Indicated for:

• Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE).

• Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement.

• Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

COUMADIN can cause major or fatal bleeding. Perform regular monitoring of INR in all treated patients. An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.

Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

COUMADIN can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors.

COUMADIN has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae.

Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk.

COUMADIN can cause fatal and serious calciphylaxis or calcium uremic arteriolopathy, which has been reported in patients with and without end-stage renal disease. When calciphylaxis is diagnosed in these patients, discontinue COUMADIN and treat calciphylaxis as appropriate. Consider alternative anticoagulation therapy. 

Anticoagulation therapy with COUMADIN may enhance the release of  atheromatous plaque emboli.

In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with COUMADIN, possibly in relation to episodes of excessive anticoagulation and hematuria.

Do not use COUMADIN as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS).

COUMADIN is contraindicated in patients with:

• Pregnancy, except in women with mechanical heart valves
• Hemorrhagic tendencies or blood dyscrasias
• Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces 
• Bleeding tendencies associated with: (a) active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract; (b) central nervous system hemorrhage; (c) cerebral aneurysms, dissecting aorta; (d) pericarditis and pericardial effusion; and (e) bacterial endocarditis
• Threatened abortion, eclampsia, and preeclampsia
• Unsupervised patients with conditions associated with potential high level of non-compliance and in any unsupervised patient with senility
• Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding
• Hypersensitivity to warfarin or to any other components of this product (e.g., anaphylaxis)
• Major regional or lumbar block anesthesia
• Malignant hypertension

In the following clinical settings, the risks of COUMADIN therapy may be increased:

• Moderate to severe hepatic impairment
• Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy)
• Use of an indwelling catheter
• Severe to moderate hypertension
• Deficiency in protein C-mediated anticoagulant response: Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with COUMADIN may minimize the incidence of tissue necrosis in these patients
• Eye surgery
• Polycythemia vera
• Vasculitis
• Diabetes mellitus

The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin. Examples of CYP2C9 Inhibitors include: amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast. Examples of CYP1A2 Inhibitors include: acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, and zileuton. Examples of CYP3A4 Inhibitors include: alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, and zileuton. 

Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin. Examples of CYP2C9 Inducers include: aprepitant, bosentan, carbamazepine, phenobarbital, and rifampin. Examples of CYP1A2 Inducers include: montelukast, moricizine, omeprazole, phenobarbital, phenytoin, and cigarette smoking. Examples of CYP3A4 Inducers include: armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, and rufinamide.

The following drugs are known to increase the risk of bleeding: Anticoagulants (argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin); Antiplatelet Agents (aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine); Nonsteroidal Anti-Inflammatory Agents (celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac); and Serotonin Reuptake Inhibitors (citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone). Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely  monitor patients receiving any such drug with warfarin.

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of COUMADIN.

Some botanicals may decrease the effects of COUMADIN (e.g., co-enzyme Q10, St. John’s wort, ginseng). Some botanicals and foods can interact with COUMADIN through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort).

The amount of vitamin K in food may affect therapy with COUMADIN. Patients taking COUMADIN should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

COUMADIN is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism. COUMADIN can cause fetal harm when administered to a pregnant woman. COUMADIN exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If COUMADIN is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for COUMADIN and any potential adverse effects on the breastfed infant from COUMADIN or from the underlying maternal condition before prescribing COUMADIN to a lactating woman.

GoToSource

• Use in patients under the age of 18. GoToSource

• Preventing recurrent transient ischemic attacks. GoToSource

• Hypertensive heart disease. GoToSource

Bleeding complications and death. GoToSource

Skin necrosis (tissue death) and hair loss. GoToSource

Venous limb gangrene. GoToSource

Calciphylaxis. GoToSource

Cholesterol microembolization syndrome. GoToSource

Osteoporotic fractures. GoToSource

Liver injury. GoToSource

Rectus sheath hematoma (blood accumulation in sheath of rectus abdominis muscle). GoToSource 

Vascular calcification (calcium buildup in body tissues). GoToSource

Lawsuits filed for bleeding, death and fractures.