ClinicalGuideforCommunityPharmaciststoEvaluateRisksandManageQTc ProlongationDuetoDrug-DrugInteractions

TracyHe1,PharmD Candidate,Certina Ho2,BScPhm,MISt,MEd,PhD1UniversityofWaterlooSchoolofPharmacy,2InstituteforSafeMedicationPracticesCanada

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Results&KeyFindingsBackground

Objectives

Methods

Conclusions&FutureDirections References

Figure1.ClinicalguideforevaluationofgeneralQTc prolongingdrug-druginteractions.3,4

Figure2.ClinicalguideforevaluationofcitalopramQTc prolongingdrug-druginteractions.8

§ LongQTsyndrome(QTprolongation)isaconditionwheretheintervalbetweenthebeginningoftheQRScomplextotheendoftheTwaveislengthened,reflectingdelayedmyocardialrepolarization.1

§ “QTc”denotestheQTintervalcorrectedforapatient’sheartrate.2§ QTc prolongationcanprecipitatetotorsades depointes(TdP),alife-

threateningventriculartachyarrhythmiathatresultsinsuddendeath.1§ Itisduetogeneticsusceptibilityandmedications.1§ ClinicalsignificanceofQTc prolongationisunderestimatedand

overvalued.§ Currently,therearenovalidatedriskscalesthatassessQTc

prolongationriskforoutpatientorambulatorypatients.

1) ToidentifytherecommendationsposedbycliniciansinevaluatingQTcprolongationrisksassociatedwiththreecommonly-encountereddrugs(citalopram,domperidone,ciprofloxacin)thatmayresultinQTcprolongationalertsinthecommunitypharmacy;and,

2) Todevelopaclinicalalgorithmortherapeuticthoughtprocessforcommunitypharmaciststoeffectivelyevaluateandmanagethesedrug-druginteractions(DDIs).

Therecommendationswerecompiledthrough2methods.1)EnvironmentalScanofNationalRegulatoryBodiesandClinical

Guidelines

2)SystematicReviewofPrimaryLiterature

RegulatoryBodies• HealthCanada• UnitedStatesFoodandDrugAdministration(FDA)

ClinicalGuidelines• CanadianNetworkforMoodandAnxietyTreatmentsAmericanPsychiatricAssociation(CANMAT)

• AmericanAssociationofGastroenterology(AAG)

• CanadianJournalofUrology(CJU)

• CanadianThoracicSociety(CTS)

• EvaluationofQTc prolongingdrug-druginteractionsishighlyreliantontheclinicaljudgmentofthecommunitypharmacist,involvingananalysisofthepatient’sriskfactorsandtheseverityofthedrug-druginteraction

• Uponassessment,thecommunitypharmacistshould:• PlacethemedicationonholdiftheTdP riskishigh• Recommendbaselineandsteady-stateECGtesting(at5half-livesofthemedication)• Providealternativedrugtherapies,ordose-adjustbasedonthepatient’srenalorhepaticfunction

• DecisionshouldalwaysbedocumentedandsignsandsymptomsofTdP shouldbecommunicatedtothepatient• Point-of-careECGtestingmayaidcommunitypharmacistsintheassessmentofpatientsatriskforTdP

Citalopram Domperidone Ciprofloxacin§ HealthCanada/FDA:>40mg

shouldnotbeused(20mg forelderly)duetodose-dependentQTc prolongation.

§ CANMAT:SSRIscarryaverylowriskofTdP andotherarrhythmias.

§ Primary literature:mostshowedincreaseinQTc interval;Beachetalconsidered40mgasmaxdosetobeoverlyconservative.5

§ Health Canada: contraindicatedinQTc prolongation,maxdailydose30mg.

§ AAG:suggestbaselineECG.§ Primary literature:Boyceetaldemonstrated a 3-foldincreaseindomperidone concentrationswithconcomitantusewithaCYP3A4inhibitor(ketoconazole) andrecommendedthatthecombinationshouldnotbeadministered.6

• Health Canada/FDA:minimalguidance.

• CJU/CTS:nomention.• Primary literature:Tsikouris

etalobservedthatciprofloxacinistheleasttorsadogenicfluoroquinolone,andinhealthypatients,a7-daytreatmentdoesnotincreasetheriskforTdP.7

Table1.Resultsfromenvironmentalscanandsystematicreview.5-7

MEDLINE(PubMed)

Search criteria:(qt prolongationORprolongedqt ORqt

intervalORqtc intervalORlongqt syndrome)AND(citalopramORdomperidone OR

ciprofloxacin)222articles

Timeframe:2006– 2016,inclusive

156articles

153articlesPatients≥19yearsold

Randomizedcontrolledtrials,meta-analysesPre-programmed“AdditionalFilter”

criterionManualperusal

7articlestotal

Citalopram:5articles

Domperidone:1 articles

Ciprofloxacin:1article

1. ProlongedQ-Tinterval.MayoClinic.http://www.mayoclinic.org/diseases-conditions/long-qt-syndrome/multimedia/prolonged-q-t-interval/img-20007972.AccessedDecember11,2016.

2. DrugsandHealthProducts.Notice– adoptionofICHguidance:TheclinicalevaluationofQT/QTc intervalprolongationandproarrhythmic potentialfornon-antiarrhythmicdrugs– ICHTopicE14.HealthCanada.http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/efficac/e14-eng.php.PublishedApril13,2006.AccessedOctober11,2016.

3. TisdaleJE.Drug-inducedQTintervalprolongationandtorsades depointes:Roleofthepharmacistinriskassessment,prevention,andmanagement.CanPharmJ.2016:149(3);139-152.

4. OverviewofLongQTSyndromeandTorsades dePointes.CredibleMeds.https://www.crediblemeds.org/healthcare-providers/practical-approach.RevisedNovember19,2015.AccessedNovember15,2016.

5. BeachS,KostisW,Celano C,etal.Meta-AnalysisofSelectiveSerotoninReuptakeInhibitor–AssociatedQTc Prolongation.JClin Psychiatry.2014;75(05):e441-e449.doi:10.4088/jcp.13r08672.

6. BoyceM,BaisleyK,WarringtonS.Pharmacokineticinteractionbetweendomperidone andketoconazoleleadstoQTprolongationinhealthyvolunteers:arandomized,placebo-controlled,double-blind,crossoverstudy.BritishJournalofClinicalPharmacology.2012;73(3):411-421.doi:10.1111/j.1365-2125.2011.04093.x.

7. Tsikouris JP,Peeters MJ,CoxCD,Meyerrose GE,SeifertCF.EffectofthreefluoroquinolonesonQTanalysisafterstandardtreatmentcourses.AnnNoninvasive Electrocardiol. 2006;11(1):52-56.doi:10.1111/j.1542-474X.2006.00082.x.

8. Celexa (citalopramhydrobromide)TabletsandOralSolution.U.S.Food&DrugAdministration.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm271275.htm.PublishedDecember2012.AccessedDecember11,2016.

Contactinformation:TracyHe(tracyy.he@gmail.com) | Dec2016.Copyright©2016.PosterdesignbyTracyHe.