Drug Interactions and Prescribing Errors
Transcript of Drug Interactions and Prescribing Errors
DrugInteractionsandPrescribingErrors
JohnR.Horn,PharmD,FCCPProfessorofPharmacy,SchoolofPharmacy
AssociateDirectorUWMedicinePharmacyServicesUniversityofWashington
Seattle,WA
FinancialDisclosureRelatedtoPresentation
JohnHornisapartnerofHanstenandHorn,LLPwhichpublishesdruginteractionreferencebookssuchasTheTop100DrugInteractions:AGuidetoPatientManagement
JohnHorndoesnotcurrentlyhaveafinancialrelationshipwithanyone,butwouldcertainlywelcomeoneasheisnearingretirement.
DDITerminology• Drug-druginteraction(DDI)
• Aclinicallymeaningfulalterationintheexposureand/orresponsetoadrugthathasoccurred asaresultoftheco-administration ofanotherdrug.
• PotentialDDI(PODDI)• Co-prescriptionorco-administrationoftwodrugsknowntointeract,andthereforeaDDIcouldoccurintheexposedpatient.
DefinitionofTerms
•ObjectDrugthedrugthatisbeingaffectedbytheinteraction
• PrecipitantDrugthedrugcausingtheinteraction
• Interactioncaneitherbeuni-directionalorbi-directional(mutual)
TypesofDrugInteractions
• PharmacokineticDrugInteractionsThoseinteractionsthatresultinachangeintheconcentration-timecourseofactivedrug/metabolitesinthecirculationand/orattheeffectortissueororgan
• PharmacodynamicDrugInteractionsThoseinteractionsinvolvingachangeinthefunctionalrelationshipbetweenthedegreeofpharmacologicresponseandthedrug/metaboliteconcentration
PharmacyResponsetoSeriousDDIs•255prescriptionsfor1of5DDIswerepresentedtocommunitypharmaciesbyreportersfromChicagoTribune
•PrimaryoutcomemeasurewasverbalindicationDDIidentifiedtopatientorMD
•8Chainpharmacies;30tests/chain•32Independentpharmacies
PharmacyResponsetoSeriousDDIs:DrugPairs
Clarithromycin– ErgotamineVerapamil– ColchicineClarithromycin– SimvastatinCiprofloxacin– TizanidineGriseofulvin– OralContraceptive
PharmacyResponsetoSeriousDDIs:CorrectlyIdentifiedbyPharmacy
40 36.7 40
63.356.7
38.5
70
56.7
28.1
01020304050607080
Percent
PharmacyResponsetoSeriousDDIs:CorrectlyIdentifiedbyDDIPair
42.9
27.5
69.5
59.3
36.2
0
10
20
30
40
50
60
70
80
Clar/Ergot Verap/Colch Clar/Simva Cipro/Tizan Griseo/OC
Percent
WhatisthePurposeofaDrugInteractionScreeningProgram?
Toidentifypotentialinteractionsandinitiatestepstopreventpossiblepatientharm
“Predictionisverydifficult.Especiallyifit’s
aboutthefuture.”NielsBohr
Prediction
Fluconazole(Diflucan)+Warfarin(Coumadin)
7peopleonwarfaringivenfluconazole100mgdailyX7dMarkedincreaseinthePTresponse(buthighvariability)Nobleedingoccurred
0
10
20
30
40
50
60
70
1 2 3 4 5 6 7
% Increase in Pro-Time
mean
Patients
Crussell-Porter LL et al. Arch Intern Med 1993;153:102-104.
Factors Influencing Drug Interaction Outcomes
CLINICALOUTCOMEOFDRUG
INTERACTIONS
PATIENTFACTORS
DRUGFACTORS
Genetics
Diseases
Diet/Nutrition
Environment
Smoking
Alcohol
Dose
Duration
DosingTimes
Sequence
Route
DosageForm
HIGHVARIABILITY Adapted from Hansten. Science & Medicine. 1998;5:16-25.
ComputerizedDIScreening:Problems
• Thesheerenormityofavailableinfo• Lackofepidemiologicalinformation•Complexityofpatients,polypharmacy•Mayrelyonliteraturereportswithoutinformedrevieworevaluation
•Mayincludeinteractionsthatare‘over’classed
PhysiciansResponsetoComputerizedDrugInteractionAlerts
• 4751DDIalerts• 3129separatepairs:Overriderate:
• Level1(Serious/substantialevidence)89.4%• Level2(Lessserious) 96.3%• Level3(Serious/someevidence) 85.4%
• MDstriedtoreentersamedrugpair26%ofthetime
Weingart SN et al. Arch Intern Med.2004;163;2625-31.
AlertOverrides:JustaBadHabit?
•Prescribersrarelyreadalertsthatareoverridden
•Timefromalertpresentationtodismissal– 8seconds – independentofacceptanceoroverrideofalert
•Morealerts=moreoverrides
McDanielRBetalJAMIA.2016;23:e138-41
ProblemsinDDIInformationProcessing
•DataGenerators: Basicandclinicalscientistsdoingcontrolledstudies(PKusually),casereports,“bigdata”mining,labeling.Hugeamountofdataofvaryingquality.
•Problem– LargevolumeofDDIdataofvaryingquality.
HornJRandHanstenPD.PharmacyTimes.May2015
CilostazolDDI:Label1/15LovastatinCo-administrationofcilostazolwithlovastatinincreaseslovastatinandß-hydroxylovastatinAUCapproximately70%.Thisismostlikelyclinicallyinsignificant.
EffectofCilostazolonCYP3A4PLETALdoesnotappeartocauseincreasedbloodlevelsofdrugsmetabolizedbyCYP3A4,asithadnoeffectonlovastatin,adrugwithmetabolismverysensitivetoCYP3A4inhibition.
DataMiningtoIdentifySevereDDIADRs
• ExtractDDI-ADRpairsfromFDAAERSforwarfarin,clopidogrel,simvastatin
• UsedSideEffectResource(SIDER– basedonpackageinserts)toIDADRsassociatedwithdrugs
• Severitygrades1(mild)to5(death)usingcommonterminologycriteriaforADR(CTCAE)
• CombinedthesesourcestoextractDDIpairsandtheADRsassociatedwiththem
JiangGetal.BioDataMining.2015;8:12
DataMiningtoIdentifySevereDDIADRs:Simvastatin
Drug1 Drug2 CTCAEGrade ADEName
Simvastatin Aspirin 5Fatal Aortic Stenosis/Coma
Simvastatin Losartan 5 CardiacArrest
Simvastatin Risiglitazone(sic)
5 LBBB/Retinopathy
Simvastatin Tegretol 4Lifethreatening Aphasia/Arrhythmia/Dermatitis
Simvastatin Amiodarone 4 Bonepain
Simvastatin Aspirin 3Severe Dermatitis
Simvastatin Viagra 3 Glucosetolerance impaired
Simvastatin Ramipril 3 Intervertebraldiscprotrusion
JiangGetal.BioDataMining.2015;8:12
ProblemsinDDIInformationProcessing
• InformationAnalysts: ReadpapersfromDataGeneratorsandwritereviews,books,andelectronicdatabases.FewspecializeinDDIinformatics;variabilityinexpertise.
•Problem– ToofewanalystswithbothgeneralandspecializedknowledgeofDDIs.
HornJRandHanstenPD.PharmacyTimes.May2015
Theophylline– Allopurinol:AMajorDrugInteraction
• ListedashighestseverityinseveralCDSdatabases,includinginstitutionallycustomizeddatabases
• TwostudiesfoundnochangeintheoPKwithallopurinol300mgdailyx7days
•Onestudyfound~25%increaseinTheoAUCandhalf-lifeafter2weeksofallopurinol300mgBIDvsday1
Theophylline– Allopurinol:AMajorDrugInteraction
Theophylline
3-Methylxanthine
1-methylurinc acid
1,3 dimethyluric acid
1-methylxanthine35%1A2 3A, 2E140%
16%1A2
Xanthine Oxidase
ProblemsinDDIInformationProcessing
• ClinicalDecisionSupportProducers: RelyonInformationAnalysts’producttomakeCDSusedbyclinicians.DecidingwhichPODDIsandhowtopresentthemisdifficultandsomedoabetterjobthanothers.AllincludePODDIsofquestionableclinicalimportance.
• Problem– InclusionoffartoomanyPODDIsinCDS
HornJRandHanstenPD.PharmacyTimes.May2015
QTcIntervalProlongationinCardiacPatients
•900ptsadmittocardiacunits•Definitions:QTcprolonged:470ms/480msformales/females
•QT-prolongingmedsfromqtdrugs.org•AdmissionQTc~460ms
TisdaleJEetal.DrugSaf.2012;35:459
QTcIntervalProlongationinCardiacPatients
• OnadmissionQTcprolongedin28%;ofptsonQTPD,31.5%hadprolongedQTc
• 18%admitswithQTc>500ms• 35%ofptswithQTcprolongationreceivedQTPD• 42%ofptswithQTc>500msreceivedQTPD;57%ofthesehadsubsequentQTcincreases>60ms
• TotalnumberofcasesofTdP=ZERO
TisdaleJEetal.DrugSaf.2012;35:459
OccurrenceofQTc-BasedDDIs
ReviewedallDDIsclassifiedasMajorinEMRDDIdatabase:N=21,944
IdentifiedDDIsthatciteprolongedQTcasthebasisoftheDDIrisk:N=5,651
26%ofallMajorDDIsareduetoQTc-basedmechanisms.
AlertFatigue
“Themuchdiscussedphenomenonofalertfatiguesuggests
thatthereistoomuchinformationtoprocessinthetypical
workflowwhenitcomestoorderprescribing.Alertshave
oftenbeenconsideredtobeduplicative,lackinginpatient-
specificcontext,orjustgenerallyspurious.”
Matuszewski KA. Pharmacy and Therapeutics. 2012;37:69.
CausesofAlertFatigue
•Refills•Lowspecificityforclinicalsignificance•Basedonnon-clinicaldata•Desiretohave“complete”listing•Legalconcerns•“It’sinthelabel”
ReducingAlertFatigue:Options
•TurnoffselectedDDIcategories•Doin-housereviewofDIdatabasetoreviseexistingalerts
•KnowledgebaseDDIprogram•PatientspecificDDIalerts
WhatNOT ToDoAboutTooManyDDIAlerts
Turnoffselectedcategories(eg,allalertsnotin“mostsevere”group)orremove“reallyirritating”alerts
Advantage– VeryeasytodoDisadvantage– Tooeasytodo
AlertOnlyMostSevereDDIs:WhatYouWillNOT See
• Amiodarone/Haloperidol– PK/PDarrhythmia• Bepridil/Clarithromycin– PK/PDarrhythmia• Colchicine/Clarithromycin– Colchicinetoxicity• Conivaptan/Ergots– Ergotism• Cyclosporine/Ketoconazole– Renaltoxicity• Cyclosporine/Rifampin– Organrejection• Simvastatin/Clarithro,Erythro,CSA– Myopathy
Horn JR, Hansten PD. Pharmacy Times. 2011;77:38
WhatYouMightDoAboutTooManyDDIAlerts
Doin-housereviewandcustomizationofsomeorallofDDIdatabase
Advantage– usuallydonebycommitteeDisadvantage– usuallydonebycommitteewithoutadequateexpertiseortraininginDDIs
InHouseDDICustomization:Identified“CriticalInteractions”
•CCBs(all)– BBs(all)[duetoAVblock]•Digoxin- Amiodarone,Macrolides,Quinidine,Verapamil,Tetracycline(Butnotazoleantifungals)
• SSRIs– Triptans• Theophylline– Allopurinol,Febuxostat
InHouseDDIDatabaseCustomization:Guidelines
• Startbydefiningwhatshouldtriggeranalert• Establishcriteriaforseriousnessclassification•Developcriteriaforassessingevidence•Developsetofrulestoguideclassificationandincreasecontinuity
InHouseDDIDatabaseCustomization:WheretoStart?
•Reviewthealertsthatarecurrentlybeingtriggered
• StartwiththeDDIscausingthemostalerts•Decreaseseriousnessofthosealertsnotmeetingcriteria
•Usepreviouslycustomizeddatabaseasstartingpoint
CustomizedDIScreeningatUniversityofWashingtonMedicalCenter
• InpreparationforCPOE,customizeDIdatabase• StartwithDIslabeledasMAJOR• About8000uniquepairsinUWMC’sdatabase(2007)• Eachpairevaluatedforappropriateclassificationindatabase(Major– Moderate– Minor)basedondataanddefinedcriteria
Horn JR et al. Am J Health-Syst Pharm. 2011;68:662-4.
CustomizedDDIDatabase
• Evaluationcriteriawasprobabilityofpatientharmandeaseofavoidance
•MAJORshouldonlyincludeDDIswhererisklikelytoexceedbenefitinmostpatients
•MAJORDDIsshouldrequirethoughtandaction:changedrug,adjustdose,and/ormonitor
Horn JR et al. Am J Health-Syst Pharm. 2011;68:662-4
CustomizedDDIDatabaseHospital TotalMAJORsin
DatabaseDIs ReducedinSeverity(%)
UWMC(2007) 7970 57
Hospital2 8404 59
Hospital3 11727 65
Hospital4 12268 77
UWMedicine(2016) 26040 71
CustomizedDDIDatabase• Reducesnumberofinappropriatealertsandpotentialforalertfatigue
• Enablesselectionofalertsbasedoninstitutionalrequirements
• Needtoeducateusersonchanges• Needtoupdate• Noopportunityforpatientspecificalerting• Labor/expertiseintensive
KnowledgeBaseDrugInteractionScreening
•Doesnotuseasimplelook-uptable• Basedondrugproperties– PK,PD
•Mechanism(ie,CYP450)based• IDsubstrate,inhibitor/inducerofCYP450s•MagnitudeofeffectonCYP450• First-Passmetabolismofobjectdrug• Therapeuticwindowofobjectdrug
Boyce E et al. IEEE Trans Info Tech Biomed, 2007;11:386-397.
Mechanism-basedDrugInteractionKnowledgeBases
Advantages:CanpredictinteractionsnotpreviouslyreportedAvoids“class”errorsPredictsinteractionsresultingfromdrugwithdrawalSupportsinteractionsbetweenthreeormoredrugsProvidesestimatesofeffectonObjectdrug
Mechanism-basedDrugInteractionKnowledgeBasesDisadvantages:MechanismsmaybeunknownPKorPDinfofordrugsmaynotbeavailableDifficulttoevaluateclinicalriskUpdatingdrugassertionsinthedatabaseEvaluatingevidenceforassertions
PatientSpecificDDIAlerts
Cleanupdatabasefirst?Createalgorithm/decisiontreewithmitigatingandriskfactorsApplyusingpatientspecificEMRdatatodecidetoalert
CommonMajorDDIAlertsUWMedicine2016:AssessmentofDDIs
ReviewtheP’col andP’kinet propertiesofobjectandprecipitantdrugsIdentifymodifying(MitigatingandRisky)factorsDrug:Dose,Duration,Route,OrderofAdministration,Co-medicationsPatient:Disease,Renalfunction,Labvalues,ECG,Pharmacogenomics,Diet,Age,Gender
CommonMajorDDIAlertsUWMedicine2016
Amiodarone/OxycodoneAmlodipine/SimvastatinCiprofloxacin/OxycodoneDiltiazem/OxycodoneFluconazole/FentanylFluconazole/OxycodoneFluconazole/Tacrolimus
Makeup58%ofMajoralerts
DoseFiltersforCommonAlerts
Amiodarone/≤40mgOxycodoneAmlodipine/≤40mgSimvastatinCiprofloxacin/≤80mgOxycodoneDiltiazem/≤80mgOxycodoneFluconazole≤200mg/FentanylFluconazole≤200mg/OxycodoneFluconazole≤200mg/Tacrolimus
AssessmentofDDIs:Fluconazole
FluconazoleCYP3A4inhibitionisdosedependent
100mg/d– 20%incr CSAAUC150mg/d– 25-50%incr MidazolamAUC100mg/d– 2-foldincr TriazolamAUC200mg/d– 4-foldincr TriazolamAUC
Fluconazole/OxycodoneDDIDecisionTree
Fluconazoledose≤200mg/day
Yes Noalert
No
ICU?No
Scheduledoxycodonedose<80mg/d
Yes
Noalert
No
Alert
Yes
Noalert
Fluconazole/OxycodoneDecisionTree• 242alertsforfluconazole/oxycodone• Flucon dose≤200mg/d:169Noalert• Flucon dose>200mg/d:73• ICU:yes– 6Noalert• ICU:no– 67•Oxydose<80mg/d:37Noalert•Oxydose>80mg/d:30Alert• ~88%reductioninalerts
Fluconazole/TacrolimusDDIDecisionTree
TacrolimusIVFormulation
Yes Noalert
No
Fluconazoledose<200mg/day
Yes
Noalert
No
Alert
Fluconazole/TacrolimusDecisionTree
•159alertsforfluconazole/tacrolimus•TacrolimusIV:39Noalert•Flucon dose<200mg/d:43Noalert•Flucon dose≥200mg/d:77Alert•~52%reductioninalerts
KCL/PotassiumSparingDiuretic
No
Yes[K]w/in48h
[K]<4.5meq
No YesAlert
Alert
Yes
Alert
No
CrCl <30ml/min
Alert
Yes
No
ACEI/ARB
KCl ≥80meq/d
No
NoAlert
Yes
Alert
EffectofDDIFilteronAlerts
Alert N Sensitivity SpecificityKincreasingDDIs;alltriggeralert
6349 100 0
K>4.0mEq/lw/in48hr priortoDDI
2226 61.1 65.7
K>4.8mEq/l48hrpriorandduringDDI
1217 74.2 95.7
Eschmann Eetal.doi:10.3233/978-1-61499-289-9-1056
76KinpatientsanalyzedforDDIsresultinginK>5.4mEq/l
AlertReductionwithFilter:Low/HighDose
0102030405060708090
100
LowDose
HighDose
%reductioninalerts
DrugInteractionAlerts:ProblemsandSolutions
SummaryandQuestions
“Never,underanycircumstances,takeasleepingpillandalaxativeonthesame
night.”
Drug Interaction to Avoid