Margaret Jin, BScPHM, PharmD, CGPMargaret Jin, BScPHM, PharmD, CGPNovember 2007November 2007

Learning ObjectivesLearning Objectives To review the mechanism of action, indications, To review the mechanism of action, indications,

contraindications, adverse reactions, & contraindications, adverse reactions, & common drug interactions of warfarincommon drug interactions of warfarin

To provide effective patient educationTo provide effective patient education To understand general concepts in warfarin To understand general concepts in warfarin

dosingdosing To be able to use vitamin K1 appropriatelyTo be able to use vitamin K1 appropriately

WarfarinWarfarin

Synthesis of Synthesis of Non Functional Non Functional

Coagulation Coagulation FactorsFactors

Antagonismof

Vitamin K

Mechanism of ActionMechanism of Action

Vitamin KVitamin K

VIIVII

IXIX

XX

IIII

Mechanism of ActionMechanism of ActionClotting CascadeClotting Cascade

Indications & Indications & Recommended Therapeutic RangeRecommended Therapeutic Range

IndicationIndication Therapeutic Therapeutic Range (INR)Range (INR)

Treatment of venous thrombosisTreatment of venous thrombosisTreatment of pulmonary embolismTreatment of pulmonary embolismPrevention of systemic embolismPrevention of systemic embolism

Tissue heart valvesTissue heart valvesValvular heart diseaseValvular heart diseaseAtrial fibrillationAtrial fibrillation

Bileaflet mechanical valve in aortic positionBileaflet mechanical valve in aortic position

2.0 – 3.02.0 – 3.0

Target = 2.5Target = 2.5

Mechanical prosthetic valvesMechanical prosthetic valvesAcute Myocardial infarctionAcute Myocardial infarction

2.5 – 3.52.5 – 3.5Target = 3.0Target = 3.0

Chest 2004;126(3 Suppl):204S-233S

ContraindicationsContraindications Pregnancy Pregnancy Risk of hemorrhage > clinical benefitsRisk of hemorrhage > clinical benefits

Active hemorrhage (e.g., GI bleed)Active hemorrhage (e.g., GI bleed) Uncontrolled alcohol/drug abuseUncontrolled alcohol/drug abuse Unsupervised dementia/psychosisUnsupervised dementia/psychosis

Unable to monitor INRUnable to monitor INR

Adverse EffectsAdverse EffectsA/E to report to MD:A/E to report to MD: Blood in stools or urineBlood in stools or urine Excessive menstrual Excessive menstrual

bleedingbleeding BruisingBruising Excessive nose Excessive nose

bleeds/bleeding gumsbleeds/bleeding gums Persistent oozing from Persistent oozing from

superficial injuriessuperficial injuries Intracranial HemorrhageIntracranial Hemorrhage

Factors that may influence Factors that may influence bleeding risk:bleeding risk:

Intensity of anticoagulationIntensity of anticoagulation Concomitant clinical Concomitant clinical

disordersdisorders Hx of bleedingHx of bleeding Hx of strokeHx of stroke Renal/Liver insufficiencyRenal/Liver insufficiency AnemiaAnemia HypertensionHypertension

Concomitant use of other Concomitant use of other medicationsmedications

Chest 2004;126(3):204S-233S

Adverse EffectsAdverse Effects Skin necrosis – 0.01-0.1%Skin necrosis – 0.01-0.1%

Day 3 – 8Day 3 – 8 Painful skin lesionsPainful skin lesions

Purple toe syndromePurple toe syndrome Week 3 – 8Week 3 – 8 Blue/purple toes/fingersBlue/purple toes/fingers

Allergic DermatitisAllergic Dermatitis Skin rash, hives, itchingSkin rash, hives, itching

VasculitisVasculitis Fever, itching, skin Fever, itching, skin

sores or blisterssores or blisters

PharmacokineticsPharmacokinetics AbsorptionAbsorption

Rapid absorptionRapid absorption Food does not Food does not

affect absorptionaffect absorption

DistributionDistribution 99% protein 99% protein

boundbound MetabolismMetabolism

LiverLiver Cytochrome Cytochrome

P450 2C9P450 2C9

Drug InteractionsDrug Interactions

Increase Warfarin ResponseIncrease Warfarin Response NSAIDS, ASANSAIDS, ASA Acetaminophen > 2g/dAcetaminophen > 2g/d AmiodaroneAmiodarone Quinolones (e.g., Cipro), Quinolones (e.g., Cipro),

sulfonamides, sulfonamides, metronidazolemetronidazole

FibratesFibrates Ginkgo, Garlic, GinsengGinkgo, Garlic, Ginseng GrapefruitGrapefruit

Decrease Warfarin Decrease Warfarin ResponseResponse

PhenobarbitalPhenobarbital CarbamazepineCarbamazepine PhenytoinPhenytoin Vitamin K rich foodsVitamin K rich foods

Green leafy Green leafy vegetablesvegetables

Effective Patient EducationEffective Patient Education Teach basic concepts of safe, effective Teach basic concepts of safe, effective

anticoagulationanticoagulation Discuss importance of regular INR monitoringDiscuss importance of regular INR monitoring Counsel on use of other medications, alcoholCounsel on use of other medications, alcohol Develop creative strategies for improving Develop creative strategies for improving

compliancecompliance Evening, same timeEvening, same time Dosettes, blisterpacksDosettes, blisterpacks

Warfarin TabletsWarfarin Tablets 1mg – pink1mg – pink 2mg – lavendar2mg – lavendar 2.5mg – green2.5mg – green 3mg – tan3mg – tan 4mg – blue4mg – blue 5mg – peach5mg – peach 6mg – teal6mg – teal 7.5mg – yellow7.5mg – yellow 10mg - white10mg - white

Warfarin MaintenanceWarfarin MaintenanceTarget INR 2.0 - 3.0Target INR 2.0 - 3.0

INRINR Dosage AdjustmentDosage Adjustment Recheck INRRecheck INR

< 1.5< 1.5 Weekly dose by 10-20%, Weekly dose by 10-20%, consider extra doseconsider extra dose 4 to 8 days4 to 8 days

1.5 – 1.91.5 – 1.9 Weekly dose by 5-10%^Weekly dose by 5-10%^ 7 to 14 days7 to 14 days

2.0 – 3.02.0 – 3.0 No changeNo change # of consecutive in-range # of consecutive in-range INRs x 1 week (max:4 wks)INRs x 1 week (max:4 wks)

3.1 – 3.93.1 – 3.9 Weekly dose by 5-10%*Weekly dose by 5-10%* 7 to 14 days7 to 14 days

4.0 - 4.94.0 - 4.9 Hold 0-1 dose,Hold 0-1 dose, weekly weekly dose by 10%dose by 10% 4 to 8 days4 to 8 days

≥ ≥ 5.05.0 Consult PHM or MDConsult PHM or MD^If INR is 1.8 to 1.9, consider no change with repeat INR in 7 to 14 days*If INR is 3.1 to 3.2, consider no change with repeat INR in 7 to 14 days

Warfarin MaintenanceWarfarin MaintenanceTarget INR 2.5 - 3.5Target INR 2.5 - 3.5

INRINR Dosage AdjustmentDosage Adjustment Recheck INRRecheck INR

< 1.5< 1.5 Weekly dose by 10-20%, Weekly dose by 10-20%, consider extra doseconsider extra dose 4 to 8 days4 to 8 days

1.5 – 2.41.5 – 2.4 Weekly dose by 5-10%^Weekly dose by 5-10%^ 7 to 14 days7 to 14 days

2.5 - 3.52.5 - 3.5 No changeNo change # of consecutive in-range INRs # of consecutive in-range INRs x 1 week (max:4 wks)x 1 week (max:4 wks)

3.6 - 4.53.6 - 4.5 Weekly dose by 5-10%*, Weekly dose by 5-10%*, consider holding one doseconsider holding one dose 7 to 14 days7 to 14 days

4.5 - 6.04.5 - 6.0 Hold 1-2 doses,Hold 1-2 doses, weekly dose weekly dose by 5-15%by 5-15% 2 to 8 days2 to 8 days

> 6.0> 6.0 Consult PHM or MDConsult PHM or MD

^If INR is 2.3 to 2.4, consider no change with repeat INR in 7 to 14 days*If INR is 3.6 to 3.7, consider no change with repeat INR in 7 to 14 days

33 33 33333333 33

MonMon TueTue WedWed ThuThu FriFri SatSat SunSun

TotalTotalWeeklyWeeklyDoseDose

21 mg21 mg

22 33 33332233 33 19 mg19 mg

22 22 33333333 22 18 mg18 mg

Warfarin Dosing ScheduleWarfarin Dosing Schedule

10%

15%

33 33 33333333 33

MonMon TueTue WedWed ThuThu FriFri SatSat SunSun

TotalTotalWeeklyWeeklyDoseDose

21 mg21 mg

44 33 33334433 33 23 mg23 mg

44 44 33333333 44 24 mg24 mg

Warfarin Dosing ScheduleWarfarin Dosing Schedule

10%

15%

Types of BleedsTypes of Bleeds

No significant bleeding = Minor bleedingNo significant bleeding = Minor bleeding BruisesBruises Reported, but does not require additional testing, referrals or Reported, but does not require additional testing, referrals or

visitsvisits Serious bleeding = Major bleedingSerious bleeding = Major bleeding

Black tarry stools, blood in urine, hematomaBlack tarry stools, blood in urine, hematoma Requiring treatment, medical evaluation or at least 2 units of Requiring treatment, medical evaluation or at least 2 units of

bloodblood Life-threatening bleedingLife-threatening bleeding

Intracranial hemorrhage, retroperitoneal bleed, leading to Intracranial hemorrhage, retroperitoneal bleed, leading to cardiac arrest, surgical/angiographic intervention, or cardiac arrest, surgical/angiographic intervention, or irreversible sequelaeirreversible sequelae

Warfarin ManagementWarfarin Management

INRINR Dosage AdjustmentDosage Adjustment

5.0 – 5.0 – 8.98.9

If If low risklow risk of bleeding, omit 1-2 doses, of bleeding, omit 1-2 doses, monitor INR more frequently, resume monitor INR more frequently, resume warfarin at 10-20% lower than original dose warfarin at 10-20% lower than original dose when INR is at therapeutic rangewhen INR is at therapeutic range

If If high riskhigh risk* of bleeding, omit 1 dose and give * of bleeding, omit 1 dose and give vitamin K1 1-2.5mg orally. Check INR in 24 vitamin K1 1-2.5mg orally. Check INR in 24 hours; if still high, administer additional hours; if still high, administer additional vitamin K1 1-2mg PO.vitamin K1 1-2mg PO.

*High risk = factors that may influence bleeding risk - Hx of bleeding, stroke, renal & liver insufficiency, anemia, hypertension, other medications

Warfarin ManagementWarfarin Management

INRINR Dosage AdjustmentDosage Adjustment

9.09.0

With no significant bleeding:With no significant bleeding:

Hold warfarinHold warfarin

Administer vitamin K1 5-10mg POAdminister vitamin K1 5-10mg PO

Check INR in 24 hoursCheck INR in 24 hours

If still high, administer vitamin K1 1-2mg POIf still high, administer vitamin K1 1-2mg PO

Resume warfarin at lower dose when INR is Resume warfarin at lower dose when INR is therapeutictherapeutic

Warfarin ManagementWarfarin Management

Serious bleeding, any INRSerious bleeding, any INR Hold WarfarinHold Warfarin Give Vitamin K1 10mg slow IV plus fresh plasma or Give Vitamin K1 10mg slow IV plus fresh plasma or

prothrombin complex concentrate, depending on urgencyprothrombin complex concentrate, depending on urgency Repeat Vitamin K1 every 12 hours as neededRepeat Vitamin K1 every 12 hours as needed

Life-threatening bleeding, any INRLife-threatening bleeding, any INR Hold warfarinHold warfarin Give prothrombin complex concentrate (or recombinant factor Give prothrombin complex concentrate (or recombinant factor

VIIa as an alternative) supplemented with vitamin K1 10mg VIIa as an alternative) supplemented with vitamin K1 10mg slow IV; repeat as neededslow IV; repeat as needed

Vitamin K1, PhytonadioneVitamin K1, Phytonadione

Injection FormulationInjection Formulation 10mg/mL – 1mL vial10mg/mL – 1mL vial 2mg/mL – 1mL vial2mg/mL – 1mL vial

Tablets are not available in CanadaTablets are not available in Canada Administer PO or IVAdminister PO or IV Do not administer SCDo not administer SC Elimination Half-life = 26-193 hoursElimination Half-life = 26-193 hours

SummarySummary Use clinical judgmentUse clinical judgment Educate patientEducate patient Adjusting warfarin dose is better than adjusting Adjusting warfarin dose is better than adjusting

patient’s quality of lifepatient’s quality of life Monitor INR appropriatelyMonitor INR appropriately Refer to Thrombosis Clinic if necessaryRefer to Thrombosis Clinic if necessary

ReferencesReferences The Thrombosis Interest Group of Canada (www.tigc.org)The Thrombosis Interest Group of Canada (www.tigc.org) Vitamin K dietVitamin K diet

www.gicare.com/pated/edtot39.htmwww.gicare.com/pated/edtot39.htm http://www.drgourmet.com/warfarin/vitaminkcontent.pdfhttp://www.drgourmet.com/warfarin/vitaminkcontent.pdf

Ansell J, et al. The pharmacology and management of the Ansell J, et al. The pharmacology and management of the vitamin K antagonists. Chest 2004;126:204S-233Svitamin K antagonists. Chest 2004;126:204S-233S

Singer DE, et al. Antithrombotic therapy in atrial fibrillation. Singer DE, et al. Antithrombotic therapy in atrial fibrillation. Chest 2004;126:429S-456SChest 2004;126:429S-456S

http://www.ccs.ca/download/consensus_conference/http://www.ccs.ca/download/consensus_conference/consensus_conference_archives/2004_Atrial_Fib_full.pdfconsensus_conference_archives/2004_Atrial_Fib_full.pdf

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