Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide.

COUMADIN is a vitamin K antagonist indicated for:
• Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism.
• Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.
• Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction Limitation of Use COUMADIN has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage.

• Individualize dosing regimen for each patient, and adjust based on INR response.
• Knowledge of genotype can inform initial dose selection.
• Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks.
• Review conversion instructions from other anticoagulants. 

Most common adverse reactions to COUMADIN are fatal and nonfatal hemorrhage from any tissue or organ.

• Pregnancy, except in women with mechanical heart valves.
• Hemorrhagic tendencies or blood dyscrasias.
• Recent or contemplated surgery of the central nervous system (CNS) or eye, or traumatic surgery resulting in large open surfaces.
• Bleeding tendencies associated with certain conditions.
• Threatened abortion, eclampsia, and preeclampsia.
• Unsupervised patients with potential high levels of non-compliance.
• Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding.
• Hypersensitivity to warfarin or any component of the product.
• Major regional or lumbar block anesthesia.
• Malignant hypertension.

• Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation. Discontinue COUMADIN and consider alternative anticoagulants if necessary.
• Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death. Discontinue COUMADIN if such emboli occur.
• Heparin-induced thrombocytopenia (HIT): Initial therapy with COUMADIN in HIT has resulted in cases of amputation and death. COUMADIN may be considered after platelet count has normalized.
• Pregnant women with mechanical heart valves: COUMADIN may cause fetal harm; however, the benefits may outweigh the risks.