Hot Topics in Anticoagulation: Warfarin Interactions

1. Hot Topics in Anticoagulation: Warfarin Interactions Alison M. Walton, PharmD, BCPS Assistant Professor of Pharmacy Practice Butler University College of Pharmacy and Health Sciences Clinical Pharmacy Specialist, St. Vincent Health

2. Disclosure Statement • No conflicts of interest to disclose

3. Objectives • List mechanisms for interaction with warfarin • Identify clinical significant drug interactions with warfarin • Describe environmental factors that may influence the effect of warfarin

4. Warfarin Therapy • Most common oral anticoagulant • Vitamin K Antagonist • Inhibits factors II, VII, IX, X • Inhibits protein C and protein S • Racemic mixture of 2 active isomers • S-isomer 5x more potent than R-isomer • Effectiveness and safety dependent on international normalized ratio (INR) values Chest 2008;133(6):160S-198S

5. Warfarin Metabolism • Rapidly absorbed from GI tract • High bioavailability • Circulates bound to plasma proteins • Accumulates in liver • Hepatic metabolism by cytochrome P450 • S-isomer: CYP450 2C9 • R-isomer: CYP450 3A4 and 1A2 Chest 2008;133(6):160S-198S

6. Environmental Factors and Drug Interactions Chest 2008;133(6):160S-198S

7. Systemic literature review: 1993 – 2004 • 181 eligible articles contained original reports on 120 drugs or foods • 72% described potentiation of warfarin’s effect • 84% of poor quality • 86% single case reports Arch Intern Med 2005;165:1095-1106

8. Rated Reports Arch Intern Med 2005;165:1095-1106

9. Mechanisms for Interaction • Stereoselective clearance (S-isomer) • Nonstereoselective clearance • Vitamin K pathway • No documented mechanism Arch Intern Med 2005;165:1095-1106

10. Options to prescribe safely… • Never prescribe or allow another medicine to be given with warfarin • Use system to evaluate interactions among patient’s entire profile of therapies • Group majority of offending interacting drugs into easier-to-remember therapeutic groups Arch Intern Med 2005;165:1095-1106

11. Chest 2008;133(6):160S-198S

12. Common Drug Interactions • Antibiotics: sulfamethoxazole/trimethoprim, azole antifungals, metronidazole, macrolides, quinolones • Cardiovascular agents: lipid-lowering agents, amiodarone, NSAIDs, aspirin • Other: SSRIs, omeprazole, cimetidine, anabolic steroids, rifampin, HIV medications • Herbal supplements: don quai, ginseng, green tea Arch Intern Med 2005;165:1095-1106

13. Acetaminophen • Considered analgesic of choice for patients using warfarin • Risk of warfarin-associated bleeding with use of NSAIDs and aspirin • Possible potentiating effect with large doses over prolonged periods of time • Variable effect in individuals • Close monitoring with doses >2g/day Pharmacotherapy 2007;27(5):675-683 Pharmacotherapy 2003;23(1):109-112

14. Menthol Cough Drops • Two documented case reports of potential interaction with warfarin • Clinically significant INR decrease • Potential Mechanism • Affect CYP system as inducer and inhibitor of certain isoenzymes that would potentially interfere with metabolism of warfarin • Menthol derived from peppermint plant Pharmacotherapy 2010;30(1):50e-52e

15. Influenza Vaccination • Prospective trial evaluated 104 patients • Primary End Points • INR variation • Warfarin weekly dose variation • Follow-up for treatment-related clinical events • Conclusions • No significant effect on INR values or weekly dosage regimens for warfarin; No fatal or major bleeding • Close monitoring not required with stable regimens Arch Intern Med 2010;170(7):609-616

16. Lifestyle Factors • Diet • Consistency • Social Factors • Activity level • Tobacco use • Alcohol use Chest 2008;133(6):160S-198S

17. Cranberry Juice • Potential interaction based on case reports • Proposed mechanism for ↑ INR • Flavonoids inhibit warfarin metabolism by CYP2C9 • Antiplatelet effects of salicyclic acid • Small controlled clinical trials do not support potential interaction • Effects of 250-600mL/day of cranberry juice • Unknown effect with supplements and larger amounts or chronic ingestion of juice Pharmacist’s Letter 2007;23(6):230614

18. Alcohol • Acute consumption • Decrease warfarin metabolism • ↑ warfarin effect • Chronic consumption • Induce warfarin metabolism • ↓ warfarin effect Pharmacist’s Letter 2008;24(1):240106

19. Disease States • Malabsorption syndromes • Warfarin highly protein bound • Hepatic dysfunction • Potentiates response to warfarin • Impaired synthesis of coagulation factors Chest 2008;133(6):160S-198S

20. Disease States continued • Heart failure • Decreased clearance of warfarin • Increased catabolism of clotting factors • Hypermetabolic states • Increases warfarin responsiveness • Increased catabolism of vitamin K-dependent coagulation factors Chest 2008;133(6):160S-198S

21. Summary • Overall poor quality of interaction literature • Translation of drug pharmacology to prediction of interaction far from certain • No drug can be deemed “safe” • Numerous environmental factors influence effect of warfarin • Regular monitoring of INR remains best protection against major harm Arch Intern Med 2005;165:1095-1106

22. Hot Topics in Anticoagulation: Warfarin Interactions Alison M. Walton, PharmD, BCPS Assistant Professor of Pharmacy Practice Butler University College of Pharmacy and Health Sciences Clinical Pharmacy Specialist, St. Vincent Health