsintowhatthepharmaceuticalindustryisdoingtoimprovethesituation.TheIndexisfundedbytheBill&MelindaGatesFoundation,theDutchMinistryofForeignAffairsandtheUKDepartmentforInternationalDevelopment.

► Access to Medicines Foundation. News release,17November2014.

New Lancet Commission on Essential Medicines PoliciesThe Lancethascommissionedagroupof19independentexpertsinavarietyofdisciplinestogenerateareportwhichisplannedtobepublishedbytheendof2015,30yearsaftertheNairobi

ConferenceontheRationalUseofDrugs.TheCommissionwillformulaterecommendations for global essential medicinepoliciesforthenexttwodecades.

Global access to essential medicines isahighlychargedpoliticalissue.Radicalcivilsocietyactionwasrequiredtoforcethepharmaceuticalsectortoprovidelife-savingARVstopeoplelivingwithHIV/AIDS.Today,thediscussions need to include second-lineandthird-lineantiretrovirals,aswellasmedicinesforcancer,hepatitisC,andnon-communicablediseases.TheCommission’s work will raise global awarenessofthecriticalimportanceofessentialmedicinespoliciestoachieveuniversalhealthcoverage.

► A new Lancet Commission on Essential Medicines [editorial]. TheLancet.384;9955:1642,8November2014.

WHO invites hepatitis medicines for prequalificationG e n e v a –WHOhasexpandeditslistofmedicinesinvitedforprequalificationtoincludetreatmentsforhepatitisBandC.The12thInvitationforExpressionofInterest (EOI) related to HIV and AIDS-relatedmedicinesincludessofosbuvir,simeprevirandribavirinformulations.Anadditionaldosagestrengthforflucytosineis also included.

►WHOPrequalificationupdate,19September2014.

Thelistsofmedicinesinvitedforprequalification(HIV/AIDSincludinghepatitisBandC,Malaria,Tuberculosis,

http://www.accesstomedicineindex.org/2014-access-medicine-index-more-being-done-progress-uneven

http://www.accesstomedicineindex.org/2014-access-medicine-index-more-being-done-progress-uneven

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62017-1/fulltext

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62017-1/fulltext

http://apps.who.int/prequal/info_press/pq_news_19September2014_EOI-HIV.htm

http://apps.who.int/prequal/info_press/pq_news_19September2014_EOI-HIV.htm

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ReproductiveHealth,Influenza,Zinc,andNeglectedTropicalDiseases)areavailableathttp://apps.who.int/prequal-Informationfor applicants - InvitationsforExpressionofInterest (EOI).

Antiviral Therapy special issue on access to HIV treatmentL o n d o n – A special issue of Antiviral Therapy onthesubjectofARVaccessinresource-poorcountrieshasbeenpublishedinpartnershipwithUNAIDS.Itincludesarticlesonallaspectsoftheselife-savingmedicines:discoveryanddevelopment,production,marketandpricing,procurementandsupply,effectiveuseintreatmentregimens,anddeliverytopatients. Thespecialissueincludesareview

oftheregulatoryframeworkforaccesstosafe,effectivequalitymedicines.Thearticlepointstothedisparitiesin regulatory capacity and describes howWHO-prequalificationandrelatedinitiativeshaveincreasedaccesstogood quality medicines worldwide and –perhapsmoreimportantly–arenowlayingthegroundworkforcollaborativeapproachesaimingtoensurethatpharmaceuticalproductsmeetthesame,stringent quality standards in all parts of theworld.

►AntivirTher.2014;19Supplement3.Full supplementfreelyavailableontheInternational Medical Press web site. RägoL,SilloH,‘tHoenE,ZweygarthM.Regulatory framework for access to safe, effectivequalitymedicines.AntivirTher.2014;19Suppl3:69-77.

Intellectual property

Interagency symposium on access to medical technologiesG e n e v a –TheWorldHealthOrganization(WHO), World Intellectual Property Organization(WIPO)andWorldTradeOrganization(WTO)haveheldtheirfourthtrilateralsymposium,titled“Innovationandaccesstomedicaltechnologies:challengesandopportunitiesformiddleincomecountries”.

Middle-income countries today include manycountrieswithapoorpublichealthsituationforlargepartsoftheirpopulation.Thesymposiumaimedtoidentifywaystostrengthenthecapacityofgovernmentstodevelopandapplypoliciesthatensureaccesstonewproductswhilefosteringanenvironmentconducivetoinnovation.

►WTONews,5November2014.

WHO report on patent status of hepatitis medicinesG e n e v a –Tohelpcountriesachieveequitableaccesstoquality,effective,affordable and safe Hepatitis C treatments,WHOhaspublishedananalysisofthepatentsituationforsevennewhepatitistreatments.Theanalysis,carriedoutbyThompsonReutersonbehalfofWHO,providescrucialinformationaboutthepatentsthemselvesandthecountrieswhichtheycover.Thisinformationisvitaltoinformgovernmentpoliciesandactionswhenselectingandpurchasingmedicinesfortheirpopulations.

►WHOpublishesanalysisofpatentsituationofnewhepatitistreatments[webpage].Published4November2014.

http://apps.who.int/prequal/info_applicants/info_for_applicants_EOIs.htm

http://apps.who.int/prequal/info_applicants/info_for_applicants_EOIs.htm

http://www.intmedpress.com/index.cfm?bSubmitted=1&pID=88&iJournalVolumeID=74&iJournalIssueAndSupplementID=316

http://www.intmedpress.com/serveFile.cfm?sUID=aaabab1f-ced7-4ae6-a01b-bd110c9d1312

http://www.intmedpress.com/serveFile.cfm?sUID=aaabab1f-ced7-4ae6-a01b-bd110c9d1312

http://www.wto.org/english/news_e/news14_e/trip_10nov14_e.htm

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NIH and FDA win top award for meningitis vaccine licensing deal Wa s h i n g t o n –TheNationalInstitutesofHealth(NIH)andtheFDAhavereceivedthe“2014DealsofDistinctionAward”fortheyear’smostoutstandingintellectualpropertylicensingdealfortechnologytransfer of a new, low-cost serogroup A meningitisvaccinenamedMenAfriVac.AccordingtoWHO,80–85%ofall

meningitisinfectionsinsub-SaharanAfricaarefromgroupA.Thevaccinehasalowproduction cost and does not require constantrefrigeration.ThetechnologywaslicensedfromtheNIHOfficeofTechnologyTransfertoPATH,aSeattle-basednon-profitleaderinglobalhealthinnovation,andthensublicensedtotheSerumInstituteofIndia(SII)undertheMeningitisVaccineProject,apartnershipof PATH and WHO.Thedealhasenabledthemanufacture

of MenAfriVac at an affordable cost for 26AfricancountrieswhereserogroupA meningitis is most common. To date, morethan150millionpeoplein12Africancountrieshavebeenvaccinated,withnoreported cases of serogroup A meningitis invaccinatedpopulations.

► LicensingExecutivesSociety(USAandCanada)Inc.PressRelease,9September2014.

Medicines for children

Improving medicines for children in CanadaO t t a w a –AnexpertpanelreportreleasedbytheCouncilofCanadianAcademiesaddressestheimportanceofdevelopingsafeandeffectivemedicinesforchildren.Thepaneladvisesthatstudyingmedicinesinchildrenisalwayspossibleandisintheirbestinterests.Thereportwas

requestedbytheMinisterofHealth,onbehalfofHealthCanada.Childrenrespondtomedicines

differentlyfromadults,andmanyofthemedicinesthattheytakehavenotbeenprovensafeandeffectiveinchildren.ThepanelfoundthatintheU.S.andtheEUpaediatricmedicinesresearchis encouraged, required, and monitored inwaysthatofferlessonsforCanada,andthat,whilepaediatricmedicinesresearchisaCanadianstrength,itrequires reinforcement and sustained capacityandinfrastructuretorealizeitsfullpotential.Thereportstressestheneed for collaboration across sectors and countries, and for tailored solutions reflectingtheuniqueCanadiancontext.Thiscomprehensive,evidence-based

assessmentofthestateofresearchandregulationsonchildren’smedicineswillserveasanimportantresourceforpolicy-makers,regulators,healthcareprofessionalsandresearchersintheyearstocome.ItisavailablebothinEnglishandinFrench.

► Council of Canadian Academies, News, 18 September 2014.

Medicines use

Study shows better drug and antibiotic use where there is policy implementationA study of public sector medicines use andprescribingindicatorsindicatesthatbetween 2002 and 2008 implementation of rational medicines use policies in countriesisassociatedwithbettermedicinesuseinthepublicsector.Forexample,therewaslessantibioticuseforupperrespiratorytractinfectioninthosecountriesthatreportedimplementationofpoliciesthaninthosethatdidnot.

http://www.lesusacanada.org/newsroom/press-releases/dda2014



http://www.scienceadvice.ca/en/news.aspx?id=139

http://www.scienceadvice.ca/en/news.aspx?id=139

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DatacamefromsurveysonmedicineusesconductedinprimaryhealthcarefacilitiesbyvariousresearchersaccordingtoamethodologyandindicatorsestablishedbyWHOincollaborationwithINRUD, and from WHO databases for 2002–2008onimplementationof36policyvariables.

Suboptimal medicine use is a global publichealthproblem.ThefindingshighlighttheimportanceofWHO’scorenormativefunctions,whichhavecomeunderthreatinrecentyears.TheauthorsemphasizetheimportanceofrecognizingthecriticalroleoftheWHOandofensuringthatitscorefunctionsaresustainedandenhanced.

► Holloway K, Henry D. WHO Essential MedicinesPoliciesandUseinDevelopingandTransitionalCountries:AnAnalysisof Reported Policy Implementation and MedicinesUseSurveys.PLoSMed11(9):e1001724.

WHO matters

Two WHO Expert Committee meetings heldG e n e v a –TheWorldHealthOrganization(WHO)ExpertCommitteesarethehighesttechnicaladvisorybodiestotheWHODirector-General and Member States. Two ExpertCommitteemeetingsonmedicineswereheldconcurrentlyinGenevaon13-17October2014.Atitsforty-ninthmeeting,theWHO

ExpertCommitteeonSpecificationsforPharmaceuticalPreparations(ECSPP)adoptedanumberofspecifications,generaltextsandInternationalChemicalReference Standards for The International Pharmacopoeia (see pages 431 ff. for anexampleofaglobalspecification).TheCommitteefurtheradopted16technicalsupplementsandeightguidelinesfor

manufacturers and regulators, including newguidanceongoodreviewpracticepreparedundertheleadershipoftheAsian-PacificEconomicCooperation’sRegulatoryHarmonizationSteeringCommittee. Atitssixty-fifthmeetingtheWHOExpert

CommitteeonBiologicalStandardization(ECBS) discussed standards and guidancerelatedtoinactivatedpoliovaccine,changesinmanufacturing,goodmanufacturing practices for biological products and regulatory risk assessment. Italsoreviewedstudiestoestablishinternationalstandards,includingthefirstWHO reference reagent for anti-malaria (Plasmodium falciparum)humanserumtosupportthedevelopmentofamalariavaccine.Cross-cuttingtopicsaddressedbyboth

Committees included collaboration and capacity-building platforms, regulatory pathwaysforapprovalofneededproducts,andsystemstopreventandmanagemedicinesshortages.TheguidelinesadoptedbytheExpert

CommitteesarepublishedasannexestotheWHOTechnicalReportSeries.Thetextsadoptedatthisyear’smeetingswillbepresentedtotheWHOGoverningBodiesin2015forinformationandfinalcomments,andwillthenconstituteWHOtechnicalguidancerecommendedforimplementation by WHO Member States andotherparties.

►ECSPP:Guidelinesareavailableat www.who.int/medicines/areas/quality_safety/quality_assurance/guidelines

►ECBSwebsite: www.who.int/biologicals/expert_committee

WHO prequalification of medicines 2013 annual reportG e n e v a –TheWHOPrequalificationTeam:medicines(PQTm)haspublished

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001724





http://www.who.int/medicines/areas/quality_safety/quality_assurance/guidelines

http://www.who.int/medicines/areas/quality_safety/quality_assurance/guidelines

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Justpublished!

CD ROMInternational PharmacopoeiaFourth Edition, 2014Including First, Second, Third and Fourth Supplements.

CD ROMQuality Assurance of Pharmaceuticals. Update 2014. WHO guidelines, related guidance and GxP training materials.IncludesatrainingvideoonGoodManufacturingPractices.

Orderonline:www.who.int/bookorders

itsannualreportfor2013.Theyearhasseenarecordnumberofproductsprequalified,includingmany‘firsts’oftheirkind.Theprequalificationteamsformedicines,vaccinesanddiagnosticshavebeenbroughttogetherwithinoneWHO unit. A wide range of supporting activities,servicesandcollaborativeinitiativesareongoingtostrengthenbothprequalificationandregulatorycapacityincountries. WHOcurrentlyhasnoregularbudget

tofunditsprequalificationactivities.FinancialsupportwasreceivedfromUNITAID,whichprovidedapproximately80%oftheoperationalcosts,fromtheBill and Melinda Gates Foundation, andfromtheGlobalFund,UNFPAandWHO’s Department of Neglected Tropical Diseases for procurement-related risk assessmentsbytheExpertReview

Panel(ERP).Althoughdonorfundingwill continue, WHO is working towards asustainablefundingmechanismthatwillcoveratleasthalfoftheoperationalcostsforprequalificationofmedicines,diagnosticsandvaccines.Inits13yearsofexistence,PQTm

hasevolvedintoaglobalplatformforregulators and manufacturers working togetheraccordingtointernationallyrecognized,harmonizedqualitystandards.Thisenablesthemtocopewiththechallengesoftoday’sincreasinglycomplexandglobalizedpharmaceuticalmarkets.Moresupportfromtheglobalcommunityisneededtoachievebroaderimpactinthiscrucial task.

►Annualreport2013.Prequalificationofmedicines:avitalservice.Geneva:WorldHealthOrganization;2014.

http://www.who.int/bookorders

http://apps.who.int/prequal/info_general/documents/annual_reports/2013/WHO-PQP_AnnualReport2013.pdf

http://apps.who.int/prequal/info_general/documents/annual_reports/2013/WHO-PQP_AnnualReport2013.pdf

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Consultation documents

The International Pharmacopoeia

FlucytosinumFlucytosine

This is a draft proposal for The International Pharmacopoeia (Working document QAS/14.599, December 2014).

The working document with line numbers is available for comment at www.who.int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, 1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: [email protected].

[Note from the Secretariat. It is proposed to revise the monograph on Flucytosine in TheInternationalPharmacopoeia.][Note from the editor. In accordance with WHO editorial policy the text reproduced below does not include tracked changes. Changes from the current monograph are indicated by insert and delete in the working document available at the above-mentioned web address.]

Molecular formula. C4H4FN3O

Relative molecular mass. 129.1

Graphic formula.

Chemical name. 5-Fluorocytosine;4-amino-5-fluoro-2(1H)-pyrimidinone; CASReg.No.2022-85-7.

Description.Awhiteoralmostwhite,crystallinepowder.

Solubility.Sparinglysolubleinwater;slightlysolubleinethanol(~750g/L)TS;practicallyinsolubleinetherR.

Category. Antifungal.

Storage. Flucytosineshouldbekeptinatightlyclosedcontainer,protectedfromlight.

Additional information.Flucytosinemeltsatabout295°C.

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RequirementsDefinition.Flucytosinecontainsnotlessthan99.0%andnotmorethan101.0%ofC4H4FN3O, calculatedwithreferencetothedriedsubstance.

Identity tests•EithertestsAaloneortestsBandCmaybeapplied.

A.Carryouttheexaminationasdescribedunder1.7Spectrophotometryintheinfraredregion.TheinfraredabsorptionspectrumisconcordantwiththespectrumobtainedfromflucytosineRSorwiththereferencespectrumofflucytosine.

B.Theabsorptionspectrumofa5.0μg/mLsolutioninhydrochloricacid(0.1mol/L)VS,whenobservedbetween230nmand350nm,exhibitsamaximumatabout286nm;theabsorbanceofa1cmlayeratthiswavelengthisabout0.36.

C.SeethetestdescribedbelowunderRelatedSubstances,TestA.Theprincipalspotobtainedwithsolution(1)correspondsinposition,appearanceandintensitywiththatobtainedwithsolution(2).

Heavy metals.Use1.0gforthepreparationofthetestsolutionasdescribedunder2.2.3Limittestforheavymetals,Procedure3;determinetheheavymetalscontentaccordingtoMethodAusingaplatinumcrucible;notmorethan20μg/g.

Clarity and colour of solution.Dissolve0.5gincarbondioxide-freewaterRanddiluteto50mLwiththesamesolvent.ThissolutionisclearandnotmoreintenselycolouredthanstandardcoloursolutionYw0whencomparedasdescribedunder1.11 Colour of liquids.

Sulfated ash.Determinethesulfatedashcontentasdescribedunder(2.3) using a platinum crucible;notmorethan1mg/g.

Loss on drying.Drytoconstantweightat105°C;itlosesnotmorethan10mg/g.

Fluorides. Prepare and store all solutions in plastic containers.

Preparethefollowingbuffersolution.Dissolve58gofsodiumchlorideRin500mLofwaterR.Add57mLofglacialaceticRand200mLofa100g/Lsolutionofcyclohexylenedinitrilotetra-aceticacidRinsodiumhydroxide(~40g/L)TS.AdjustthepHto5.0–5.5withsodiumhydroxide(~200g/L)TSanddiluteto1000mLwithwaterR.

Preparethefollowingsolutions.Forsolution(1)dissolve1.00gofthetestsubstanceinwaterRanddiluteto100.0mLwiththesamesolvent.Forsolution(2)dissolve4.42gofsodiumfluorideR,previouslydriedat120˚Cfor2hoursinwaterRtoobtainasolutioncontaining1.9mgfluorideionpermL.Dilutesolution(2)furthertoobtainstandardsolutionswiththefollowingconcentrations:solution(3)19µg/mL;solution(4)1.9µg/mL;andsolution(5)0.19µg/mL.

Addto20.0mLeachofsolution(1),(3),(4)and(5)10.0mLofthebuffersolutionandstirthesolutionusingamagneticstirrerandaplastic-coatedstirringbar.Useafluoride-ion-selectiveelectrodeandasilver/silverchloridereferenceelectrodesystem,connectedtoapotentiometercapableofindicatingreproduciblyaminimumof±0.2mV.Insertthepreviouslyrinsedanddriedelectrodesintothesolutions,stirfor5minutesandreadthepotentialinmV.Plotthelogarithmsofthefluorideionconcentrationinsolution(3),(4)and(5)versusthemeasuredpotential.

Determinetheconcentrationoffluorideioninsolution(1),readingofffromthestandardcurvethevalueofμgoffluorideionpermLcorrelatingwiththemeasuredpotentialanddividebythesamplemasstakentoobtainthecontentinthesample;notmorethan200μg/g.

http://apps.who.int/phint/en/d/Jb.7.1.7/#toc_1_7

http://apps.who.int/phint/en/d/Jb.7.1.7/#toc_1_7

http://apps.who.int/phint/en/d/Jb.7.2.2.3/#toc_2_2_3

http://apps.who.int/phint/en/d/Jb.7.2.2.3/#toc_2_2_3

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Related Substances. EithertestAortestBmaybeapplied.

A.ImpurityA(fluorouracil)andimpurityB.Carryoutthetestasdescribedunder1.14.1 Thin-layerchromatographyusingsilicagelR6asthecoatingsubstanceandamixtureof60volumesofnitromethaneR,20volumesofmethanolR,10volumesofethylacetateRand10volumesofwaterRasthemobilephase.Applyseparatelytotheplate1μLofeachofthefollowingtwosolutions.Useamixturecomposedof60volumesofmethanolR,35volumesofwaterRand5volumesofglacialaceticacidRasthesolvent.Forsolution(1)use10mgofthetestsubstancepermL.Forsolution(2)use10mgofflucytosineRSpermL.Applyalso20μLofeachofthefollowingtwosolutions.Usethesamesolventasdescribedabove.Forsolution(3)use20mgofthetestsubstancepermL.Forsolution(4)use30μgoffluorouracilRSpermL.Afterapplicationallowthespotstodryinacurrentofcoolair.Developoverapathof9cminanunsaturatedchromatographicchamber.Afterremovingtheplatefromthechromatographicchamberallowittodryexhaustivelyinacurrentofair.Examinethechromatograminultravioletlight(254nm).Flucytosine,impurityA(fluorouracil)andimpurityBareelutedwiththefollowingRfvalues:flucytosineabout0.26,impurityA(fluorouracil)about0.54andimpurityBabout0.74.

Inthechromatogramobtainedwithsolution(3)anyspotcorrespondingtoimpurityA(fluorouracil)orimpurityBisnotmoreintensethantheprincipalspotinthechromatogramobtainedwithsolution(4)(0.15%).

B.Carryoutthetestasdescribedunder1.14.4High-performanceliquidchromatography usingastainlesssteelcolumn(25cmx4.6mm)packedwithbase-deactivatedparticlesofsilicagelthesurfaceofwhichhasbeenmodifiedwithchemically-bondedoctadecylsilylgroups(5μm).

Asthemobilephaseuseasolutionpreparedasfollows.Dissolve13.6gofpotassiumdihydrogenphosphateRin950mLofwaterR,adjusttopH2.0byaddingphosphoricacidRandadd50mLofmethanolR.

Preparethefollowingsolutionsinadissolutionsolventpreparedbydissolving13.6gofpotassiumdihydrogenphosphateRin950mLofwaterRandadding50mLofmethanolR.Forsolution(1)use0.3mgofthetestsubstancepermL.Forsolution(2)diluteasuitablevolumeofsolution(1)toobtainaconcentrationof0.3µgofflucytosinepermL.Forsolution(3)use0.3µgoffluorouracilRSpermL.Forsolution(4)mix1.0mLofsolution(2)and1.0mLofsolution(3).

Operatewithaflowrateof1.1mLperminute.Asadetectoruseanultravioletspectrophotometersetatawavelengthofabout260nm.

Injectseparately20μLeachofsolution(1),(2),(3)and(4)andrecordthechromatogramsfor15timestheretentiontimeofflucytosine.

Usethechromatogramobtainedwithsolution(3)toidentifythepeakduetoimpurityA(fluorouracil).ImpurityBiselutedatarelativeretentionofabout12withreferencetoflucytosine(retentiontimeabout2.2minutes).

ThetestisnotvalidunlesstheresolutionbetweenthepeaksduetoflucytosineandimpurityA(fluorouracil)inthechromatogramobtainedwithsolution(4)isnotlessthan5.0andthesymmetryfactorforthepeakduetoflucytosineinthechromatogramobtainedwithsolution(2)isnotmorethan2.0.

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Inthechromatogramobtainedwithsolution(1):

• theareaofanypeakduetoimpurityA(fluorouracil)isnotgreaterthan1.5timestheareaofthecorrespondingpeakobtainedwithsolution(3)(0.15%);

• theareaofanypeakduetotheimpurityB,whenmultipliedbyacorrectionfactorof0.6,isnotgreaterthan1.5timestheareaoftheprincipalpeakobtainedwithsolution(2)(0.15%);

• theareaofanyotherpeak,otherthantheprincipalpeak,isnotgreaterthan0.5timestheareaoftheprincipalpeakinthechromatogramobtainedwithsolution(2)(0.05%);

• thesumoftheareaofanypeakcorrespondingtoimpurityA(fluorouracil),thecorrectedareaofanypeakcorrespondingtoimpurityBandtheareasofallotherpeaks,otherthantheprincipalpeak,isnotgreaterthan3timestheareaoftheprincipalpeakobtainedwithsolution(2)(0.3%).Disregardanypeakwithanarealessthan0.3timestheareaoftheprincipalpeakinthechromatogramobtainedwithsolution(2)(0.03%).

AssayDissolveabout0.1g,accuratelyweighed,inamixtureof40mLofaceticanhydrideRand100mLofglacialaceticacidR1,andtitratewithperchloricacid(0.1mol/L)VS,determiningtheend-pointpotentiometrically.EachmLofperchloricacid(0.1mol/L)VSisequivalentto12.91mgofC4H4FN3O.

Impurities

A.5-fluoropyrimidine-2,4(1H,3H)-dione(fluorouracil)

B.2-ethoxy-5-fluoropyrimidin-4(3H)-one

Reagent to be establishedCyclohexylenedinitrilotetra- acetic acid Rtrans-Cyclohexylene-1,2-dinitrilo-N,N,N’,N’-tetra-aceticacid,C14H22N2O8,H2O.

Description.Awhiteoralmostwhite,crystallinepowder.

Melting point.About204°C.

***

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Flucytosini infusio intravenoFlucytosineintravenousinfusion

This is a draft proposal for The International Pharmacopoeia (Working document QAS/14.600, December 2014).

The working document with line numbers is available for comment at www.who.int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, 1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: [email protected].

Description.Flucytosineintravenousinfusionisaclear,colourlessoralmostcolourlesssolution.

Category. Antifungal.

Storage.Flucytosineintravenousinfusionshouldbekeptinatightly-closedcontainer,protectedfromlight.

Additional information.StrengthsinthecurrentWHOModelListofEssentialMedicines(EML):2.5gin250mL.StrengthsinthecurrentEMLforChildren:2.5gin250mL.

RequirementsComplywiththemonographforParenteral preparations.

Definition.FlucytosineintravenousinfusionisasterilesolutioncontainingFlucytosine.Itissupplied as a ready-to-use solution.

Flucytosineintravenousinfusioncontainsnotlessthan90.0%andnotmorethan110.0%oftheamount of Flucytosine (C4H4FN3O)statedonthelabel.

Identity tests•EithertestAortestsBandCmaybeapplied.

A. Evaporate10mLoftheinfusiontodrynessonawater-bathanddrytheresidueat105°Cforabout1hour.Carryouttheexaminationasdescribedunder1.7 Spectrophotometryintheinfraredregion.TheinfraredabsorptionspectrumisconcordantwiththespectrumobtainedfromflucytosineRSorwiththereferencespectrumofflucytosine.

B. Carryoutthetestasdescribedunder1.14.1Thin-layerchromatography using silica gelR6asthecoatingsubstanceandamixtureof60volumesofnitromethaneR,20volumesofmethanolR,10volumesofethylacetateRand10volumesofwaterRasthemobilephase.Applyseparatelytotheplate1μLofeachofthefollowingtwosolutions.Useamixturecomposedof60volumesofmethanolR,35volumesofwaterRand5volumesofglacialaceticacidRasthesolvent.Forsolution(A)useanaliquotoftheinfusiontobetested.Forsolution(B)use10mgofflucytosineRSpermL.Afterapplicationallowthespotstodryinacurrentofcoolair.Developoverapathof9cminanunsaturatedchromatographicchamber.Afterremovingtheplatefromthechromatographicchamberallowittodryexhaustivelyinacurrentofair.Examinethechromatograminultravioletlight(254nm).Theprincipalspotobtainedwithsolution(A)correspondsinposition,appearanceandintensitywiththatobtainedwithsolution(B).







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C.Theabsorptionspectrum(1.6)ofthefinalsolutionpreparedforAssayA,whenobservedbetween230nmand350nm,exhibitsamaximumatabout286nmandaminimumatabout245nm.

pH value (1.13).pHoftheinfusion,6.0–8.0.

Pyrogens.Carryoutthetestasdescribedunder3.5Testforpyrogens,perkgoftherabbit’sweight,10ml.

Related substancesCarryoutthetestasdescribedunder1.14.4High-performanceliquidchromatography using astainlesssteelcolumn(25cm×4.6mm)packedwithbase-deactivatedparticlesofsilicagelthesurfaceofwhichhasbeenmodifiedwithchemically-bondedoctadecylsilylgroups(5μm).

Asthemobilephaseuseasolutionpreparedasfollows.Dissolve13.6gofpotassiumdihydrogenphosphateRin950mLofwaterR,adjusttopH2.0byaddingphosphoricacidRandadd50mLofmethanolR.

Preparethefollowingsolutionsinadissolutionsolventpreparedbydissolving13.6gofpotassiumdihydrogenphosphateRin950mLofwaterRandadding50mLofmethanolR.Forsolution(1)diluteaquantityoftheinfusiontoobtainaconcentrationof0.3mgofflucytosinepermL.Forsolution(2)diluteasuitablevolumeofsolution(1)toobtainaconcentrationof0.3µgofflucytosinepermL.Forsolution(3)use0.3µgoffluorouracilRSpermL.Forsolution(4)mix1.0mLofsolution(2)add1.0mLsolution(3).

Operatewithaflowrateof1.1mLperminute.Asadetectoruseanultravioletspectrophotometersetatawavelengthofabout260nm.

Injectseparately20μLeachofsolution(1),(2),(3)and(4)andrecordthechromatogramsfor15timestheretentiontimeofflucytosine.

Usethechromatogramobtainedwithsolution(3)toidentifythepeakduetoimpurityA(fluorouracil).Flucytosineiselutedataretentiontimeabout2.2minutes.

ThetestisnotvalidunlesstheresolutionbetweenthepeaksduetoflucytosineandimpurityA(fluorouracil)inthechromatogramobtainedwithsolution(4)isnotlessthan5.0andthesymmetryfactorforthepeakduetoflucytosineinthechromatogramobtainedwithsolution(2)isnotmorethan2.0.

Inthechromatogramobtainedwithsolution(1):

• theareaofanypeakduetotheimpurityA(fluorouracil)isnotgreaterthan5timestheareaofthecorrespondingpeakobtainedwithsolution(3)(0.5%);

AssayDiluteanaccuratelymeasuredvolumeoftheinfusionwithhydrochloricacid(0.1mol/L)VStogiveasolutioncontainingabout0.1mgpermLofFlucytosine.Dilute5.0mLoftheresultingsolutionto100.0mLwiththesamesolvent.Measuretheabsorbanceoftheresultingsolutionina1cmlayeratthemaximumatabout286nm.CalculatethecontentofFlucytosine(C4H4FN3O)usingtheabsorptivityvalueof70.9( =709).

ImpuritiesTheimpuritylimitedbytherequirementsofthismonographislistedinthemonographforFlucytosine.

***


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ATC/DDD ClassificationATC/DDDClassification(Temporary)

The following ATC codes and DDDs were agreed at the meeting of the WHO International Working Group for Drug Statistics Methodology in October 2014.Comments or objections to the decisions from the meeting should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology before 1 February 2015. If no objections are received before this date, the new ATC codes and DDDs will be considered final and included in the January 2016 version of the ATC/DDD Index.

New ATC 5th level codes:

ATC level name/INN ATC codeasfotase alfa A16AB13ataluren M09AX03atazanavirandcobicistat J05AR15belinostat L01XX49benzylalcohol P03AX06blinatumomab L01XC19brivaracetam N03AX23bupropionandnaltrexone A08AA62ceftolozaneandenzymeinhibitor J01DI54dasabuvir J05AX16dasabuvir,ombitasvir,paritaprevirandritonavir J05AX66drospirenone G03AC10efinaconazole D01AC19emtricitabineandtenofoviralafenamide J05AR17emtricitabine,tenofoviralafenamide,elvitegravirandcobicistat J05AR18insulin degludec and liraglutide A10AE56isavuconazole J02AC05lamivudineandraltegravir J05AR16lenvatinib L01XE29luliconazole D01AC18metforminandempagliflozin A10BD20nemonoxacin J01MB08nintedanib L01XE31nivolumab L01XC17obeticholicacid A05AA04octenidine R02AA21olodaterol and tiotropium bromide R03AL06ombitasvir,paritaprevirandritonavir J05AX67papillomavirus(humantypes6,11,16,18,31,33,45,52,58) J07BM03pembrolizumab L01XC18

Continued/

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WHO Drug Information Vol. 28, No. 4, 2014 ATC/DDD Classification (Temporary)

/Continued

ATC level name/INN ATC codepitolisant N07XX11rosuvastatinandvalsartan C10BX10sebelipase alfa A16AB14sirolimus S01XA23smallpox,liveattenuated J07BX01sofosbuvirandledipasvir J05AX65sonidegib L01XX48tasimelteon N05CH03tedizolid J01XX11

New DDDs: ATC level name/INN DDD unit Adm. R.a ATC codeabarelix 3.6 mg P L02BX01albiglutide 5.7 mg P A10BX13aripiprazole 13.3 mg P depot N05AX12azilsartanmedoxomil 40 mg O C09CA09canagliflozin 0.2 g O A10BX11cobicistat 0.15 g O V03AX03daclatasvir 60 mg O J05AX14dexmethylphenidate 15 mg O N06BA11lomitapide 40 mg O C10AX12loxapine 9.1 mg Inhalpowder2) N05AH01misoprostol 0.2 mg V1) G02AD06olodaterol 5 mcg Inhalsol R03AC19peginterferon beta-1a 8.9 mcg P L03AB13riociguat 4.5 mg O C02KX05siltuximab 37 mg P L04AC11simeprevir 0.15 g O J05AE14sucroferricoxyhydroxide 1.5 g O V03AE05vedolizumab 5.4 mg P L04AA33

a Route of administration (Adm.R): O=oral; P=parenteral; V=vaginal; Inhal=inhalation1) vaginal insert, refers to the content of one vaginal insert2) delivered dose æ

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ATC/DDDClassification(Final)

The following ATC codes, DDDs and alterations were agreed at the meeting of the WHO International Working Group for Drug Statistics Methodology in March 2014. These are considered as final and will be included in the January 2015 version of the ATC/DDD Index.

New ATC 5th level codes:ATC level name/INN ATC codeasunaprevir J05AE15ceritinib L01XE28daclatasvir J05AX14dasiprotimut-T L03AX19decamethoxine D08AJ10evolocumab C10AX13fabomotizole N05BX04fimasartan C09CA10fluticasonefuroate R03BA09ivermectin D11AX22linagliptinandempagliflozin A10BD19macimorelin V04CD06metformin and gemigliptin A10BD18mifepristone, combinations G03XB51siltuximab L04AC11sofosbuvir J05AX15susoctocog alfa B02BD14trifluridine,combinations L01BC59vorapaxar B01AC26

Change of ATC level name:Previous New ATC codeSulfonamides,ureaderivatives Sulfonylureas A10BB

New DDDs:ATC level name/INN DDD unit Adm. R.a ATC codealemtuzumab 0.13 mg P L04AA34benzydamide 9 mg O A01AD02dexlansoprazole 30 mg O A02BC06fabomotizole 30 mg O N05BX04granisetron 3.1 mg TD A04AA02macitentan 10 mg O C02KX04sofosbuvir 0.4 g O J05AX15vortioxetine 10 mg O N06AX26

a Route of administration (Adm.R): O=oral; P=parenteral; TD=transdermal æ

WHO Drug Information, Vol. 28, No. 4, 2014 Proposed INN: List 112

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International Nonproprietary Names for Pharmaceutical Substances (INN)

Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances, the names given in the list on the following pages are under consideration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a name in the lists of Proposed International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy.

Lists of Proposed (1–109) and Recommended (1–70) International Nonproprietary Names can be found in Cumulative List No. 15, 2013 (available in CD-ROM only). The statements indicating action and use are based largely on information supplied by the manufacturer. This information is merely meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will neither be revised nor included in the Cumulative Lists of INNs.

Dénominations communes internationales des Substances pharmaceutiques (DCI) Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques les dénominations ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisation de la substance correspondante en médecine ou en pharmacie.

On trouvera d'autres listes de Dénominations communes internationales proposées (1–109) et recommandées (1–70) dans la Liste récapitulative No. 15, 2013 (disponible sur CD-ROM seulement). Les mentions indiquant les propriétés et les indications des substances sont fondées sur les renseignements communiqués par le fabricant. Elles ne visent qu'à donner une idée de l'utilisation potentielle des nouvelles substances au moment où elles sont l'objet de propositions de DCI. L'OMS n'est pas en mesure de confirmer ces déclarations ni de faire de commentaires sur l'efficacité du mode d'action ainsi décrit. En raison de leur caractère provisoire, ces informations ne figureront pas dans les listes récapitulatives de DCI.

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI) De conformidad con lo que dispone el párrafo 3 del "Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas", se comunica por el presente anuncio que las denominaciones detalladas en las páginas siguientes están sometidas a estudio por la Organización Mundial de La Salud como Denominaciones Comunes Internacionales Propuestas. La inclusión de una denominación en las listas de las DCI Propuestas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia.

Las listas de Denominaciones Comunes Internacionales Propuestas (1–109) y Recomendadas (1–70) se encuentran reunidas en Cumulative List No. 15, 2013 (disponible sólo en CD-ROM). Las indicaciones sobre acción y uso que aparecen se basan principalmente en la información facilitada por los fabricantes. Esta información tiene por objeto dar una idea únicamente de las posibilidades de aplicación de las nuevas sustancias a las que se asigna una DCI Propuesta. La OMS no está facultada para respaldar esas indicaciones ni para formular comentarios sobre la eficacia de la acción que se atribuye al producto. Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listas recapitulativas de DCI.

Proposed INN: List 112 WHO Drug Information, Vol. 28, No. 4, 2014

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Proposed International Nonproprietary Names: List 112 Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme of the World Health Organization within four months of the date of their publication in WHO Drug Information, i.e., for List 112 Proposed INN not later than 15 May 2015. Publication date: 16/01/2015

Dénominations communes internationales proposées: Liste 112 Des observations ou des objections formelles à l'égard des dénominations proposées peuvent être adressées par toute personne au Programme des Dénominations communes internationales de l'Organisation mondiale de la Santé dans un délai de quatre mois à compter de la date de leur publication dans WHO Drug Information, c'est à dire pour la Liste 112 de DCI Proposées le 15 mais 2015 au plus tard. Date de publication : 16/01/2015

Denominaciones Comunes Internacionales Propuestas: Lista 112 Cualquier persona puede dirigir observaciones u objeciones respecto de las denominaciones propuestas, al Programa de Denominaciones Comunes Internacionales de la Organización Mundial de la Salud, en un plazo de cuatro meses, contados desde la fecha de su publicación en WHO Drug Information, es decir, para la Lista 112 de DCI Propuestas el 15 mde Mayo de 2015 a más tardar. Fecha de publicación: 16/01/2015

Proposed INN (Latin, English, French, Spanish) DCI Proposée DCI Propuesta

Chemical name or description: Action and use: Molecular formula Chemical Abstracts Service (CAS) registry number: Graphic formula Nom chimique ou description: Propriétés et indications: Formule brute: Numéro dans le registre du CAS: Formule développée Nombre químico o descripción: Acción y uso: Fórmula molecular Número de registro del CAS: Fórmula desarrollada

abemaciclibum abemaciclib N-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl}-5-fluoro-

4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol- 6-yl]pyrimidin-2-amine antineoplastic

abémaciclib N-{5-[(4-éthylpipérazin-1-yl)méthyl]pyridin-2-yl}-5-fluoro- 4-[4-fluoro-2-méthyl-1-(propan-2-yl)-1H-benzimidazol- 6-yl]pyrimidin-2-amine antinéoplasique

abemaciclib N-{5-[(4-etilpiperazin-1-il)metil]piridin-2-il}-5-fluoro- 4-[4-fluoro-2-metil-1-(propan-2-il)-1H-benzoimidazol- 6-il]pirimidin-2-amina antineoplásico

C27H32F2N8 1231929-97-7

N

N

NH

NN

H3C

CH3H3C

FN

N

N CH3

F


487

amiselimodum amiselimod 2-amino-2-{2-[4-(heptyloxy)-

3-(trifluoromethyl)phenyl]ethyl}propane-1,3-diol immunomodulator

amisélimod 2-amino-2-{2-[4-(heptyloxy)- 3-(trifluorométhyl)phényl]éthyl}propane-1,3-diol immunomodulateur

amiselimod 2-amino-2-{2-[4-(heptiloxi)- 3-(trifluorometil)fenil]etil}propano-1,3-diol inmunomodulador

C19H30F3NO3

942399-20-4

OH3C

OH

NH2

OH

CF3

asinerceptum # asinercept fusion protein for immune applications (FPIA) comprising

the Homo sapiens FAS (Fas cell surface death receptor, TNFRSF6, tumor necrosis factor receptor (TNFR) superfamily member 6, FAS1, APO-1, CD95) extracellular domain, fused with Homo sapiens immunoglobulin G1 Fc fragment; Homo sapiens FAS precursor fragment 26-172 (1-147) -gamma1 chain H-CH2-CH3 fragment [Homo sapiens IGHG1*03 (hinge 5-15 (148-158), CH2 (159-268), CH3 (269-373), CHS (374-375))] (148-375); dimer (148-148':154-154':157-157')-trisdisulfide immunomodulator

asinercept protéine de fusion pour applications immunitaires (FPIA) comprenant le domaine extracellulaire d’Homo sapiens FAS (récepteur de mort membranaire Fas, TNFRSF6, membre 6 de la superfamille des récepteurs du facteur de nécrose tumorale (TNFR), FAS1, APO-1, CD95), fusionné au fragment Fc de l’immunoglobuline G1 d’Homo sapiens; Homo sapiens FAS fragment 26-172 du précurseur (1-147)-fragment H-CH2-CH3 de la chaîne gamma1 [Homo sapiens IGHG1*03 (charnière 5-15 (148-158), CH2 (159-268), CH3 (269-373), CHS (374-375))] (148-375); dimère (148-148':154-154':157-157')-trisdisulfure immunomodulateur


488

asinercept proteína de fusión para aplicaciones inmunitarias (FPIA) que comprende el dominio extracelular de Homo sapiens FAS (receptor de muerte Fas de membrana, TNFRSF6, miembro 6 de la superfamilia de receptores del factor de necrosis tumoral (TNFR), FAS1, APO-1, CD95), fusionado con el fragmento Fc de la inmunoglobulina G1 de Homo sapiens; FAS de Homo sapiens fragmento 26-172 del precursor (1-147) -fragmento H-CH2-CH3 de la cadena gamma1 [Homo sapiens IGHG1*03 (bisagra 5-15 (148-158), CH2 (159-268), CH3 (269-373), CHS (374-375))] (148-375); dímero (148-148':154-154':157-157')-trisdisulfuro inmunomodulador

1450882-18-4 Fused chain / chaine fusionnée / cadena fusionada

QVTDINSKGL ELRKTVTTVE TQNLEGLHHD GQFCHKPCPP GERKARDCTV 50NGDEPDCVPC QEGKEYTDKA HFSSKCRRCR LCDEGHGLEV EINCTRTQNT 100KCRCKPNFFC NSTVCEHCDP CTKCEHGIIK ECTLTSNTKC KEEGSRSCDK 150THTCPPCPAP ELLGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE 200VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK 250VSNKALPAPI EKTISKAKGQ PREPQVYTLP PSREEMTKNQ VSLTCLVKGF 300YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFFLYSKLTV DKSRWQQGNV 350FSCSVMHEAL HNHYTQKSLS LSPGK 375 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntrachain FAS 34-48 38-57 60-76 79-94 82-102 104-118 121-132 124-140 34'-48' 38'-57' 60'-76' 79'-94' 82'-102' 104'-118' 121'-132' 124'-140' IGHG1 (C23-C104) 189-249 295-353 189'-249' 295'-353' Interchain IGHG1 (h5, h 11, h 14) 148-148' 154-154' 157-157'

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónFAS: 93, 111, 93', 111': complex mono-, bi-, tri- and tetra-antennary oligosaccharides, partially sialylated, oligosaccharides complexes de structure ramifiée (de 1 à 4 branches), partiellementsialylés, oligosacáridos complejos mono-bi, tri y tetra-antenado, parcialmente sialiladosIGHG1 CH2 N84.4: 225, 225': complex mono- and biantennary non-sialylated oligosaccharides, oligosaccharides complexes de structure ramifiée (de 1 à 2 branches) non-sialylés, oligosacáridos complejo mono- and biantenado non-sialilado

Other post-translational modifications / Autres modifications post-traductionnelles / Otras modificaciones post-traduccionales:H CHS K2 C-terminal lysine clipping, coupure de la lysine C-terminale, supresión de lisina C-terminal:375, 375'

atezolizumabum # atezolizumab immunoglobulin G1-kappa, anti-[Homo sapiens CD274

(programmed death ligand 1, PDL1, PD-L1, B7 homolog 1, B7H1)], humanized monoclonal antibody; gamma1 heavy chain (1-448) [humanized VH (Homo sapiens IGHV3-23*04 (86.70%) -(IGHD)-IGHJ4*01) [8.8.11] (1-118) -Homo sapiens IGHG1*03 (CH1 R120>K (215) (119-216), hinge (217-231), CH2 N84.4>A (298) (232-341), CH3 (342-446), CHS (447-448)) (119-448)], (221-214')-disulfide with kappa light chain (1’-214’) [humanized V-KAPPA (Homo sapiens IGKV1-5*01 (87.90%) -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimer (227-227":230-230")-bisdisulfide immunomodulator, antineoplastic


489

atézolizumab immunoglobuline G1-kappa, anti-[Homo sapiens CD274 (ligand 1 de mort programmée, PDL1, PD-L1, homologue 1 de B7, B7H1)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-448) [VH humanisé (Homo sapiens IGHV3-23*04 (86.70%) -(IGHD)-IGHJ4*01) [8.8.11] (1-118) -Homo sapiens IGHG1*03 (CH1 R120>K (215) (119-216), charnière (217-231), CH2 N84.4>A (298) (232-341), CH3 (342-446), CHS (447-448)) (119-448)], (221-214')-disulfure avec la chaîne légère kappa (1’-214’) [V-KAPPA humanisé (Homo sapiens IGKV1-5*01 (87.90%) -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (227-227":230-230")-bisdisulfure immunomodulateur, antinéoplasique

atezolizumab inmunoglobulina G1-kappa, anti-[Homo sapiens CD274 (ligando 1 de muerte programada, PDL1, PD-L1, homólogo 1 de B7, B7H1)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-448) [VH humanizado (Homo sapiens IGHV3-23*04 (86.70%) -(IGHD)-IGHJ4*01) [8.8.11] (1-118) -Homo sapiens IGHG1*03 (CH1 R120>K (215) (119-216), bisagra (217-231), CH2 N84.4>A (298) (232-341), CH3 (342-446), CHS (447-448)) (119-448)], (221-214')-disulfuro com la cadena ligera kappa (1’-214’) [V-KAPPA humanizado (Homo sapiens IGKV1-5*01 (87.90%) -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (227-227":230-230")-bisdisulfuro inmunomodulador, antineoplásico

1380723-44-3

Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG LVQPGGSLRL SCAASGFTFS DSWIHWVRQA PGKGLEWVAW 50ISPYGGSTYY ADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCARRH 100WPGGFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYAST 300YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448

Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCRASQDVS TAVAWYQQKP GKAPKLLIYS 50ASFLYSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YLYHPATFGQ 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H (C23-C104) 22-96 145-201 262-322 368-426 22''-96'' 145''-201'' 262''-322'' 368''-426''Intra-L (C23-C104) 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L (h 5-CL 126) 221-214' 221''-214''' Inter-H-H (h 11, h 14) 227-227'' 230-230''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónH CH2 N84.4>A (298, 298'):No N-glycosylation sites/pas de sites de N-glycosylation/ Ningun posición de N-glicosilación

avoralstatum avoralstat 3-{2-[(4-carbamimidoylphenyl)carbamoyl]-4-ethenyl-5-

methoxyphenyl}-6-[(cyclopropylmethyl)carbamoyl]pyridine-2-carboxylic acid kallikrein inhibitor


490

avoralstat acide 3-{2-[(4-carbamimidoylphenyl)carbamoyl]-4-éthényl-5-méthoxyphényl}- 6-[(cyclopropylméthyl)carbamoyl]pyridine-2-carboxylique inhibiteur de la kallicréine

avoralstat ácido 3-{2-[(4-carbamimidoilfenil)carbamoil]-4-etenil- 5-metoxifenil}-6-[(ciclopropilmetil)carbamoil]piridina- 2-carboxílico inhibidor de la kalikreína

C28H27N5O5

918407-35-9

N CO2HNH

OCH3

CH2

HN

OH2N

NH

O

axalimogenum filolisbacum # axalimogene filolisbac a live attenuated recombinant strain of Listeria

monocytogenes (Lm) bacterium bioengineered to secrete an antigen-adjuvant fusion (tLLO-E7) protein consisting of non-hemolytic listeriolysin O (truncated LLO, tLLO) fused to the human papilloma virus-16 (HPV-16) E7 protein, contained within the multi-copy plasmid pGG-55. The bacterial strain used, XFL-7, had been attenuated by excision of the essential transcription activator gene for virulence gene expression prfA (10403S ∆ prfA) and complemented with a mutated, less active prfA to maintain in vivo retention. In plasmid pGG-55, the Lm hly promoter drives the expression of fusion protein tLLO-E7, an approximately 67-kDa protein. The tLLO fragment of the fusion gene codes for the first 440 amino acids of full-length listeriolysin and is genetically fused to the E7 gene using the restriction site XhoI. The plasmid pGG55 is retained in XFL-7 in vivo due to the expression of the mutated PrfA protein. gene therapy product (antineoplastic)


491

axalimogène filolisbac souche bactérienne vivante atténuée de Listeria monocytogenes (Lm) recombinante qui secrétant une protéine de fusion antigène-adjuvant (tLLO-E7) qui comprend une listériolysine O non-hémolytique (LLO tronquée, tLLO), fusionnée à la protéine E7 du papillomavirus humain de type 16 (HPV-16), contenue dans le plasmide à copies multiples pGC-55. La souche bactérienne utilisée, XFL-7, a été atténuée par excision du gène prfA essentiel à l’activation de la transcription des gènes de virulence (10403S ∆ prfA) et complémenté par un gène prfA muté, moins actif, afin de maintenir une rétention in vivo. Dans le plasmide pGC-55, le promoteur Lm hly contrôle l’expression de la protéine de fusion tLLO-E7, une protéine d’approximativement 67 kDa. Le fragment tLLO du gène de fusion code les premiers 440 acides aminés de la listériolysine et est génétiquement fusionné au gène E7 en utilisant le site de restriction XhoI. Le plasmide pGG55 est retenu dans XFL-7 in vivo par l’expression de la protéine PrfA mutée. produit de thérapie génique (antinéoplasique)

axalimogén filolisbac Cepa bacteriana viva atenuada de Listeria monocytogenes (Lm) recombinante secretando una proteína de fusión antígeno-adyuvante (tLLO-E7) que consiste en una listeriolisina O no-hemolítica (LLO truncada, tLLO), fusionada con la proteína E7 del papilomavirus humano de tipo 16 (HPV-16) contenida en el plásmido multicopia pGC-55. La cepa bacteriana utilizada, XFL-7, se ha atenuado por escisión del gen prfA esencial a la activación de la transcripción de los genes de virulencia (10403S ∆ prfA) y completada por un gen prfA mutado, menos activo, con el fín de mantener la retención in vivo. En el plásmido pGC-55, el promotor Lm hly controla la expresión de la proteína de fusión tLLO-E7, una proteína de aproximadamente 67 kDa. El fragmento tLLO del gen de fusión codifica los primeros 440 aminoácidos de la listeriolisina y se fusiona genéticamente con el gen E7 utilizando el sitio de restricción XhoI. El plásmido pGG55 es retenido en XFL-7 in vivo por la expresión de la proteína PrfA mutada. producto para terapia génica (antineoplásico)

balixafortidum balixafortide cyclo[L-alanyl-L-cysteinyl-L-seryl-L-alanyl-D-prolyl-(2S)-2,4-

diaminobutanoyl-L-arginyl-L-tyrosyl-L-cysteinyl-L-tyrosyl- L-glutaminyl-L-lysyl-D-prolyl-L-prolyl-L-tyrosyl-L-histidyl] (2-9)-disulfide chemokine CXCR4 receptor antagonist

balixafortide (2-9)-disulfure de cyclo[L-alanyl-L-cystéinyl-L-séryl-L-alanyl-D-prolyl-(2S)-2,4-diaminobutanoyl-L-arginyl-L-tyrosyl- L-cystéinyl-L-tyrosyl-L-glutaminyl-L-lysyl-D-prolyl-L-prolyl- L-tyrosyl-L-histidyl] antagoniste du récepteur CXCR4 de chimiokine


492

balixafortida (2-9)-disulfuro de ciclo[L-alanil-L-cisteinil-L-seril-L-alanil- D-prolil-(2S)-2,4-diaminobutanoil-L-arginil-L-tirosil- L-cisteinil-L-tirosil-L-glutaminil-L-lisil-D-prolil-L-prolil-L-tirosil-L-histidil] antagonista del receptor de quimiokina CXC tipo 4 (CXCR4)

C84H118N24O21S2 1051366-32-5

NH

H

NH2

1

1016His

Ala

Tyr

Cys

Pro

Ser

D-Pro

Ala

Lys

D-Pro

Gln Tyr Cys Tyr

O

Arg

bovhyaluronidasum azoximerum # bovhyaluronidase azoximer hyaluronidase-2 bovine (hyaluronoglucosaminidase-2,

Hyal-2, EC 3.2.1.35) Bos taurus precursor protein linked to poly{[1-(carboxymethyl)piperazin-1-ium-1,4-diyl bromide]ethylene-co-[(piperazine-1,4-diyl 1-oxide)ethylene]} by an amido covalent bond enzyme

bovhyaluronidase azoximère précurseur de la hyaluronidase-2 bovine (hyaluronoglucosaminidase-2, Hyal-2, EC 3.2.1.35) Bos taurus lié au poly{[bromure de 1-(carboxyméthyl)pipérazin-1-ium-1,4-diyl]éthylène-co-[(1-oxyde de pipérazin- 1,4-diyl)éthylène]} par une liaison covalente amide enzyme

bovhialuronidasa azoxímero precursor de la hialuronidasa-2 bovina (hialuronoglucosaminidasa-2, Hyal-2, EC 3.2.1.35) Bos taurus unido al poli{[bromuro de 1-(carboximetil)piperazin-1-io-1,4-diil]etileno-co-[(1-óxido de piperazin- 1,4-diil)etileno]} por un enlace covalente amida enzima

1383710-57-3

N+

NxBr N N

Oy

n

R

O

R =

OH

NH Enz

or / ou / o

Hyal-2 Bos taurus seq. (H2N-Enz) / Hyal-2 Bos taurus seq. (H2N-Enz) / Hyal-2 Bos taurus seq. (H2N-Enz)MWTGLGPAVT LALVLVVAWA TELKPTAPPI FTGRPFVVAW DVPTQDCGPR 50HKMPLDPKDM KAFDVQASPN EGFVNQNITI FYRDRLGMYP HFNSVGRSVH 100GGVPQNGSLW VHLEMLKGHV EHYIRTQEPA GLAVIDWEDW RPVWVRNWQD 150KDVYRRLSRH LVAIRHPDWP PERVAKEAQY EFEFAARQFM LETLRFVKAF 200RPRHLWGFYL FPDCYNHDYV QNWETYTGRC PDVEVSRNDQ LAWLWAESTA 250LFPSVYLEET LASSTHGRNF VSFRVQEALR VADVHHANHA LPVYVFTRPT 300YSRGLTGLSE MDLISTIGES AALGAAGVIL WGDAGFTTSN ETCRRLKDYL 350TRSLVPYVVN VSWAAQYCSW AQCHGHGRCV RRDPNAHTFL HLSASSFRLV 400PSHAPDEPRL RPEGELSWAD RNHLQMHFRC QCYLGWGGEQ CQWDRRRAAG 450GASGAWAGSH LTGLLAVAVL AFT 473

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro47-343 214-230 368-379 373-430 432-441

Glycosylation sites (N) / Sites de glycosylation (N) / Posiciones de glicosilación (N)Asn-77 Asn-106 Asn-340 Asn-360

Carrier & Hyal-2 (H2N-Enz) / Transporteur & Hyal-2 (H2N-Enz) / Transportador & Hyal-2 (H2N-Enz)


493

brolucizumabum # brolucizumab immunoglobulin scFv, anti-[Homo sapiens VEGFA

(vascular endothelial growth factor A, VEGF-A, VEGF)], humanized monoclonal antibody single chain; scFv (1-252) [methionyl (1) -humanized V-KAPPA (Homo sapiens IGKV1-5*01 (87.60%)-IGKJ2*01 E125>T (108), I126>V (109), K127>L (110) [6.3.12] (2-111) -21-mer (glycyl-tetrakis(tetraglycyl-seryl)) linker (112-132) -humanized VH (Homo sapiens IGHV3-66*01 (80.40%)-(IGHD)-IGHJ1*01 [9.7.13] (133-252) angiogenesis inhibitor

brolucizumab immunoglobuline scFv, anti-[Homo sapiens VEGFA (facteur de croissance A de l’endothélium vasculaire, VEGF-A, VEGF)], anticorps monoclonal humanisé à chaîne unique; scFv (1-252) [méthionyl (1) -V-KAPPA humanisé (Homo sapiens IGKV1-5*01 (87.60%)- IGKJ2*01 E125>T (108), I126>V (109), K127>L (110) [6.3.12] (2-111) -21-mer (glycyl-tétrakis(tétraglycyl-séryl)) linker (112-132) -VH humanisé (Homo sapiens IGHV3-66*01 (80.40%)-(IGHD)-IGHJ1*01 [9.7.13] (133-252) inhibiteur de l'angiogénèse

brolucizumab inmunoglobulina scFv, anti-[VEGFA de Homo sapiens (factor de crecimiento A del endotelio vascular, VEGF-A, VEGF)], anticuerpo monoclonal humanizado monocatenario; scFv (1-252) [metionil (1) -V-KAPPA humanizado (Homo sapiens IGKV1-5*01 (87.60%)- IGKJ2*01 E125>T (108), I126>V (109), K127>L (110) [6.3.12] (2-111) -21-mer (glicil-tetrakis(tetraglicil-seril)) conector (112-132) -VH humanizado (Homo sapiens IGHV3-66*01 (80.40%)-(IGHD)-IGHJ1*01 [9.7.13] (133-252) inhibidor de la angiogénesis

1531589-13-5

MEIVMTQSPS TLSASVGDRV IITCQASEII HSWLAWYQQK PGKAPKLLIY 50LASTLASGVP SRFSGSGSGA EFTLTISSLQ PDDFATYYCQ NVYLASTNGA 100NFGQGTKLTV LGGGGGSGGG GSGGGGSGGG GSEVQLVESG GGLVQPGGSL 150RLSCTASGFS LTDYYYMTWV RQAPGKGLEW VGFIDPDDDP YYATWAKGRF 200TISRDNSKNT LYLQMNSLRA EDTAVYYCAG GDHNSGWGLD IWGQGTLVTV 250SS 252

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-chain C23 C104 24-89 154-228

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónNone

centanafadinum centanafadine (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane

monoamine transport inhibitor

centanafadine (1R,5S)-1-(naphtalén-2-yl)-3-azabicyclo[3.1.0]hexane inhibiteur du transport des monoamines


494

centanafadina (1R,5S)-1-(naftalen-2-il)-3-azabiciclo[3.1.0]hexano inhibidor del transporte de monoaminas

C15H15N

924012-43-1

HN

H

crisaborolum crisaborole 4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-

5-yl)oxy]benzonitrile non-steroidal anti-inflammatory

crisaborole 4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol- 5-yl)oxy]benzonitrile anti-inflammatoire non-stéroïdien

crisaborol 4-[(1-hidroxi-1,3-dihidro-2,1-benzoxaborol- 5-il)oxi]benzonitrilo antiinflamatorio no esteroide

C14H10BNO3

906673-24-3

OB

OH

O

NC

dectrekumabum # dectrekumab immunoglobulin G1-kappa, anti-[Homo sapiens L13

(interleukin 13, IL-13)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-450) [Homo sapiens VH (IGHV3-33*01 (98.00%) -(IGHD)-IGHJ3*02) [8.8.13] (1-120) -IGHG1*03 (CH1 (121-218), hinge (219-233), CH2 (234-343), CH3 (344-448), CHS (449-450)) (121-450)], (223-216')-disulfide with kappa light chain (1'-216') [Homo sapiens V-KAPPA (IGKV3-11*01 (95.80%) -IGKJ2*01) [6.3.11] (1'-109') -IGKC*01 (110'-216')]; dimer (229-229'':232-232'')-bisdisulfide immunomodulator

dectrékumab immunoglobuline G1-kappa, anti-[Homo sapiens IL13 (interleukine 13, IL-13)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-450) [Homo sapiens VH (IGHV3-33*01 (98.00%) -(IGHD)-IGHJ3*02) [8.8.13] (1-120) -IGHG1*03 (CH1 (121-218), charnière (219-233), CH2 (234-343), CH3 (344-448), CHS (449-450)) (121-450)], (223-216')-disulfure avec la chaîne légère kappa (1'-216') [Homo sapiens V-KAPPA (IGKV3-11*01 (95.80%) -IGKJ2*01) [6.3.11] (1'-109') -IGKC*01 (110'-216')]; dimère (229-229'':232-232'')-bisdisulfure immunomodulateur


495

dectrekumab inmunoglobulina G1-kappa, anti-[IL13 de Homo sapiens (interleukina 13, IL-13)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-450) [VH de Homo sapiens (IGHV3-33*01 (98.00%) -(IGHD)-IGHJ3*02) [8.8.13] (1-120) -IGHG1*03 (CH1 (121-218), bisagra (219-233), CH2 (234-343), CH3 (344-448), CHS (449-450)) (121-450)], (223-216')-disulfuro con la cadena ligera kappa (1'-216') [V-KAPPA de Homo sapiens (IGKV3-11*01 (95.80%) -IGKJ2*01) [6.3.11] (1'-109') -IGKC*01 (110'-216')]; dímero (229-229'':232-232'')-bisdisulfuro inmunomodulador

1528523-94-5

Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAI 50IWYDGSNKYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARLW 100FGDLDAFDIW GQGTMVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK 150DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT 200YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP 250KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 300STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ 350VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK 450

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPAT LSLSPGERAI LSCRAGQSVS SYLVWYQQKP GQAPRLLIYD 50ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSSWPPVYTF 100GQGTKLEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW 150KVDNALQSGN SQESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH 200QGLSSPVTKS FNRGEC 216


N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónH CH2 N84.4:300, 300''

Other post-translational modifications / Autres modifications post-traductionnelles / Otras modificaciones post-traduccionalesH CHS K2 C-terminal lysine clipping:450, 450'

desfesoterodinum desfesoterodine 2-{(1R)-3-[bis(propan-2-yl)amino]-1-phenylpropyl}-

4-(hydroxymethyl)phenol muscarinic receptor antagonist

desfésotérodine 2-{(1R)-3-[bis(propan-2-yl)amino]-1-phénylpropyl}- 4-(hydroxyméthyl)phénol antagoniste des récepteurs muscariniques

desfesoterodina 2-{(1R)-3-[bis(propan-2-il)amino]-1-fenilpropil}- 4-(hidroximetil)fenol antagonista de los receptores muscarinicos


496

C22H31NO2

207679-81-0

OH

N CH3

H3C

CH3

CH3

H

OH

deutetrabenazinum deutetrabenazine rac-(3R,11bR)-9,10-di[(2H3)methoxy]-3-(2-methylpropyl)-

1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one antipsychotic

deutétrabénazine rac-(3R,11bR)-9,10-di[(2H3)méthoxy]-3-(2-méthylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoléin- 2-one antipsychotique

deutetrabenazina rac-(3R,11bR)-3-(2-metilpropi)-9,10-di[(2H3)metoxi]-1,3,4,6,7,11b-hexahidro-2H-pirido[2,1-a]isoquinolein-2-ona antipsicótico

C19H21(2H6)NO3

1392826-25-3

N2H3CO

2H3CO

O

CH3

CH3

H

H

rac

durvalumabum # durvalumab immunoglobulin G1-kappa, anti-[Homo sapiens CD274

(programmed death ligand 1, PDL1, PD-L1, B7 homolog 1, B7H1)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-451) [Homo sapiens VH (IGHV3-7*01 (99.00%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -IGHG1*03 (CH1 (122-219), hinge (220-234), CH2 (235-344) L1.3>F (238), L1.2>E (239), P116>S (335), CH3 (345-449), CHS (450-451)) (122-451)], (224-215')-disulfide with kappa light chain (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (96.90%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dimer (230-230'':233-233'')-bisdisulfide immunomodulator, antineoplastic


497

durvalumab immunoglobuline G1-kappa, anti-[Homo sapiens CD274 (ligand 1 de mort programmée, PDL1, PD-L1, homologue 1 de B7, B7H1)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-451) [Homo sapiens VH (IGHV3-7*01 (99.00%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -IGHG1*03 (CH1 (122-219), charnière (220-234), CH2 (235-344) L1.3>F (238), L1.2>E (239), P116>S (335), CH3 (345-449), CHS (450-451)) (122-451)], (224-215')-disulfure avec la chaîne légère kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (96.90%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dimère (230-230'':233-233'')-bisdisulfure immunomodulateur, antinéoplasique

durvalumab inmunoglobulina G1-kappa, anti-[Homo sapiens CD274 (ligando 1 de muerte programada, PDL1, PD-L1, homólogo 1 de B7, B7H1)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-451) [Homo sapiens VH (IGHV3-7*01 (99.00%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -IGHG1*03 (CH1 (122-219),bisagra (220-234), CH2 (235-344) L1.3>F (238), L1.2>E (239), P116>S (335), CH3 (345-449), CHS (450-451)) (122-451)], (224-215')-disulfuro con la cadena ligera kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (96.90%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dímero (230-230'':233-233'')-bisdisulfuro inmunomodulador, antineoplásico

1428935-60-7

Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG LVQPGGSLRL SCAASGFTFS RYWMSWVRQA PGKGLEWVAN 50IKQDGSEKYY VDSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAREG 100GWFGELAFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV 150KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ 200TYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPEFEG GPSVFLFPPK 250PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPASIEKTI SKAKGQPREP 350QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP 400VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG 450K 451

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPGT LSLSPGERAT LSCRASQRVS SSYLAWYQQK PGQAPRLLIY 50DASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYGSLPWTFG 100QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200GLSSPVTKSF NRGEC 215



elafibranorum elafibranor 2-(2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxoprop-

1-en-1-yl}phenoxy)-2-methylpropanoic acid peroxisome proliferator activating receptor (PPAR) agonist


498

élafibranor acide 2-(2,6-diméthyl-4-{3-[4-(méthylsulfanyl)phényl]-

3-oxoprop-1-én-1-yl}phénoxy)-2-méthylpropanoïque agoniste des récepteurs activés par les proliférateurs de peroxysomes

elafibranor ácido 2-(2,6-dimetil-4-{3-[4-(metilsulfanil)fenil]-3-oxoprop- 1-en-1-il}fenoxi)-2-metilpropanoico agonista de los receptores activados por factores de proliferación de peroxisomas

C22H24O4S

824932-88-9

O

CH3

CH3

CH3

CH3

CO2HO

SH3C

eleclazinum eleclazine 4-[(pyrimidin-2-yl)methyl]-7-[4-(trifluoromethoxy)phenyl]-

3,4-dihydro-1,4-benzoxazepin-5(2H)-one coronary vasodilator and antiarrhythmic

éléclazine 4-[(pyrimidin-2-yl)méthyl)-7-[4-(trifluorométhoxy)phényl]-3,4-dihydro-1,4-benzoxazépin-5(2H)-one vasodilatateur coronnaire et antiarythmique

eleclazina 4-[(pirimidin-2-il)metil)-7-[4-(trifluorometoxi)fenil]3,4-dihidro-1,4-benzoxazepin-5(2H)-ona vasodilatador coronario y antiarrítmico

C21H16F3N3O3

1443211-72-0

N

O

O N

N

OF3C

elgemtumabum # elgemtumab immunoglobulin G1-kappa, anti-[Homo sapiens ERBB3

(receptor tyrosine-protein kinase erbB-3, HER3)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-447) [Homo sapiens VH (IGHV3-23*01 (94.90%) -(IGHD)-IGHJ4*01) [8.8.10] (1-117) -IGHG1*03 (CH1 (118-215), hinge (216-230), CH2 (231-340), CH3 (341-445), CHS (446-447)) (118-447)], (220-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV1-12*01 (94.70%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimer (226-226'':229-229'')-bisdisulfide immunomodulator, antineoplastic


499

elgemtumab immunoglobuline G1-kappa, anti-[Homo sapiens ERBB3

(récepteur à activité tyrosine kinase erbB-3, HER3)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-447) [Homo sapiens VH (IGHV3-23*01 (94.90%) -(IGHD)-IGHJ4*01) [8.8.10] (1-117) -IGHG1*03 (CH1 (118-215), charnière (216-230), CH2 (231-340), CH3 (341-445), CHS (446-447)) (118-447)], (220-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-12*01 (94.70%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (226-226'':229-229'')-bisdisulfure immunomodulateur, antinéoplasique

elgemtumab inmunoglobulina G1-kappa, anti-[ERBB3 de Homo sapiens (receptor tirosina-proteína kinasa erbB-3, HER3)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-447) [Homo sapiens VH (IGHV3-23*01 (94.90%) -(IGHD)-IGHJ4*01) [8.8.10] (1-117) -IGHG1*03 (CH1 (118-215), bisagra (216-230), CH2 (231-340), CH3 (341-445), CHS (446-447)) (118-447)], (220-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-12*01 (94.70%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (226-226'':229-229'')-bisdisulfuro inmunomodulador, antineoplásico

1512559-37-3

Heavy chain / Chaîne lourde / Cadena pesadaEVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSA 50INSQGKSTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARWG 100DEGFDIWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF 150PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC 200NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT 250LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY 300RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT 350LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK 447

Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCRASQGIS NWLAWYQQKP GKAPKLLIYG 50ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSSFPTTFGQ 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



Other post-translational modifications / Autres modifications post-traductionnelles / Otrasmodificaciones post-traduccionalesH CHS K2 C-terminal lysine clipping:447, 447'

emeramidum emeramide N1,N3-bis(2-sulfanylethyl)benzene-1,3-dicarboxamide

chelating agent

éméramide N1,N3-bis(2-sulfanyléthyl)benzène-1,3-dicarboxamide chélateur


500

emeramida N1,N3-bis(2-sulfaniletil)benceno-1,3-dicarboxamida quelante

C12H16N2O2S2

351994-94-0

HN

SH

HN

HS

O O

epetraborolum epetraborole (3S)-3-(aminomethyl)-7-(3-hydroxypropoxy)-

2,1-benzoxaborol-1(3H)-ol antibacterial

épétraborole (3S)-3-(aminométhyl)-7-(3-hydroxypropoxy)- 2,1-benzoxaborol-1(3H)-ol antibactérien

epetraborol (3S)-3-(aminometil)-7-(3-hidroxipropoxi)-2,1-benzoxaborol-1(3H)-ol antibacteriano

C11H16BNO4

1093643-37-8

OB

OH

H

NH2

OHO

eprociclovirum eprociclovir 2-amino-9-{[(1S,2R)-1,2-

bis(hydroxymethyl)cyclopropyl]methyl}-1,9-dihydro- 6H-purin-6-one antiviral (veterinary drug)

éprociclovir 2-amino-9-{[(1S,2R)-1,2-bis(hydroxyméthyl)cyclopropyl]méthyl}-1,9-dihydro- 6H-purin-6-one antiviral (usage vétérinaire)

eprociclovir 2-amino-9-{[(1S,2R)-1,2-bis(hidroximetil)ciclopropil]metil}-1,9-dihidro-6H-purin-6-ona antiviral (uso veterinario)

C11H15N5O3

145512-85-2

HN

N N

N

H2N

O

H

HO

OH


501

eptacogum beta (activatum) # eptacog beta (activated) recombinant DNA derived blood-coagulation factor VII

(activated), extracted from transgenic rabbits’ milk: blood-coagulation factor VII (EC 3.4.21.21, proconvertin, serum prothrombin conversion accelerator), human factor VII light chain (135-262)-disulfide with human factor VII heavy chain blood coagulation factor

eptacog bêta (activé) facteur VII de la coagulation sanguine (activé) à partir d'ADN recombinant, extrait du lait de lapins transgéniques: facteur VII de la coagulation sanguine (EC 3.4.21.21, proconvertine, accélérateur de conversion de la prothrombine sérique), (135-262) disulfure entre la chaîne légère et la chaîne lourde du facteur VII humain, glycoforme bêta facteur de coagulation sanguine

eptacog beta (activado) factor VII de la coagulación sanguínea (activado) a partir de ADN recombinante, extraído de leche de conejas transgénicas: factor VII de la coagulación sanguínea (EC 3.4.21.21, proconvertina, acelerador de conversión de la protrombina sérica), (135-262) disulfuro entre la cadena ligera y la cadena pesada del factor VII humano, glicoforma beta factor de coagulación sanguínea

1228539-24-9

HO2CCO2H

NH2H

HO HHO2C CO2H

NH2HHO2C

Light chain / Chaîne légère / Cadena ligeraANAFLEELRP GSLERECKEE QCSFEEAREI FKDAERTKLF WISYSDGDQC 50ASSPCQNGGS CKDQLQSYIC FCLPAFEGRN CETHKDDQLI CVNENGGCEQ 100YCSDHTGTKR SCRCHEGYSL LADGVSCTPT VEYPCGKIPI LEKRNASKPQ 150GR 152

Heavy chain / Chaîne lourde / Cadena pesada IVGGKVCP KGECPWQVLL LVNGAQLCGG TLINTIWVVS AAHCFDKIKN 200WRNLIAVLGE HDLSEHDGDE QSRRVAQVII PSTYVPGTTN HDIALLRLHQ 250PVVLTDHVVP LCLPERTFSE RTLAFVRFSL VSGWGQLLDR GATALELMVL 300NVPRLMTQDC LQQSRKVGDS PNITEYMFCA GYSDGSKDSC KGDSGGPHAT 350HYRGTWYLTG IVSWGQGCAT VGHFGVYTRV SQYIEWLQKL MRSEPRPGVL 400LRAPFP 406

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro17-22 50-61 55-70 72-81 91-102 98-112114-127 135-262 159-164 178-194 310-329 340-368

Modified residues / Résidus modifiés / Restos modificados

E6-7-14-16-19-20

25-26-29-354-carboxyGlu

D63

(3R)-3-hydroxyAsp

Glycosylation sites (S, N) / Sites de glycosylation (S, N) / Posiciones de glicosilación (S, N)Ser-52 Ser-60 Asn-145 Asn-322

erlosibanum erlosiban [(2S,4Z)-2-(hydroxymethyl)-4-(methoxyimino)pyrrolidin-

1-yl](2'-methyl[1,1'-biphenyl]-4-yl)methanone oxytocin antagonist

erlosiban [(2S,4Z)-2-(hydroxyméthyl)-4-(méthoxyimino)pyrrolidin- 1-yl](2'-méthyl[1,1'-biphényl]-4-yl)méthanone antagoniste de l'oxytocine


502

erlosibán [(2S,4Z)-2-(hidroximetil)-4-(metoxiimino)pirrolidin- 1-il](2'-metil[1,1'-bifenil]-4-il)metanona antagonista de la oxitocina

C20H22N2O3

1477482-19-1

NCH3

O

H

OH

N

O CH3

evinacumabum # evinacumab immunoglobulin G4-kappa, anti-[Homo sapiens ANGPTL3

(angiopoietin-like 3)], human monoclonal antibody; gamma4 heavy chain (1-453) [Homo sapiens VH (IGHV3-43*02 (92.90%) -(IGHD)-IGHJ3*02) [8.8.19](1-126) -IGHG4*01 (CH1(127-224), hinge S10>P(234) (225-236), CH2 (237-346), CH3(347-451),CHS (452-453)) (127-453)], (140-214')-disulfide with kappa light chain (1’-214’) [Homo sapiens (V-KAPPA (IGKV1-5*03 (98.90%) -IGKJ2*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimer (232-232":235-235")-bisdisulfide hypolipidaemic

évinacumab immunoglobuline G4-kappa, anti-[Homo sapiens ANGPTL3 (angiopoïétine-like 3)], anticorps monoclonal humain; chaîne lourde gamma4 (1-453) [Homo sapiens VH (IGHV3-43*02 (92.90%) -(IGHD)-IGHJ3*02) [8.8.19] (1-126) -IGHG4*01 (CH1 (127-224), charnière S10>P (234) (225-236), CH2 (237-346), CH3 (347-451), CHS (452-453)) (127-453)], (140-214')-disulfure avec la chaîne légère kappa (1’-214’) [Homo sapiens (V-KAPPA (IGKV1-5*03 (98.90%) -IGKJ2*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (232-232":235-235")-bisdisulfure hypolipémiant

evinacumab inmunoglobulina G4-kappa, anti-[ANGPTL3 (angiopoyetina-like 3) de Homo sapiens], anticuerpo monoclonal humano; cadena pesada gamma4 (1-453) [VH de Homo sapiens (IGHV3-43*02 (92.90%) -(IGHD)-IGHJ3*02) [8.8.19] (1-126) -IGHG4*01 (CH1 (127-224), bisagra S10>P (234) (225-236), CH2 (237-346), CH3 (347-451), CHS (452-453)) (127-453)], (140-214')-disulfuro con la cadena ligera kappa (1’-214’) [Homo sapiens (V-KAPPA (IGKV1-5*03 (98.90%) -IGKJ2*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (232-232":235-235")-bisdisulfuro hipolipemiante


503

1446419-85-7

Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA 50ISGDGGSTYY ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL 100RNTIFGVVIP DAFDIWGQGT MVTVSSASTK GPSVFPLAPC SRSTSESTAA 150LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS 200SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP 250PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE 300QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR 350EPQVYTLPPS QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT 400PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS 450LGK 453

Light chain / Chaîne légère / Cadena ligeraDIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK 50ASSLESGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ 100GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H (C23-C104) 22-96 153-209 267-327 373-431 22''-96'' 153''-209'' 267''-327'' 373''-431''Intra-L (C23-C104) 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L (CH1 10-CL 126) 140-214' 140''-214''' Inter-H-H (h 8, h 11) 232-232'' 235-235''


flutafuranolum (18F) flutafuranol (18F) 2-{2-[18F]fluoro-6-(methylamino)pyridin-3-yl}-1-benzofuran-

5-ol radiodiagnostic agent

flutafuranol (18F) 2-{2-[18F]fluoro-6-(méthylamino)pyridin-3-yl}-1-benzofuran-5-ol produit de radiodiagnostic

flutafuranol (18F) 2-{2-[18F]fluoro-6-(metilamino)piridin-3-il}-1-benzofuran-5-ol agente de radiodiagnóstico

C14H1118FN2O2

1211333-21-9

O

N

NH

CH3HO18F

follitropinum delta # follitropin delta recombinant DNA derived heterodimer of human

glycoprotein hormones alpha chain and follitropin subunit beta (FSH-beta) follicle-stimulating hormone, expressed in PER.C6 cells, glycoform delta follicle stimulating hormone

follitropine delta hétérodimère constitué de la chaîne alpha des hormones glycoprotéiques et de la sous-unité bêta de la follitropine (HFS-bêta) humaines, hormone folliculostimulante, exprimée dans les cellules PER.C6 à partir d'ADN recombinant, forme glycosylée delta hormone folliculostimulante


504

folitropina delta heterodímero constituido por la cadena alfa de las hormonas glicoproteícas y la subunidad beta de la folitropina (HFS-beta) humanas, hormona estimulante del folículo, expresada en células PER.C6 a partir de ADN recombinante, forma glicosilada delta hormona estimulante del folículo

146479-72-3 alpha chain / chaîne alpha / cadena alfa

APDVQDCPEC TLQENPFFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ 50KNVTSESTCC VAKSYNRVTV MGGFKVENHT ACHCSTCYYH KS 92

beta chain / chaîne bêta / cadena betaNSCELTNITI AIEKEECRFC ISINTTWCAG YCYTRDLVYK DPARPKIQKT 50'CTFKELVYET VRVPGCAHHA DSLYTYPVAT QCHCGKCDSD STDCTVRGLG 100'PSYCSFGEMK E 111'

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro7-31 10-60 28-82 32-84 59-87 3'-51' 17'-66' 20'-104' 28'-82' 32'-84' 87'-94'

Glycosylation sites (N) / Sites de glycosylation (N) / Posiciones de glicosilación (N)Asn-52 Asn-78 Asn-7' Asn-24'

gepotidacinum gepotidacin (2R)-2-[(4-{[(3,4-dihydro-2H-pyrano[2,3-c]pyridin-

6-yl)methyl]amino}piperidin-1-yl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione antibacterial

gépotidacine (2R)-2-[(4-{[(3,4-dihydro-2H-pyrano[2,3-c]pyridin- 6-yl)méthyl]amino}pipéridin-1-yl)méthyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacénaphthylène-3,8-dione antibactérien

gepotidacina (2R)-2-[(4-{[(3,4-dihidro-2H-pirano[2,3-c]piridin- 6-il)metil]amino}piperidin-1-il)metil]-1,2-dihidro- 3H,8H-2a,5,8a-triazaacenaftileno-3,8-diona antibacteriano

C24H28N6O3

1075236-89-3

N

NH

NO

HN

N

N

O

O

gilteritinibum gilteritinib 6-ethyl-3-{3-methoxy-4-[4-(4-methylpiperazin-

1-yl)piperidin-1-yl]anilino}-5-[(oxan-4-yl)amino]pyrazine- 2-carboxamide tyrosine kinase inhibitor, antineoplastic

giltéritinib 6-éthyl-3-{3-méthoxy-4-[4-(4-méthylpipérazin- 1-yl)pipéridin-1-yl]anilino}-5-[(oxan-4-yl)amino]pyrazine- 2-carboxamide inhibiteur de la tyrosine kinase, antinéoplasique


505

gilteritinib 6-etil-3-{4-[4-(4-metilpiperazin-1-il)piperidin-1-il]- 3-metoxianilino}-5-[(oxan-4-il)amino]pirazina- 2-carboxamida inhibidor de la tirosina kinasa, antineoplásico

C29H44N8O3

1254053-43-4

N

N

HN

H2N O

NH

H3C

OCH3

N

N

NOCH3

ibiglustatum ibiglustat (3S)-1-azabicyclo[2.2.2]octan-3-yl N-{2-[2-(4-fluorophenyl)-

1,3-thiazol-4-yl]propan-2-yl}carbamate ceramide glucosyltransferase inhibitor

ibiglustat N-{2-[2-(4-fluorophényl)-1,3-thiazol-4-yl]propan- 2-yl}carbamate de (3S)-1-azabicyclo[2.2.2]octan-3-yle inhibiteur de la céramide glucosyltransférase

ibiglustat N-{2-[2-(4-fluorofenil)-1,3-tiazol-4-il]propan-2-il}carbamato de (3S)-1-azabiciclo[2.2.2]octan-3-ilo inhibidor de la ceramida glucosiltransferasa

C20H24FN3O2S

1401090-53-6

NH

O

O

N

CH3H3C

N

S

F

H

H

indimilastum indimilast N-{cis-4-[1-(4'-{[(3R,5S)-3,5-dimethylpiperazin-

1-yl]methyl}[1,1'-biphenyl]-3-yl)-6-fluoro-2,4-dioxo- 1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl]cyclohexyl}- 2-methyl-1,3-thiazole-4-carboxamide phosphodiesterase IV inhibitor

indimilast N-{cis-4-[1-(4'-{[(3R,5S)-3,5-diméthylpipérazin- 1-yl]méthyl}[1,1'-biphényl]-3-yl)-6-fluoro-2,4-dioxo- 1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl]cyclohexyl}- 2-méthyl-1,3-thiazole-4-carboxamide inhibiteur de la phosphodiestérase IV


506

indimilast N-{cis-4-[1-(4'-{[(3R,5S)-3,5-dimetilpiperazin-1-il]metil}[1,1'-bifenil]-3-il)-6-fluoro-2,4-dioxo-1,4-dihidropirido[2,3-d]pirimidin-3(2H)-il]ciclohexil}-2-metil-1,3-tiazol- 4-carboxamida inhibidor de la fosfodiesterasa IV

C37H40FN7O3S

1038825-85-2

N

NN

N

NH

O

OH

HN

HO

N

SCH3

H

CH3

H3C H

F

indusatumabum # indusatumab immunoglobulin G1-kappa, anti-[Homo sapiens GUCY2C

(guanylate cyclase 2C, guanylyl cyclase C, GCC, guanylate cyclase C, GC-C, heat-stable enterotoxin receptor, hSTAR, intestinal guanylate cyclase)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV4-34*01 (94.80%) -(IGHD)-IGHJ1*01) [8.7.13] (1-119)-IGHG1*01 (CH1 (120-217), hinge (218-232), CH2 (233-342), CH3 (343-447), CHS (448-449)) (120-449)], (222-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-15*01 (95.80%) -IGKJ1*01 K123>N (103) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimer (228-228'':231-231'')-bisdisulfide immunomodulator, antineoplastic

indusatumab immunoglobuline G1-kappa, anti-[Homo sapiens GUCY2C (guanylate cyclase 2C, guanylyl cyclase C, GCC, guanylate cyclase C, GC-C, récepteur d’entérotoxine résistante à la chaleur, hSTAR, guanylate cyclase intestinale)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV4-34*01 (94.80%) -(IGHD)-IGHJ1*01) [8.7.13] (1-119)-IGHG1*01 (CH1 (120-217), charnière (218-232), CH2 (233-342), CH3 (343-447), CHS (448-449)) (120-449)], (222-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-15*01 (95.80%) -IGKJ1*01 K123>N (103) [6.3.9](1'-107') -IGKC*01 (108'-214')]; dimère (228-228'':231-231'')-bisdisulfure immunomodulateur, antinéoplasique


507

indusatumab inmunoglobulina G1-kappa, anti-[GUCY2C de Homo sapiens (guanilato ciclasa 2C, guanilil ciclasa C, GCC, guanilato ciclasa C, GC-C, receptor de enterotoxina resistente al calor, hSTAR, guanilato ciclasa intestinal)], anticuerpo monoclona de Homo sapiens; cadena pesada gamma1 (1-449) [VH de Homo sapiens (IGHV4-34*01 (94.80%) -(IGHD)-IGHJ1*01) [8.7.13] (1-119) -IGHG1*01 (CH1 (120-217), bisagra (218-232), CH2 (233-342), CH3 (343-447), CHS (448-449)) (120-449)], (222-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA de Homo sapiens (IGKV3-15*01 (95.80%) -IGKJ1*01 K123>N (103) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (228-228'':231-231'')-bisdisulfuro inmunomodulador, antineoplásico

1497400-26-6

Heavy chain / Chaîne lourde / Cadena pesadaQVQLQQWGAG LLKPSETLSL TCAVFGGSFS GYYWSWIRQP PGKGLEWIGE 50INHRGNTNDN PSLKSRVTIS VDTSKNQFAL KLSSVTAADT AVYYCARERG 100YTYGNFDHWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligeraEIVMTQSPAT LSVSPGERAT LSCRASQSVS RNLAWYQQKP GQAPRLLIYG 50ASTRATGIPA RFSGSGSGTE FTLTIGSLQS EDFAVYYCQQ YKTWPRTFGQ 100GTNVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



indusatumabum vedotinum # indusatumab vedotin immunoglobulin G1-kappa, anti-[Homo sapiens GUCY2C

(guanylate cyclase 2C, guanylyl cyclase C, GCC, guanylate cyclase C, GC-C, heat-stable enterotoxin receptor, hSTAR, intestinal guanylate cyclase)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV4-34*01 (94.80%) -(IGHD)-IGHJ1*01) [8.7.13] (1-119)-IGHG1*01 (CH1 (120-217), hinge (218-232), CH2 (233-342), CH3 (343-447), CHS (448-449)) (120-449)], (222-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-15*01 (95.80%) -IGKJ1*01 K123>N (103) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimer (228-228'':231-231'')-bisdisulfide; conjugated, on an average of 3 to 4 cysteinyl, to monomethylauristatin E (MMAE), via a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker For the vedotin part, please refer to the document “INN for pharmaceutical substances: Names for radicals, groups and others”*. immunomodulator, antineoplastic


508

indusatumab védotine immunoglobuline G1-kappa, anti-[Homo sapiens GUCY2C (guanylate cyclase 2C, guanylyl cyclase C, GCC, guanylate cyclase C, GC-C, récepteur d’entérotoxine résistante à la chaleur, hSTAR, guanylate cyclase intestinale)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV4-34*01 (94.80%) -(IGHD)-IGHJ1*01) [8.7.13] (1-119)-IGHG1*01 (CH1 (120-217), charnière (218-232), CH2 (233-342), CH3 (343-447), CHS (448-449)) (120-449)], (222-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-15*01 (95.80%) -IGKJ1*01 K123>N (103) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (228-228'':231-231'')-bisdisulfure; conjugué, sur 3 à 4 cystéinyl en moyenne, au monométhylauristatine E (MMAE), via un linker clivable de type maléimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) Pour la partie védotine, veuillez-vous référer au document “INN for pharmaceutical substances: Names for radicals, groups and others”*.

immunomodulateur, antinéoplasique

indusatumab vedotina inmunoglobulina G1-kappa, anti-[GUCY2C de Homo sapiens (guailato ciclasa 2C, guanilil ciclasa C, GCC, guanilato ciclasa C, GC-C, receptor de enterotoxina resistente al calor, hSTAR, guanilato cyclase intestinale)], Homo sapiens anticuerpo monoclonal; cadena pesada gamma1 (1-449) [Homo sapiens VH (IGHV4-34*01 (94.80%) -(IGHD)-IGHJ1*01) [8.7.13] (1-119) -IGHG1*01 (CH1 (120-217), bisagra (218-232), CH2 (233-342), CH3 (343-447), CHS (448-449)) (120-449)], (222-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-15*01 (95.80%) -IGKJ1*01 K123>N (103) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (228-228'':231-231'')-bisdisulfuro; conjugada, en una media de 3 a 4 cisteinil, con monometilauristatina E (MMAE), mediante un conector escindible de tipo maleimidocaproil-valil-citrulinil- p-aminobenciloxicarbonil (mc-val-cit-PABC) La fracción vedotina, pueden encontrarla en el documento “INN for pharmaceutical substances: Names for radicals, groups and others”*.

inmunomodulador, antineoplásico

1514889-12-3 Heavy chain / Chaîne lourde / Cadena pesada

QVQLQQWGAG LLKPSETLSL TCAVFGGSFS GYYWSWIRQP PGKGLEWIGE 50INHRGNTNDN PSLKSRVTIS VDTSKNQFAL KLSSVTAADT AVYYCARERG 100YTYGNFDHWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligeraEIVMTQSPAT LSVSPGERAT LSCRASQSVS RNLAWYQQKP GQAPRLLIYG 50ASTRATGIPA RFSGSGSGTE FTLTIGSLQS EDFAVYYCQQ YKTWPRTFGQ 100GTNVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H (C23-C104) 22-95 146-202 263-323 369-427 22''-95'' 146''-202'' 263''-323'' 369''-427''Intra-L (C23-C104) 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L* (h 5-CL 126) 222-214' 222''-214''' Inter-H-H* (h 11, h 14) 228-228'' 231-231'' *Two or three of the inter-chain disulfide bridges are not present, an average of 3 to 4 cysteinyl being conjugated each via a thioether bond to a drug linker.*Deux ou trois des ponts disulfures inter-chaînes ne sont pas présents, 3 à 4 cystéinyl en moyenne étant chacun conjugué via une liaison thioéther à un linker-principe actif.*Faltan dos o tres puentes disulfuro inter-catenarios, una media de 3 a 4 cisteinil está conjugada a conectores de principio activo.



509

infigratinibum infigratinib N'-(2,6-dichloro-3,5-dimethoxyphenyl)-N-{6-[4-(4-

ethylpiperazin-1-yl)anilino]pyrimidin-4-yl}-N-methylurea tyrosine kinase inhibitor, antineoplastic

infigratinib N'-(2,6-dichloro-3,5-diméthoxyphényl)-N-{6-[4-(4-éthylpipérazin-1-yl)anilino]pyrimidin-4-yl}-N-méthylurée inhibiteur de la tyrosine kinase, antinéoplasique

infigratinib N'-(2,6-dicloro-3,5-dimetoxifenil)-N-{6-[4-(4-etilpiperazin- 1-il)anilino]pirimidin-4-il}-N-metilurea inhibidor de la tirosina kinasa, antineoplásico

C26H31Cl2N7O3

872511-34-7

N NH

ONN

NH

N

NH3C

CH3

Cl

OCH3

OCH3

Cl

isatuximabum # isatuximab immunoglobulin G1-kappa, anti-[Homo sapiens CD38

(ADP-ribosyl cyclase 1, cyclic ADP-ribose hydrolase 1, cADPr hydrolase 1, T10)], chimeric monoclonal antibody; gamma1 heavy chain (1-450) [Mus musculus VH (IGHV1-7*01 (80.60%) -(IGHD)-IGHJ4*01) [8.8.13] (1-120) -Homo sapiens IGHG1*01 (CH1 (121-218), hinge (219-233), CH2 (234-343), CH3 (344-448), CHS (449-450)) (121-450)], (223-214')-disulfide with kappa light chain (1'-214') [Mus musculus V-KAPPA (IGKV6-17*01 (89.50%) -IGKJ2*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimer (229-229'':232-232'')-bisdisulfide immunomodulator, antineoplastic

isatuximab immunoglobuline G1-kappa, anti-[Homo sapiens CD38 (ADP-ribosyl cyclase 1, ADP-ribose cyclique hydrolase 1, cADPr hydrolase 1, T10)], anticorps monoclonal chimérique; chaîne lourde gamma1 (1-450) [Mus musculus VH (IGHV1-7*01 (80.60%) -(IGHD)-IGHJ4*01) [8.8.13] (1-120) -Homo sapiens IGHG1*01 (CH1 (121-218), charnière (219-233), CH2 (234-343), CH3 (344-448), CHS (449-450)) (121-450)], (223-214')-disulfure avec la chaîne légère kappa (1'-214') [Mus musculus V-KAPPA (IGKV6-17*01 (89.50%) -IGKJ2*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (229-229'':232-232'')-bisdisulfure immunomodulateur, antinéoplasique


510

isatuximab inmunoglobulina G1-kappa, anti-[CD38 de Homo sapiens (ADP-ribosil ciclasa 1, hidrolasa 1 de ADP-ribosa cíclica, cADPr hidrolasa 1, T10)], anticuerpo monoclonal quimérico; cadena pesada gamma1 (1-450) [Mus musculus VH (IGHV1-7*01 (80.60%) -(IGHD)-IGHJ4*01) [8.8.13] (1-120) -Homo sapiens IGHG1*01 (CH1 (121-218), bisagra (219-233), CH2 (234-343), CH3 (344-448), CHS (449-450)) (121-450)], (223-214')-disulfuro con la cadena ligera kappa (1'-214') [Mus musculus V-KAPPA (IGKV6-17*01 (89.50%) -IGKJ2*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (229-229'':232-232'')-bisdisulfuro inmunomodulador, antineoplásico

1461640-62-9

Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT 50IYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD 100YYGSNSLDYW GQGTSVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK 150DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT 200YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP 250KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 300STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ 350VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK 450

Light chain / Chaîne légère / Cadena ligeraDIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS 50ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG 100GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



lanopepdenum lanopepden N-[(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-

6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]- 2-methylpyrimidin-4-yl}hydrazin-1-yl)-3-oxopropyl]- N-hydroxyformamide antibacterial

lanopepdène N-[(2R)-2-(cyclopentylméthyl)-3-(2-{5-fluoro- 6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]- 2-méthylpyrimidin-4-yl}hydrazin-1-yl)-3-oxopropyl]- N-hydroxyformamide antibactérien

lanopepdén N-[(2R)-2-(ciclopentilmetil)-3-(2-{5-fluoro- 6-[(9aS)-hexahidropirazino[2,1-c][1,4]oxazin-8(1H)-il]- 2-metilpirimidin-4-il}hidrazin-1-il)-3-oxopropil]- N-hidroxiformamida antibacteriano


511

C22H34FN7O4

1152107-25-9

O

N

O

H

NH

HN

N N

CH3

F

N

N

O

H

OH

lascufloxacinum lascufloxacin 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidin-

1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid quinolone antibacterial

lascufloxacine acide 7-{(3S,4S)-3-[(cyclopropylamino)méthyl]- 4-fluoropyrrolidin-1-yl}-6-fluoro-1-(2-fluoroéthyl)-8-méthoxy-4-oxo-1,4-dihydroquinoléine-3-carboxylique quinolone, antibiotique

lascufloxacino ácido 7-{(3S,4S)-3-[(ciclopropilamino)metil]- 4-fluoropirrolidin-1-il}-6-fluoro-1-(2-fluoroetil)-8-metoxi- 4-oxo-1,4-dihidroquinoleina-3-carboxílico quinolona, antibiótico

C21H24F3N3O4

848416-07-9

N

OCH3

N

F

CO2H

O

F

FH

HNH

lavamilastum lavamilast 4-[(3,5-dichloropyridin-4-yl)amino]-7-methoxy-

8-{[6-(morpholin-4-yl)hexyl]oxy}quinolin-2(1H)-one phosphodiesterase IV inhibitor

lavamilast 4-[(3,5-dichloropyridin-4-yl)amino]-7-méthoxy- 8-{[6-(morpholin-4-yl)hexyl]oxy}quinoléin-2(1H)-one inhibiteur de la phosphodiestérase IV

lavamilast 4-[(3,5-dicloropiridin-4-il)amino]-7-metoxi-8-{[6-(morfolin- 4-il)hexil]oxi}quinolein-2(1H)-ona inhibidor de la fosfodiesterasa IV


512

C25H30Cl2N4O4

1218778-89-2

HN

NH

O

O

H3CO

N

Cl

Cl

N

O

lilotomabum # lilotomab immunoglobulin G1-kappa, anti-[Homo sapiens

CD37(TSPAN26, tetraspanin-26)], Mus musculus monoclonal antibody; gamma1 heavy chain (1-443) [Mus musculus VH (IGHV1S135*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -IGHG1*01 (CH1 E84>Q (177), P95>T (193), R96>W (194) (120-216), hinge (217-229), CH2 (230-336), CH3 N84.2>D (395), N84.4>D (397) (337-441), CHS (442-443)) (120-443)], (221-214')-disulfide with kappa light chain (1'-214') [Mus musculus V-KAPPA (IGKV6-25*01 (93.70%) -IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimer (223-223'':226-226'':228-228'')-trisdisulfide immunomodulator, antineoplastic

lilotomab immunoglobuline G1-kappa, anti-[Homo sapiens CD37 (TSPAN26, tétraspanine-26)], Mus musculus anticorps monoclonal; chaîne lourde gamma1 (1-443) [Mus musculus VH (IGHV1S135*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -IGHG1*01 (CH1 E84>Q (177), P95>T (193), R96>W (194) (120-216), charnière (217-229), CH2 (230-336), CH3 N84.2>D (395), N84.4>D (397) (337-441), CHS (442-443)) (120-443)], (221-214')-disulfure avec la chaîne légère kappa (1'-214') [Mus musculus V-KAPPA (IGKV6-25*01 (93.70%) -IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (223-223'':226-226'':228-228'')-trisdisulfure immunomodulateur, antinéoplasique

lilotomab inmunoglobulina G1-kappa, anti-[CD37 de Homo sapiens (TSPAN26, tetraspanina-26)], anticuerpo monoclonal de Mus musculus; cadena pesada gamma1 (1-443) [VH de Mus musculus (IGHV1S135*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -IGHG1*01 (CH1 E84>Q (177), P95>T (193), R96>W (194) (120-216), bisagra (217-229), CH2 (230-336), CH3 N84.2>D (395), N84.4>D (397) (337-441), CHS (442-443)) (120-443)], (221-214')-disulfuro con la cadena ligera kappa (1'-214') [Mus musculus V-KAPPA (IGKV6-25*01 (93.70%) -IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (223-223'':226-226'':228-228'')-trisdisulfuro inmunomodulador, antineoplásico


513

1453362-55-4

Heavy chain / Chaîne lourde / Cadena pesadaEIQLQQSGPE LVKPGASVKV SCKASGYSFT DYNMYWVKQS HGKSLEWIGY 50IDPYNGDTTY NQKFKGKATL TVDKSSSTAF IHLNSLTSED SAVYYCARSP 100YGHYAMDYWG QGTSVTVSSA KTTPPSVYPL APGSAAQTNS MVTLGCLVKG 150YFPEPVTVTW NSGSLSSGVH TFPAVLQSDL YTLSSSVTVP SSTWPSETVT 200CNVAHPASST KVDKKIVPRD CGCKPCICTV PEVSSVFIFP PKPKDVLTIT 250LTPKVTCVVV DISKDDPEVQ FSWFVDDVEV HTAQTQPREE QFNSTFRSVS 300ELPIMHQDWL NGKEFKCRVN SAAFPAPIEK TISKTKGRPK APQVYTIPPP 350KEQMAKDKVS LTCMITDFFP EDITVEWQWN GQPAENYKNT QPIMDTDGSY 400FVYSKLNVQK SNWEAGNTFT CSVLHEGLHN HHTEKSLSHS PGK 443

Light chain / Chaîne légère / Cadena ligeraDIVMTQSHKL LSTSVGDRVS ITCKASQDVS TAVDWYQQKP GQSPKLLINW 50ASTRHTGVPD RFTGSGSGTD YTLTISSMQA EDLALYYCRQ HYSTPFTFGS 100GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI 150DGSERQNGVL NSWTDQDSKD STYSMSSTLT LTKDEYERHN SYTCEATHKT 200STSPIVKSFN RNEC 214

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H (C23-C104) 22-96 146-201 257-317 363-421 22''-96'' 146''-201'' 257''-317'' 363''-421''Intra-L (C23-C104) 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L (h 5-CL 126) 221-214' 221''-214''' Inter-H-H (h 7, h 10, h 12) 223-223'' 226-226'' 228-228''


lokivetmabum # lokivetmab immunoglobulin G2-kappa, anti-[Canis lupus familiaris IL31

(interleukin 31)], caninized monoclonal antibody; gamma2 heavy chain (1-452) [caninized VH (Canis lupus familiaris IGHV-E2RCC8 (85.90%) -(IGHD)-IGHJ) [8.8.11] (1-118) -Canis lupus familiaris IGHG2*01 (CH1 (119-216), hinge (217-234), CH2 (235-344), CH3 (345-451), CHS (452)) (119-452)], (133-217')-disulfide with kappa light chain (1'-217') [caninized V-KAPPA (Canis lupus familiaris IGKV-F1PNY2 (56.00%) -IGKJ) [10.3.9] (1'-111') -Canis lupus familiaris IGKC*01 (112'-217')]; dimer (230-230'':233-233'')-bisdisulfide immunomodulator (veterinary use)

lokivetmab immunoglobuline G2-kappa, anti-[Canis lupus familiaris IL31 (interleukine 31)], anticorps monoclonal caninisé; chaîne lourde gamma2 (1-452) [VH caninisé (Canis lupus familiaris IGHV-E2RCC8 (85.90%) -(IGHD)-IGHJ) [8.8.11] (1-118) -Canis lupus familiaris IGHG2*01 (CH1 (119-216), charnière (217-234), CH2 (235-344), CH3 (345-451), CHS (452)) (119-452)], (133-217')-disulfure avec la chaîne légère kappa (1'-217') [V-KAPPA caninisé (Canis lupus familiaris IGKV-F1PNY2 (56.00%) -IGKJ) [10.3.9] (1'-111') -Canis lupus familiaris IGKC*01 (112'-217')]; dimère (230-230'':233-233'')-bisdisulfure immunomodulateur (usage vétérinaire)


514

lokivetmab inmunoglobulina G2-kappa, anti-[Canis lupus familiaris IL31 (interleukina 31)], anticuerpo monoclonal caninizado; cadena pesada gamma2 (1-452) [VH caninizado (Canis lupus familiaris IGHV-E2RCC8 (85.90%) -(IGHD)-IGHJ) [8.8.11] (1-118) -Canis lupus familiaris IGHG2*01 (CH1 (119-216), bisagra (217-234), CH2 (235-344), CH3 (345-451), CHS (452)) (119-452)], (133-217')-disulfuro con la caden ligera kappa (1'-217') [V-KAPPA caninizado (Canis lupus familiaris IGKV-F1PNY2 (56.00%) -IGKJ) [10.3.9] (1'-111') -Canis lupus familiaris IGKC*01 (112'-217')]; dímero (230-230'':233-233'')-bisdisulfuro inmunomodulador (uso veterinario)

1533403-95-0 Heavy chain / Chaîne lourde / Cadena pesada

EVQLVESGGD LVKPGGSLRL SCVASGFTFS NYGMSWVRQA PGKGLQWVAT 50ISYGGSYTYY PDNIKGRFTI SRDNAKNTLY LQMNSLRAED TAMYYCVRGY 100GYDTMDYWGQ GTLVTVSSAS TTAPSVFPLA PSCGSTSGST VALACLVSGY 150FPEPVTVSWN SGSLTSGVHT FPSVLQSSGL YSLSSMVTVP SSRWPSETFT 200CNVAHPASKT KVDKPVPKRE NGRVPRPPDC PKCPAPEMLG GPSVFIFPPK 250PKDTLLIART PEVTCVVVDL DPEDPEVQIS WFVDGKQMQT AKTQPREEQF 300NGTYRVVSVL PIGHQDWLKG KQFTCKVNNK ALPSPIERTI SKARGQAHQP 350SVYVLPPSRE ELSKNTVSLT CLIKDFFPPD IDVEWQSNGQ QEPESKYRTT 400PPQLDEDGSY FLYSKLSVDK SRWQRGDTFI CAVMHEALHN HYTQESLSHS 450PG 452

Light chain / Chaîne légère / Cadena ligeraEIVMTQSPAS LSLSQEEKVT ITCKASQSVS FAGTGLMHWY QQKPGQAPKL 50LIYRASNLEA GVPSRFSGSG SGTDFSFTIS SLEPEDVAVY YCQQSREYPW 100TFGQGTKLEI KRNDAQPAVY LFQPSPDQLH TGSASVVCLL NSFYPKDINV 150KWKVDGVIQD TGIQESVTEQ DKDSTYSLSS TLTMSSTEYL SHELYSCEIT 200HKSLPSTLIK SFQRSEC 217

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H (C23-C104) 22-96 145-201 265-325 371-431 22''-96'' 145''-201'' 265''-325'' 371''-431''Intra-L (C23-C104) 23'-92' 138'-197' 23'''-92''' 138'''-197''' Inter-H-L (CH1 11-CL 126) 133-217' 133''-217''' Inter-H-H (h 14, h 17) 230-230'' 233-233''


Other post-translational modifications / Autres modifications post-traductionnelles / Otras modificaciones post-traduccionalesLacking H chain C-terminal lysine (CHS K2>del)

lopixibati chloridum lopixibat chloride 1-{[4-({4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-

1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ6-benzothiepin- 5-yl]phenoxy}methyl)phenyl]methyl}- 1,4-diazabicyclo[2.2.2]octan-1-ium chloride ileal bile acid transporter inhibitor

chlorure de lopixibat chlorure de 1-{[4-({4-[(4R,5R)-3,3-dibutyl- 7-(diméthylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tétrahydro-1H-1λ6-benzothiépin-5-yl]phénoxy}méthyl)phényl]méthyl}-1,4-diazabicyclo[2.2.2]octan-1-ium inhibiteur du transporteur iléal d'acides biliaires

cloruro de lopixibat cloruro de 1-{[4-({4-[(4R,5R)-3,3-dibutil-7-(dimetilamino)- 4-hidroxi-1,1-dioxo-2,3,4,5-tetrahidro-1H-1λ6-benzotiepin-5-il]fenoxi}metil)fenil]metil}-1,4-diazabiciclo[2.2.2]octan-1-io inhibidor del transportador ilíaco de ácidos biliares


515

C40H56ClN3O4S

228113-66-4

SOO

H

N

CH3

CH3

H3C

O

N

N

HOH

H3C

Cl

lutetium (177Lu) lilotomabum satetraxetanum # lutetium (177Lu) lilotomab satetraxetan immunoglobulin G1-kappa, anti-[Homo sapiens CD37

(TSPAN26, tetraspanin-26)], Mus musculus monoclonal antibody, lutetium (Lu 177) radiolabelled satetraxetan (DOTA derivative) conjugate; gamma1 heavy chain (1-443) [Mus musculus VH (IGHV1S135*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -IGHG1*01 (CH1 E84>Q (177), P95>T (193), R96>W (194) (120-216), hinge (217-229), CH2 (230-336), CH3 N84.2>D (395), N84.4>D (397) (337-441), CHS (442-443)) (120-443)], (221-214')-disulfide with kappa light chain (1'-214') [Mus musculus V-KAPPA (IGKV6-25*01 (93.70%) -IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimer (223-223'':226-226'':228-228'')-trisdisulfide, an average of 1 to 2 amino groups (N6 of lysines) are substituted: N-[rac-(4-{[(2R)-1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl]methyl}phenyl)carbamothioyl] (177Lu)lutetium(3+) chelate

immunomodulator, antineoplastic

lutécium (177Lu) lilotomab satétraxétan immunoglobuline G1-kappa, anti-[Homo sapiens CD37 (TSPAN26, tétraspanine-26)], Mus musculus anticorps monoclonal; conjugué au satétraxétan (dérivé DOTA) radiomarqué au lutétium (Lu 177); chaîne lourde gamma1 (1-443) [Mus musculus VH (IGHV1S135*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -IGHG1*01 (CH1 E84>Q (177), P95>T (193), R96>W (194) (120-216), charnière (217-229), CH2 (230-336), CH3 N84.2>D (395), N84.4>D (397) (337-441), CHS (442-443)) (120-443)], (221-214')-disulfure avec la chaîne légère kappa (1'-214') [Mus musculus V-KAPPA (IGKV6-25*01 (93.70%) -IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (223-223'':226-226'':228-228'')-trisdisulfure, une moyenne de 1 à 2 groupes amino (N6 de lysines) sont substitués: N-[rac-(4-{[(2R)-1,4,7,10-tétrakis(carboxyméthyl)-1,4,7,10-tétraazacyclododécan-2-yl]méthyl}phényl)carbamothioyl] chélate de (177Lu)lutétium(3+)



516

lutecio (177Lu) lilotomab satetraxetán inmunoglobulina G1-kappa, anti-[CD37 de Homo sapiens (TSPAN26, tetraspanina-26)], anticuerpo monoclonal de Mus musculus, conjugado al satetraxetán (derivado DOTA) radiomarcado con lutecio (Lu 177); cadena pesada gamma1 (1-443) [VH de Mus musculus (IGHV1S135*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -IGHG1*01 (CH1 E84>Q (177), P95>T (193), R96>W (194) (120-216), bisagra (217-229), CH2 (230-336), CH3 N84.2>D (395), N84.4>D (397) (337-441), CHS (442-443)) (120-443)], (221-214')-disulfuro con la cadena ligera kappa (1'-214') [Mus musculus V-KAPPA (IGKV6-25*01 (93.70%) -IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (223-223'':226-226'':228-228'')-trisdisulfuro; una medida de 1 a 2 groupos amino (N6 de lisinas) están sustituidos: N-[rac-(4-{[(2R)-1,4,7,10-tetrakis(carboximetil)-1,4,7,10-tetraazaciclododecan-2-il]metil}fenil)carbamotioil] quelato de (177Lu)lutecio(3+)


1453362-90-7

N

N

N

N

CO2O2C

177Lu3+

O2C

O2C

NH

C

SHH

racR =

Heavy chain / Chaîne lourde / Cadena pesadaEIQLQQSGPE LVKPGASVKV SCKASGYSFT DYNMYWVKQS HGKSLEWIGY 50IDPYNGDTTY NQKFKGKATL TVDKSSSTAF IHLNSLTSED SAVYYCARSP 100YGHYAMDYWG QGTSVTVSSA KTTPPSVYPL APGSAAQTNS MVTLGCLVKG 150YFPEPVTVTW NSGSLSSGVH TFPAVLQSDL YTLSSSVTVP SSTWPSETVT 200CNVAHPASST KVDKKIVPRD CGCKPCICTV PEVSSVFIFP PKPKDVLTIT 250LTPKVTCVVV DISKDDPEVQ FSWFVDDVEV HTAQTQPREE QFNSTFRSVS 300ELPIMHQDWL NGKEFKCRVN SAAFPAPIEK TISKTKGRPK APQVYTIPPP 350KEQMAKDKVS LTCMITDFFP EDITVEWQWN GQPAENYKNT QPIMDTDGSY 400FVYSKLNVQK SNWEAGNTFT CSVLHEGLHN HHTEKSLSHS PGK 443

Light chain / Chaîne légère / Cadena ligeraDIVMTQSHKL LSTSVGDRVS ITCKASQDVS TAVDWYQQKP GQSPKLLINW 50ASTRHTGVPD RFTGSGSGTD YTLTISSMQA EDLALYYCRQ HYSTPFTFGS 100GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI 150DGSERQNGVL NSWTDQDSKD STYSMSSTLT LTKDEYERHN SYTCEATHKT 200STSPIVKSFN RNEC 214

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H (C23-C104) 22-96 146-201 257-317 363-421 22''-96'' 146''-201'' 257''-317'' 363''-421''Intra-L (C23-C104) 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L (h 5-CL 126) 221-214' 221''-214''' Inter-H-H (h 7, h 10, h 12) 223-223'' 226-226'' 228-228''



KAn average of 1 to 2 are N-substituted by R

Environ 1 à 2 sont N-substitués par RUna medida de 1 a 2 están N-sustituidos por R

mereletinibum mereletinib N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-

5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin- 2-yl]amino}phenyl)prop-2-enamide tyrosine kinase inhibitor, antineoplastic

mérélétinib N-(2-{[2-(diméthylamino)éthyl](méthyl)amino}-4-méthoxy- 5-{[4-(1-méthyl-1H-indol-3-yl)pyrimidin- 2-yl]amino}phényl)prop-2-énamide inhibiteur de la tyrosine kinase, antinéoplasique


517

mereletinib N-(2-{[2-(dimetilamino)etil](metil)amino}-4-metoxi-5-{[4-(1-

metil-1H-indol-3-il)pirimidin-2-il]amino}fenil)prop-2-enamida inhibidor de la tirosina kinasa, antineoplásico

C28H33N7O2

1421373-65-0

NH

O

N

CH3

NCH3

CH3

OCH3

NH

N

NNH3C

H2C

motolimodum motolimod 2-amino-N,N-dipropyl-8-[4-(pyrrolidine-1-carbonyl)phenyl]-

3H-1-benzazepine-4-carboxamide immunomodulator, antineoplastic

motolimod 2-amino-N,N-dipropyl-8-[4-(pyrrolidine-1-carbonyl)phényl]-3H-1-benzazépine-4-carboxamide immunomodulateur, antinéoplasique

motolimod 2-amino-N,N-dipropil-8-[4-(pirrolidina-1-carbonil)fenil]- 3H-1-benzazepina-4-carboxamida inmunomodulador, antineoplásico

C28H34N4O2

926927-61-9

NNH2

N

O

CH3

CH3

O

N

necuparanibum necuparanib low molecular mass heparan sulfate mimetic compound

that is obtained by nitrous sodium depolymerization of heparin from porcine intestinal mucosa, sodium periodate glycol split oxidation of uronic acids elements and sodium borohydride reduction of aldehydes produced during oxidation; the majority of the components have a splited uronic acid structure at the non-reducing end and a 2,5-anhydromannitol structure at the reducing end of their chain; the average molecular weight range is 5000 to 8000 Da; the degree of sulfatation is about 2 per disaccharidic unit antineoplastic


518

nécuparanib dérivé de basse masse moléculaire à action mimétique du sulfate d’héparane, obtenu par dépolymérisation d’héparine de muqueuse intestinale de porc, catalysée par du nitrite de sodium, puis dégradation oxydative des glycols des unités uroniques par le périodate de sodium et réduction, par le borohydrure de sodium, des aldéhydes produits; la majorité des composants ont, une structure éclatée d’acide uronique à leur extrémité non-réductrice et une structure 2,5-anhydromannitol à leur extrémité réductrice, une masse molaire comprise entre 4500 et 7200 daltons et un degré de sulfatation d’environ de 2 par unité disaccharide antinéoplasique

necuparanib derivado de baja masa molecular de acción mimética de la del sulfato de heparán, obtenido por despolimerización de heparina de mucosa intestinal de cerdo, catalizada por nitrito de sodio, seguida de degradación oxidativa, con peryodato de sodio, de los glicoles de las unidades urónicas y reducción, con borohidruro de sodio, de los aldehídos producidos; la mayoría de los componentes tienen , una estructura abierta de ácido urónico en su extremo no-reductor y una estructura 2,5-anhidromanitol en el reductor, el peso molecular medio está comprendido entre 4500 y 7200 daltons et el grado de sulfatación es aproximadamente de 2 por unidad de disacárido antineoplásico

1415139-34-2

O

O

O

O

NH

O

O

O

O

O

O

HOR1O

HO2C

R1O HO OH

HO2C

NH

HO3S

OR1 OR1

HO3S

R1 = H, SO3H

R

R2

R2 = COCH3, SO3H

O

OR1

HO HO

n n'

n = 6 - 12

n' = 1 - 2HO

O

O

HO2C

HO SO3H

orouó

HO

O

OH

HO2C

R =

neladenosoni dalanas neladenoson dalanate 2-{4-[2-({[2-(4-chlorophenyl)-1,3-thiazol-

4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl L-alanyl-L-alaninate adenosine receptor agonist

dalanate de néladénoson L-alanyl-L-alaninate de 2-{4-[2-({[2-(4-chlorophényl)- 1,3-thiazol-4-yl]méthyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin- 1-yl)pyridin-4-yl]phénoxy}éthyle agoniste des récepteurs de l’adénosine


519

dalanato de neladenosón L-alanil-L-alaninato de 2-{4-[2-({[2-(4-clorofenil)-1,3-tiazol-4-il]metil}sulfanil)-3,5-diciano-6-(pirrolidin-1-il)piridin- 4-il]fenoxi}etilo agonista del receptor de la adenosina

C35H34ClN7O4S2

1239309-58-0

N

N

CN

CN

SN

S

Cl

O

O

HN

O

CH3

H

O

NH2

H

CH3

neloniclinum nelonicline (3R,4s,5S)-4-[(5-phenyl-1,3,4-thiadiazol-2-yl)oxy]-

1-azaadamantane nicotinic acetylcholine receptor agonist

nélonicline (3R,4s,5S)-4-[(5-phényl-1,3,4-thiadiazol-2-yl)oxy]- 1-azaadamantane agoniste du récepteur nicotinique à l'acétylcholine

neloniclina (3R,4s,5S)-4-[(5-fenil-1,3,4-tiadiazol-2-il)oxi]- 1-azaadamantano agonista del receptor nicotínico de la acetilcolina

C17H19N3OS

1026134-63-3

N

O S

NN

nemolizumabum # nemolizumab immunoglobulin G2-kappa, anti-[Homo sapiens IL31RA

(interleukin 31 receptor subunit alpha)], humanized monoclonal antibody; gamma2 heavy chain (1-445) [humanized VH (Homo sapiens IGHV1-2*02 (83.70%) -(IGHD)-IGHJ5*01) [8.8.14] (1-121) -Homo sapiens IGHG2*01 (CH1 C10>S (135), R12>K (137), E16>G (141), S17>G (142) (122-219), hinge C4>S (223) (220-231), CH2 H30>Q (268) (232-340), CH3 R11>Q (355), Q98>E (419) (341-445)) (122-445)], (224-214')-disulfide with kappa light chain (1’-214’) [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (82.10%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimer (227-227":230-230")-bisdisulfide immunomodulator


520

némolizumab immunoglobuline G2-kappa, anti-[Homo sapiens IL31RA (sous-unité alpha du récepteur de l’interleukine 31)], anticorps monoclonal humanisé; chaîne lourde gamma2 (1-445) [VH humanisé (Homo sapiens IGHV1-2*02 (83.70%) -(IGHD)-IGHJ5*01) [8.8.14] (1-121) -Homo sapiens IGHG2*01 (CH1 C10>S (135), R12>K (137), E16>G (141), S17>G (142) (122-219), charnière C4>S (223) (220-231), CH2 H30>Q (268) (232-340), CH3 R11>Q (355), Q98>E (419) (341-445)) (122-445)], (224-214')-disulfure avec la chaîne légère kappa (1’-214’) [V-KAPPA humanisé (Homo sapiens IGKV1-39*01 (82.10%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (227-227":230-230")-bisdisulfure immunomodulateur

nemolizumab inmunoglobulina G2-kappa, anti-[IL31RA de Homo sapiens (subunidad alfa del receptor de la interleukina 31)], anticuerpo monoclonal humanizado; cadena pesada gamma2 (1-445) [VH humanizado (Homo sapiens IGHV1-2*02 (83.70%) -(IGHD)-IGHJ5*01) [8.8.14] (1-121) -Homo sapiens IGHG2*01 (CH1 C10>S (135), R12>K (137), E16>G (141), S17>G (142) (122-219), bisagra C4>S (223) (220-231), CH2 H30>Q (268) (232-340), CH3 R11>Q (355), Q98>E (419) (341-445)) (122-445)], (224-214')-disulfuro con la cadena ligera kappa (1’-214’) [V-KAPPA humanizado (Homo sapiens IGKV1-39*01 (82.10%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (227-227":230-230")-bisdisulfuro inmunomodulador

1476039-58-3

Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VKKPGASVKV SCKASGYTFT GYIMNWVRQA PGQGLEWMGL 50INPYNGGTDY NPQFQDRVTI TADKSTSTAY MELSSLRSED TAVYYCARDG 100YDDGPYTLET WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV 150KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSNFGTQ 200TYTCNVDHKP SNTKVDKTVE RKSCVECPPC PAPPVAGPSV FLFPPKPKDT 250LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTF 300RVVSVLTVVH QDWLNGKEYK CKVSNKGLPA PIEKTISKTK GQPREPQVYT 350LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPMLDS 400DGSFFLYSKL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSP 445

Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCQASEDIY SFVAWYQQKP GKAPKLLIYN 50AQTEAQGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQH HYDSPLTFGG 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



Other post-translational modifications / Autres modifications post-traductionnelles / Otras modificaciones post-traduccionalesLacking H chain C-terminal glycine and lysine (CHS G1>del, K2>del)


521

nusinersenum # nusinersen all-P-ambo-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-

(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)guanosine Survival Motor Neuron (SMN2) protein production

nusinersen tout-P-ambo-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiouridylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiocytidylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-P-thioadénylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiocytidylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiouridylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiouridylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiouridylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiocytidylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-P-thioadénylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiouridylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-P-thioadénylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-P-thioadénylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiouridylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-P-thioguanylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiocytidylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-5-méthyl-P-thiouridylyl-(3'→5')-2'-O-(2-méthoxyéthyl)-P-thioguanylyl-(3'→5')-2'-O-(2-méthoxyéthyl)guanosine production de la protéine de survie des motoneurones (SMN2)

nusinersén todo-P-ambo-2'-O-(2-metoxietil)-5-metil-P-tiouridilil-(3'→5')-2'-O-(2-metoxietil)-5-metil-P-tiocitidilil-(3'→5')-2'-O-(2-metoxietil)-P-tioadenilil-(3'→5')-2'-O-(2-metoxietil)-5-metil-P-tiocitidilil-(3'→5')-2'-O-(2-metoxietil)-5-metil-P-tiouridilil-(3'→5')-2'-O-(2-metoxietil)-5-metil-P-tiouridilil-(3'→5')-2'-O-(2-metoxietil)-5-metil-P-tiouridilil-(3'→5')-2'-O-(2-metoxietil)-5-metil-P-tiocitidilil-(3'→5')-2'-O-(2-metoxietil)-P-tioadenilil-(3'→5')-2'-O-(2-metoxietil)-5-metil-P-tiouridilil-(3'→5')-2'-O-(2-metoxietil)-P-tioadenilil-(3'→5')-2'-O-(2-metoxietil)-P-tioadenilil-(3'→5')-2'-O-(2-metoxietil)-5-metil-P-tiouridilil-(3'→5')-2'-O-(2-metoxietil)-P-tioguanilil-(3'→5')-2'-O-(2-metoxietil)-5-metil-P-tiocitidilil-(3'→5')-2'-O-(2-metoxietil)- 5-metil-P-tiouridilil-(3'→5')-2'-O-(2-metoxietil)-P-tioguanilil-(3'→5')-2'-O-(2-metoxietil)guanosina producción de la proteína de la supervivencia de las motoneuronas (SMN2)


522

C234H340N61O128P17S17 1258984-36-9

[2'-O-(2-methoxyethyl)](3'-5')(P-thio)(mU-mC-A-mC-mU-mU-mU-mC-A-mU-A- A-mU-G-mC-mU-G-G)

N

HNO O

O

HO O

OH

CH3

OCH3

N

NO NH2

O

HO

OH

CH3

O

mC

OCH3

mU

O

HO O

OH

N N

N

N NH2

OCH3

A

O

HO O

OH

N N

NH

N O

H2N

OCH3

G

onalespibum onalespib [2,4-dihydroxy-5-(propan-2-yl)phenyl]{5-[(4-

methylpiperazin-1-yl)methyl]-1,3-dihydro-2H-isoindol- 2-yl}methanone antineoplastic

onalespib [2,4-dihydroxy-5-(propan-2-yl)phényl]{5-[(4-méthylpipérazin-1-yl)méthyl]-1,3-dihydro-2H-isoindol- 2-yl}méthanone antinéoplasique

onalespib [2,4-dihidroxi-5-(propan-2-il)fenil]{5-[(4-metilpiperazin-

1-il)metil]-1,3-dihidro-2H-isoindol-2-il}metanona antineoplásico

C24H31N3O3

912999-49-6

OHHO

H3C

CH3

N

O

N

N

CH3

ozanimodum ozanimod 5-(3-{(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-

4-yl}-1,2,4-oxadiazol-5-yl)-2-[(propan-2-yl)oxy]benzonitrile immunomodulator

ozanimod 5-(3-{(1S)-1-[(2-hydroxyéthyl)amino]-2,3-dihydro-1H-indén-4-yl}-1,2,4-oxadiazol-5-yl)-2-[(propan-2-yl)oxy]benzonitrile immunomodulateur

ozanimod 5-(3-{(1S)-1-[(2-hidroxietil)amino]-2,3-dihidro-1H-inden- 4-il}-1,2,4-oxadiazol-5-il)-2-[(propan-2-il)oxi]benzonitrilo inmunomodulador

C23H24N4O3

1306760-87-1

CN

OH3C

CH3N

NO

NH

HOH


523

pegpleranibum # pegpleranib 5’-O-{[(6-{N2,N6-bis[α-carbonyl-ω-methoxypoly(oxyethane-

1,2-diyl)]-DL-lysylamido}hexyl)oxy]hydroxyphosphoryl}- 2’-deoxycytidylyl-(3’→5’)-2’-deoxyadenylyl-(3’→5’)-2’-deoxyguanylyl-(3’→5’)-2’-deoxyguanylyl-(3’→5’)-2’-deoxycytidylyl-(3’→5’)-2’-deoxy-2’-fluorouridylyl-(3’→5’)-2’-deoxyadenylyl-(3’→5’)-2’-deoxy-2’-fluorocytidylyl-(3’→5’)-2’-O-methylguanylyl-(3’→17)-hydroxy[(17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl)oxy]phosphoryl-(1→5’)-2’-deoxycytidylyl-(3’→5’)-2’-deoxyguanylyl-(3’→5’)-thymidylyl-(3’→5’)-2’-deoxyadenylyl-(3’→5’)-2’-O-methylguanylyl-(3’→5’)-2’-deoxyadenylyl-(3’→5’)-2’-O-methylguanylyl-(3’→5’)-2’-deoxycytidylyl-(3’→5’)-2’-deoxyadenylyl-(3’→5’)-2’-deoxy-2’-fluorouridylyl-(3’→5’)-2’-deoxy- 2’-fluorocytidylyl-(3’→5’)-2’-O-methyladenylyl-(3’→17)-hydroxy[(17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl)oxy]phosphoryl-(1→5’)-thymidylyl-(3’→5’)-2’-deoxyguanylyl-(3’→5’)-2’-deoxyadenylyl-(3’→5’)-thymidylyl-(3’→5’)-2’-deoxy-2’-fluorocytidylyl-(3’→5’)-2’-deoxy-2’-fluorocytidylyl-(3’→5’)-2’-deoxy- 2’-fluorouridylyl-(3’→5’)-2’-O-methylguanylyl-(3’→3’)-thymidine angiogenesis inhibitor

pegpléranib 5’-O-{[(6-{N2,N6-bis[α-carbonyl-ω-méthoxypoly(oxyéthane-1,2-diyl)]-DL-lysylamido}hexyl)oxy]hydroxyphosphoryl}- 2’-déoxycytidylyl-(3’→5’)-2’-déoxyadénylyl-(3’→5’)-2’-déoxyguanylyl-(3’→5’)-2’-déoxyguanylyl-(3’→5’)-2’-déoxycytidylyl-(3’→5’)-2’-déoxy-2’-fluorouridylyl-(3’→5’)-2’-déoxyadénylyl-(3’→5’)-2’-déoxy-2’-fluorocytidylyl-(3’→5’)-2’-O-méthylguanylyl-(3’→17)-hydroxy[(17-hydroxy-3,6,9,12,15-pentaoxaheptadécyl)oxy]phosphoryl-(1→5’)-2’-déoxycytidylyl-(3’→5’)-2’-déoxyguanylyl-(3’→5’)-thymidylyl-(3’→5’)-2’-déoxyadénylyl-(3’→5’)-2’-O-méthylguanylyl-(3’→5’)-2’-déoxyadénylyl-(3’→5’)-2’-O-méthylguanylyl-(3’→5’)-2’-déoxycytidylyl-(3’→5’)-2’-déoxyadénylyl-(3’→5’)-2’-déoxy-2’-fluorouridylyl-(3’→5’)-2’-déoxy- 2’-fluorocytidylyl-(3’→5’)-2’-O-méthyladénylyl-(3’→17)-hydroxy[(17-hydroxy-3,6,9,12,15-pentaoxaheptadécyl)oxy]phosphoryl-(1→5’)-thymidylyl-(3’→5’)-2’-déoxyguanylyl-(3’→5’)-2’-déoxyadénylyl-(3’→5’)-thymidylyl-(3’→5’)-2’-déoxy-2’-fluorocytidylyl-(3’→5’)-2’-déoxy-2’-fluorocytidylyl-(3’→5’)-2’-déoxy-2’-fluorouridylyl-(3’→5’)-2’-O-méthylguanylyl-(3’→3’)-thymidine inhibiteur de l'angiogénèse


524

pegpleranib 5’-O-{[(6-{N2,N6-bis[α-carbonil-ω-metoxipoli(oxietano- 1,2-diil)]-DL-lisilamido}hexil)oxi]hidroxifosforil}- 2’-desoxicitidilil-(3’→5’)-2’-desoxiadenilil-(3’→5’)-2’-desoxiguanilil-(3’→5’)-2’-desoxiguanilil-(3’→5’)-2’-desoxicitidilil-(3’→5’)-2’-desoxi-2’-fluorouridilil-(3’→5’)-2’-desoxiadenilil-(3’→5’)-2’-desoxi-2’-fluorocitidilil-(3’→5’)-2’-O-metilguanilil-(3’→17)-hidroxi[(17-hidroxi-3,6,9,12,15-pentaoxaheptadecil)oxi]fosforil-(1→5’)-2’-desoxicitidilil-(3’→5’)-2’-desoxiguanilil-(3’→5’)-timidilil-(3’→5’)-2’-desoxiadenilil-(3’→5’)-2’-O-metilguanilil-(3’→5’)-2’-desoxiadenilil-(3’→5’)-2’-O-metilguanilil-(3’→5’)-2’-desoxicitidilil-(3’→5’)-2’-desoxiadenilil-(3’→5’)-2’-desoxi- 2’-fluorouridilil-(3’→5’)-2’-desoxi-2’-fluorocitidilil-(3’→5’)-2’-O-metiladenilil-(3’→17)-hidroxi[(17-hidroxi-3,6,9,12,15-pentaoxaheptadecil)oxi]fosforil-(1→5’)-timidilil-(3’→5’)-2’-desoxiguanilil-(3’→5’)-2’-desoxiadenilil-(3’→5’)-timidilil-(3’→5’)-2’-desoxi-2’-fluorocitidilil-(3’→5’)-2’-desoxi- 2’-fluorocitidilil-(3’→5’)-2’-desoxi-2’-fluorouridilil-(3’→5’)-2’-O-metilguanilil-(3’→3’)-timidina inhibidor de la angiogénesis

1618657-13-8

(3'-5')-R-dC-dA-dG-dG-dC-dUfl-dA-dCfl-Gm3'-17Xp1- 5'dC-dG-dT-dA-Gm-dA-Gm-dC-dA-dUfl-dCfl-Am3'- 17Xp1-5'dT-dG-dA-dT-dCfl-dCfl-dUfl-Gm3'-3'dT

d (as prefix) = 2'-deoxy fl (as suffix) = 2'-fluoro m (as suffix) = 2'-O-methyl

O

PO

OH

O 6

Xp

H3CO

O NH

HN

O

O

NH

O

O

H

O

OCH3

x

y

x + y = n

P

O

OH

rac

R =

pexidartinibum pexidartinib 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-

N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridin-2-amine tyrosine kinase inhibitor, antineoplastic

pexidartinib 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)méthyl]- N-{[6-(trifluorométhyl)pyridin-3-yl]méthyl}pyridin-2-amine inhibiteur de la tyrosine kinase, antinéoplasique

pexidartinib 5-[(5-cloro-1H-pirrolo[2,3-b]piridin-3-il) metil]- N-{[6-(trifluorometil)piridin-3-il]metil}piridin-2-amina inhibidor de la tirosina kinasa, antineoplásico

C20H15ClF3N5 1029044-16-3

NHNHN N

CF3

N

Cl


525

pinometostatum pinometostat 9-{5-deoxy-5-[{cis-3-[2-(5-tert-butyl-1H-benzimidazol-

2-yl)ethyl]cyclobutyl}(propan-2-yl)amino]- β-D-ribofuranosyl}-9H-purin-6-amine antineoplastic

pinométostat 9-{5-déoxy-5-[{cis-3-[2-(5-tert-butyl-1H-benzimidazol- 2-yl)éthyl]cyclobutyl}(propan-2-yl)amino]- β-D-ribofuranosyl}-9H-purin-6-amine antinéoplasique

pinometostat 9-{5-desoxi-5-[{cis-3-[2-(5-terc-butil-1H-benzoimidazol- 2-il)etil]ciclobutil}(propan-2-il)amino]-β-D-ribofuranosil}- 9H-purin-6-amina antineoplásico

C30H42N8O3

1380288-87-8

O N N

N

N NH2N CH3

CH3HHH

N

N

HO OHH3C

CH3

CH3

radalbuvirum radalbuvir 5-(3,3-dimethylbut-1-yn-1-yl)-3-{(1R)-N-[(1s,4s)-4-hydroxy-

4-({[(3S)-oxolan-3-yl]oxy}methyl)cyclohexyl]- 4-methylcyclohex-3-ene-1-carboxamido}thiophene- 2-carboxylic acid antiviral

radalbuvir acide 5-(3,3-diméthylbut-1-yn-1-yl)-3-{(1R)-N-[(1s,4s)-4-hydroxy-4-({[(3S)-oxolan-3-yl]oxy}méthyl)cyclohexyl]- 4-méthylcyclohex-3-ène-1-carboxamido}thiophène- 2-carboxylique antiviral

radalbuvir ácido 5-(3,3-dimetilbut-1-in-1-il)-3-{(1R)-N-[(1s,4s)-4-hidroxi-4-({[(3S)-oxolan-3-il]oxi}metil)ciclohexil]- 4-metilciclohex-3-eno-1-carboxamido}tiofeno-2-carboxílico antiviral

C30H41NO6S

1314795-11-3

S

N

H3C

H3CCH3

CO2H

O

OH

H

H

CH3

OH

O


526

ralinepagum ralinepag {[trans-4-({[(4-chlorophenyl)(phenyl)carbamoyl]

oxy}methyl)cyclohexyl]methoxy}acetic acid prostaglandin receptor agonist

ralinépag acide {[trans-4-({[(4-chlorophényl)(phényl)carbamoyl] oxy}méthyl)cyclohexyl]methoxy}acétique agoniste des récepteurs de prostaglandines

ralinepag ácido {[trans-4-({[(4-clorofenil)(fenil)carbamoil]oxi}metil) ciclohexil]metoxi}acético agonista del receptor de prostaglandina

C23H26ClNO5

1187856-49-0

N

O O

Cl

O CO2H

relebactamum relebactam (1R,2S,5R)-2-[(piperidin-4-yl)carbamoyl]-7-oxo-

1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate beta-lactamase inhibitor

rélébactam hydrogénosulfate de (1R,2S,5R)-2-[(pipéridin- 4-yl)carbamoyl]-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yle inhibiteur de la bêta-lactamase

relebactam hidrógenosulfato de (1R,2S,5R)-2-[(piperidin- 4-il)carbamoil]-7-oxo-1,6-diazabiciclo[3.2.1]octan-6-ilo inhibidor de la beta lactamasa

C12H20N4O6S

1174018-99-5

N

N

H

OS

O

HO H

OO

O

NH

NH

ridinilazolum ridinilazole 2,2'-di(pyridin-4-yl)-1H,1'H-5,5'-bi(benzimidazole)

antibiotic

ridinilazole 2,2'-di(pyridin-4-yl)-1H,1'H-5,5'-bi(benzimidazole) antibiotique

ridinilazol 2,2'-di(piridin-4-il)-1H,1'H-5,5'-bi(benzoimidazol) antibiótico


527

C24H16N6 308362-25-6

N

HN

N

NH

N

N

roneparstatum roneparstat heparan sulfate mimetic compound that is obtained by

N-des-sulfo and N-acetyl reactions on heparin from porcine intestinal mucosa, sodium periodate glycol split oxidation of uronic acids elements and sodium borohydride reduction of aldehydes produced during oxidation; the majority of the components have a glucuronic acid (coming from the heparin starting material) and glucosamine (formed via decomposition of the glucuronic acid) structure at the non-reducing end and iduronic acid 2-sulphate or glycol split structure at the reducing end of their chain; the average molecular weight range is 15000 to 25000 Da; the degree of glycol split is about 25% [m/(n+m)] and the degree of sulfatation is about 1.2 per disaccharidic unit antineoplastic

ronéparstat dérivé à action mimétique du sulfate d’héparane, obtenu par des réactions conduisant à la N-acétyl- N-désulfohéparine de muqueuse intestinale de porc, puis dégradation oxydative des glycols des unités uroniques par le périodate de sodium et réduction, par le borohydrure de sodium, des aldéhydes produits; la majorité des composants ont, une structure acide glucuronique (présente dans l’héparine de départ) et glucosamine (formé par décomposition de l’acide glucuronique) à leur extrémité non-réductrice et une structure dérivée de l’acide iduronique soit l’ester sulfurique soit sa forme acyclique à leur extrémité réductrice, une masse molaire comprise entre 15000 et 25000 daltons, la proportion d’acide uronique ouvert [m/(n+m)] est d’environ 25% et un degré de sulfatation d’environ de 1.2 par unité disaccharide antinéoplasique

roneparstat derivado de acción mimética de la del sulfato de heparán, obtenido por reacciones que producen N-acetil- N-desulfoheparina de mucosa intestinal de cerdo, que se somete a degradación oxidativa con peryodato de sodio de los glicoles de las unidades urónicas y a reducción, por borohidruro de sodio de los aldehídos producidos; la mayoría de cuyos componentes tienen una estructura de ácido glucurónico (presente en la heparina de partida) y glucosamina (formado por descomposición del ácido glucurónico) en su extremo no-reductor y una estructura derivada del ácido idurónico que puede ser su éster sulfúrico o su forma acíclica en su extremo reductor, masa molar comprendida entre 15000 y 25000 daltons, la proporción de ácido urónico abierto [m/(n+m)] es de alrededor de 25% y el grado de sulfatación de alrededor de 1.2 par unidad de disacárido antineoplásico


528

1407492-04-9

O

O

O

O

NH

O

O

O

O

O

O

HOR1O

HO2C

R1O HO

R'

OH

HO2C

NH

OR1 OR1

HO3S

R

n mCH3

O

CH3

O

n =20-22 m = 6-8 R1= H or SO3H R = H , glucosiduronic acid R’ = H

sacrosidasum # sacrosidase invertase 2 (beta-fructofuranosidase 2, saccharase,

EC=3.2.1.26) from Saccharomyces cerevisiae (strain ATCC 204508 / S288c, Baker’s yeast) enzyme

sacrosidase invertase 2 (bêta-fructofuranosidase 2, saccharase, EC=3.2.1.26) de Saccharomyces cerevisiae (souche ATCC 204508 / S288c, levure de boulanger) enzyme

sacrosidasa invertasa 2 (beta-fructofuranosidasea 2, sacarasa,

EC=3.2.1.26) de Saccharomyces cerevisiae (cepa ATCC 204508 / S288c, levadura de cerveza) enzima

85897-35-4

Sequence / Séquence / SecuenciaSMTNETSDRP LVHFTPNKGW MNDPNGLWYD EKDAKWHLYF QYNPNDTVWG 50TPLFWGHATS DDLTNWEDQP IAIAPKRNDS GAFSGSMVVD YNNTSGFFND 100TIDPRQRCVA IWTYNTPESE EQYISYSLDG GYTFTEYQKN PVLAANSTQF 150RDPKVFWYEP SQKWIMTAAK SQDYKIEIYS SDDLKSWKLE SAFANEGFLG 200YQYECPGLIE VPTEQDPSKS YWVMFISINP GAPAGGSFNQ YFVGSFNGTH 250FEAFDNQSRV VDFGKDYYAL QTFFNTDPTY GSALGIAWAS NWEYSAFVPT 300NPWRSSMSLV RKFSLNTEYQ ANPETELINL KAEPILNISN AGPWSRFATN 350TTLTKANSYN VDLSNSTGTL EFELVYAVNT TQTISKSVFA DLSLWFKGLE 400DPEEYLRMGF EVSASSFFLD RGNSKVKFVK ENPYFTNRMS VNNQPFKSEN 450DLSYYKVYGL LDQNILELYF NDGDVVSTNT YFMTTGNALG SVNMTTGVDN 500LFYIDKFQVR EVK 513

Glycosylation sites (potential) / Sites potentiels de glycosylation / Posiciones potenciales deglicosilaciónAsn-4 Asn-45 Asn-78 Asn-92 Asn-99 Asn-146 Asn-247Asn-256 Asn-337 Asn-350 Asn-365 Asn-379 Asn-493

sapanisertibum sapanisertib 3-(2-amino-1,3-benzoxazol-5-yl)-1-(propan-2-yl)-

1H-pyrazolo[3,4-d]pyrimidin-4-amine antineoplastic

sapanisertib 3-(2-amino-1,3-benzoxazol-5-yl)-1-(propan-2-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine antinéoplasique

sapanisertib 3-(2-amino-1,3-benzoxazol-5-il)-1-(propan-2-il)- 1H-pirazolo[3,4-d]pirimidin-4-amina antineoplásico


529

C15H15N7O

1224844-38-5

N

O

NN

NN

H3C

H3CNH2

NH2

seletalisibum seletalisib 3-(8-chloro-3-{(1R)-1-[(pyrido[3,2-d]pyrimidin-4-yl)amino]-

2,2,2-trifluoroethyl}quinolin-2-yl)pyridine N-oxide immunomodulator, phosphatidylinositol 3-kinase inhibitor

sélétalisib N-oxyde de 3-(8-chloro-3-{(1R)-1-[(pyrido[3,2-d]pyrimidin-4-yl)amino]-2,2,2-trifluoroéthyl}quinoléin-2-yl)pyridine immunomodulateur, inhibiteur de la kinase phosphatidylinositol 3

seletalisib N-óxido de 3-(8-cloro-3-{(1R)-1-[(pirido[3,2-d]pirimidin- 4-il)amino]-2,2,2-trifluoroetil}quinolein-2-il)piridina inmunomodulador, inhibidor de la fosfatidilinositol 3 kinasa

C23H14ClF3N6O

1362850-20-1

N

NH

N

N

N

CF3H

Cl

O

N

setmelanotidum setmelanotide N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-

D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide, cyclic (2-8)-disulfide melanocortin receptor agonist

setmélanotide (2-8)-disulfure cyclique du N2-acétyl-L-arginyl-L-cystéinyl- D-alanyl-L-histidyl-D-phénylalanyl-L-arginyl-L-tryptophyl- L-cystéinamide agoniste du récepteur de la mélanocortine

setmelanotida (2-8)-disulfuro cíclico del N2-acetil-L-arginil-L-cisteinil- D-alanil-L-histidil-D-fenilalanil-L-arginil-L-triptofil- L-cisteinamida agonista del receptor de melanocortina


530

C49H68N18O9S2

920014-72-8

Arg Cys D-Ala His D-Phe Arg Trp Cys NH2

H3C

O

solcitinibum solcitinib N-{5-[4-(3,3-dimethylazetidine-

1-carbonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin- 2-yl}cyclopropanecarboxamide tyrosine kinase inhibitor

solcitinib N-{5-[4-(3,3-diméthylazétidine- 1-carbonyl)phényl][1,2,4]triazolo[1,5-a]pyridin- 2-yl}cyclopropanecarboxamide inhibiteur de la tyrosine kinase

solcitinib N-{5-[4-(3,3-dimetilazetidina- 1-carbonil)fenil][1,2,4]triazolo[1,5-a]piridin- 2-il}ciclopropanocarboxamida inhibidor de la tirosina kinasa

C22H23N5O2 1206163-45-2

N

N

N

NH

O O

N

CH3

CH3

somapacitanum # somapacitan [101-{S-[(8S,22S,27S)-8-carbamoyl-22,27-dicarboxy-

2,10,19,24,29,38,42,42,44-nonaoxo-59-(1H-tetrazol-5-yl)-12,15,31,34-tetraoxa-42-λ6-thia-3,9,18,23,28,37,43-heptaazanonapentacontyl]-L-cysteine}]human somatropin growth hormone derivative

somapacitan [101-{S-[(8S,22S,27S)-8-carbamoyl-22,27-dicarboxy-2,10,19,24,29,38,42,42,44-nonaoxo-59-(1H-tétrazol-5-yl)-12,15,31,34-tétraoxa-42-λ6-thia-3,9,18,23,28,37,43-heptaazanonapentacontyl]-L-cystéine}]somatropine humaine dérivé de l'hormone de croissance

somapacitán [101-{S-[(8S,22S,27S)-8-carbamoil-22,27-dicarboxi-2,10,19,24,29,38,42,42,44-nonaoxo-59-(1H-tetrazol-5-il)-12,15,31,34-tetraoxa-42-λ6-tia-3,9,18,23,28,37,43-heptaazanonapentacontil]-L-cisteina}]somatropina humana derivado de la hormona de crecimiento


531

1338578-34-9

OO

O

NH

NH2

H

O

NH

CH2

O

HN

O

NH

CO2HHONH

H

HO2C

OO

ONH

O

S

HN

O

O

O

NN

NNH

S

CO2HH2N

H

101-Cys =

Sequence / Séquence / SecuenciaFPTIPLSRLF DNAMLRAHRL HQLAFDTYQE FEEAYIPKEQ KYSFLQNPQT 50SLCFSESIPT PSNREETQQK SNLELLRISL LLIQSWLEPV QFLRSVFANS 100CVYGASDSNV YDLLKDLEEG IQTLMGRLED GSPRTGQIFK QTYSKFDTNS 150HNDDALLKNY GLLYCFRKDM DKVETFLRIV QCRSVEGSCG F 191

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro53-165 182-189

Modified residue / Résidu modifié / Resto modificado

C101

somavaratanum # somavaratan rDNA derived human somatropin (growth hormone of 191

residues) fusion protein with a hydrophilic amino acid sequence* (913 residues) at the N-terminus and another** (146 residues) at the C-terminus, produced in Escherichia coli. * starting with alanine plus 76 dodecapeptides: EPAGSPTSTEEG (AE3G2P2S2T2), three different sequences of AG3P2S4T2 and 72 of 4 different sequences of AE2G2P2S3T2 ** starting with glycylglycine plus 12 dodecapeptides of 4 different sequences of AE2G2P2S3T2 growth hormone derivative

somavaratan protéine de fusion entre la somatropine humaine (facteur de croissance de 191 résidus) et deux protéines hydrophiles, l’une*, de 913 résidus, sur son acide aminé N-terminal, et l’autre**, de 146 résidus, sur son acide aminé C-terminal, obtenue par la technique de l’ADN recombinant à partir de culture d’Escherichia coli. *constituée d’alanine suivie de 76 dodécapeptides, EPAGSPTSTEEG (AE3G2P2S2T2) puis trois différentes séquences de AG3P2S4T2 et 72 de 4 différentes séquences de AE2G2P2S3T2 **constituée de glycylglycine suivie de 12 dodécapeptides de 4 différentes séquences de AE2G2P2S3T2 dérivé de l'hormone de croissance

somavaratán proteína de fusión entre la somatropina humana (factor de crecimiento 191 restos) y dos proteínas hidrófilas, una*, de 913 restos, en el extremo N-terminal, y otra**, de 146 restos, en el extremo C-terminal, obtenida por técnicas de ADN recombinante en cultivos d’Escherichia coli. *constituida por alanina seguida de 76 dodecapéptidos, EPAGSPTSTEEG (AE3G2P2S2T2) tres secuencias diferentes de AG3P2S4T2 y 72 de 4 secuencias diferentes de AE2G2P2S3T2 **constituida por glicilglicina seguida de 12 dodecapéptidos de 4 secuencias diferentes de AE2G2P2S3T2 derivado de la hormona de crecimiento


532

1448335-08-7

Sequence / Sequence / SecuenciaAEPAGSPTST EEGTPGSGTA SSSPGSSTPS GATGSPGASP GTSSTGSPGS 50PAGSPTSTEE GTSESATPES GPGTSTEPSE GSAPGSPAGS PTSTEEGTST 100EPSEGSAPGT STEPSEGSAP GTSESATPES GPGSEPATSG SETPGSEPAT 150SGSETPGSPA GSPTSTEEGT SESATPESGP GTSTEPSEGS APGTSTEPSE 200GSAPGSPAGS PTSTEEGTST EPSEGSAPGT STEPSEGSAP GTSESATPES 250GPGTSTEPSE GSAPGTSESA TPESGPGSEP ATSGSETPGT STEPSEGSAP 300GTSTEPSEGS APGTSESATP ESGPGTSESA TPESGPGSPA GSPTSTEEGT 350SESATPESGP GSEPATSGSE TPGTSESATP ESGPGTSTEP SEGSAPGTST 400EPSEGSAPGT STEPSEGSAP GTSTEPSEGS APGTSTEPSE GSAPGTSTEP 450SEGSAPGSPA GSPTSTEEGT STEPSEGSAP GTSESATPES GPGSEPATSG 500SETPGTSESA TPESGPGSEP ATSGSETPGT SESATPESGP GTSTEPSEGS 550APGTSESATP ESGPGSPAGS PTSTEEGSPA GSPTSTEEGS PAGSPTSTEE 600GTSESATPES GPGTSTEPSE GSAPGTSESA TPESGPGSEP ATSGSETPGT 650SESATPESGP GSEPATSGSE TPGTSESATP ESGPGTSTEP SEGSAPGSPA 700GSPTSTEEGT SESATPESGP GSEPATSGSE TPGTSESATP ESGPGSPAGS 750PTSTEEGSPA GSPTSTEEGT STEPSEGSAP GTSESATPES GPGTSESATP 800ESGPGTSESA TPESGPGSEP ATSGSETPGS EPATSGSETP GSPAGSPTST 850EEGTSTEPSE GSAPGTSTEP SEGSAPGSEP ATSGSETPGT SESATPESGP 900GTSTEPSEGS APGFPTIPLS RLFDNAMLRA HRLHQLAFDT YQEFEEAYIP 950KEQKYSFLQN PQTSLCFSES IPTPSNREET QQKSNLELLR ISLLLIQSWL 1000EPVQFLRSVF ANSLVYGASD SNVYDLLKDL EEGIQTLMGR LEDGSPRTGQ 1050IFKQTYSKFD TNSHNDDALL KNYGLLYCFR KDMDKVETFL RIVQCRSVEG 1100SCGFGGTSES ATPESGPGTS TEPSEGSAPG TSTEPSEGSA PGTSESATPE 1150SGPGTSTEPS EGSAPGTSTE PSEGSAPGTS ESATPESGPG TSTEPSEGSA 1200PGTSTEPSEG SAPGTSTEPS EGSAPGSPAG SPTSTEEGTS TEPSEGSAPG 1250

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro966-1078 1095-1102

spanlecortemlocelum spanlecortemlocel consists of human expanded CD34+ haematopoietic stem

cells that have been isolated from umbilical cord blood and cultured in vitro in media supplemented with THPO (thrombopoietin), KITLG (KIT ligand, stem cell factor, SCF), IL6 (interleukin 6), FLT3LG (fms-related tyrosine kinase 3 (FLT3) ligand), and an antagonist of AHR (aryl hydrocarbon receptor); typically contains >10% of cells expressing CD34 cell therapy product (hematopoietic stem cell transplantation)

spanlécortemlocel cellules souches hématopoïétiques humaines exprimant CD34+ isolées du sang de cordon ombilical et mises en culture in vitro en milieu enrichi en THPO (thrombopoïétine), KITLG (ligand de KIT, facteur de cellules souches, SCF), IL6 (interleukine 6), FLT3LG (ligand de tyrosine kinase 3 fms-like (FLT3)) et un antagoniste d’AHR (récepteur des hydrocarbures aromatiques); typiquement, contient >10% de cellules exprimant CD34. produit de thérapie cellulaire (transplantation de cellules souches hématopoïétiques)

espanlecortemlocel células madre hematopoyéticas humanas que expresan CD34+ aisladas de sangre de cordón umbilical y cultivadas in vitro en un medio enriquecido en THPO (trombopoyetina), KITLG (ligante de KIT, factor de células madre (SCF)), IL6 (interleukina 6), FLT3LG (ligando de tirosina kinasa 3 fms-like (FLT3)) y un antagonista de AHR (receptor de hidrocarburos arílicos); normalmente, contiene >10% de células que expresan CD34 producto de terapia celular (transplante de células madre hematopoyéticas)

2211447-77-1


533

spebrutinibum spebrutinib N-[3-({5-fluoro-2-[4-(2-methoxyethoxy)anilino]pyrimidin-

4-yl}amino)phenyl]prop-2-enamide tyrosine kinase inhibitor, antineoplastic

spébrutinib N-[3-({5-fluoro-2-[4-(2-méthoxyéthoxy)anilino]pyrimidin- 4-yl}amino)phényl]prop-2-énamide inhibiteur de la tyrosine kinase, antinéoplasique

espebrutinib N-[3-({5-fluoro-2-[4-(2-metoxietoxi)anilino]pirimidin- 4-il}amino)fenil]prop-2-enamida inhibidor de la tirosina kinasa, antineoplásico

C22H22FN5O3

1202757-89-8

H2C

O

HN

HN

N N

HN

OO

CH3

F

susoctocogum alfa # susoctocog alfa recombinant DNA derived B-domain deleted porcine blood-

coagulation factor VIII analogue, produced in BHK21 cells: des-(753-1418)-blood-coagulation factor VIII (procoagulant component) Sus scrofa, glycosylated blood coagulation factor

susoctocog alfa analogue du facteur de coagulation VIII porcin dont le domaine B a été supprimé, produit dans des cellules BHK21, à partir d'ADN recombinant: dès-(753-1418)-facteur VIII de coagulation (composant procoagulant) de Sus scrofa (porc), glycosylé facteur de coagulation sanguine

susoctocog alfa análogo del factor de coagulación VIII porcino del cual se ha suprimido el dominio B, producido en células BHK21 a partir de ADN recombinante: des-(753-1418)-factor VIII de coagulación (componante procoagulante) de Sus scrofa (cerdo), glicosilado factor de coagulación sanguínea


534

1339940-90-7

CO2H

NH2HO

SHO

O O

Sequence / Séquence / SecuenciaAIRRYYLGAV ELSWDYRQSE LLRELHVDTR FPATAPGALP LGPSVLYKKT 50VFVEFTDQLF SVARPRPPWM GLLGPTIQAE VYDTVVVTLK NMASHPVSLH 100AVGVSFWKSS EGAEYEDHTS QREKEDDKVL PGKSQTYVWQ VLKENGPTAS 150DPPCLTYSYL SHVDLVKDLN SGLIGALLVC REGSLTRERT QNLHEFVLLF 200AVFDEGKSWH SARNDSWTRA MDPAPARAQP AMHTVNGYVN RSLPGLIGCH 250KKSVYWHVIG MGTSPEVHSI FLEGHTFLVR HHRQASLEIS PLTFLTAQTF 300LMDLGQFLLF CHISSHHHGG MEAHVRVESC AEEPQLRRKA DEEEDYDDNL 350YDSDMDVVRL DGDDVSPFIQ IRSVAKKHPK TWVHYISAEE EDWDYAPAVP 400SPSDRSYKSL YLNSGPQRIG RKYKKARFVA YTDVTFKTRK AIPYESGILG 450PLLYGEVGDT LLIIFKNKAS RPYNIYPHGI TDVSALHPGR LLKGWKHLKD 500MPILPGETFK YKWTVTVEDG PTKSDPRCLT RYYSSSINLE KDLASGLIGP 550LLICYKESVD QRGNQMMSDK RNVILFSVFD ENQSWYLAEN IQRFLPNPDG 600LQPQDPEFQA SNIMHSINGY VFDSLQLSVC LHEVAYWYIL SVGAQTDFLS 650VFFSGYTFKH KMVYEDTLTL FPFSGETVFM SMENPGLWVL GCHNSDLRNR 700GMTALLKVYS CDRDIGDYYD NTYEDIPGFL LSGKNVIEPR SFAQNSRPPS 750ASAPKPPVLR RHQRDISLPT FQPEEDKMDY DDIFSTETKG EDFDIYGEDE 800NQDPRSFQKR TRHYFIAAVE QLWDYGMSES PRALRNRAQN GEVPRFKKVV 850FREFADGSFT QPSYRGELNK HLGLLGPYIR AEVEDNIMVT FKNQASRPYS 900FYSSLISYPD DQEQGAEPRH NFVQPNETRT YFWKVQHHMA PTEDEFDCKA 950WAYFSDVDLE KDVHSGLIGP LLICRANTLN AAHGRQVTVQ EFALFFTIFD 1000ETKSWYFTEN VERNCRAPCH LQMEDPTLKE NYRFHAINGY VMDTLPGLVM 1050AQNQRIRWYL LSMGSNENIH SIHFSGHVFS VRKKEEYKMA VYNLYPGVFE 1100TVEMLPSKVG IWRIECLIGE HLQAGMSTTF LVYSKECQAP LGMASGRIRD 1150FQITASGQYG QWAPKLARLH YSGSINAWST KDPHSWIKVD LLAPMIIHGI 1200MTQGARQKFS SLYISQFIIM YSLDGRNWQS YRGNSTGTLM VFFGNVDASG 1250IKHNIFNPPI VARYIRLHPT HYSIRSTLRM ELMGCDLNSC SMPLGMQNKA 1300ISDSQITASS HLSNIFATWS PSQARLHLQG RTNAWRPRVS SAEEWLQVDL 1350QKTVKVTGIT TQGVKSLLSS MYVKEFLVSS SQDGRRWTLF LQDGHTKVFQ 1400GNQDSSTPVV NALDPPLFTR YLRIHPTSWA QHIALRLEVL GCEAQDLY 1448

Disulfide bridges location / Positions des ponts disulfure / Posiciones de los puentes disulfuro154-180 249-330 528-554 630-711 948-974 1015-1019 1137-1285 1290-1442


Y346-718-719-723-780-796

O-sulfoTyr

Glycosylation sites (N,S,T) / Sites de glycosylation (N,S,T) / Posiciones de glicosilación (N,S,T)Ser-44 Asn-214 Asn-240 Ser-353 Asn-582Ser-741 Ser-752 Thr-770 Asn-926 Asn-1234

tazemetostatum tazemetostat N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-

5-[ethyl(oxan-4-yl)amino]-4-methyl-4'-[(morpholin- 4-yl)methyl][1,1'-biphenyl]-3-carboxamide antineoplastic

tazémétostat N-[(4,6-diméthyl-2-oxo-1,2-dihydropyridin-3-yl)méthyl]- 5-[éthyl(oxan-4-yl)amino]-4-méthyl-4'-[(morpholin- 4-yl)méthyl][1,1'-biphényl]-3-carboxamide antinéoplasique

tazemetostat N-[(4,6-dimetil-2-oxo-1,2-dihidropiridin-3-il)metil]- 5-[etil(oxan-4-il)amino]-4-metil-4'-[(morfolin-4-il)metil][1,1'-bifenil]-3-carboxamida antineoplásico

C34H44N4O4

1403254-99-8

NH

CH3

N

N

O

H3C

O

O

NH

CH3

CH3O


535

temsavirum temsavir 1-(4-benzoylpiperazin-1-yl)-2-[4-methoxy-7-(3-methyl-

1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]ethane-1,2-dione antiviral

temsavir 1-(4-benzoylpipérazin-1-yl)-2-[4-méthoxy-7-(3-méthyl- 1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]éthane-1,2-dione antiviral

temsavir 1-(4-benzoilpiperazin-1-il)-2-[4-metoxi-7-(3-metil- 1H-1,2,4-triazol-1-il)-4-metoxi-1H-pirrolo[2,3-c]piridin- 3-il]etano-1,2-diona antiviral

C24H23N7O4

701213-36-7

N

N

O

O

O

HN

N

OCH3

N

N

N

H3C

tesidolumabum # tesidolumab immunoglobulin G1-lambda2, anti-[Homo sapiens C5

(complement C5)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-446) [Homo sapiens VH (IGHV1-69*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -IGHG1*03 (CH1 (117-214), hinge (215-229), CH2 (230-339) L1.3>A (233), L1.2>A (234), CH3 (340-444), CHS (445-446) (117-446)], (219-213')-disulfide with lambda2 light chain (1'-214') [Homo sapiens V-LAMBDA (IGLV3-9*01 (88.20%) -IGLJ2*01) [6.3.11] (1'-108') -IGLC2*01 (109'-214')]; dimer (225-225'':228-228'')-bisdisulfide immunomodulator

tésidolumab immunoglobuline G1-lambda2, anti-[Homo sapiens C5 (complément C5)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-446) [Homo sapiens VH (IGHV1-69*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -IGHG1*03 (CH1 (117-214), charnière (215-229), CH2 (230-339) L1.3>A (233), L1.2>A (234), CH3 (340-444), CHS (445-446) (117-446)], (219-213')-disulfure avec la chaîne légère lambda2 (1'-214') [Homo sapiens V-LAMBDA (IGLV3-9*01 (88.20%) -IGLJ2*01) [6.3.11] (1'-108') -IGLC2*01 (109'-214')]; dimère (225-225'':228-228'')-bisdisulfure immunomodulateur


536

tesidolumab inmunoglobulina G1-lambda2, anti-[C5 (complemento C5) de Homo sapiens], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-446) [Homo sapiens VH (IGHV1-69*01 (96.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -IGHG1*03 (CH1 (117-214), bisagra (215-229), CH2 (230-339) L1.3>A (233), L1.2>A (234), CH3 (340-444), CHS (445-446) (117-446)], (219-213')-disulfuro con la cadena ligera lambda2 (1'-214') [Homo sapiens V-LAMBDA (IGLV3-9*01 (88.20%) -IGLJ2*01) [6.3.11] (1'-108') -IGLC2*01 (109'-214')]; dímero (225-225'':228-228'')-bisdisulfuro inmunomodulador

1531594-08-7

Heavy chain / Chaîne lourde / Cadena pesadaEVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISWVRQA PGQGLEWMGG 50IGPFFGTANY AQKFQGRVTI TADESTSTAY MELSSLRSED TAVYYCARDT 100PYFDYWGQGT LVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP 150EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN 200VNHKPSNTKV DKRVEPKSCD KTHTCPPCPA PEAAGGPSVF LFPPKPKDTL 250MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR 300VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYTL 350PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD 400GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK 446

Light chain / Chaîne légère / Cadena ligeraSYELTQPLSV SVALGQTARI TCSGDSIPNY YVYWYQQKPG QAPVLVIYDD 50SNRPSGIPER FSGSNSGNTA TLTISRAQAG DEADYYCQSF DSSLNAEVFG 100GGTKLTVLGQ PKAAPSVTLF PPSSEELQAN KATLVCLISD FYPGAVTVAW 150KADSSPVKAG VETTTPSKQS NNKYAASSYL SLTPEQWKSH RSYSCQVTHE 200GSTVEKTVAP TECS 214



toreforantum toreforant 5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-

N-[3-(1-methylpiperidin-4-yl)propyl]pyrimidin-2-amine histamine H4 receptor antagonist

toréforant 5-(4,6-diméthyl-1H-benzimidazol-2-yl)-4-méthyl- N-[3-(1-méthylpipéridin-4-yl)propyl]pyrimidin-2-amine antagoniste des récepteurs H4 de l'histamine

toreforant 5-(4,6-dimetil-1H-benzoimidazol-2-il)-4-metil- N-[3-(1-metilpiperidin-4-il)propil]pirimidin-2-amina antagonista del receptor H4 de histamina

C23H32N6

952494-46-1

N

NHN

NCH3

CH3

HN

N

CH3

H3C


537

trofinetidum trofinetide glycyl-2-methyl-L-prolyl-L-glutamic acid

neuroprotectant

trofinétide acide glycyl-2-méthyl-L-prolyl-L-glutamique neuroprotecteur

trofinetida ácido glicil-2-metil-L-prolil-L-glutámico neuroprotector

C13H21N3O6

853400-76-7

N

OH2N O

NH

CO2H

H

CO2H

CH3

vandortuzumabum vedotinum # vandortuzumab vedotin immunoglobulin G1-kappa, anti-[Homo sapiens STEAP1

(six-transmembrane epithelial antigen of the prostate 1, PRSS24, STEAP)], humanized monoclonal antibody; gamma1 heavy chain (1-454) [humanized VH (Homo sapiens IGHV3-48*03 (80.80%) -(IGHD)-IGHJ4*01) [9.7.17] (1-124) -Homo sapiens IGHG1*03 (CH1 R120>K (221) (125-222), hinge (223-237),CH2 (238-347), CH3 (348-452), CHS (453-454)) (125-454)], (227-220')-disulfide with kappa light chain (1’-220’) [humanized V-KAPPA (Homo sapiens IGKV1-16*01 (81.20%) -IGKJ1*01) [12.3.9] (1'-113') -Homo sapiens IGKC*01 (114'-220')]; dimer (233-233":236-236")-bisdisulfide; conjugated, on an average of 3 to 4 cysteinyl, to monomethylauristatin E (MMAE), via a cleavable maleimidocaproyl-valyl-citrullinyl- p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker For the vedotin part, please refer to the document “INN for pharmaceutical substances: Names for radicals, groups and others”*.

immunomodulator, antineoplastic

vandortuzumab védotine immunoglobuline G1-kappa, anti-[Homo sapiens STEAP1 (antigène épithélial 1 à six-transmembrane de la prostate, PRSS24, STEAP)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-454) [VH humanisé (Homo sapiens IGHV3-48*03 (80.80%) -(IGHD)-IGHJ4*01) [9.7.17] (1-124) -Homo sapiens IGHG1*03 (CH1 R120>K (221) (125-222), charnière (223-237), CH2 (238-347), CH3 (348-452), CHS (453-454)) (125-454)], (227-220')-disulfure avec la chaîne légère kappa (1’-220’) [V-KAPPA humanisé (Homo sapiens IGKV1-16*01 (81.20%) -IGKJ1*01) [12.3.9] (1'-113') -Homo sapiens IGKC*01 (114'-220')]; dimère (233-233":236-236")-bisdisulfure; conjugué, sur 3 à 4 cystéinyl en moyenne, au monométhylauristatine E (MMAE), via un linker clivable de type maléimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) Pour la partie védotine, veuillez-vous référer au document “INN for pharmaceutical substances: Names for radicals, groups and others”*.



538

vandortuzumab vedotina inmunoglobulina G1-kappa, anti-[STEAP1 de Homo

sapiens (antígeno epitelial 1 seis-transmembrana de la próstata, PRSS24, STEAP)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-454) [VH humanizada (Homo sapiens IGHV3-48*03 (80.80%) -(IGHD)-IGHJ4*01) [9.7.17] (1-124) -Homo sapiens IGHG1*03 (CH1 R120>K (221) (125-222), bisagra (223-237),CH2 (238-347), CH3 (348-452), CHS (453-454)) (125-454)], (227-220')-disulfuro con la cadena ligera kappa (1’-220’) [V-KAPPA humanizado (Homo sapiens IGKV1-16*01 (81.20%) -IGKJ1*01) [12.3.9] (1'-113') -Homo sapiens IGKC*01 (114'-220')]; dímero (233-233":236-236")-bisdisulfuro; conjugado, en 3 – 4 restos cisteinil por término medio, con monometilauristatina E (MMAE), mediante una secuencia de conexión escindible de tipo maleimidocaproil-valil-citrulinil-p-aminobenciloxicarbonil (mc-val-cit-PABC) La fracción vedotina pueden encontrarla en el documento “INN for pharmaceutical substances: Names for radicals, groups and others”*.


1471985-92-8

Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG LVQPGGSLRL SCAVSGYSIT SDYAWNWVRQ APGKGLEWVG 50YISNSGSTSY NPSLKSRFTI SRDTSKNTLY LQMNSLRAED TAVYYCARER 100NYDYDDYYYA MDYWGQGTLV TVSSASTKGP SVFPLAPSSK STSGGTAALG 150CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL 200GTQTYICNVN HKPSNTKVDK KVEPKSCDKT HTCPPCPAPE LLGGPSVFLF 250PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE 300EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP 350REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT 400TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL 450SPGK 454Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCKSSQSLL YRSNQKNYLA WYQQKPGKAP 50KLLIYWASTR ESGVPSRFSG SGSGTDFTLT ISSLQPEDFA TYYCQQYYNY 100PRTFGQGTKV EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC LLNNFYPREA 150KVQWKVDNAL QSGNSQESVT EQDSKDSTYS LSSTLTLSKA DYEKHKVYAC 200EVTHQGLSSP VTKSFNRGEC 220

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H (C23-C104) 22-96 151-207 268-328 374-432 22''-96'' 145''-207'' 268''-328'' 374''-432''Intra-L (C23-C104) 23'-94' 140'-200' 23'''-94''' 140'''-200''' Inter-H-L* (h 5-CL 126) 227-220' 227''-220''' Inter-H-H* (h 11, h 14) 233-233'' 236-236'' *Two or three of the inter-chain disulfide bridges are not present, an average of 3 to 4 cysteinyl being conjugated each via a thioether bond to a drug linker.*Deux ou trois des ponts disulfures inter-chaînes ne sont pas présents, 3 à 4 cystéinyl en moyenne étant chacun conjugué via une liaison thioéther à un linker-principe actif.*Faltan dos o tres puentes disulfuro inter-catenarios, una media de 3 a 4 cisteinil está conjugada a conectores de principio activo.

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónH CH2 N84.4:304, 304'

verosudilum verosudil rac-(2R)-2-(dimethylamino)-N-(1-oxo-

1,2-dihydroisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide Rho-associated protein kinase inhibitor

vérosudil rac-(2R)-2-(diméthylamino)-N-(1-oxo- 1,2-dihydroisoquinoléin-6-yl)-2-(thiophén-3-yl)acétamide inhibiteur de la protéine kinase asociée à la protéine Rho

verosudil rac-(2R)-2-(dimetilamino)-N-(1-oxo-1,2-dihidroisoquinolein-6-il)-2-(tiofen-3-il)acetamida inhibidor de la proteína kinasa asociada al Rho


539

C17H17N3O2S

1414854-42-4

CH3

N

O

NH

NH

O

H3C

H

S

rac

verubecestatum verubecestat N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-

1,2,5,6-tetrahydro-1λ6,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide beta-secretase inhibitor

vérubécestat N-{3-[(5R)-3-amino-2,5-diméthyl-1,1-dioxo- 1,2,5,6-tétrahydro-1λ6,2,4-thiadiazin-5-yl]-4-fluorophényl}-5-fluoropyridine-2-carboxamide inhibiteur de la sécrétase bêta

verubecestat N-{3-[(5R)-3-amino-2,5-dimetil-1,1-dioxo-1,2,5,6-tetrahidro-1λ6,2,4-tiadiazin-5-il]-4-fluorofenil}-5-fluoropiridina- 2-carboxamida inhibidor de la secretasa beta

C17H17F2N5O3S

1286770-55-5

N

F

HN

OF

N

N

SH3C

OO

CH3

NH2

vosoritidum vosoritide a modified recombinant human C-type natriuretic peptide

(CNP) consisting of 39 amino acids comprised of the 37 C-terminal amino acids of the human CNP sequence plus the addition of 2 amino acids (Pro-Gly) on the N-terminus, produced in Escherichia coli: L-prolylglycyl-(human C-type natriuretic peptide-(17-53)-peptide (CNP-37)), cyclic-(23-39)-disulfide natriuretic peptide

vosoritide peptide natriurétique de type C humain modifié consistant en une séquence de 39 acides aminés comprenant les 37 acides aminés C-terminaux du peptide humain CNP plus deux acides aminés (Pro-Gly) N-terminaux, produit par Escherichia coli: L-prolylglycyl-(peptide natriurétique de type C humain-(17-53)-peptide (CNP-37)), (23-39)-disulfure cyclique peptide natriurétique


540

vosoritida péptido natriurético de tipo C humano modificado consistente en una secuencia de 39 aminoácidos que comprende los 37 aminoácidos C-terminales del péptido humano CNP más dos aminoácidos (Pro-Gly) N-terminales, producido por Escherichia coli: L-prolilglicil-(péptido natriurético de tipo C humano-(17-53)-péptido (CNP-37)), (23-39)-disulfuro cíclico péptido natriurético

C176H290N56O51S3

1480724-61-5

Sequence / Séquence / SecuenciaPGQEHPNARK YKGANKKGLS KGCFGLKLDR IGSMSGLGC 39

Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro23-39

zuretinoli acetas zuretinol acetate (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-

1-en-1-yl)nona-2,4,6,8-tetraen-1-yl acetate 11-cis-retinol replacement

acétate de zurétinol acétate de (2E,4E,6Z,8E)-3,7-diméthyl-9-(2,6,6-triméthylcyclohex-1-én-1-yl)nona-2,4,6,8-tétraén-1-yle remplacement du 11-cis-rétinol

acetato de zuretinol acetato de (2E,4E,6Z,8E)-3,7-dimetil-9-(2,6,6-trimetilciclohex-1-en-1-il)nona-2,4,6,8-tetraen-1-ilo tratamiento de sustitución de 11-cis retinol

C22H32O2

29584-22-3

CH3H3C

CH3

CH3

O

O

CH3

H3C

# Electronic structure available on Mednet: http://mednet.who.int/ # Structure électronique disponible sur Mednet: http://mednet.who.int/ # Estructura electrónica disponible en Mednet: http://mednet.who.int/

* http://www.who.int/medicines/services/inn/publication/en/


541

Names for Radicals and Groups Some substances for which a proposed international nonproprietary name has been established may be used in the form of salts or esters. The radicals or groups involved may be of complex composition and it is then inconvenient to refer to them in a systematic chemical nomenclature. Consequently, shorter nonproprietary names for some radicals and groups have been devised or selected, and they are suggested for use with the proposed international nonproprietary names. Dénominations applicables aux radicaux et groupes Certaines substances pour lesquelles une dénomination commune internationale proposée a été établie sont parfois utilisées sous forme de sels ou d'esters. Les radicaux ou groupes correspondants sont alors quelques fois si complexes qu'il est malcommode de les désigner conformément à la nomenclature chimique systématique. Des denominations communes abrégées ont donc été formées ou choisies pour certains d'entre eux et il est suggéré de les employer avec les dénominations communes internationales proposées. Denominaciones para Radicales y Grupos Ciertas sustancias para las cuales hay establecidas una denominación común internacional pueden usarse en forma de sales o de ésteres. Los radicales o grupos correspondientes pueden llegar a tener una composición tan compleja que resulte incómodo referirse a ellos mediante la nomenclatura química sistemática. Las siguientes denominaciones comunes abreviadas han sido ideadas o elegidas para algunos de estos radicales y grupos y se sugiere que se empleen con las denominaciones comunes internacionales propuestas. dalanas

dalanate L-alanyl-L-alaninate (ester)

dalanate L-alanyl-L-alaninate (ester)

dalanato L-alanil-L-alaninato (ester)

C6H11N2O3

H2N

NH

O

O

O

*

satetraxetanum

satetraxetan rac-(4-{[(2R)-1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-

2-yl]methyl}phenyl)carbamothioyl

satétraxétan rac-(4-{[(2R)-1,4,7,10-tétrakis(carboxyméthyl)-1,4,7,10-tétraazacyclododécan-

2-yl]méthyl}phényl)carbamothioyle

satetraxetán rac-(4-{[(2R)-1,4,7,10-tetrakis(carboximetil)-1,4,7,10-tetraazaciclododecan-

2-il]metil}fenil)carbamotioilo

C24H34N5O8S

N

N

N

N

CO2HHO2C

rac

HO2C

HO2C

NH

SH


542

AMENDMENTS TO PREVIOUS LISTS

MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES

Proposed International Nonproprietary Names (Prop. INN): List 60 Dénominations communes internationales proposées (DCI Prop.): Liste 60 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 60 (WHO Drug Information, Vol. 2, No. 4, 1988) p. 13 natrii pentosani polysulfas pentosan polysulfate sodium replace the chemical name, the molecular formula and the

structure by the following ones pentosane polysulfate sodique remplacer le nom chimique, la formule moléculaire et la

structure par les suivants pentosano polisulfato de sodio sustitúyase el nombre químico, la fórmula molecular y la

estructura por los siguientes

a mixture of the sodium salts of linear polymers of (1→4)-β-D-xylopyranan usually sulfated at the 2-and 3-positions and occasionally (approximately 1 in every 10 residues) substituted at the 2-position with a (4-O-methyl- 2,3-di-O-sulfo-α-D-glucopyranosyluronic acid) group; the average molecular weight lies between 4000 and 6000 with a total molecular weight range of 1000 to 40000

un mélange de sels de sodium de polymères linéaires de (1→4)-β-D-xylopyranane habituellement sulfatés en positions 2 et 3 et parfois (approximativement 1 résidu sur 10) substitué en position 2 avec un groupe acide 4-O-méthyl-2,3-di-O-sulfo-α-D-glucopyranosyluronique; le poids moléculaire moyen est compris entre 4000 et 6000 avec un poids moléculaire total compris entre 1000 et 40000

una mezcla de sales sódicas de polímeros lineales de (1→4)-β-D-xilopiranano generalmente sulfatados en posiciones 2 y 3 y ocasionalmente (aproximadamente 1 resto cada 10) sustituido en posición 2 por un grupo ácido 4-O-metil-2,3-di-O-sulfo-α-D-glucopiranosilurónico; el peso molecular medio está comprendido entre 4000 y 6000 con un peso molecular total comprendido entre 1000 y 40000

(C5H6Na2O10S2)n (C7H8Na2O9S)0.1n (Na2O7S2), average n = ca 11 to 16

O

O

O

O O

S-O

O

O

S O-

O

O

S

O-

OO R

chain length n = ca. 11-16

Na+

Na+

Na+Na+Na+

O

*

OSO3-

OCH3

OSO3-R = Na+ -O

O

or * SO3- Na+

ratio = ca. 1:9

n


543

Proposed International Nonproprietary Names (Prop. INN): List 95 Dénominations communes internationales proposées (DCI Prop.): Liste 95 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 95 (WHO Drug Information, Vol. 20, No. 2, 2006)

p. 123 beroctocogum alfa # & 124 beroctocog alfa replace the description by the following one béroctocog alfa remplacer la description par la suivante beroctocog alfa sustitúyase la descripción por la siguiente

human blood-coagulation factor VIII-(1-741)-peptide complex with human

blood-coagulation factor VIII-(1649-2332)-peptide

combinaison du facteur VIII de coagulation humain-(1-741)-peptide avec le facteur VIII de coagulation humain-(1649-2332)-peptide

combinación del factor VIII de coagulación humano-(1-741)-péptido con el factor VIII de coagulación humano-(1649-2332)-péptido

Proposed International Nonproprietary Names (Prop. INN): List 98 Dénominations communes internationales proposées (DCI Prop.): Liste 98 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 98 (WHO Drug Information, Vol. 21, No. 4, 2007) p. 353 & beroctocogum alfa # 354 beroctocog alfa replace the structure by the following one béroctocog alfa remplacer la structure par la suivante beroctocog alfa sustitúyase la estructura por la siguiente

CO2H

NH2HO

SHO

O O

Heavy chain / Chaîne lourde / Cadena pesadaATRRYYLGAV ELSWDYMQSD LGELPVDARF PPRVPKSFPF NTSVVYKKTL 50FVEFTDHLFN IAKPRPPWMG LLGPTIQAEV YDTVVITLKN MASHPVSLHA 100VGVSYWKASE GAEYDDQTSQ REKEDDKVFP GGSHTYVWQV LKENGPMASD 150PLCLTYSYLS HVDLVKDLNS GLIGALLVCR EGSLAKEKTQ TLHKFILLFA 200VFDEGKSWHS ETKNSLMQDR DAASARAWPK MHTVNGYVNR SLPGLIGCHR 250KSVYWHVIGM GTTPEVHSIF LEGHTFLVRN HRQASLEISP ITFLTAQTLL 300MDLGQFLLFC HISSHQHDGM EAYVKVDSCP EEPQLRMKNN EEAEDYDDDL 350TDSEMDVVRF DDDNSPSFIQ IRSVAKKHPK TWVHYIAAEE EDWDYAPLVL 400APDDRSYKSQ YLNNGPQRIG RKYKKVRFMA YTDETFKTRE AIQHESGILG 450PLLYGEVGDT LLIIFKNQAS RPYNIYPHGI TDVRPLYSRR LPKGVKHLKD 500FPILPGEIFK YKWTVTVEDG PTKSDPRCLT RYYSSFVNME RDLASGLIGP 550LLICYKESVD QRGNQIMSDK RNVILFSVFD ENRSWYLTEN IQRFLPNPAG 600VQLEDPEFQA SNIMHSINGY VFDSLQLSVC LHEVAYWYIL SIGAQTDFLS 650VFFSGYTFKH KMVYEDTLTL FPFSGETVFM SMENPGLWIL GCHNSDFRNR 700GMTALLKVSS CDKNTGDYYE DSYEDISAYL LSKNNAIEPR S 741

Light chain / Chaîne légère / Cadena ligera EI 1650TRTTLQSDQE EIDYDDTISV EMKKEDFDIY DEDENQSPRS FQKKTRHYFI 1700AAVERLWDYG MSSSPHVLRN RAQSGSVPQF KKVVFQEFTD GSFTQPLYRG 1750ELNEHLGLLG PYIRAEVEDN IMVTFRNQAS RPYSFYSSLI SYEEDQRQGA 1800EPRKNFVKPN ETKTYFWKVQ HHMAPTKDEF DCKAWAYFSD VDLEKDVHSG 1850LIGPLLVCHT NTLNPAHGRQ VTVQEFALFF TIFDETKSWY FTENMERNCR 1900APCNIQMEDP TFKENYRFHA INGYIMDTLP GLVMAQDQRI RWYLLSMGSN 1950ENIHSIHFSG HVFTVRKKEE YKMALYNLYP GVFETVEMLP SKAGIWRVEC 2000LIGEHLHAGM STLFLVYSNK CQTPLGMASG HIRDFQITAS GQYGQWAPKL 2050ARLHYSGSIN AWSTKEPFSW IKVDLLAPMI IHGIKTQGAR QKFSSLYISQ 2100FIIMYSLDGK KWQTYRGNST GTLMVFFGNV DSSGIKHNIF NPPIIARYIR 2150LHPTHYSIRS TLRMELMGCD LNSCSMPLGM ESKAISDAQI TASSYFTNMF 2200ATWSPSKARL HLQGRSNAWR PQVNNPKEWL QVDFQKTMKV TGVTTQGVKS 2250LLTSMYVKEF LISSSQDGHQ WTLFFQNGKV KVFQGNQDSF TPVVNSLDPP 2300LLTRYLRIHP QSWVHQIALR MEVLGCEAQD LY 2332

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro153-179 248-329 528-554 630-711 1832-1858 1899-1903 2021-2169 2174-2326


Y346-718-719-723-1664-1680

O-sulfoTyr

Glycosylation sites (N) / Sites de glycosylation (N) / Posiciones de glicosilación (N)Asn-41 Asn-239 Asn-1810 Asn-2118

delete/supprimer/suprimáse


544

C3821H5813N1003O1139S35 + C3547H5400N956O1033S35

Proposed International Nonproprietary Names (Prop. INN): List 109 Dénominations communes internationales proposées (DCI Prop.): Liste 109 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 109 (WHO Drug Information, Vol. 27, No. 2, 2013)

p. 169 ombitasvirum ombitasvir replace the chemical name by the following one ombitasvir remplacer le nom chimique par le suivant ombitasvir sustitúyase el nombre químico por el siguiente

dimethyl N,N'-([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-

2,5-diyl]bis{4,1-phenyleneazanediylcarbonyl[(2S)-pyrrolidine- 2,1-diyl][(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate

N,N'-([(2S,5S)-1-(4-tert-butylphényl)pyrrolidine-2,5-diyl]bis{4,1-phénylèneazanediylcarbonyl[(2S)-pyrrolidine-2,1-diyl][(2S)-3-méthyl-1-oxobutane-1,2-diyl]})biscarbamate de diméthyle

N,N'-([(2S,5S)-1-(4-terc-butilfenil)pirrolidina-2,5-diil]bis{4,1-fenilenoazanodiilcarbonil[(2S)-pirrolidina-2,1-diil][(2S)-3-metil- 1-oxobutano-1,2-diil]})biscarbamato de dimetilo

p. 171 & paclitaxelum trevatidum 172 paclitaxel trevatide replace the chemical name by the following one paclitaxel trévatide remplacer le nom chimique par le suivant paclitaxel trevatida sustitúyase el nombre químico por el siguiente

short modified fragment of human amyloid beta A4 protein

covalently linked to three molecules of paclitaxel through succinyl linkers: N2.1,N6.10,N6.15-tris(4-{[(1S,2R)-1-benzamido-3-{[4,10β-bis(acetyloxy)-2α-(benzoyloxy)-5β,20-epoxy-1,7β-dihydroxy- 9-oxotax-11-en-13α-yl]oxy}-3-oxo-1-phenylpropan-2-yl]oxy}- 4-oxobutanoyl) ([318-L-threonine(P>T1),324-L-serine(C>S7), 325-L-arginine(G>R8),327-L-lysine(N>K10),332-L-lysine(D>K15)] human amyloid beta A4 protein precursor-(318-336)-peptide)

fragment court et modifié de la protéine bêta A4 amyloïde humaine lié de façon covalente à trois molécules de paclitaxel par autant de succinyles : N2.1,N6.10,N6.15-tris(4-{[(1S,2R)-1-benzamido-3-{[4,10β-bis(acétyloxy)-2α-(benzoyloxy)-5β,20-époxy-1,7β-dihydroxy- 9-oxotax-11-en-13α-yl]oxy}-3-oxo-1-phénylpropan-2-yl]oxy}- 4-oxobutanoyl) ([318-L-thréonine(P>T1),324-L-sérine(C>S7), 325-L-arginine(G>R8),327-L-lysine(N>K10),332-L-lysine(D>K15)] précurseur de la protéine amyloïde bêta A4 humaine-(318-336)-peptide)

fragmento corto y modificado de la proteína beta A4 amiloide humana unido covalentemente a tres moléculas de paclitaxel mediante succinilos : N2.1,N6.10,N6.15-tris(4-{[(1S,2R)-1-benzamido-3-{[4,10β-bis(acetiloxi)-2α-(benzoiloxi)-5β,20-epoxi-1,7β-dihidroxi-9-oxotax-11-en- 13α-il]oxi}-3-oxo-1-fenilpropan-2-il]oxi}-4-oxobutanoil) ([318-L-treonina(P>T1),324-L-serina(C>S7),325-L-arginina(G>R8),327-L-lisina(N>K10),332-L-lisina(D>K15)] precursor de la proteína amiloide beta A4 humana-(318-336)-péptido


545

p. 191 vedroprevirum vedroprevir replace the chemical name by the following one védroprévir remplacer le nom chimique par le suivant vedroprevir sustitúyase el nombre químico por el siguiente

(1R,2R)-1-{(2S,4R)-1-{(2S)-2-[({[(1R,3r,5S)-bicyclo[3.1.0]hexan- 3-yl]oxy}carbonyl)amino]-3,3-dimethylbutanoyl}-4-[(8-chloro- 7-[2-(morpholin-4-yl)ethoxy]-2-{2-[(propan-2-yl)amino]-1,3-thiazol-4-yl}quinolin-4-yl)oxy]pyrrolidine-2-carboxamido}- 2-ethylcyclopropane-1-carboxylic acid

acide (1R,2R)-1-{(2S,4R)-1-{(2S)-2-[({[(1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl]oxy}carbonyl)amino]- 3,3-diméthylbutanoyl}-4-[(8-chloro-7-[2-(morpholin-4-yl)éthoxy]- 2-{2-[(propan-2-yl)amino]-1,3-thiazol-4-yl}quinoléin- 4-yl)oxy]pyrrolidine-2-carboxamido}-2-éthylcyclopropane- 1-carboxylique

ácido (1R,2R)-1-{(2S,4R)-1-{(2S)-2-[({[(1R,3r,5S)-biciclo[3.1.0]hexan-3-il]oxi}carbonil)amino]-3,3-dimetilbutanoil}- 4-[(8-cloro-7-[2-(morfolin-4-il)etoxi]-2-{2-[(propan-2-il)amino]- 1,3-tiazol-4-il}quinolin-4-il)oxi]pirrolidina-2-carboxamido}- 2-etilciclopropano-1-carboxílico

p. 201 delete/supprimer/suprimáse insert/insérer/insertese velcalcetidum etelcalcetidum velcalcetide etelcalcetide velcalcétide ételcalcétide velcalcetida etelcalcetida Proposed International Nonproprietary Names (Prop. INN): List 110 Dénominations communes internationales proposées (DCI Prop.): Liste 110 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 110 (WHO Drug Information, Vol. 27, No. 4, 2013) p. 422 lotilanerum lotilaner remplacer le mécanisme d’action par le suivant lotilaner sustitúyase el mecanismo de acción por el siguiente

insecticide (usage vétérinaire) insecticida (uso veterinario) Proposed International Nonproprietary Names (Prop. INN): List 111 Dénominations communes internationales proposées (DCI Prop.): Liste 111 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 111 (WHO Drug Information, Vol. 28, No. 2, 2014) p. 214 suprimáse insertese albenatide albenatida


546

p. 229 eflapegrastimum # & 230 eflapegrastim replace the description and the structure by the following ones éflapégrastim remplacer la description et la structure par les suivantes eflapegrastim sustitúyase la descripción y la estructura por las siguientes

human granulocyte colony-stimulating factor and human IgG4 Fc

dimer linked together with polyethylene glycol derivative, produced in Escherichia coli: Nα.1,N1.9'-[ω-(oxypropane-1,3-diyl)-α-(propane- 1,3-diyl)poly(oxyethylene)] des-(1-L-alanine,37-39)- [18-L-serine(C>S),69-L-serine(P>S)]human granulocyte colony-stimulating factor (G-CSF, pluripoietin) (1-174)-peptide and des-(1-8)-human immunoglobulin G4 Fc fragment (IGHG4*01 H-CH2-CH3) (9'-229')-peptide dimer (11'-11'')-disulfide

le facteur de stimulation de colonies de granulocytes humain et le dimère du fragment Fc de l’IgG4 humaine, produits par Escherichia coli, reliés par un radical substituant dérivé du polyéthylèneglycol: Nα.1,N1.9'-[ω-(oxypropane-1,3-diyl)-α-(propane- 1,3-diyl)poly(oxyethylene)] dès-(1-L-alanine,37-39)- [18-L-sérine(C>S), 69-L-sérine(P>S)]facteur de stimulation de colonies de granulocytes humain (G-CSF, pluripoiétine) (1-174)-peptide et (11'-11'')-disulfure du dimère de dès-(1-8)-fragment Fc de l’immunoglobuline G4 humaine (IGHG4*01 H-CH2-CH3) (9'-229')-peptide

producto de la unión, mediante un radical derivado del polietilenglicol, del factor estimulante de colonias de granulocitos humano y el dímero del fragmento Fc de la IgG4 humana, producidos por Escherichia coli. Nα.1,N1.9'-[ω-(oxipropano-1,3-diil)-α-(propano-1,3-diil)poli(oxietileno)] des-(1-L-alanina,37-39)-[18-L-serina(C>S),69-L-serina(P>S)]]factor estimulante de colonias de granulocitos humano (G-CSF, pluripoyetina (1-174)-péptido y (11'-11'')-disulfuro del dímero de des-(1-8)-fragmento Fc de la inmunoglobulina G4 humana (IGHG4*01 H-CH2-CH3) (9'-229')-péptido

O NH

ON

H CO2H

CH3HO

H

CO2H

H

n

P - T9' - 1

Human G-CSF derivative sequence / Séquence dérivée du G-CSF humain / Secuencia derivada de G-CSF humanoTPLGPASSLP QSFLLKSLEQ VRKIQGDGAA LQEKLCATYK LCHPEELVLL 50GHSLGIPWAP LSSCSSQALQ LAGCLSQLHS GLFLYQGLLQ ALEGISPELG 100PTLDTLQLDV ADFATTIWQQ MEELGMAPAL QPTQGAMPAF ASAFQRRAGG 150VLVASHLQSF LEVSYRVLRH LAQP 174 hIGHG4 Fc monomer / Monomère du Fc de hIGHG4 / Monómero de Fc de hIGHG4 PS CPAPEFLGGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSQ 50'EDPEVQFNWY VDGVEVHNAK TKPREEQFNS TYRVVSVLTV LHQDWLNGKE 100'YKCKVSNKGL PSSIEKTISK AKGQPREPQV YTLPPSQEEM TKNQVSLTCL 150'VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ 200'EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 229'

hIGHG4 Fc monomer / Monomère du Fc de hIGHG4 / Monómero de Fc de hIGHG4 PS CPAPEFLGGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSQ 50''EDPEVQFNWY VDGVEVHNAK TKPREEQFNS TYRVVSVLTV LHQDWLNGKE 100''YKCKVSNKGL PSSIEKTISK AKGQPREPQV YTLPPSQEEM TKNQVSLTCL 150''VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ 200''EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 229''

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro11'-11'' 36-42 43'-103' 43''-103'' 64-74 149'-207' 149''-207''



547

p. 238 suprimáse insertese funapide funapida p. 250 suprimáse insertese olipudase alfa olipudasa alfa p. 252 peficitinibum peficitinib replace the chemical name by the following one péficitinib remplacer le nom chimique par le suivant peficitinib sustitúyase el nombre químico por el siguiente

4-{[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}-

1H-pyrrolo[2,3-b]pyridine-5-carboxamide

4-{[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}- 1H-pyrrolo[2,3-b]pyridine-5-carboxamide

4-{[(1R,2s,3S,5s,7s)-5-hidroxiadamantan-2-il]amino}- 1H-pirrolo[2,3-b]piridina-5-carboxamida

p. 270 velpatasvirum velpatasvir replace the chemical name by the following one velpatasvir remplacer le nom chimique par le suivant velpatasvir sustitúyase el nombre químico por el siguiente

methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-

[(methoxycarbonyl)amino]-2-phenylacetyl}- 4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-4-yl}- 1,11-dihydro[2]benzopyrano[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)- 5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(méthoxycarbonyl)amino]-2-phénylacétyl}- 4-(méthoxyméthyl)pyrrolidin-2-yl]-1H-imidazol-4-yl}- 1,11-dihydro[2]benzopyrano[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)- 5-méthylpyrrolidin-1-yl]-3-méthyl-1-oxobutan-2-yl}carbamate de méthyle

{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(metoxicarbonil)amino]-2-fenilacetil}-4-(metoximetil)pirrolidin-2-il]-1H-imidazol-4-il}-1,11-dihidro[2]benzopirano[4',3':6,7]nafto[1,2-d]imidazol-2-il)-5-metilpirrolidin-1-il]-3-metil-1-oxobutan- 2-il}carbamato de metilo


548

ANNEX 1

PROCEDURE FOR THE SELECTION OF RECOMMENDED INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL

SUBSTANCES1

The following procedure shall be followed by the World Health Organization (hereinafter also referred to as “WHO”) in the selection of recommended international nonproprietary names for pharmaceutical substances, in accordance with resolution WHA3.11 of the World Health Assembly, and in the substitution of such names. Article 1 - Proposals for recommended international nonproprietary names and proposals for substitution of such names shall be submitted to WHO on the form provided therefore. The consideration of such proposals shall be subject to the payment of an administrative fee designed only to cover the corresponding costs of the Secretariat of WHO (“the Secretariat”). The amount of this fee shall be determined by the Secretariat and may, from time to time, be adjusted. Article 2 - Such proposals shall be submitted by the Secretariat to the members of the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations designated for this purpose, such designated members hereinafter referred to as “the INN Expert Group”, for consideration in accordance with the “General principles for guidance in devising International Nonproprietary Names for Pharmaceutical Substances”, annexed to this procedure2. The name used by the person discovering or first developing and marketing a pharmaceutical substance shall be accepted, unless there are compelling reasons to the contrary. Article 3 - Subsequent to the examination provided for in article 2, the Secretariat shall give notice that a proposed international nonproprietary name is being considered. a) Such notice shall be given by publication in WHO Drug Information3

and by letter to Member States and to national and regional pharmacopoeia commissions or other bodies designated by Member States.

i) Notice shall also be sent to the person who submitted the proposal (“the original applicant”) and other persons known to be concerned with a name under consideration.

b) Such notice shall:

i) set forth the name under consideration; ii) identify the person who submitted the proposal for naming the substance, if so requested by such person; iii) identify the substance for which a name is being considered; iv) set forth the time within which comments and objections will be received and the person and place to whom they should be directed; v) state the authority under which WHO is acting and refer to these rules of procedure.

1 See Annex 1 in WHO Technical Report Series, No. 581, 1975. The original text was adopted by the Executive Board in resolution

EB15.R7 and amended in resolutions EB43.R9 and EB115.R4.

2 See Annex 2.

3 Before 1987, lists of international nonproprietary names were published in the Chronicle of the World Health Organization.


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c) In forwarding the notice, the Secretariat shall request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the proposed name during the period it is under consideration by WHO.

Article 4 - Comments on the proposed name may be forwarded by any person to WHO within four months of the date of publication, under article 3, of the name in WHO Drug Information. Article 5 - A formal objection to a proposed name may be filed by any interested person within four months of the date of publication, under article 3, of the name in WHO Drug Information.

Such objection shall:

i) identify the person objecting;

ii) state his or her interest in the name; iii) set forth the reasons for his or her objection to the name proposed. Article 6 - Where there is a formal objection under article 5, WHO may either reconsider the proposed name or use its good offices to attempt to obtain withdrawal of the objection. Without prejudice to the consideration by WHO of a substitute name or names, a name shall not be selected by WHO as a recommended international nonproprietary name while there exists a formal objection thereto filed under article 5 which has not been withdrawn. Article 7 - Where no objection has been filed under article 5, or all objections previously filed have been withdrawn, the Secretariat shall give notice in accordance with subsection (a) of article 3 that the name has been selected by WHO as a recommended international nonproprietary name. Article 8 - In forwarding a recommended international nonproprietary name to Member States under article 7, the Secretariat shall: a) request that it be recognized as the nonproprietary name for the substance; and b) request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the name and to prohibit registration of the name as a trademark or trade name. Article 9 a) In the extraordinary circumstance that a previously recommended international nonproprietary name gives rise to errors in medication, prescription or distribution, or a demonstrable risk thereof, because of similarity with another name in pharmaceutical and/or prescription practices, and it appears that such errors or potential errors cannot readily be resolved through other interventions than a possible substitution of a previously recommended international nonproprietary name, or in the event that a previously recommended international nonproprietary name differs substantially from the nonproprietary name approved in a significant number of Member States, or in other such extraordinary circumstances that justify a substitution of a recommended international nonproprietary name, proposals to that effect may be filed by any interested person. Such proposals shall be submitted on the form provided therefore and shall: i) identify the person making the proposal;

ii) state his or her interest in the proposed substitution; and iii) set forth the reasons for the proposal; and

iv) describe, and provide documentary evidence regarding the other interventions undertaken in an effort to resolve the situation, and the reasons why these other interventions were inadequate.


550

Such proposals may include a proposal for a new substitute international nonproprietary name, devised in accordance with the General principles, which takes into account the pharmaceutical substance for which the new substitute international nonproprietary name is being proposed. The Secretariat shall forward a copy of the proposal, for consideration in accordance with the procedure described in subsection (b) below, to the INN Expert Group and the original applicant or its successor (if different from the person bringing the proposal for substitution and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations). In addition, the Secretariat shall request comments on the proposal from:

i) Member States and national and regional pharmacopoeia commissions or other bodies designated by Member States (by including a notice to that effect in the letter referred to in article 3(a), and

ii) any other persons known to be concerned by the proposed substitution.

The request for comments shall:

i) state the recommended international nonproprietary name that is being proposed for substitution (and the proposed substitute name, if provided);

ii) identify the person who submitted the proposal for substitution (if so requested by such

person);

iii) identify the substance to which the proposed substitution relates and reasons put forward for substitution;

iv) set forth the time within which comments will be received and the person and place to whom they should be directed; and v) state the authority under which WHO is acting and refer to these rules of procedure.

Comments on the proposed substitution may be forwarded by any person to WHO within four months of the date of the request for comments. b) After the time period for comments referred to above has elapsed, the Secretariat shall forward any comments received to the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution. If, after consideration of the proposal for substitution and the comments received, the INN Expert Group, the person bringing the proposal for substitution and the original applicant or its successor all agree that there is a need to substitute the previously recommended international nonproprietary name, the Secretariat shall submit the proposal for substitution to the INN Expert Group for further processing. Notwithstanding the foregoing, the original applicant or its successor shall not be entitled to withhold agreement to a proposal for substitution in the event the original applicant or its successor has no demonstrable continuing interest in the recommended international nonproprietary name proposed for substitution.

In the event that a proposal for substitution shall be submitted to the INN Expert Group for further processing, the INN Expert Group will select a new international nonproprietary name in accordance with the General principles referred to in article 2 and the procedure set forth in articles 3 to 8 inclusive. The notices to be given by the Secretariat under article 3 and article 7, respectively, including to the original applicant or its successor (if not the same as the person proposing the substitution, and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations), shall in such event indicate that the new name is a substitute for a previously recommended international nonproprietary name and that Member States may wish to make transitional arrangements in order to accommodate existing products that use the previously recommended international nonproprietary name on their label in accordance with national legislation.


551

If, after consideration of the proposal for substitution and the comments received in accordance

with the procedure described above, the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution do not agree that there are compelling reasons for substitution of a previously recommended international nonproprietary name, this name shall be retained (provided always that the original applicant or its successor shall not be entitled to withhold agreement to a proposal for substitution in the event that the original applicant or its successor has no demonstrable continuing interest in the recommended international nonproprietary name proposed to be substituted). In such an event, the Secretariat shall advise the person having proposed the substitution, as well as the original applicant or its successor (if not the same as the person proposing the substitution, and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations), Member States, national and regional pharmacopoeia commissions, other bodies designated by Member States, and any other persons known to be concerned by the proposed substitution that, despite a proposal for substitution, it has been decided to retain the previously recommended international nonproprietary name (with a description of the reason(s) why the proposal for substitution was not considered sufficiently compelling).

ANNEX 2 GENERAL PRINCIPLES FOR GUIDANCE IN DEVISING INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES1

1. International Nonproprietary Names (INN) should be distinctive in sound and spelling. They should not be inconveniently long and should not be liable to confusion with names in common use. 2. The INN for a substance belonging to a group of pharmacologically related substances should, where appropriate, show this relationship. Names that are likely to convey to a patient an anatomical, physiological, pathological or therapeutic suggestion should be avoided. These primary principles are to be implemented by using the following secondary principles: 3. In devising the INN of the first substance in a new pharmacological group, consideration should be given to the possibility of devising suitable INN for related substances, belonging to the new group. 4. In devising INN for acids, one-word names are preferred; their salts should be named without modifying the acid name, e.g. “oxacillin” and “oxacillin sodium”, “ibufenac” and “ibufenac sodium”. 5. INN for substances which are used as salts should in general apply to the active base or the active acid. Names for different salts or esters of the same active substance should differ only in respect of the name of the inactive acid or the inactive base. For quaternary ammonium substances, the cation and anion should be named appropriately as separate components of a quaternary substance and not in the amine-salt style. 6. The use of an isolated letter or number should be avoided; hyphenated construction is also undesirable. 7. To facilitate the translation and pronunciation of INN, “f” should be used instead of “ph”, “t” instead of “th”, “e” instead of “ae” or “oe”, and “i” instead of “y”; the use of the letters “h” and “k” should be avoided. 1

In its Twentieth report (WHO Technical Report Series, No. 581, 1975), the WHO Expert committee on Nonproprietary Names for Pharmaceutical Substances reviewed the general principles for devising, and the procedures for selecting, INN in the light of developments in pharmaceutical compounds in recent years. The most significant change has been the extension to the naming of synthetic chemical substances of the practice previously used for substances originating in or derived from natural products. This practice involves the use of a characteristic “stem” indicative of a common property of the members of a group. The reason for, and the implications of, the change are fully discussed. The guiding principles were updated during the 13th Consultation on nonproprietary names for pharmaceutical substances (Geneva, 27-29 April 1983) (PHARM S/NOM 928 13 May 1983, revised 18 August 1983).


552

8. Provided that the names suggested are in accordance with these principles, names proposed by the person discovering or first developing and marketing a pharmaceutical preparation, or names already officially in use in any country, should receive preferential consideration. 9. Group relationship in INN (see General principle 2) should if possible be shown by using a common stem. The following list contains examples of stems for groups of substances, particularly for new groups. There are many other stems in active use.1 Where a stem is shown without any hyphens it may be used anywhere in the name. Latin English -acum -ac anti-inflammatory agents, ibufenac derivatives -adolum -adol } analgesics -adol- -adol-} -astum -ast antiasthmatic, antiallergic substances not acting primarily

as antihistaminics -astinum -astine antihistaminics -azepamum -azepam diazepam derivatives bol bol steroids, anabolic -cain- -cain- class I antiarrhythmics, procainamide and lidocaine

derivatives -cainum -caine local anaesthetics cef- cef- antibiotics, cefalosporanic acid derivatives -cillinum -cillin antibiotics, 6-aminopenicillanic acid derivatives -conazolum -conazole systemic antifungal agents, miconazole derivatives cort cort corticosteroids, except prednisolone derivatives -coxibum -coxib selective cyclo-oxygenase inhibitors -entanum -entan endothelin receptor antagonists gab gab gabamimetic agents gado- gado- diagnostic agents, gadolinium derivatives -gatranum -gatran thrombin inhibitors, antithrombotic agents gest gest steroids, progestogens gli gli antihyperglycaemics io- io- iodine-containing contrast media -metacinum -metacin anti-inflammatory, indometacin derivatives -mycinum -mycin antibiotics, produced by Streptomyces strains -nidazolum -nidazole antiprotozoal substances, metronidazole derivatives -ololum -olol β-adrenoreceptor antagonists -oxacinum -oxacin antibacterial agents, nalidixic acid derivatives -platinum -platin antineoplastic agents, platinum derivatives -poetinum -poetin erythropoietin type blood factors -pril(at)um -pril(at) angiotensin-converting enzyme inhibitors -profenum -profen anti-inflammatory substances, ibuprofen derivatives prost prost prostaglandins -relinum -relin pituitary hormone release-stimulating peptides -sartanum -sartan angiotensin II receptor antagonists, antihypertensive (non-

peptidic) -vaptanum -vaptan vasopressin receptor antagonists vin- vin- } vinca-type alkaloids -vin- -vin-} 1 A more extensive listing of stems is contained in the working document WHO/EMP/RHT/TSN/2013.1 which is regularly updated and can be requested from the INN Programme, WHO, Geneva.


553

ANNEXE 1

PROCEDURE A SUIVRE EN VUE DU CHOIX DE DENOMINATIONS COMMUNES INTERNATIONALES RECOMMANDEES POUR LES

SUBSTANCES PHARMACEUTIQUES1

L’Organisation mondiale de la Santé (également désignée ci-après sous l’appellation « OMS ») observe la procédure exposée ci-dessous pour l’attribution de dénominations communes internationales recommandées pour les substances pharmaceutiques, conformément à la résolution WHA3.11 de l’Assemblée mondiale de la Santé, et pour le remplacement de telles dénominations. Article 1 - Les propositions de dénominations communes internationales recommandées et les propositions de remplacement de telles dénominations sont soumises à l’OMS sur la formule prévue à cet effet. L’examen de telles propositions est soumis au paiement d’une taxe administrative destinée uniquement à couvrir les coûts correspondants assumés par le Secrétariat de l’OMS (« le Secrétariat »). Le montant de cette taxe est déterminé par le Secrétariat et peut être modifié de temps à autre. Article 2 - Ces propositions sont soumises par le Secrétariat aux experts désignés à cette fin parmi les personnalités inscrites au Tableau d’experts de la Pharmacopée internationale et des Préparations pharmaceutiques, ci-après désignés sous l’appellation « le Groupe d’experts des DCI » ; elles sont examinées par les experts conformément aux « Directives générales pour la formation de dénominations communes internationales pour les substances pharmaceutiques » reproduites ci-après2.

La dénomination acceptée est la dénomination employée par la personne qui découvre ou qui, la première, fabrique et lance sur le marché une substance pharmaceutique, à moins que des raisons majeures n’obligent à s’écarter de cette règle. Article 3 - Après l’examen prévu à l’article 2, le Secrétariat notifie qu’un projet de dénomination commune internationale est à l’étude. a) Cette notification est faite par une insertion dans WHO Drug Information3 et par l’envoi d’une lettre aux Etats Membres et aux commissions nationales et régionales de pharmacopée ou autres organismes désignés par les Etats Membres.

i) Notification est également faite à la personne qui a soumis la proposition (« le demandeur initial ») et à d’autres personnes portant à la dénomination mise à l’étude un intérêt notoire.

b) Cette notification contient les indications suivantes :

i) dénomination mise à l’étude;

ii) nom de l’auteur de la proposition tendant à attribuer une dénomination à la substance, si cette personne le demande ;

iii) définition de la substance dont la dénomination est mise à l’étude ;

iv) délai pendant lequel seront reçues les observations et les objections à l’égard de cette dénomination ; nom et adresse de la personne habilitée à recevoir ces observations et objections ;

v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement.

1 Voir annexe 1 dans OMS, Série de Rapports techniques, N° 581, 1975. Le texte original a été adopté par le Conseil exécutif dans sa résolution EB15.R7 et amendé dans ses résolutions EB43.R9 et EB115.R4.

2 Voir annexe 2. 3

Avant 1987, les listes de dénominations communes internationales étaient publiées dans la Chronique de l’Organisation mondiale de la Santé.


554

c) En envoyant cette notification, le Secrétariat demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur la dénomination proposée pendant la période au cours de laquelle cette dénomination est mise à l’étude par l’OMS. Article 4 - Des observations sur la dénomination proposée peuvent être adressées à l’OMS par toute personne, dans les quatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3). Article 5 - Toute personne intéressée peut formuler une objection formelle contre la dénomination proposée dans les quatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3). Cette objection doit s’accompagner des indications suivantes :

i) nom de l’auteur de l’objection ; ii) intérêt qu’il ou elle porte à la dénomination en cause ; iii) raisons motivant l’objection contre la dénomination proposée. Article 6 - Lorsqu’une objection formelle est formulée en vertu de l’article 5, l’OMS peut soit soumettre la dénomination proposée à un nouvel examen, soit intervenir pour tenter d’obtenir le retrait de l’objection. Sans préjudice de l’examen par l’OMS d’une ou de plusieurs appellations de remplacement, l’OMS n’adopte pas d’appellation comme dénomination commune internationale recommandée tant qu’une objection formelle présentée conformément à l’article 5 n’est pas levée. Article 7 - Lorsqu’il n’est formulé aucune objection en vertu de l’article 5, ou que toutes les objections présentées ont été levées, le Secrétariat fait une notification conformément aux dispositions du paragraphe a) de l’article 3, en indiquant que la dénomination a été choisie par l’OMS en tant que dénomination commune internationale recommandée. Article 8 - En communiquant aux Etats Membres, conformément à l’article 7, une dénomination commune internationale recommandée, le Secrétariat : a) demande que cette dénomination soit reconnue comme dénomination commune de la substance considérée ; et b) demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur cette dénomination et interdire le dépôt de cette dénomination comme marque ou appellation commerciale. Article 9 - a) Dans le cas exceptionnel où une dénomination commune internationale déjà recommandée donne lieu à des erreurs de médication, de prescription ou de distribution ou en comporte un risque démontrable, en raison d’une similitude avec une autre appellation dans la pratique pharmaceutique et/ou de prescription, et où il apparaît que ces erreurs ou ces risques d’erreur ne peuvent être facilement évités par d’autres interventions que le remplacement éventuel d’une dénomination commune internationale déjà recommandée, ou dans le cas où une dénomination commune internationale déjà recommandée diffère sensiblement de la dénomination commune approuvée dans un nombre important d’Etats Membres, ou dans d’autres circonstances exceptionnelles qui justifient le remplacement d’une dénomination commune internationale recommandée, toute personne intéressée peut formuler une proposition dans ce sens. Cette proposition est présentée sur la formule prévue à cet effet et doit s’accompagner des indications suivantes :

i) nom de l’auteur de la proposition ;

ii) intérêt qu’il ou elle porte au remplacement proposé ;

iii) raisons motivant la proposition ; et


555

iv) description, faits à l’appui, des autres interventions entreprises pour tenter de régler le problème et exposé des raisons pour lesquelles ces interventions ont échoué.

Les propositions peuvent comprendre une proposition de nouvelle dénomination commune internationale de remplacement, établie conformément aux Directives générales, compte tenu de la substance pharmaceutique pour laquelle la nouvelle dénomination commune internationale de remplacement est proposée. Le Secrétariat transmet une copie de la proposition pour examen, conformément à la procédure exposée plus loin au paragraphe b), au Groupe d’experts des DCI et au demandeur initial ou à son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles). De plus, le Secrétariat demande aux entités et personnes ci-après de formuler des observations sur la proposition :

i) les Etats Membres et les commissions nationales et régionales de pharmacopée ou d’autres organismes désignés par les Etats Membres (en insérant une note à cet effet dans la lettre mentionnée à l’article 3.a), et

ii) toutes autres personnes portant au remplacement proposé un intérêt notoire. La demande d’observations contient les indications suivantes :

i) dénomination commune internationale recommandée pour laquelle un remplacement est proposé (et la dénomination de remplacement proposée, si elle est fournie) ;

ii) nom de l’auteur de la proposition de remplacement (si cette personne le demande) ;

iii) définition de la substance faisant l’objet du remplacement proposé et raisons avancées pour le remplacement ;

iv) délai pendant lequel seront reçus les commentaires et nom et adresse de la personne habilitée à recevoir ces commentaires ; et

v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement. Des observations sur la proposition de remplacement peuvent être communiquées par toute personne à l’OMS dans les quatre mois qui suivent la date de la demande d’observations. b) Une fois échu le délai prévu ci-dessus pour la communication d’observations, le Secrétariat transmet les observations reçues au Groupe d’experts des DCI, au demandeur initial ou à son successeur et à l’auteur de la proposition de remplacement. Si, après avoir examiné la proposition de remplacement et les observations reçues, le Groupe d’experts des DCI, l’auteur de la proposition de remplacement et le demandeur initial ou son successeur reconnaissent tous qu’il est nécessaire de remplacer la dénomination commune internationale déjà recommandée, le Secrétariat soumet la proposition de remplacement au Groupe d’experts des DCI pour qu’il y donne suite.

Nonobstant ce qui précède, le demandeur initial ou son successeur n’est pas habilité à refuser son accord à une proposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il est proposé de remplacer.

Dans le cas où une proposition de remplacement est soumise au Groupe d’experts des DCI pour

qu’il y donne suite, le Groupe choisit une nouvelle dénomination commune internationale conformément aux Directives générales mentionnées à l’article 2 et selon la procédure décrite dans les articles 3 à 8 inclus. La notification faite par le Secrétariat en vertu de l’article 3 et de l’article 7, respectivement, y compris au demandeur initial ou à son successeur (si ce n’est pas la même personne que celle qui a proposé le remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse


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être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles), doit dans un tel cas indiquer que la nouvelle dénomination remplace une dénomination commune internationale déjà recommandée et que les Etats Membres peuvent souhaiter prendre des mesures transitoires pour les produits existants qui utilisent la dénomination commune internationale déjà recommandée sur leur étiquette conformément à la législation nationale.

Si, après examen de la proposition de remplacement et des observations communiquées

conformément à la procédure exposée plus haut, le Groupe d’experts des DCI, le demandeur initial ou son successeur et l’auteur de la proposition de remplacement ne s’accordent pas sur le fait qu’il y a des raisons impératives de remplacer une dénomination commune internationale déjà recommandée, cette dernière est conservée (étant entendu toujours que le demandeur initial ou son successeur n’est pas habilité à refuser son accord à une proposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il est proposé de remplacer). Dans un tel cas, le Secrétariat informe l’auteur de la proposition de remplacement, ainsi que le demandeur initial ou son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles), les Etats Membres, les commissions nationales et régionales de pharmacopée, les autres organismes désignés par les Etats Membres et toutes autres personnes portant un intérêt notoire au remplacement proposé que, malgré une proposition de remplacement, il a été décidé de conserver la dénomination commune internationale déjà recommandée (avec une brève description de la ou des raisons pour lesquelles la proposition de remplacement n’a pas été jugée suffisamment impérative).

ANNEXE 2

DIRECTIVES GENERALES POUR LA FORMATION DE DENOMINATIONS

COMMUNES INTERNATIONALES APPLICABLES AUX SUBSTANCES PHARMACEUTIQUES1

1. Les dénominations communes internationales (DCI) devront se distinguer les unes des autres par leur consonance et leur orthographe. Elles ne devront pas être d’une longueur excessive, ni prêter à confusion avec des appellations déjà couramment employées. 2. La DCI de chaque substance devra, si possible, indiquer sa parenté pharmacologique. Les dénominations susceptibles d’évoquer pour les malades des considérations anatomiques, physiologiques, pathologiques ou thérapeutiques devront être évitées dans la mesure du possible. Outre ces deux principes fondamentaux, on respectera les principes secondaires suivants : 3. Lorsqu’on formera la DCI de la première substance d’un nouveau groupe pharmacologique, on tiendra compte de la possibilité de former ultérieurement d’autres DCI appropriées pour les substances apparentées du même groupe. 4. Pour former des DCI des acides, on utilisera de préférence un seul mot. Leurs sels devront être désignés par un terme qui ne modifie pas le nom de l’acide d’origine : par exemple «oxacilline» et «oxacilline sodique», «ibufénac» et «ibufénac sodique». 5. Les DCI pour les substances utilisées sous forme de sels devront en général s’appliquer à la base active (ou à l’acide actif). Les dénominations pour différents sels ou esters d’une même substance active ne différeront que par le nom de l’acide inactif (ou de la base inactive). 1

Dans son vingtième rapport (OMS, Série de Rapports techniques, N° 581, 1975), le Comité OMS d’experts des Dénominations communes pour les Substances pharmaceutiques a examiné les directives générales pour la formation des dénominations communes internationales et la procédure à suivre en vue de leur choix, compte tenu de l’évolution du secteur pharmaceutique au cours des dernières années. La modification la plus importante a été l’extension aux substances de synthèse de la pratique normalement suivie pour désigner les substances tirées ou dérivées de produits naturels. Cette pratique consiste à employer des syllabes communes ou groupes de syllabes communes (segments-clés) qui sont caractéristiques et indiquent une propriété commune aux membres du groupe des substances pour lequel ces segments-clés ont été retenus. Les raisons et les conséquences de cette modification ont fait l’objet de discussions approfondies. Les directives ont été mises à jour lors de la treizième consultation sur les dénominations communes pour les substances pharmaceutiques (Genève, 27-29 avril 1983) (PHARM S/NOM 928, 13 mai 1983, révision en date du 18 août 1983).


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En ce qui concerne les substances à base d’ammonium quaternaire, la dénomination s’appliquera de façon appropriée au cation et à l’anion en tant qu’éléments distincts d’une substance quaternaire. On évitera de choisir une désignation évoquant un sel aminé. 6. On évitera d’ajouter une lettre ou un chiffre isolé ; en outre, on renoncera de préférence au trait d’union. 7. Pour simplifier la traduction et la prononciation des DCI, la lettre « f » sera utilisée à la place de « ph », « t » à la place de « th », « e » à la place de « ae » ou « oe », et « i » à la place de « y » ; l’usage des lettres « h » et « k » sera aussi évité. 8. On retiendra de préférence, pour autant qu’elles respectent les principes énoncés ici, les dénominations proposées par les personnes qui ont découvert ou qui, les premières, ont fabriqué et lancé sur le marché les préparations pharmaceutiques considérées, ou les dénominations déjà officiellement adoptées par un pays. 9. La parenté entre substances d’un même groupe (voir Directive générale 2) sera si possible indiquée dans les DCI par l’emploi de segments-clés communs. La liste ci-après contient des exemples de segments-clés pour des groupes de substances, surtout pour des groupes récents. Il y a beaucoup d’autres segments-clés en utilisation active. 1 Les segments-clés indiqués sans trait d’union pourront être insérés n’importe où dans une dénomination. Latin Français -acum -ac substances anti-inflammatoires du groupe de l’ibufénac -adolum -adol } analgésiques -adol- -adol- }

-astum -ast antiasthmatiques, antiallergiques n’agissant pas principalement en tant qu’antihistaminiques -astinum -astine antihistaminiques -azepamum -azépam substances du groupe du diazépam bol bol stéroïdes anabolisants -cain- -caïn- antiarythmiques de classe I, dérivés du procaïnamide et de la lidocaïne -cainum -caïne anesthésiques locaux cef- céf- antibiotiques, dérivés de l’acide céphalosporanique -cillinum -cilline antibiotiques, dérivés de l’acide 6-aminopénicillanique -conazolum -conazole agents antifongiques systémiques du groupe du miconazole cort cort corticostéroïdes, autres que les dérivés de la prednisolone -coxibum -coxib inhibiteurs sélectifs de la cyclo-oxygénase -entanum -entan antagonistes du récepteur de l’endothéline gab gab gabamimétiques gado- gado- agents diagnostiques, dérivés du gadolinium -gatranum -gatran antithrombines, antithrombotiques gest gest stéroïdes progestogènes gli gli antihyperglycémiants io- io- produits de contraste iodés -metacinum -métacine substances anti-inflammatoires du groupe de l’indométacine -mycinum -mycine antibiotiques produits par des souches de Streptomyces -nidazolum -nidazole substances antiprotozoaires du groupe du métronidazole -ololum -olol antagonistes des récepteurs β-adrénergiques -oxacinum -oxacine substances antibactériennes du groupe de l’acide nalidixique -platinum -platine antinéoplasiques, dérivés du platine -poetinum -poétine facteurs sanguins de type érythropoïétine -pril(at)um -pril(ate) inhibiteurs de l’enzyme de conversion de l’angiotensine -profenum -profène substances anti-inflammatoires du groupe de l’ibuprofène prost prost prostaglandines

1 Une liste plus complète de segments-clés est contenue dans le document de travail WHO/EMP/RHT/TSN/2013.1 qui est régulièrement mis

à jour et qui peut être demandé auprès du programme des DCI, OMS, Genève.


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-relinum -réline peptides stimulant la libération d’hormones hypophysaires -sartanum -sartan antagonistes d’un récepteur de l’angiotensine II, antihypertenseurs (non peptidiques) -vaptanum -vaptan antagonistes du récepteur de la vasopressine vin- vin- } alcaloïdes du type vinca -vin- -vin- }

ANEXO 1

PROCEDIMIENTO DE SELECCIÓN DE DENOMINACIONES COMUNES INTERNACIONALES RECOMENDADAS PARA SUSTANCIAS FARMACÉUTICAS1

La Organización Mundial de la Salud (OMS) seguirá el procedimiento que se expone a continuación tanto para seleccionar denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas, de conformidad con lo dispuesto en la resolución WHA3.11, como para sustituir esas denominaciones. Artículo 1 - Las propuestas de denominaciones comunes internacionales recomendadas y las propuestas de sustitución de esas denominaciones se presentarán a la OMS en los formularios que se proporcionen a estos efectos. El estudio de estas propuestas estará sujeto al pago de una tasa destinada a sufragar los costos de administración que ello suponga para la Secretaría de la OMS («la Secretaría»). La Secretaría establecerá la cuantía de esa tasa y podrá ajustarla periódicamente. Artículo 2 - Estas propuestas serán sometidas por la Secretaría a los miembros del Cuadro de Expertos en Farmacopea Internacional y Preparaciones Farmacéuticas encargados de su estudio, en adelante de-signados como «el Grupo de Expertos en DCI», para que las examinen de conformidad con los «Principios generales de orientación para formar denominaciones comunes internacionales para sus-tancias farmacéuticas», anexos a este procedimiento.2 A menos que haya poderosas razones en contra, la denominación aceptada será la empleada por la persona que haya descubierto o fabricado y comer-cializado por primera vez esa sustancia farmacéutica. Artículo 3 - Tras el examen al que se refiere el artículo 2, la Secretaría notificará que está en estudio un proyecto de denominación internacional. a) Esa notificación se hará mediante una publicación en Información Farmacéutica OMS3

y el envío de una carta a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por los Estados Miembros.

i) La notificación será enviada también a la persona que haya presentado la propuesta («el solicitante inicial») y a otras personas que tengan un interés especial en una denominación objeto de estudio.

b) En esa notificación se incluirán los siguientes datos: i) la denominación sometida a estudio; ii) la identidad de la persona que ha presentado la propuesta de denominación de la sustancia, si lo pide esa persona; iii) la identidad de la sustancia cuya denominación está en estudio;

1 Véase el anexo 1 en OMS, Serie de Informes Técnicos, Nº 581, 1975. El texto vigente fue adoptado por el Consejo Ejecutivo en su resolución EB15.R7 y modificado en las resoluciónes EB43.R9 y EB115.R4..

2 Véase el anexo 2.

3 Hasta 1987 las listas de DCI se publicaban en la Crónica de la Organización Mundial de la Salud.


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iv) el plazo fijado para recibir observaciones y objeciones, así como el nombre y la dirección de la persona a quien deban dirigirse; y v) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento.

c) Al enviar esa notificación, la Secretaría solicitará de los Estados Miembros la adopción de todas las medidas necesarias para impedir la adquisición de derechos de patente sobre la denominación propuesta, durante el periodo en que la OMS la tenga en estudio. Artículo 4 - Toda persona puede formular a la OMS observaciones sobre la denominación propuesta dentro de los cuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3. Artículo 5 - Toda persona interesada puede presentar una objeción formal a una denominación propuesta dentro de los cuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3. Esa objeción deberá acompañarse de los siguientes datos:

i) la identidad de la persona que formula la objeción; ii) las causas que motivan su interés por la denominación; y iii) las causas que motivan su objeción a la denominación propuesta.

Artículo 6 - Cuando se haya presentado una objeción formal en la forma prevista en el artículo 5, la OMS podrá reconsiderar el nombre propuesto o utilizar sus buenos oficios para intentar lograr que se retire la objeción. La OMS no seleccionará como denominación común internacional una denominación a la que se haya hecho una objeción formal, presentada según lo previsto en el artículo 5, que no haya sido retirada, todo ello sin perjuicio de que la Organización examine otra denominación o denominaciones sustitutivas. Artículo 7 - Cuando no se haya formulado ninguna objeción en la forma prevista en el artículo 5, o cuando todas las objeciones presentadas hayan sido retiradas, la Secretaría notificará, conforme a lo dispuesto en el párrafo a) del artículo 3, que la denominación ha sido seleccionada por la OMS como denominación común internacional recomendada. Artículo 8 - Al comunicar a los Estados Miembros una denominación común internacional, conforme a lo previsto en el artículo 7, la Secretaría: a) solicitará que esta denominación sea reconocida como denominación común para la sustancia de que se trate; y b) solicitará a los Estados Miembros que adopten todas las medidas necesarias para impedir la adquisición de derechos de patente sobre la denominación, y prohíban que sea registrada como marca de fábrica o como nombre comercial. Artículo 9 a) En el caso excepcional de que, debido a su semejanza con otra denominación utilizada en las prácticas farmacéuticas y/o de prescripción, una denominación común internacional recomendada anteriormente ocasione errores de medicación, prescripción o distribución, o suponga un riesgo manifiesto de que esto ocurra, y parezca que tales errores o potenciales errores no sean fácilmente subsanables con otras medidas que no sean la posible sustitución de esa denominación común internacional recomendada anteriormente; en el caso de que una denominación común internacional recomendada anteriormente difiera considerablemente de la denominación común aprobada en un número importante de Estados Miembros, o en otras circunstancias excepcionales que justifiquen el cambio de una denominación común internacional recomendada, cualquier persona interesada puede presentar propuestas en este sentido. Esas propuestas se presentarán en los formularios que se proporcionen a estos efectos e incluirán los siguientes datos:


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i) la identidad de la persona que presenta la propuesta; ii) las causas que motivan su interés en la sustitución propuesta;

iii) las causas que motivan la propuesta; y

iv) una descripción, acompañada de pruebas documentales, de las otras medidas que se hayan adoptado con el fin de resolver la situación y de los motivos por los cuales dichas medidas no han sido suficientes.

Entre esas propuestas podrá figurar una relativa a una nueva denominación común

internacional sustitutiva, formulada con arreglo a los Principios generales y que tenga en cuenta la sustancia farmacéutica para la que se proponga la nueva denominación común internacional sustitutiva.

La Secretaría enviará al Grupo de Expertos en DCI y al solicitante inicial o a su sucesor (en el caso de que sea una persona diferente de la que ha presentado la propuesta de sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales) una copia de la propuesta, para que sea examinada de conformidad con el procedimiento descrito en el párrafo b) infra. Además, la Secretaría solicitará observaciones sobre la propuesta:

i) a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por los Estados Miembros (ello se hará incluyendo una notificación a tal efecto en la carta a la que se refiere el párrafo a) del artículo 3), y

ii) a cualquier persona que tenga un interés especial en la sustitución propuesta.

Al solicitar que se formulen estas observaciones se facilitarán los siguientes datos: i) la denominación común internacional recomendada que se propone sustituir (y la denominación sustitutiva propuesta, si se ha facilitado);

ii) la identidad de la persona que ha presentado la propuesta de sustitución (si lo pide esa persona); iii) la identidad de la sustancia a la que se refiere la sustitución propuesta y las razones para presentar la propuesta de sustitución; iv) el plazo fijado para recibir observaciones, así como el nombre y la dirección de la persona a quien deban dirigirse; y

v) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento.

Toda persona puede formular a la OMS observaciones sobre la sustitución propuesta dentro de los cuatro meses siguientes a la fecha en que se realizó la solicitud de observaciones. b) Una vez agotado el mencionado plazo para la formulación de observaciones, la Secretaría enviará todos los comentarios recibidos al Grupo de Expertos en DCI, al solicitante inicial o a su sucesor, y a la persona que haya presentado la propuesta de sustitución. Si después de examinar la propuesta de sustitución y las observaciones recibidas, el Grupo de Expertos en DCI, la persona que haya presentado la propuesta de sustitución y el solicitante inicial, o su sucesor, están de acuerdo en la necesidad de sustituir la denominación común internacional recomendada anteriormente, la Secretaría remitirá la propuesta de sustitución al Grupo de Expertos en DCI para que la tramite. No obstante lo anterior, el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta de sustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuya sustitución se propone.

En caso de que la propuesta de sustitución sea presentada al Grupo de Expertos en DCI para que la tramite, este grupo seleccionará una nueva denominación común internacional de conformidad con los


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Principios generales a los que se refiere el artículo 2 y al procedimiento establecido en los artículos 3 a 8 inclusive. En ese caso, en las notificaciones que la Secretaría ha de enviar con arreglo a los artículos 3 y 7, respectivamente, incluida la notificación al solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales), se indicará que la nueva denominación sustituye a una denominación común internacional recomendada anteriormente y que los Estados Miembros podrán, si lo estiman oportuno, adoptar disposiciones transitorias aplicables a los productos existentes en cuya etiqueta se utilice, con arreglo a la legislación nacional, la denominación común internacional recomendada anteriormente que se haya sustituido.

En caso de que, después de haber estudiado la propuesta de sustitución y los comentarios recibidos de conformidad con el procedimiento descrito anteriormente, el Grupo de Expertos en DCI, el solicitante inicial o su sucesor y la persona que haya presentado la propuesta de sustitución no lleguen a un acuerdo sobre la existencia de razones poderosas para sustituir una denominación común internacional recomendada anteriormente, esta denominación se mantendrá (siempre en el entendimiento de que el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta de sustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuya sustitución se propone). En ese caso, la Secretaría comunicará a la persona que haya propuesto la sustitución, así como al solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales), a los Estados Miembros, a las comisiones nacionales y regionales de las farmacopeas o a otros organismos designados por los Estados Miembros y a cualquier otra persona que tenga interés en la sustitución propuesta, que, pese a la presentación de una propuesta de sustitución, se ha decidido mantener la denominación común internacional recomendada anteriormente (con una descripción de la o las razones por las que se ha considerado que la propuesta de sustitución no estaba respaldada por razones suficientemente poderosas).

ANEXO 2

PRINCIPIOS GENERALES DE ORIENTACIÓN PARA FORMAR DENOMINACIONES COMUNES INTERNACIONALES PARA SUSTANCIAS FARMACÉUTICAS1

1. Las denominaciones comunes internacionales (DCI) deberán diferenciarse tanto fonética como ortográficamente. No deberán ser incómodamente largas, ni dar lugar a confusión con denominaciones de uso común. 2. La DCI de una sustancia que pertenezca a un grupo de sustancias farmacológicamente emparentadas deberá mostrar apropiadamente este parentesco. Deberán evitarse las denominaciones que puedan tener connotaciones anatómicas, fisiológicas, patológicas o terapéuticas para el paciente. Estos principios primarios se pondrán en práctica utilizando los siguientes principios secundarios: 3. Al idear la DCI de la primera sustancia de un nuevo grupo farmacológico, deberá tenerse en cuenta la posibilidad de poder formar DCI convenientes para las sustancias emparentadas que se agreguen al nuevo grupo. 4. Al idear DCI para ácidos, se preferirán las de una sola palabra; sus sales deberán denominarse sin modificar el nombre del ácido: p. ej. «oxacilina» y «oxacilina sódica», «ibufenaco» y «ibufenaco sódico». 1 En su 20º informe (OMS, Serie de Informes Técnicos, Nº 581, 1975), el Comité de Expertos de la OMS en Denominaciones Comunes para las Sustancias Farmacéuticas revisó los Principios generales para formar denominaciones comunes internacionales (DCI), y su procedimiento de selección, a la luz de las novedades registradas en los últimos años en materia de compuestos farmacéuticos. El cambio más importante había consistido en hacer extensivo a la denominación de sustancias químicas sintéticas el método utilizado hasta entonces para las sustancias originadas en productos naturales o derivadas de éstos. Dicho método conlleva la utilización de una «partícula» característica que indica una propiedad común a los miembros de un grupo. En el citado informe se examinan en detalle las razones y consecuencias de este cambio. Los Principios generales de orientación se actualizaron durante la 13ª consulta sobre denominaciones comunes para sustancias farmacéuticas (Ginebra, 27 a 29 de abril de 1983) (PHARM S/NOM 928, 13 de mayo de 1983, revisado el 18 de agosto de 1983).


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5. Las DCI para las sustancias que se usan en forma de sal deberán en general aplicarse a la base activa o al ácido activo. Las denominaciones para diferentes sales o esteres de la misma sustancia activa solamente deberán diferir en el nombre del ácido o de la base inactivos. En los compuestos de amonio cuaternario, el catión y el anión deberán denominarse adecuadamente por separado, como componentes independientes de una sustancia cuaternaria y no como sales de una amina. 6. Deberá evitarse el empleo de letras o números aislados; también es indeseable el empleo de guiones. 7. Para facilitar la traducción y la pronunciación, se emplearán de preferencia las letras «f» en lugar de «ph», «t» en lugar de «th», «e» en lugar de «ae» u «oe», e «i» en lugar de «y»; se deberá evitar el empleo de las letras «h» y «k». 8. Siempre que las denominaciones propuestas estén de acuerdo con estos principios, recibirán una consideración preferente las denominaciones propuestas por la persona que haya descubierto las sus-tancias, o que fabrique y comercialice por primera vez una sustancia farmacéutica, así como las deno-minaciones ya adoptadas oficialmente en cualquier país. 9. El parentesco entre sustancias del mismo grupo se pondrá de manifiesto en las DCI (véase el Principio 2) utilizando una partícula común. En la lista que figura a continuación se indican ejemplos de partículas para grupos de sustancias, en particular para grupos nuevos. Existen muchas otras partículas que se usan habitualmente.1 Cuando una partícula aparece sin guión alguno, puede utilizarse en cualquier lugar de la palabra. Latin Español -acum -aco antiinflamatorios derivados del ibufenaco -adolum -adol ) analgésicos -adol- -adol- ) -astum -ast antiasmáticos, sustancias antialérgicas cuya acción principal no es la antihistamínica -astinum -astina antihistamínicos -azepamum -azepam derivados del diazepam bol bol esteroides anabolizantes -cain- -caína- antiarrítmicos de clase I, derivados de procainamida y lidocaína -cainum -caína- anestésicos locales cef- cef- antibióticos, derivados del ácido cefalosporánico -cillinum - cilina antibióticos derivados del ácido 6-aminopenicilánico -conazolum -conazol antifúngicos sistémicos derivados del miconazol cort cort corticosteroides, excepto derivados de prednisolona -coxibum -coxib inhibidores selectivos de ciclooxigenasa -entanum -entán antagonistas del receptor de endotelina gab gab gabamiméticos gado- gado- agentes para diagnóstico derivados de gadolinio -gartranum -gatrán inhibidores de la trombina antitrombóticos gest gest esteroides progestágenos gli gli hipoglucemiantes, antihiperglucémicos io- io- medios de contraste iodados -metacinum -metacina antiinflamatorios derivados de indometacina -mycinum -micina antibióticos producidos por cepas de Streptomyces -nidazolum -nidazol antiprotozoarios derivados de metronidazol -ololum -olol antagonistas de receptores -adrenérgicos -oxacinum -oxacino antibacterianos derivados del ácido nalidíxico -platinum -platino antineoplásicos derivados del platino 1 En el documento de trabajo WHO/EMP/RHT/TSN/2013.1, que se actualiza periódicamente y puede solicitarse al Programa sobre Denominaciones Comunes Internacionales, OMS, Ginebra, figura una lista más amplia de partículas.


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-poetinum -poetina factores sanguíneos similares a la eritropoyetina -pril(at)um -pril(at) inhibidores de la enzima conversora de la angiotensina -profenum -profeno antiinflamatorios derivados del ibuprofeno prost prost prostaglandinas -relinum -relina péptidos estimulantes de la liberación de hormonas hipofisarias -sartanum -sartán antihipertensivos (no peptídicos) antagonistas del receptor de angiotensina II -vaptanum -vaptán antagonistas del receptor de vasopresina vin- vin- ) alcaloides de la vinca -vin- -vin- )

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