Warfarin

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Contents 1 Introduction 2 Indications 3 Contraindications 4 Dosage 5 Pharmacokinetics 6 Monitor 7 Adverse-effects 8 Drug-interactions 9 Laboratory 10 Mechanism-of-action 11 Management 12 More General Terms 13 Additional Terms 14 Internet Database 15 References

Introduction

• Tradenames: Coumadin, Panwarfin. (warfarin sodium)

Indications

• prophylaxis & treatment of deep vein thrombosis (DVT)
• atrial fibrillation
• pulmonary embolism
• acute myocardial infarction ( AMI)
• transient ischemic attacks ( TIA)
• prosthetic heart valves

Contraindications

• (also see warfarin & surgery)
• active bleeding, prior hemorrhage
• pregnancy
• renal insufficiency
• predisposition to falls
• barriers to adherence
• alcohol or drug abuse
• warfarin resistance
• does not lower the risk for catheter-related thromboses in patients with cancer [19]
  

• pregnancy category = x
• safety in lactation = +

Dosage

• load 5-10 mg PO QD for 1-2 days, then adjust dose to target: INR: 2-3 standard therapy, but indication-dependent (2-10 mg PO QD) (see protocol for warfarin anticoagulation)
• supplement with 100-200 ug/day of vitamin K1 ( phytonadione, phylloquinone) if unstable INR [21,22]
• deep vein thrombosis (DVT): duration of warfarin therapy: 3 months

• Tabs: 1, 2, 2.5, 5, 7, 10 mg.

Pharmacokinetics

• well absorbed from the GI tract
• 97% of the drug is bound to plasma proteins, primarily albumin
• full anticoagulation is achieved 3-7 days after initiation of therapy (even with therapeutic INR) [11]
• because prothrombin 1/2 life is 24 hours, anticoagulation is not achieved until 24-48 hours after reaching therapeutic INR; the early rise in INR is due to a decrease in factor V ( 1/2life 5 hours)
• metabolized in the liver by CYP1A2, CYP2C9, CYP2C19, CYP3A4
• polymorphisms in VKORC1 associated with warfarin resistance
• moderate to severe renal impairment may be associated with a reduction in warfarin dose requirements [24]
  

• elimination via liver
• 1/2life = 22-52 hours
• protein binding = 99 %

Monitor

• international normalized ratio ( INR)

• point of care testing (fingerstick) for home testing may be useful for patients with stable INR [23]

• see protocol for warfarin anticoagulation
• check INR within 3 days after starting antibiotic

Adverse-effects

• not common (1-10%)

• alopecia, stomach cramps, nausea, vomiting, diarrhea, leukopenia

• uncommon (< 1%)

• mouth ulcers, renal damage, discolored toes ( blue toe syndrome), hepatotoxicity, skin rash, agranulocytosis, anorexia, epidermal necrosis

• other

• bleeding, especially GI bleeding

• 6 fold increased risk of intracerebral hemorrhage [13,15]
• risk of major hemorrhage 13.1 events/100 patient years in elderly >= 80 vs 4.75 in patients < 80 [18]

• long-term use may increased the risk of bone fracture [5]
• teratogenic
• heavy menstrual bleeding
• hemorrhage from postovulatory cysts
• sensation of cold [9]
• may cause skin necrosis & thrombosis in patients with protein C deficiency

• heart disease, liver disease, kidney disease, cancer, anemia & history of stroke are risk factors for adverse events in patients who receive warfarin [6]

Drug-interactions

• (also see prothrombin time) [10]
• AMIODARONE, METRONIDAZOLE, TRIMETHOPRIM, SULFAMETHOXAZOLE ( BACTRIM): significant increase in anticoagulant effect
• agents that may increase effect of warfarin:

• antibiotics alter intestinal flora that synthesize vitamin K

• ciprofloxacin & other quinolones
• some cephalosporins ( cefamandole, cefotetan, cefmetazole, cefoperazone)
• erythromycin & other macrolides
• sulfonamides, sulfamethoxazole/trimethoprim (see above)
• antifungals: miconazole fluconazole, griseofulvin, ketoconazole [26]
• isoniazid, rifampin
• tetracycline
• metronidazole (see above)

• oral glucocorticoids
• hypolipidemic agents

• lovastatin, simvastatin (& presumably other HMG CoA reductase inhibitors, except perhaps pravastatin)
• clofibrate, cholestyramine, gemfibrozil, colestipol

• acute alcohol intoxication, disulfiram, acetaminophen
• aspirin, NSAIDs, salicylates, phenylbutazone, sulfinpyrazone
• dextrothyroxine, methimazole, propylthiouracil, thyroid hormones
• thiazides, ethacrynic acid
• allopurinol, aminoglutethimide, anabolic steroids, chloral hydrate, cimetidine, glutethimide, glucagon, mercaptopurine, pentoxifylline, phenytoin, propafenone, quinidine, quinine, tamoxifen, vitamin E

• agents that may decrease effect of warfarin:

• chronic alcohol, barbiturates, carbamazepine, estrogen- containing contraceptives, rifampin, spironolactone, trazodone, sucralfate, vitamin K, griseofulvin, nafcillin

• any drug which inhibits CYP1A2, CYP2C9, CYP2C19, CYP3A4 can increase warfarin levels
• any drug which induces CYP1A2, CYP2C9, CYP2C19, CYP3A4 can diminish warfarin levels
• also see dietary interactions with warfarin
  

• Toxicity:
  
• bleeding [13,14]

• hold warfarin administration until therapeutic INR & cessation of bleeding
• vitamin K 1 mg IV in 15-20 mL of normal saline or 2.5-5.0 mg PO for minor bleeding or INR > 9#*
• fresh frozen plasma (severe bleeding)
• prothrombin complex concentrate (life-threatening hemorrhage)
• for INR 5-9*, in the absence of bleeding, administration of vitamin K is controversial [20]
  

• * Also see risk factors for persistently elevated INR
• # vitamin K 2.5 mg PO as effective as 1 mg IV [12]; PO & IV more effective than SC [14];
• * ref [27] suggests INR of 10 prior to vitamin K
  

• drug interaction(s) of aspirin, clopidogrel & warfarin
• drug interaction(s) of trimethoprim/sulfamethoxazole with warfarin
• drug interaction(s) of antibiotics with warfarin
• drug interaction(s) of glucocorticoids with warfarin
• drug interaction(s) of propranolol with warfarin
• drug interaction(s) of warfarin with Panax quinquefolius
• drug interaction(s) of warfarin with ginseng
• drug interaction(s) of warfarin with Hyperocum perforatum
• drug interaction(s) of warfarin with antiplatelet agents
• drug interaction(s) of warfarin with chondroitin sulfate
• drug interaction(s) of warfarin with glucosamine
• drug interaction(s) of Vaccinium macrocarpon with warfarin

Laboratory

• specimen: serum, plasma ( EDTA)
• methods: HPLC, GLC, spectrophotometric
• interferences:

• fluorometry & spectrophotometry are non-specific
• dicumarol, thiopental, salicylate may interfere with with spectrophotometric assays

• therapeutic level generally assessed by:

• prothrombin time (PT)
• international normalized ratio ( INR)

• genetic testing (see warfarin sensitivity testing)

• vitamin K epoxide reductase alleles ( VKORC1)
• CYP2C9 variants

Mechanism-of-action

• anticoagulant
• interferes with hepatic synthesis of vitamin K-dependent coagulation factors (II, VII, IX & X)
• anticoagulant activities are due to inhibition of factors II & X; inhibition of factors VII & IX do not prevent thrombosis [6]

Management

• Patient education:

• patient compliance is crucial for safety & efficacy of anticoagulation with warfarin
• patients should notify physician in the event of unusual bleeding, especially:

• gums
• nose
• vagina
• hematuria
• melena
• excessive bruising

• female patients should inform physician of pregnancy plans
• travel should be discussed with physician

More General Terms

• heterocyclic compound, 2 rings
• lactone
• ketone
• anticoagulant

Additional Terms

• anticoagulation
• dietary interactions with warfarin
• International normalized ratio (INR)
• protocol for warfarin anticoagulation
• risk factors for persistently elevated INR
• warfarin & surgery or other invasive procedures
• warfarin resistance
• warfarin sensitivity testing (CYP2C9 & VKORC1)
• warfarin-induced epidermal necrosis

Internet Database

PubChem: 6691
PubChem: 31424
PubChem: 17464
PubChem: 5683

References

1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
2. Clinical Guide to Laboratory Tests, 3rd edition, NW Tietz ed, WB Saunders, Philadelphia, 1995
3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
5. Prescriber's Letter 6(10):60, Oct, 1999
6. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, American College of Physicians, Philadelphia 1998, 2009
7. Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
8. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: [1] (subscription needed) [2]
9. Prescriber's Letter 8(12):68 2001
10. Prescriber's Letter 9(3):14 2002
11. Prescriber's Letter 10(6):35 2003
12. Journal Watch 24(1):2, 2004 Lubetsky A et al Arch Intern Med 163:2469, 2003 PMID: [3]
13. Goldstein JN et al, Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage Stroke 2006; 37:151 PMID: [4]
14. DeZee KJ et al, Treatment of excessive anticoagulation with phytonadione (vitamin K): A meta-analysis. Arch Intern Med 2006; 166:391 PMID: [5]
15. Flaherty ML et al, The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology 2007, 68:116 PMID: [6]
16. Prescriber's Letter 14(4): 2007 Warfarin and Corticosteroid Interaction Detail-Document#: [7] (subscription needed) [8]
17. FDA Medwatch [9]
18. Hylek EM et al, Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007, 115:2689 PMID: [10]
    - Wyse DG Bleeding while starting anticoagulation for thromboembolism prophylaxis in elderly patients with atrial fibrillation: From bad to worse. Circulation 2007, 115:2684 PMID: [11]
19. Young AM et al, Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial Lancet 2009 373:567-574 PMID: [12]
20. Prescriber's Letter 16(4): 2009 How to Manage High INRs in Warfarin Patients Detail-Document#: [13] (subscription needed) [14]
21. Prescriber's Letter 16(6): 2009 How to Manage High INRs in Warfarin Patients Use of Low-Dose Vitamin K Supplements to Stabilize INR PATIENT HANDOUT: What You Should Know About Your Diet and Warfarin COMMENTARY: Use of Low-Dose Vitamin K Supplements to Stabilize INR CHART: How to Manage High INRs in Warfarin Patients GUIDELINES: Pharmacology and Management of the Vitamin K Antagonists (ACCP, 8th edition, Summary) Detail-Document#: [15] (subscription needed) [16]
22. Hirsh AJ et al, Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):160S-198S PMID: [17]
23. Matchar DB et al, Effect of Home Testing of International Normalized Ratio on Clinical Events N Engl J Med 2010 Oct 21; 363:1608. <PubMed> PMID: [18] <Internet> [19]
24. Limdi NA et al. Warfarin dosing in patients with impaired kidney function. Am J Kidney Dis 2010 Nov; 56:823 <PubMed> PMID: [20] <Internet> [21]
25. Wieloch M et al. Anticoagulation control in Sweden: Reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J 2011 Sep 18; 32:2282 PMID: [22]
26. Baillargeon J et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med 2012 Feb; 125:183. PMID: [23]
27. Prescriber's Letter 19(5): 2012 CHART: How to Manage High INRs in Warfarin Patients GUIDELINES: Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (2012) Detail-Document#: [24] (subscription needed) [25]
28. National Guideline Clearinghouse Pharmacology and management of the vitamin K antagonists. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). ngc-guideline: [26]
    - Anticoagulation - warfarin. Singapore Ministry of Health. ngc-guideline: [27]
    - Warfarin therapy - management during invasive procedures and surgery. Medical Services Commission, British Columbia ngc-guideline: [28]
    - Warfarin therapy management. Medical Services Commission, British Columbia ngc-guideline: [29]

warfarin (Coumadin, Panwarfin)