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ANNUAL REPORT
Danish Health and Medicines Authority’s Annual Pharmacovigilance Report 2014
ANNUAL REPORT 2
ANNUAL PHARMACOVIGILANCE REPORT 2014
Contents
3 Preface
4 ADR reports in 2014
6 ADR reports from Danish hospitals in 2014 by region
8 Preparing and implementing Action Plan III (2014-2015)
9 DHMA national campaign targeting mental health centres across the regions
10 Web service can make it easier to report adverse reactions to medicines
11 New procedure for collecting additional information on received ADR reports
12 Focus areas in 2014
12 The HPV vaccine is still monitored closely
13 Statementsonreportedadversereactionstoseasonalinfluenzavaccines
14 Antihistaminepromethazine(Phenergan®etc.)becameprescriptiononly
14 Analysis of reported suspected adverse reactions and reported adverse events associated with
usinglabour-stimulatingmedicinesforinductionoflabour
15 Focus on users of antiepileptics and reported ADRs related to these medicines
17 ADR signals 2014
19 The Drug Interaction Database
20 International pharmacovigilance collaboration
22 Quality and prioritisation – focus areas in 2015
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In2014,theDanishdatabaseofadversereactionsreachednearly100,000ADRreports–reportsthattheDHMAhasreceivedsince1967.ThevastmajorityoftheADRreportscomefromdoctors,but2014suggeststhatthetrendmaybechanging.
Theprerequisitesforeffectivepharmacovigilancearegooddataandoptimumdataexploitation.WhileitwasthereforeessentialforustoencouragethesubmissionofmoreADRreportsin2014aspartofourpharmacovigilanceactivities,weparticularlydevotedeffortstocreateabasisforreceivingADR reports that are of good enough quality and ensure that we increasingly use the data and tools availabletousinourpharmacovigilancework.
Wehavebenefitedhighlyfromouranalysistoolforanalysisofadversereactionsandidentificationofpotentialpatternsincomplexreportingdata.BasedontheADRreportsreceivedinDenmark,weworkeddeterminedlyin2014toidentifyandanalysedatatherein,andwehighlightedseveralproblems.
Media cases impacting pharmacovigilance activitiesLiketheyearbefore,2014wasayearwithseveralmediacasesthatshapedourpharmacovigilanceactivities.Especiallythesafetyofvaccineswasinthespotlight–notonlytheHPVvaccineagainstcervicalcancer,butalsotheseasonalinfluenzavaccinesandlatelytheMMRvaccine.Itisnothingnewthatcasesinthemedia'sspotlighthaveawayofgrowingandalsoaffectADRreportingstatistics–wehaveseenitbefore,andwewillseeitagain–thetrendisheretostay,andwemustrelatetoitandintegrateitinourwork.
New web service for easier ADR reporting now availableIn2014,weconcludedourworkwithanewwebservicethateasestheburdenofADRreportingfordoctorsbyextractingdatafromtheirmedicalsystemstotheelectronicreportingform–anactivityhighlightedasparticularlyimportantbytheDanishPharmacovigilanceCouncil.Theobjectivesofthewebservicearetoreusedata,reducereportingtime,eliminateerrorsandgeneratebetterADRreports.Thewebserviceismadeavailabletothecompaniesthatdelivermedicalsystemstomedicalpractices,regions,municipalitiesandpharmacies.
Midwives to report adverse reactionsOn1April2014,newrulesenteredintoforcemakingitmandatoryformidwivestoreportadversereactionsonequaltermsasdoctors.Thus,midwivesarenowobligatedtoreportsuspectedadversereactions–anobligationwhichenjoyedwidespreadsupport.Ithasbeenverygratifyingtoseethatthemidwiveshavetakenonthistaskinaconstructivemanner.
Preface
PREFACE
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In2014,thenumberofadversedrugreaction(ADR)reportsintheDanishadversereactiondatabasecamecloseto100,000.TheADRreportsgoasfarbackasthelate1960swhenthefirstnationalsystemforregistrationofadversereactions,asweknowittoday,wasestablished.Backthen,onlydoctorscouldreportadversereactions,butinrecentyears,wehaveseenanincreasinginflowofADRreportsfromotherhealthcareprofessionalsandmedicineusers.Figure1showstheaccumulatedshareofADRreportsdistributedbetweendifferenttypesofreportersfrom1967to2014.
ADR REPORTS IN 2014
ADR reports in 2014
Figure 1: Accumulated share of ADR reports by reporter type (1967-2014)
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Medicine users, other non-healthcare professionals, lawyers, etc.
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Figure 2: Number of ADR reports in 2014 including duplicates, broken down by serious and non-serious adverse reactions. Duplicates cover ADR reports that have been submitted more than once to the DHMA. This would occur when for example both the doctor and the patient report the adverse reaction. In 2014, the DHMA received 6,499 ADR reports including duplicates, and 6,046 excluding duplicates.
Serious ADR reportsNon-serious ADR reports
61.5%(3,999)
38.5%(2,500)
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ADR REPORTS IN 2014
Many reports from medicine users or their representativesEversince2003whenmedicineusersweregiventheopportunitytoreportsuspectedadversereactions themselves to the DHMA, the share of ADR reports from medicine users, their representativesandothernon-healthcareprofessionalshasgrown.In2014,thisgroupaccountedfor28%ofallADRreportsreceivedin2014and15%ofthetotalvolumeofADRreportsinthedatabase.
ADRreportsfrommedicineusersortheirrepresentativescontributesignificantlyinquantityaswellasqualitytothetotalnumberofADRreportsreceived,andtheyarearegenerallywell-documented,providingvaluableinformation.Yet,reportsfrommedicineusersarenotanalternativetoreportsfromdoctorsandotherhealthcareprofessionals,buttheADRreportsfromthetwosegmentscomplementeachother.ReadmoreintheDHMA'sreportfrom2012:Adverse drug reaction reports (ADRs) from consumers may improve patient safety (in Danish only).
2014alsosawanincreaseinADRreportsfromotherhealthcareprofessionals(e.g.dentists,nurses,pharmacistsandmidwives).Theyaccountedformorethan20%ofADRreportsin2014.However,reportsfromthissegmentonlymakeupasmallproportionofallreportsintheDanishadversereactiondatabase.
Decline in reports from doctorsTheshareofADRreportsfromdoctorshasdecreasedsteadily,andalthoughdoctorsarestillbehindmostofthereportsoverall,theyonlyaccountedfor44%ofallADRreportsin2014.Thisisthelowestlevelever,andthefallcannotonlybeexplainedbythefactthatothersegmentsarenowsubmittingmorereportsbecausethereisalsoafallinabsolutenumbers–therewere300fewerADRreportsfromdoctorsin2014comparedto2013.ADRreportsfromdoctorshavespecialqualitiesandareimportantintheDHMA’sactivitiesofmonitoringmedicinesafety.
Weknowfromsurveysthatdoctorsdowanttoreportsuspectedadversereactions,buttimeisalimitingfactor.Inacknowledgementthereof,wehavedevelopedawebservicethatcaneasetheburdenofreportingadversereactionsfordoctors.Readmoreaboutthewebserviceonpage 10. DHMA stays focused on encouraging doctors to report more adverse reactionsAttheDHMA,wecontinuallyfocusonfurtheringtheincentivesandpossibilitiesfordoctorstoreportadversereactions.In2014,wecompletedacampaigntargetingdoctorsinmentalhealthcentresacrossDenmark.Readmoreaboutthecampaignonpage 9.
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In2014,theDHMAreceivedaltogether1,330ADRreportsfromhospitalsacrossDenmark1–includingreportsfrommentalhealthcentresinthefiveregions.ThedistributionofADRreportsbetweentheindividualregionsisshowninFigure3.TworeportscamefromhospitalsinGreenlandandtheFaroeIslandsanddonotappearinthefigure.
ThetotalnumberofADRreportsfromhospitalswashigherin2014comparedto2013.EspeciallytheCapitalRegionofDenmarkandRegionZealandsawlargeincreasesinthenumberofADRreports.
ADR manager role makes a differenceOnereasonwhythenumberofADRreportshasincreasedfromtheCapitalRegionofDenmarkandRegionZealandisthatthesespecificregionshaveanADRmanager2.EversincetheCapitalRegionofDenmarkgotanADRmanagerin2013,ADRreportshaveincreasedsteadilyfromthisregion.ItislikelythatweareseeingthesametrendfromRegionZealand,whichimplementedanADRmanagerroleinFebruary2014.
TheDHMAhasenteredintoaformalcollaborationwiththeADRmanagersintheCapitalRegionofDenmarkandRegionZealand.Aspartofthiscollaboration,wesupplymonthlyoverviewsoftheADRreportswereceivefromtheADRmanagers.ThetworegionsthenusetheseoverviewstoevaluatetheADRmanagerroleandtocontinuallyenhancepatientsafety.
ADR reports from Danish hospitals in 2014 by region
1 Onlyreportsreceiveddirectlyfromthehospitalsareincludedinthisreport.2 A regional ADR manager assists doctors in the region with reporting suspected adverse reactions to the Danish Health and Medicines Authority.Thedoctorhasmerelytostatethepatient'snameandcivilregistrationnumber,suspectedadversereactionaswellasthe suspectedmedicine,andthentheADRmanagertakescareofsubmittingtheADRreporttotheDHMA.
ADR REPORTS FROM DANISH HOSPITALS IN 2014 BY REGION
Figure 3: ADR reports from Danish hospitals in 2013 and 2014 by region. Two reports were received from two different regions and are therefore included in both regions. Adjustments have not been made for the population size of the respective five regions.
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Overall increase in ADR reports across the regions’ mental health centresIn 2014, we received twice as many reports from the regions’ mental health centres than we did in 2013 –whichcouldbearesultoftheDHMA'snationalcampaigntargetingregionalmentalhealthcentres,whichwaslaunchedinMarch2014.ThecampaignobjectivewastoencourageregionalmentalhealthcentrestosubmitmoreADRreports.
ADR REPORTS FROM DANISH HOSPITALS IN 2014 BY REGION
Figure 4: ADR reports from mental health centres in 2013 and 2014
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Action Plan III entered into force in 2014 and carries on the experience and initiatives from the Action PlanforStrengthenedPharmacovigilance2011-2013,whichpursuedPharmacovigilanceActionPlan2008.TheseactionplansaimtoincreasethenumberofADRreports,facilitatereporting,strengthentheDHMA'sprofessionalandcommunicativeworkwithadversereactionsandstrengthencollaborationbetweenallplayersactiveinpharmacovigilancework.ActionPlanIIIhastwooverallobjectives,namelymoreandbetterADRreportsandoptimisationoftheactualpharmacovigilancework–nationallyandinternationally. ADR report quality in focusThethirdactionplanhasspecialfocusonthequalityofADRreportsandnotjustquantity.Specifically,thishasresultedinafocusedfollow-upprocedureforADRreports,whichimpliesthatresourcesareusedoncollectingfollow-upinformationonpreciselythoseADRreportsconsideredtobringmostvaluetotheassessment.MoreovertheDHMAhasformedaQualityForumforAdverseReactionswhichistoworktoimprovethepossibilitiesofenhancingADRreportqualityanddetailhowqualitycanbeimproved.Readmoreaboutthenewfollow-upprocedureonpage 11.
Strengthened education in ADR reporting for doctors and medical studentsInordertoimprovethequalityofADRreports,aninitiativehasbeenlaunchedtoteachdoctorsaspartoftheirmedicaleducation.Actionshavebeentakentostrengthentraininginpharmacovigilance,bothaspartofthemedicaleducationandthepost-graduatespecialtyeducation.Effortsarebeingmadetointegratetraininginotherhealthcareprofessionaleducations,e.g.innursingeducation.
Collaboration with the National Agency for Patients' Rights and ComplaintsIn2014,theDHMAexpandeditscollaborationwiththeNationalAgencyforPatients'RightsandComplaints,whichreceives(anonymous)informationaboutadversereactionscausedbymedicationerrors(adverseevents)sothatcoordinatedannouncementscanbemade.Inparallel,theDHMAandtheNationalAgencyforPatients'RightsandComplaintshavestrengthenedcollaborationintheanalysisareasothatanalysesofsafetyissueswillprovideabroaderperspective.
Preparing and implementing Action Plan III (2014-2015)
PREPARING AND IMPLEMENTING ACTION PLAN III (2014-2015)
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In2014,wecompletedanationalcampaigntargetingregionalmentalhealthcentresacrosstheregions.ThecampaignranfromMarchtoOctober2014.TheobjectivewastoraiseawarenessofADRreportingandofdoctors'obligationtoreportsuspectedunexpectedandseriousadversereactions.Inaddition,the campaign was to inform patients in mental care and their relatives that they too can report adverse reactionstotheDHMA.
Campaign backgroundGenerally,theDHMAreceivesveryfewADRreportsfromdoctorsandpatientsortheirrepresentativesin the mental healthcare area, and yet, medical treatment of mental disorders frequently causes many adversereactions–andincertaincasesseriousadversereactions.Moreover,asurveyconductedbytheDHMAin2013showedthatthereisgenerallynotenoughknowledgeaboutandfocusonadversereactionsinthementalhealthcarearea.
In2013,theDHMAreceivedonly78ADRreportsfromallmentalhealthcentresintheregions,whichisthelevelseenforseveralyears.
Campaign resultsIn2014,wereceivedatotalof158ADRreportsfrommentalhealthcentres(seeFigure4).Whenthecampaignwasevaluated,itnotsurprisinglyreceivedbothcriticismandpraise,butoverall,thecampaignpaidoff–insomeregionsmorethanothers.Thevastmajorityoftheregionssaidthecampaignhadputmorefocusonthereportingofadversereactionsthanbeforeinadditiontohavingmadeitclearerwhichadversereactionsaremandatorytoreport.IntheCentralDenmarkRegion,thecampaignledtothedecisionofintroducinganADRmanagerrolespecificallytoservicetheregion’smentalhealthcentres.
DHMA NATIONAL CAMPAIGN TARGETING MENTAL HEALTH CENTRES ACROSS THE REGIONS
DHMA national campaign targeting mental health centres across the regions
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InJune2014,welaunchedanewwebserviceforeasierreportingofadversereactions.Thewebservicegiveshealthcareprofessionalsthepossibilitytoreportadversereactionstomedicinesdirectlyfromthemedicalsystemstheyuseonadailybasis.TheDHMAexpectstheservicewillencouragemorehealthprofessionalstoreportadversereactions,thuscontributingtoabetteroverviewofthesafetyofmedicinesmarketedinDenmark.Notonlywillhealthprofessionalsbeabletoreportdirectlyfrome.g.an electronic patient record at the hospital or a medical practice, they will also avoid having to enter a numberofbasicinformationaboutthemselves,thepatientandthemedicineheorsheistaking.
Available from the National Service PlatformIt is up to the owners and suppliers of IT systems in the healthcare sector whether to integrate the new webserviceinlocalsystems.ThenewwebserviceismadeavailableontheNationalServicePlatform(NSP)whereamoredetaileddescriptionanddocumentationofthewebservicecanalsobefound.
Readmoreaboutthewebservice:NSP Service: ADR reporting (in Danish only).
Web service can make it easier to report adverse reactions to medicines
WEB SERVICE CAN MAKE IT EASIER TO REPORT ADVERSE REACTIONS TO MEDICINES
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When the DHMA receives an ADR report, it is sometimes necessary to collect further information from thereporterinorderfortheassessmentoftheADRreporttobeassufficientaspossible.
Attheendof2014,weimplementedanewfollow-upprocedure,whichistoensureafocusedandrelevantprocessforcollectingadditionalinformationonADRreports.KeytothisprocessisthattheadditionalinformationmustsignificantlycontributetothescientificassessmentoftheADRreport.
Before,companieshadtheopportunityofsubmittingfollow-upquestionstoanyADRreport,butthenewprocedureintroducesanumberofwell-definedcriteriadescribingwhenadditionalinformationonanADRreportcanbecollected.Thisappliesto:
• All serious ADR reports3 • Seriousandnon-seriousADRreportsrelatedtomedicinesmarketedforlessthantwoyears.
Inaddition,additionalinformationtonon-seriouscasesmaybecollectedwhenthefollowingcriteriaaresatisfied:
• Medicines on the DHMA's follow up list.• Pregnancy cases• Mother/child cases, or congenital defects• Off-labeluseinchildren
Follow-upcanalsoberequestedifothersignificantadditionalinformationmaysignificantlyalterthescientificassessmentoftheADRreport.
TheprocedurehasbeendevelopedincollaborationwiththeDanishPharmacovigilanceCounciland upon discussions with the Danish Medical Association and other relevant health professional organisationsaswellastheindustry'sorganisations.
Theprocesswillbeevaluatedonanongoingbasisincollaborationwiththerelevantparties.
ReadmoreaboutthecollectionofadditionalinformationonADRreportsontheDHMAwebsite:Follow-up on adverse reaction reports.
3 Areportisseriouswhenoneormoreoftheadversereactionsareserious.Aseriousadversereactioncausedbyamedicineforhumanuse isareactionthatresultsindeath,islife-threatening,requireshospitalisationorprolongationofhospitalisation,orwhichresultsinpersistent orsignificantdisabilityorincapacity,orisacongenitalanomalyorbirthdefect.
New procedure for collecting additional information on received ADR reports
NEW PROCEDURE FOR COLLECTING ADDITIONAL INFORMATION ON RECEIVED ADR REPORTS
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The HPV vaccine is still monitored closely
In2014,theDHMAonceagainhadfocusonthesafetyoftheHPVvaccine.
Overall,thenumberofreportsofsuspectedadversereactionstotheHPVvaccinefellsignificantlyfrom2013to2014,butduringthesameperiodtheshareofseriousADRreportsincreased.AllseriousADRreportsareevaluatedbyadoctor,andwecontinuedin2014topublishtheresultingconclusionsinour newsletter Danish Pharmacovigilance Update.
Focus areas in 2014
POTS as a possible adverse reaction to the HPV vaccineIn2013,DanishADRreportspromptedustorequesttheEuropeanMedicinesAgency,EMA,toinvestigatePOTS(PosturalOrthostaticTachycardiaSyndrome)asapossibleadversereactiontotheHPVvaccine.
EMA'sevaluationprogressedin2014,andthePharmacovigilanceRiskAssessmentCommittee,PRAC,concludedinDecember2014anannualreviewofthesafetyoftheHPVvaccineGardasil®,whichincludedathoroughevaluationofapossiblecausallinkbetweentheHPVvaccineandPOTS.ThePRACconcludedthatatthetimeitwasnotpossibletoconfirmordisprovethatthereisacausalrelationshipbetweenGardasil®vaccinationandtheoccurrenceofPOTS.Therefore,POTSshouldbemonitoredcloselyinfuturereviewsofGardasil®safety,andaspecialinitiativeintheformofanewquestionnairehasbeenlaunchedtoensureappropriatefollow-uponADRreportsthatdescribesymptomssuggestiveofPOTS.
Figure 5: Reports of suspected adverse reactions to the HPV vaccine from 2009-2014, broken down by serious and non-serious ADR reports
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Public funds earmarked for information about the safety of the HPV vaccineInJune2014,apublicfundsagreement(arateadjustmentpool)earmarkedfundsforactivitiesconcerningtheHPVvaccinein2014.Inthisconnection,theDHMApreparedinformativematerialforhealthprofessionals,whichisavailableontheDHMAwebsiteAdverse reactions from the HPV vaccine.Inaddition,theDHMAproducedaleafletthatdoctorscanhandouttogirlswhoaretobevaccinatedandtheirparentstodiscussandexplainthebenefitsandrisksofthevaccination.
Monitoring continues for suspected adverse reactions to the HPV vaccineAspartoftheDHMA'spharmacovigilanceactivities,weworktogetherwithexpertstofurtheranalysetheDanishreportsofpossibleadversereactionstotheHPVvaccine.AnyconclusionsfromtheseanalyseswillbeincludedintheongoingassessmentoftheHPVvaccine.
Statements on reported adverse reactions to seasonal influenza vaccinesVaccinesandtheirsafetytookupalotofmediaspacein2014.InNovember2014,theDHMAthereforepublishedastatementonreportedadversereactionstotheseasonalinfluenzavaccinescoveringthepasttenyears.InourelectronicnewsletterDanishPharmacovigilanceUpdate,wealsoreviewedtheADRreportsofthe2014/2015influenzaseasonandevaluatedallthereportedadversereactions.Thisreviewofreportsaboutsuspectedadversereactionstotheseasonalinfluenzavaccineshasbecomeapermanentfeatureinournewsletter,whichwebringtwiceduringaninfluenzaseason.
Reports of adverse reactions related to seasonal influenza vaccines in the past ten yearsThestatementpublishedinNovember2014showedthatduringthepasttenyears,wehavereceivedatotalof384ADRreportsrelatedtoinfluenzavaccination.141ofthereportswereclassifiedasserious.AmongtheseriousADRreportsweremostlyknownadversereactionssuchasGuillain-Barrésyndromeandthrombocytopenia.
Amongthenon-seriousreports,knownadversereactionswerealsofrequentlydescribed,e.g.fever,muscleandjointpain–adversereactionsthatoftensubsideduringthecourseof1-2days.
Duringtheten-yearperiod,therehavebeen13reportsinwhichthesuspectedadversereactionledtoafataloutcome.Thesecasesprimarilyinvolvedelderly,weakenedpersonsintheriskgroup.TheDHMAassessedthattenofthecaseswerenotconnectedtothevaccine,whereasapossiblecausalconnectioncouldnotberuledoutinthelastthreecases.Thesethreecasesinvolveneurologicaladversereactionsthataredescribedintheproductinformation.
DHMA conclusion to the statementOverall,theconclusiontothisstatementwasthatwestillassessthatthebenefitsoutweighthepossiblerisksandstillrecommendinfluenzavaccinationforriskgroupsbasedontheoverallscientificevidence.
ReadthestatementontheDHMAwebsite:Influenza vaccination is still assessed as effective and safe for risk groups (in Danish only) and our review in Danish Pharmacovigilance Update, December 2014.
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Antihistamine promethazine (Phenergan® etc.) became prescription only Afterarecentreviewofthesafetyofpromethazineusedforthetreatmentofallergicdiseases,motionsicknessandinsomnia,theDHMAchangedthemedicine'sstatusfromover-the-countertoprescription-onlyinDecember2014.Theprescription-onlystatuswasaffectedforbothPhenergan®/PrometazinERA25mgfilm-coatedtabletsinunitsof100andPhenergan®1mg/mloralsolutionforchildrenfromtwoyearsofage.
Thiswasprecededbylong-termconcernsaboutpromethazine'spotentialforabuse,whichlateronwasconfirmedinpractice.Wethereforeinitiatedalarge-scaleanalysisoftheuseofpromethazine,theresultofwhichnowmeansthemedicineisavailableonlyonprescription.
Increased focus on promethazine safety after enquiry by a proprietor pharmacistIt was a report from a proprietor pharmacist that prompted us to put focus on the use of promethazine.InDanish Pharmacovigilance Update, December 2012, we reported that we were monitoringpromethazinecloselyandencouragedthereportingofanysuspicionaboutexcessiveuseorabuseofthemedicine.Wesubsequentlyreceivedanewreportaboutsuspectedpromethazineabuse,andwewereconcurrentlyinformedthattheDanishPoisonControlHotlinehadreceivedseveralcallsaboutinappropriateuseofpromethazine.TheDHMAthereforejoinedforceswiththeDanishPoisonControlHotlinetoidentifypotentialsafetyproblemsassociatedwithpromethazine.
Why promethazine was made prescription-onlyWeidentifiedfourserioussafetyproblemsassociatedwithusingPhenergan®andPrometazinERA25mgfilm-coatedtabletsinunitsof100,whichiswhythemedicineisnowavailableonlyonprescription:
1. Abuse–useofhigherdosesthanrecommended2. Seriousadversereactionsatrecommendeddoses3. Seriousinteractionswithpsychoactivedrugs4. Heavysedativeeffectcompromisingtheabilitytodrive
ReadmoreaboutpromethazineinDanish Pharmacovigilance Update, December 2014.
Analysis of reported suspected adverse reactions and reported adverse events associated with using labour-stimulating medicines for induction of labour
The DHMA's Plan for the monitoring and supervision of the Danish regions' use of labour-inducing medicines (in Danish only)4fromAugust2013e.g.providesthatcross-cuttinganalysesofreportedsuspectedadversereactionsandreportedadverseeventsrelatedtomedically-inducedlabourwillbeimplementedin2014-2016.
TheDHMApublishedthefirstoftheseanalysesinDanish Pharmacovigilance Update, December 2014.
4 Themainpurposeoftheplanistoincreasethequality,safetyandsecurityofmedically-inducedlabour.Theplanwaspreparedatthe requestoftheMinistryofHealth.
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The analysis in briefTheanalysiswaspreparedjointlybytheDHMAandtheNationalAgencyforPatients'RightsandComplaintsandcoversthemedicinesdinoprostone,misoprostolandoxytocin.
WeanalysedADRreportsandadverseeventsthathadbeenreportedin2013.Weidentified30birthprocessesforwhichsuspectedadversereactionshadbeenreportedtotheDHMAand37adverseeventsrelatedtobirthprocessesreportedtotheDanishPatientSafetyDatabase.
On this basis, we identified five problems
1. Administrationofmisoprostolathigherdosesthanrecommended2. Inductionoflabourinwomenwithpreviouscaesareansections3. Temporarydischargeafteradministrationofmisoprostolinhospital4. Incorrectoxytocindoses5. Problemswiththeoxytocinivdrip.
DHMA continues to monitor medicines for induction of labourThe DHMA will continue monitoring and supervising closely the regions' use of medicines for induction oflabour.In2014,aprojectwaslaunchedjointlybytheDHMA,theDanishSocietyofObstetricsandGynaecology,theDanishAssociationofMidwivesandtheDanishStateSerumInstitute(SSI).Theprojectaimstoinvestigatethepossibilityofimplementingaregistrystudyofadversereactionsoccurringintheuseofmedicinesforinductionoflabour.ThepossibilityofimplementingsuchregistrystudydependsonthedataqualityoftheentriesintheMedicalBirthRegistryandtheNationalPatientRegistry.Attheendof2014,westartedcollectinginformationfromdeliverycentresacrossDenmark,andthisinformationwillbecomparedtotheinformationintheregisters.
Focus on users of antiepileptics and reported ADRs related to these medicines Afterareassessmentofreimbursementstatusforantiepileptics,theDHMAdecidedinspring2014thatitwouldberelevanttoanalyseusersofantiepilepticsandreportedsuspectedadversereactionsrelatedtothesemedicines.
TheDHMApreparedareportinthisconnection.Thereportincludesaliteraturereviewwithfocusonadversereactionsrelatedtoantiepileptics,ananalysisofthenumberofusersofthedifferenttypesofantiepilepticsfrom2003-2012aswellasananalysisofthesuspectedadversereactionsrelatedtothesemedicinesthatwerereportedtotheDHMAinthesameperiod.
Analysis resultThe literature review showed, among other things, that most of the serious chronic adverse reactions wererelatedtotheolderantiepileptics.Forthenewantiepileptics,noseriouschronicirreversibleadversereactionswereseenintheperiod,however,withsomeexceptions,e.g.pigmentchangestotheeyeandskininretigabinetreatment.Itshouldbenoted,however,thatmanyofthesenewmedicineshaveonlybeenusedforashorttime,andtheirprofilesofadversereactionsaremonitoredclosely.
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Benzodiazepines have the most usersFortheperiodreviewed,thenumberofadultuserswashighestforbenzodiazepines(clobazam,clonazepam,diazepamandmidazolam)andmedicineswithgabapentin,pregabalinandlamotrigine.Thevastmajorityofusersofbenzodiazepinesaswellasgabapentinandpregabalinhadbeenprescribedthesemedicinesforindicationsotherthanepilepsy.
Thenumberofusersperyearhadespeciallyincreasedforgabapentin,lamotrigineandpregabalin.Inregardtogabapentinandpregabalin,theincreasewasprimarilyduetopatientswhohadbeenprescribedthemedicinesforindicationsotherthanepilepsy.
ADR reports followed the number of usersByandlarge,thenumberofADRreportsrelatedtoantiepilepticsfollowedthenumberofusers,i.e.thereweremostADRreportsaboutmedicineswiththemostusers.
MostoftheADRreportsdescribedwell-knownsymptomsappearingfromthesummariesofproductcharacteristicssuchasdizziness,rash,nauseaandvomiting.
ReadthefullreportontheDHMAwebsite:Users and adverse reactions of antiepileptics in Denmark (in Danish only).
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Everyweek,wemonitortheADRreportsinthedatabaseofadversereactionstodetectpossiblenewADRsignals.AnADRsignalreflectsanewpossiblecausalrelationshipbetweenanadversereactionandacertaintypeofmedicineoranewangleonanalreadyknowncausality.Inaddition,wefocusmuchoncorrectuseofmedicineinclinicalpractice,i.e.theextenttowhichmedicineisusedincompliancewithitscurrentguidelineandsummaryofproductcharacteristics.
ADR signals could come from many other sources than ADR reports such as monitoring programmes, scientificliterature,varioustypesofstudies,drugregulatoryauthoritiesinothercountries,themediaorfromcitizensandhealthcareprofessionals.
In2014,theDHMAmonitoredanddetectedanumberofADRsignalsfromdifferentsources.
Table1brieflydescribestheADRsignalsweprocessedin2014.
ADR signals 2014
Medicine ADR signal Source Status and informative action if any
Benzodiazepines Alzheimer’sdisease Literature Signalclosed.Recommendation from PRACforcontinuedroutinemonitoring.
Cetirizin Intense itching after discontinuation.
Routine monitoring Signalclosed.Themarketingauthorisation holder will update the product information.
Citalopram QTprolongationinconcurrent treatment with methadone.
Routine monitoring Signalclosed.ArticleinDanish Pharmacovigilance Update,November2014.
Dentocain(articaine) Severeallergicreaction.Suspicion of product defect.
Information from health professional
Signalclosed.
Docetaxel "Hospira" Chestpain.Suspicionofproductdefect.
Information from health professional
Signalclosed.
Dopamine agonists Dopamine agonist withdrawalsyndrome.
Literature Signalawaitsassessment.
Epirubicin”Medac”and Sendoxan (cyclophosphamide)
Fever in patients with low neutrophil, white bloodcell,count(febrileneutropenia).Suspicionofproductdefect.
Information from health professional
Signalisbeingmonitored
Fosphenytoin Dose error due to mix up with another product
Danish Patient Safety Database(DPSD)
Signalclosed.ArticleinDanish Pharmacovigilance UpdateandbulletinfromtheNationalAgencyfor Patients' Rights and ComplaintsinJune2014.
Lamotrigine Hairloss. Routine monitoring Signalawaitsassessment.DisseminatedintheEUnetwork.
ADR SIGNALS 2014
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Assessment of ADR signalsItisbothcomplicatedandtime-consumingtodetectandassessADRsignals,andallsignalsarethereforeprioritisedbasedonaclinicalassessmentandlikelyconsequencesforpatientsandpublichealthingeneral.Whenanewsignalisdetected,itfirstneedstobevalidatedandconfirmedbeforeanyfurthermeasuresaretaken.Asignalcanbeclosedanytimeduringtheprocessifforexamplenocausalrelationshipcanbeestablishedbetweenthemedicineandtheadversereaction.Sometimesithappensearlyintheprocess,sometimesnotuntiltheevaluationhasfinished,andfurtheractionshavebeendecided.TheDHMA'ssignalprocessisshowninfigure6.
Anactioncouldbetoclosethesignalwithoutfurthermeasures,toinformDanishhealthprofessionalsandcitizensofthesignal,toforwardthesignalintheEUsystemtothePharmacovigilanceRiskAssessmentCommittee(PRAC)ortheEUmemberstatewithoverallresponsibilityforauthorisationand monitoring of the medicine or to continue monitoring the signal through either a surveillance programmeorthroughtheDHMA’sandthepharmaceuticalcompany'sroutinemonitoring.
Information about ADR signalsOnourwebsitedhma.dk and in our newsletter Danish Pharmacovigilance Update,weroutinelykeepDanishmedicineusersandhealthprofessionalsupdatedonADRsignalsandproblemsimportanttopatientsafety.
Detectsignal
Validatesignal
Closesignal
Confirmsignal OutcomeAssess
signal
Figure 6: The DHMA signal process
Levemir Lump formation and sorenessattheinjectionsite.
Routine monitoring Signalclosed.
Meropenem Severe allergic reaction Suspicion of product defect.
Information from health professional
Signalisbeingassessed.
Methylphenidate Treatmentofschizophreniawith mehylphenidate is contraindicated.
Surveillance programme Signalclosed.ArticleinDanish Pharmacovigilance Updateisplanned.
Methylphenidate "Sandoz"
Lackofefficacy. Routine monitoring Signalclosed.ArticleinDanish Pharmacovigilance Updateisplanned.
Pregabalin Abuse. Surveillance programme Signalisbeingassessed.
Warfarin and miconazoleoral cavity gel
Increasedriskofbleeding(knowninteraction).
Routine monitoring Signalclosed.ArticleinDanish Pharmacovigilance Updateisplanned.
Table 1. List of ADR signals that the DHMA focused on in 2014
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In2014,theDHMAcompleteditsclosecollaborationwiththedepartmentsofclinicalpharmacologyatAarhusUniversityHospital,OdenseUniversityHospitalandBispebjergHospitalofexpandingthescientificcontentoftheDrugInteractionDatabase.
The project in briefTheprojectaimwastoexpandtheDrugInteractionDatabasewithdatafromtheinteractionsparagraphsinthemedicines'summariesofproductcharacteristics(SPCs).Previously,thedatabasewasmainlyupdatedbasedondatafrompublishedstudies,which,particularlyfornewmedicines,couldproveinadequatebecauseatthetimeofauthorisationtheSPCscouldholdknowledgeaboutinteractionsnotyetpublishedinstudies.Weimprovedthisin2014,andnowtheDrugInteractionDatabaseincludesalsothenewestknowledgefromtheSPCsthathasnotyetbeenpublishedinthescientificliterature.
Inaddition,allinteractionsadvisedagainstintheDrugInteractionDatabase(redinteractions)werereviewedoncemoretoensurethewarningsintheDrugInteractionDatabasearegenuineandclinicallymeaningful.ReadmoreabouttheprojectinDanish Health and Medicines Authority’s annual pharmacovigilance report 2013.
Drug Interaction Database integrated in doctors' medical systemsIn2014,wealsoworkedonasolution,whichmakesitpossibletointegratedatafromtheDrugInteractionDatabaseinoneofthemedicalsystemsthatdoctorsuseintheirdailywork,therebygivingthemabetteroverviewofthemedicine’ssafetywhentheyprescribemedicinesandultimatelyenhancingpatientsafety.Itisanimportantinitiativethatwewilldevelopfurtherin2015.
FurtherinformationabouttheDrugInteractionDatabaseisavailableinDanishatinteraktionsdatabasen.dk.
The Drug Interaction Database
THE DRUG INTERACTION DATABASE
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TheEuropeanPharmacovigilanceRiskAssessmentCommittee(PRAC)meetseverymonthintheEuropeanMedicinesAgency(EMA)inLondon.EveryEUMemberStatehasonememberandonealternateinthecommittee.ThePRACalsohassixexpertswithinpharmacoepidemiology,vaccinesandcommunicationaswellasrepresentativesofhealthprofessionalsandpatientorganisations.ThePRACassessesthesafetyofallmarketedmedicinesbasedonallavailabledata,e.g.ADRreportsandresultsofpharmacoepidemiologicalstudies.
TheDanishHealthandMedicinesAuthorityisanactiveplayerinthisinternationalcollaborationinwhichwealsospearheadthesafetyreviewsofalineofmedicinalproducts.
WeregularlycommunicatetheresultsofthePRACreviewsinourmonthlynewsletterDanish Pharmacovigilance Update(issuedinDanishandEnglish)andalsoviadirectcommunicationtodoctorsandrelevantorganisations.ThecasesreviewedbythePRACin2014included:
• Diacereineforthetreatmentofosteoarthritisandriskofseverediarrhoeaandeffects on the liver
• Domperidoneforthetreatmentofnauseaandriskofheartarrhythmia
• Zolpidemforthetreatmentofinsomniaandriskofnext-morningmedicineeffect
• Angiotensin-receptorblockers,angiotensin-convertingenzymeinhibitorsanddirectrenininhibitorsforthetreatmentofhypertension,heartdiseaseandproteinuriaandriskofhyperkalaemia,hypotensionandkidneyimpairmentincombinationtreatmentwithanytwoofthesemedicines
• Agomelatineforthetreatmentofdepressionandriskofeffectsontheliver
• Valproateforthetreatmentofepilepsyorbipolardisorderandriskofcongenitalmalformations when used during pregnancy
• Testosterone for the treatment of hypogonadism and effects on the heart
• Ponatinibforthetreatmentofleukaemiaandriskofbloodclots
• Ivabradineforthetreatmentofanginapectorisandriskofbradycardia.
ThePRAC'smeetingagendasandminutesarepublishedontheEMAwebsite.TheminutesarealsopublishedontheDHMAwebsite:The EU Pharmacovigilance Risk Assessment Committee (PRAC).
International pharmacovigilance collaboration
INTERNATIONAL PHARMACOVIGILANCE COLLABORATION
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DHMA is active in various international working groups
Throughout2014,theDHMAalsoparticipatedactivelyintheEuropeanjointactionprojectSCOPE–StrengtheningCollaborationsforOperatingPharmacovigilanceinEurope.
SCOPEaimstosupportknowledgeandexperiencesharingbetweentheEUMemberStatesintheareaofpharmacovigilance.Theprojectistogivethenationalauthoritiesanoverview,acommonunderstandingandpracticaltoolswithinanumberofareastoenhancemedicinesafetyforpatientsthroughoutEurope.
Theworkin2014wasparticularlyfocusedoncreatinganoverviewofthecurrentstatusofprocessesandworkflowsemployedbyeachEUMemberStatewithinvariousdefinedareas. Denmarkcontributeswithinformationinallareas,butisespeciallyactiveintheareaofADRsignalmanagementandcommunication.TheSCOPEprojectrunsuntiltheendof2016.
INTERNATIONAL PHARMACOVIGILANCE COLLABORATION
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ANNUAL PHARMACOVIGILANCE REPORT 2014
We must continually ensure that we spend our resources in areas that will give us most health value formoney.Therefore,aspartofthepharmacovigilanceactionplanfor2014-2015,whichhasbeendevelopedincollaborationwiththeDanishPharmacovigilanceCouncil,theDHMAhasestablishedaqualityforumwhichistohelpusidentifyareasinwhichwecansimplifyandrationalisetasksthatyieldonlyapoorhealthandsafetyoutput.Typically,thiswouldbemodificationsinourworkpracticeswithe.g.doctorsandthepharmaceuticalindustrywherewecanmakethepharmacovigilanceactivitiesevenmorerelevantandfocusedthroughchangesandadjustments.Wehavealreadyrearrangedtheprocedureforrequestingadditionalinformationonreportedsuspectedadversereactions.
Still focus on simplifying ADR reportingReportsfrompatientsortheirrepresentativesremainanimportantelementinpharmacovigilance.Itisachallenge–notonlyinDenmarkbutinternationally–tomaketheADRformsosimplethatitcanbefilledoutbyeveryonewithouttheneedforspecialqualifications.In2015,wewillmakespecialeffortstoeasereportingformedicineusers–oneelementwillbeashortfilmonhowtoreportanadversereactionandapracticalstep-by-steppresentationofthespecialelectronicADRformtobeusedinreporting.
Intherecentyears,wehavedevelopedtheDHMA’swayofworkingwithpharmacovigilanceincollaborationwiththeDanishPharmacovigilanceCouncil.NewITsystemshavebeenimplemented,newscientificworkingareashavebeenprioritised,andcommunicationhasbeenintensified.ButitisimportantthatwefollowhowtheotherEUMemberStatesarehandlingthetasksandseeifwecanlearnfromthem.In2015,wewillthereforebevisitingoneormoreofoursisterorganisationstodiscussspecificallyselectedareastofindoutifthereareareasinwhichwecandobetteratevenbetterqualityaspermittedbyourownframework.
Further involvement of patients and medicine usersItisimportanttotheDHMAthatweinvolveusersinourwork.Andthereforewewillcontinuein2015tocollaboratewithselectedpatientorganisationsanddiscussboththechallengesandpossibilitieswehavetogetherofcollaboratingonmedicinesafety.
ThenumberofreportedadversereactionsishighinDenmark–thisisgoodasitcontributestoenhancingmedicinesafety.Butwemustnotfocusonquantityalone–itisreallyimportantthatwemaintainanddevelopthequalityofADRreports.Toaccommodatethis,wewillcontinuein2015tolaunchanumberofinitiativestoenhancethequalityofADRreports.Ourapproachwillbetargetedthroughcollaborationwithhealthprofessionalsanddesignedtoreducebureaucraticburdens.Wemustgivequalityandprioritisationevenmoreprecedencein2015.
Quality and prioritisation – focus areas in 2015
QUALITY AND PRIORITISATION – FOCUS AREAS IN 2015
