1. Margaret Jin, BScPHM, PharmD, CGP November 2007

2. Learning Objectives To review the mechanism of action, indications, contraindications, adverse reactions, & common drug interactions of warfarin To review the mechanism of action, indications, contraindications, adverse reactions, & common drug interactions of warfarin To provide effective patient education To provide effective patient education To understand general concepts in warfarin dosing To understand general concepts in warfarin dosing To be able to use vitamin K1 appropriately To be able to use vitamin K1 appropriately

3. Warfarin Synthesis of Non Functional Coagulation Factors Antagonism of Vitamin K Mechanism of Action Vitamin K VII IX X II

4. Mechanism of Action Clotting Cascade

5. Indications & Recommended Therapeutic Range Indication Therapeutic Range (INR) Treatment of venous thrombosis Treatment of pulmonary embolism Prevention of systemic embolism Tissue heart valves Valvular heart disease Atrial fibrillation Bileaflet mechanical valve in aortic position 2.0 – 3.0 Target = 2.5 Mechanical prosthetic valves Acute Myocardial infarction 2.5 – 3.5 Target = 3.0 Chest 2004;126(3 Suppl):204S-233S

6. Contraindications Pregnancy Pregnancy Risk of hemorrhage > clinical benefits Risk of hemorrhage > clinical benefits  Active hemorrhage (e.g., GI bleed)  Uncontrolled alcohol/drug abuse  Unsupervised dementia/psychosis Unable to monitor INR Unable to monitor INR

7. Adverse Effects A/E to report to MD: Blood in stools or urine Blood in stools or urine Excessive menstrual bleeding Excessive menstrual bleeding Bruising Bruising Excessive nose bleeds/bleeding gums Excessive nose bleeds/bleeding gums Persistent oozing from superficial injuries Persistent oozing from superficial injuries Intracranial Hemorrhage Intracranial Hemorrhage Factors that may influence bleeding risk: Intensity of anticoagulation Intensity of anticoagulation Concomitant clinical disorders Concomitant clinical disorders  Hx of bleeding  Hx of stroke  Renal/Liver insufficiency  Anemia  Hypertension Concomitant use of other medications Concomitant use of other medications Chest 2004;126(3):204S-233S

8. Adverse Effects Skin necrosis – 0.01-0.1% Skin necrosis – 0.01-0.1%  Day 3 – 8  Painful skin lesions Purple toe syndrome Purple toe syndrome  Week 3 – 8  Blue/purple toes/fingers Allergic Dermatitis Allergic Dermatitis  Skin rash, hives, itching Vasculitis Vasculitis  Fever, itching, skin sores or blisters

9. Pharmacokinetics Absorption Absorption  Rapid absorption  Food does not affect absorption Distribution Distribution  99% protein bound Metabolism Metabolism  Liver  Cytochrome P450 2C9

10. Drug Interactions Increase Warfarin Response NSAIDS, ASA NSAIDS, ASA Acetaminophen > 2g/d Acetaminophen > 2g/d Amiodarone Amiodarone Quinolones (e.g., Cipro), sulfonamides, metronidazole Quinolones (e.g., Cipro), sulfonamides, metronidazole Fibrates Fibrates Ginkgo, Garlic, Ginseng Ginkgo, Garlic, Ginseng Grapefruit Grapefruit Decrease Warfarin Response Phenobarbital Phenobarbital Carbamazepine Carbamazepine Phenytoin Phenytoin Vitamin K rich foods Vitamin K rich foods  Green leafy vegetables

11. Effective Patient Education Teach basic concepts of safe, effective anticoagulation Teach basic concepts of safe, effective anticoagulation Discuss importance of regular INR monitoring Discuss importance of regular INR monitoring Counsel on use of other medications, alcohol Counsel on use of other medications, alcohol Develop creative strategies for improving compliance Develop creative strategies for improving compliance  Evening, same time  Dosettes, blisterpacks

12. Warfarin Tablets 1mg – pink 1mg – pink 2mg – lavendar 2mg – lavendar 2.5mg – green 2.5mg – green 3mg – tan 3mg – tan 4mg – blue 4mg – blue 5mg – peach 5mg – peach 6mg – teal 6mg – teal 7.5mg – yellow 7.5mg – yellow 10mg - white 10mg - white

13. Warfarin Maintenance Target INR 2.0 - 3.0 INR Dosage Adjustment Recheck INR < 1.5  Weekly dose by 10-20%, consider extra dose 4 to 8 days 1.5 – 1.9  Weekly dose by 5-10%^ 7 to 14 days 2.0 – 3.0 No change # of consecutive in-range INRs x 1 week (max:4 wks) 3.1 – 3.9  Weekly dose by 5-10%* 7 to 14 days 4.0 - 4.9 Hold 0-1 dose,  weekly dose by 10% 4 to 8 days ≥ 5.0 Consult 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

14. Warfarin Maintenance Target INR 2.5 - 3.5 INR Dosage Adjustment Recheck INR < 1.5  Weekly dose by 10-20%, consider extra dose 4 to 8 days 1.5 – 2.4  Weekly dose by 5-10%^ 7 to 14 days 2.5 - 3.5 No change # of consecutive in-range INRs x 1 week (max:4 wks) 3.6 - 4.5  Weekly dose by 5-10%*, consider holding one dose 7 to 14 days 4.5 - 6.0 Hold 1-2 doses,  weekly dose by 5-15% 2 to 8 days > 6.0 Consult 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

15. 3333333 MonTueWedThuFriSatSun TotalWeeklyDose 21 mg 2 333 2 33 19 mg 22 3333 2 18 mg Warfarin Dosing Schedule  10%  15%

16. 3333333 MonTueWedThuFriSatSun TotalWeeklyDose 21 mg 4 333 4 33 23 mg 44 3333 4 24 mg Warfarin Dosing Schedule  10%  15%

17. Types of Bleeds No significant bleeding = Minor bleeding No significant bleeding = Minor bleeding  Bruises  Reported, but does not require additional testing, referrals or visits Serious bleeding = Major bleeding Serious bleeding = Major bleeding  Black tarry stools, blood in urine, hematoma  Requiring treatment, medical evaluation or at least 2 units of blood Life-threatening bleeding Life-threatening bleeding  Intracranial hemorrhage, retroperitoneal bleed, leading to cardiac arrest, surgical/angiographic intervention, or irreversible sequelae

18. Warfarin Management INR Dosage Adjustment 5.0 – 8.9 If low risk of bleeding, omit 1-2 doses, monitor INR more frequently, resume warfarin at 10-20% lower than original dose when INR is at therapeutic range If high risk* of bleeding, omit 1 dose and give vitamin K1 1-2.5mg orally. Check INR in 24 hours; if still high, administer additional vitamin K1 1-2mg PO. *High risk = factors that may influence bleeding risk - Hx of bleeding, stroke, renal & liver insufficiency, anemia, hypertension, other medications

19. Warfarin Management INR Dosage Adjustment  9.0 With no significant bleeding: Hold warfarin Administer vitamin K1 5-10mg PO Check INR in 24 hours If still high, administer vitamin K1 1-2mg PO Resume warfarin at lower dose when INR is therapeutic

20. Warfarin Management Serious bleeding, any INR Serious bleeding, any INR  Hold Warfarin  Give Vitamin K1 10mg slow IV plus fresh plasma or prothrombin complex concentrate, depending on urgency  Repeat Vitamin K1 every 12 hours as needed Life-threatening bleeding, any INR Life-threatening bleeding, any INR  Hold warfarin  Give prothrombin complex concentrate (or recombinant factor VIIa as an alternative) supplemented with vitamin K1 10mg slow IV; repeat as needed

21. Vitamin K1, Phytonadione Injection Formulation Injection Formulation  10mg/mL – 1mL vial  2mg/mL – 1mL vial Tablets are not available in Canada Tablets are not available in Canada Administer PO or IV Administer PO or IV Do not administer SC Do not administer SC Elimination Half-life = 26-193 hours Elimination Half-life = 26-193 hours

22. Summary Use clinical judgment Use clinical judgment Educate patient Educate patient Adjusting warfarin dose is better than adjusting patient’s quality of life Adjusting warfarin dose is better than adjusting patient’s quality of life Monitor INR appropriately Monitor INR appropriately Refer to Thrombosis Clinic if necessary Refer to Thrombosis Clinic if necessary

23. References The Thrombosis Interest Group of Canada (www.tigc.org) The Thrombosis Interest Group of Canada (www.tigc.org) Vitamin K diet Vitamin K diet  www.gicare.com/pated/edtot39.htm  http://www.drgourmet.com/warfarin/vitaminkcontent.pdf Ansell J, et al. The pharmacology and management of the vitamin K antagonists. Chest 2004;126:204S-233S Ansell J, et al. The pharmacology and management of the vitamin K antagonists. Chest 2004;126:204S-233S Singer DE, et al. Antithrombotic therapy in atrial fibrillation. Chest 2004;126:429S-456S Singer DE, et al. Antithrombotic therapy in atrial fibrillation. Chest 2004;126:429S-456S http://www.ccs.ca/download/consensus_conference/consens us_conference_archives/2004_Atrial_Fib_full.pdf http://www.ccs.ca/download/consensus_conference/consens us_conference_archives/2004_Atrial_Fib_full.pdf

24. Questions