Margaret Jin, BScPHM, PharmD, CGP November 2007

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 provide effective patient education • To understand general concepts in warfarin dosing • To be able to use vitamin K1 appropriately

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

4. Mechanism of ActionClotting Cascade

5. Indications & Recommended Therapeutic Range Chest 2004;126(3 Suppl):204S-233S

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

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

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

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

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

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

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

13. Warfarin MaintenanceTarget INR 2.0 - 3.0 ^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 MaintenanceTarget INR 2.5 - 3.5 ^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. 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Warfarin Dosing Schedule Total Weekly Dose Mon Tue Wed Thu Fri Sat Sun 21 mg 19 mg 2 2  10%  15% 18 mg 2 2 2

16. 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Warfarin Dosing Schedule Total Weekly Dose Mon Tue Wed Thu Fri Sat Sun 21 mg 23 mg 4 4  10%  15% 24 mg 4 4 4

17. Types of Bleeds • No significant bleeding = Minor bleeding • Bruises • Reported, but does not require additional testing, referrals or visits • 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 • Intracranial hemorrhage, retroperitoneal bleed, leading to cardiac arrest, surgical/angiographic intervention, or irreversible sequelae

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

19. Warfarin Management

20. Warfarin Management • 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 • 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 • 10mg/mL – 1mL vial • 2mg/mL – 1mL vial • Tablets are not available in Canada • Administer PO or IV • Do not administer SC • Elimination Half-life = 26-193 hours

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

23. References • The Thrombosis Interest Group of Canada (www.tigc.org) • 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 • Singer DE, et al. Antithrombotic therapy in atrial fibrillation. Chest 2004;126:429S-456S • http://www.ccs.ca/download/consensus_conference/consensus_conference_archives/2004_Atrial_Fib_full.pdf

24. Questions