423 WHO Drug Information Vol. 28, No. 4, 2014 Continued WHO Drug Information Contents WHO Prequalification 425 Building quality-assured manufacturing capacity in Nigeria Pharmacopoeial standards 431 Global specifications: the example of capreomycin Medicines quality assurance 434 A harmonized self-assessment tool for procurement agencies Safety news 448 Unchanged recommendations Testosterone; Agomelatine449 Restricted use Intravenous nicardipine; Bromocriptine; Colistimethate sodium; Valproate; Sulfur hexafluoride451 Safety warnings Ivabradine; Carvedilol; Voriconazole; Immunoglobulins; Simeprevir; Basiliximab; Ustekinumab; Ponatinib; Diclofenac and other NSAIDs; Denosumab; Pregabalin; Zopiclone; Bupropion; Galantamine hydrobromide; Dimethyl fumarate; Omalizumab457 Risk minimization measures Methylphenidate457 Medicines review started 458 Manufacturing quality issues Health Canada restricts imports from various Indian sites 458 Site review started Regulatory news 459 Ebola Update on treatments and vaccines 460 Clinical trials transparency EMA adopts policy on publication of clinical reports 461 Pre-market assessment EMA revises guidance on biosimilars ; EMA proposes harmonized clinical trials plan for vaccine in children; EMA pilot to seek patient views on medicines risks and benefits; Australia to recognize EU conformity assessment for medical devices 462 Pharmacovigilance Canada passes Vanessa’s Law; EU project on using smartphones for drug safety information; EMA expands public web access to reports on suspected side effects ; Australia, Switzerland create web portals to report adverse reactions; New MHRA guidance on reporting adverse drug reactions in children 464 Organizations Australia and New Zealand to keep separate regulatory authorities 464 Veterinary medicines EU proposes veterinary medicines legislation revisions ; Sales of veterinary antibiotics in Europe decrease 465 Approved Netupitant and palonosetron; Naloxegol; Dulaglutide; Antihaemophilic factor (recombinant), porcine sequence; Nonacog gamma; Afamelanotide; Darunavir & cobicistat; Ledipasvir & sofosbuvir; Dasabuvir; Ombitasvir & paritaprevir & ritonavir; Meningococcus B vaccine; Pembrolizumab; Ramucirumab; Secukinumab; Pirfenidone; Nintedanib; Olaparib; Blinatumomab; Abuse-deterrent hydrocodone469 Labelling changes approved Ketoconazole; UlipristalPublications and events 471 Access to treatment 2014 Access to Medicines Index launched; New Lancet Commission on Essential Medicines Policies; WHO invites hepatitis medicines for prequalification; Antiviral Therapy special issue on access to HIV treatment
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Continued
WHO Drug InformationContents
WHO Prequalification425 Building quality-assured manufacturing
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;
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
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;
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
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.pmda.go.jp/english/index.htm)lSwissmedic SwissAgencyforTherapeuticProducts(www.swissmedic.ch)TGA TherapeuticGoodsAdministration,Australia(www.tga.gov.au)U.S. United States of America
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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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
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
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
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).
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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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.
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
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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.
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
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
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
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.
4 WHO. ListofallAPIsandFPPsinvitedforprequalification,andnumberprequalifiedorcurrently under assessment per product.(25September2014).Availablefromapps.who.int/prequal - Information for applicants.
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.
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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.
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
2 WHO. Assessmenttoolbasedonthemodelquality assurance system for procurement agencies:aide-memoireforinspection. Annex4.In:WHOTechnicalReportSeries986,2014.
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
Steps in the procedure for assessment:1. InspecttheindividualrequirementsineachsystemofeachModule.2. Allocatethepercentagetoindicatethelevelofcompliance(0–100%.Incasethe
24 Aprocedureisfollowedforidentification,collection,indexing,retrieval,storage, maintenance, disposal of and access to all applicable documents and records.
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.
productsandmanufacturingsitesarepubliclyavailable. Product information, screening and evaluation
40 Productinformationisreceivedinasuitableformatwithnecessarycontentssuchasaproductdossier(detailasdescribedbyWHO,e.g.seeAppendix6oftheModel quality assurance system for procurement agencies.
42 Thereisanappropriatesystemandinfrastructureforthereceivingandprocessingofproductinformation.Thescreeningofproductinformationsubmitted is done according to an SOP and records are maintained. Written proceduresarefollowedforevaluation.Evaluationreportsarepreparedforeachproductwhichincludesarecommendationforacceptanceorrejection.Theevaluationandthereportaredonewithinappropriatetimeframes.
44 Whereappropriate(basedonriskassessment)samplessubmittedtogetherwithproductinformationpackagesaretestedatlaboratoriesmeetingdefinedstandards recommended by WHO.
procurement.Proceduresareinplacefor: -theestablishmentoftechnicalspecifications; -quantificationofrequirements; - issuing of a tender (as appropriate); - selection of product(s) and manufacturer(s)
76 Adequatelaboratoryservicesareusedtotestproductsindependentlyaccordingtoapprovedspecificationsandstandards.Thelaboratorymeetsgeneralrequirementsforgoodpracticescovering,e.g.facilities,policiesandprocedures, personnel, equipment, etc.
recalled, returned products and suspected counterfeits.82 Storageareashavesufficientspaceandventilationandfirecontrolmeasures.83 Temperaturemappingofthestorageareaswasdoneinanappropriate
86 Productsthatshouldbestoredunderspecifiedcoldconditions(requiringcold-chain)arehandledappropriatelyduringtransport,delivery,receivingandstorage. Temperature mapping studies were done for cold rooms; and power generatorsareavailableincaseofpowerfailure.Proceduresarefollowedtoensurethaticepacksareusedinthecorrectmannerincold-chainboxes.Containersusedforthetransportarevalidatedtoensurethatcoolproductsremainattherequiredtemperatureduringtransport.
97 Anauthorizedpersonisidentifiedtodecideonthedispositionofreturnedgoods.Thedecisionisbasedon,e.g.thenatureoftheproductreturned,specialstorageconditionsrequired,itsconditionandhistory;andthetimeelapsed since it was issued.
identificationofcontentsandsource).Wherespecialtransportand/orstorageconditionsarerequired,thesearestatedincludinganyspeciallegalrequirements, safety symbols, etc.
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c) Model report format
Section 1: General informationNameoforganization:Websitereference:Physicaladdress:Postaladdress:Tel.:Fax:Contactperson:Emailaddress:Activities(tickallthatapply): Prequalification
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)
► (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
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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.
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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
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/
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
Carvedilol: Rare severe skin reactionsN e w Z e a l a n d –Themarketingauthorizationholderofcarvedilol(Dilatrend®)hasinformedhealthprofessionalsthatveryrarecasesofseverecutaneousadversereactions
► 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
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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
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
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
remain45mgofponatinibonceaday.Thecardiovascularstatusofthepatientshouldbeassessedbeforestartingtherapyandregularly monitored during treatment. Healthcareprofessionalsshould
consider a dose reduction in patients with‘chronicphase’CMLwhoarerespondingwelltotreatment,andwhomightbeatparticularriskofbloodvesselblockage.Dosemodificationsortreatmentinterruptionshouldbeconsideredtomanagetreatmenttoxicity;ifareduceddoseisused,patientsshouldbemonitoredformaintenanceoftherapeuticresponse.Ponatinibshouldbestoppediftherehasbeennoresponseafterthreemonthsoftreatment.Patientsshouldbemonitoredforhighbloodpressureorsignsofheartproblems.Educationalmaterialwillbeprovidedto
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
therecommendeddosesandforshortdurations,inappropriateuseoroverusecanposeasignificanthealthrisk.TheTGAhasremindedhealthprofessionalsofprescribing recommendations for NSAIDs, andhasencouragedthemtoeducatepatientsonthesignsandsymptomsofseriouscardiovasculartoxicityandtheneedtoseekmedicalattentionimmediatelyiftheyoccur.Therecommendationsarebasedona
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
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
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
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.
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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)
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
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).
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Sitereviewstarted
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
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.
TheEbolacrisishaspromptedanunprecedented cooperation between regulators tosupportWHOandtoadviseonpossiblepathwaysforthedevelopment,evaluationandapprovalofmedicinestofightEbola.Progresstowardsprovisionoftreatmentsandvaccinesissummarizedbelow.
InAugust2014,aWHO-convenedpanelhadagreedunanimouslythatisethicallyacceptabletouseofexperimentalmedicinesandvaccinesundertheexceptionalcircumstancesoftheEbolaepidemic (1). In early September, WHO convenedaconsultationonpotentialEbolatherapiesandvaccines(2).Theimportanceofsupportivecareandcommunityresponsewasstressedinthisand subsequent discussions.
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
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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,
complementarytoolaheadoftheimplementationofthenewEUClinicalTrialsRegulationthatwillcomeintoforcenotbeforeMay2016.Publicaccesstoclinical reports will enable academics and researcherstore-assessdatasets,andwillhelptoavoidduplicationofclinicaltrial
► EMA Press release, 2 October 2014.
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
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
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.
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
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.
►EMAPressrelease,6October2014.
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
► (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
Australia and New Zealand to keep separate regulatory authoritiesTheAustralianandNewZealandGovernmentshaveagreedtoceaseeffortstoestablishajointtherapeuticproductsregulator,theAustraliaNewZealandTherapeuticProductsAgency(ANZTPA).Thedecisionwastakenafterareviewofprogressandanassessmentofthecostsandbenefitsinvolved.Thetwocountries will continue to co-operate on theregulationoftherapeuticproducts.(1)TheNewZealandauthorityhas
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
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.
Benefits:Addedeffectivenessinpreventingvomitingepisodesintheacute,delayedandoverallphasesafterthestartofcancerchemotherapy,comparedwithoralpalonosetrone alone. ► FDA News release, 10 October 2014.
Naloxegol: for opioid-induced constipation Product name:Movantik®Class:Peripherallyactingopioidreceptor
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
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
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
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
Ombitasvir & paritaprevir & ritonavir: for hepatitis C infectionProduct name:Viekirax®Class:Fixed-dosecombinationoftwoantiviralagents,inhibitorsofNS5A(ombitasvir)andNS3/4A(paritaprevir),withritonavirasapharmacokineticenhancer.ATCcode(temporaryclassification):J05AX67
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
Use:Treatmentofadvancedorunresectablemelanomanolongerrespondingtootherdrugs (ipilimumab, or ipilimumab and a BRAFinhibitorinpatientswhosetumorsexpressaBRAFV600mutation)
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.
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®;
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
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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;
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.
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,
► 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.
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.
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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.
Improving medicines for children in CanadaO t t a w a –AnexpertpanelreportreleasedbytheCouncilofCanadianAcademiesaddressestheimportanceofdevelopingsafeandeffectivemedicinesforchildren.Thepaneladvisesthatstudyingmedicinesinchildrenisalwayspossibleandisintheirbestinterests.Thereportwas
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
► 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.
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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.
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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.
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.
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.
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].
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).
Related substancesCarryoutthetestasdescribedunder1.14.4High-performanceliquidchromatography using astainlesssteelcolumn(25cm×4.6mm)packedwithbase-deactivatedparticlesofsilicagelthesurfaceofwhichhasbeenmodifiedwithchemically-bondedoctadecylsilylgroups(5μm).
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 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.
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
