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Black Box Warning
WARNING: BLEEDING RISK
See full prescribing information for complete Boxed Warning.
* Coumadin can cause major or fatal bleeding.
Perform regular monitoring of INR in all treated patients.
Drugs, dietary changes, and other factors affect INR levels achieved with Coumadin therapy.
Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding.
The dosage and administration of COUMADIN must be individualized for each patient according to the patient’s INR response to the drug. Adjust the dose based on the patient’s INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with COUMADIN [see References (15)].
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.
Venous Thromboembolism
Dosing Information
Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:
For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended.
For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient.
For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.
Atrial Fibrillation
Dosing Information
In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).
In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.
In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.
For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended.
For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.
Mechanical and Bioprosthetic Heart Valves
Dosing Information
For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended.
For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended.
For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended.
For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.
Post-Myocardial Infarction
Dosing Information
For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.
Recurrent Systemic Embolism and Other Indications
Dosing Information
Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Antiphospholipid Syndrome
Developed by: ACCP
Class of Recommendation: Class IIa
Strength of Evidence: Category B
Dosing Information
In patients with antiphospholipid syndrome with previous arterial or VTE, vitamin K antagonists, such as warfarin, should be titrated to a moderate-intensity INR range (INR 2 to 3), rather than higher intensity (INR 3 to 4.5).[1]
Non–Guideline-Supported Use
Prophylaxis of Coronary Arteriosclerosis
Dosing Information
Warfarin, dosed at an average of 4.1 mg daily to achieve a goal INR of 1.5, with or without aspirin significantly reduced overall ischemic heart disease events in a primary prevention study.[2]
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Adequate and well-controlled studies with COUMADIN have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Warfarin (oral) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Warfarin (oral) in pediatric patients.
Contraindications
Pregnancy
COUMADIN is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1) ]. 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 [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1) ].
Hemorrhagic tendencies or blood dyscrasias
Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces [see Warnings and Precautions (5.7) ]
Bleeding tendencies associated with:
Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract
Central nervous system hemorrhage
Cerebral aneurysms, dissecting aorta
Pericarditis and pericardial effusions
Bacterial endocarditis
Threatened abortion, eclampsia, and preeclampsia
Unsupervised patients with conditions associated with potential high level of non-compliance
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) [see Adverse Reactions (6) ]
Major regional or lumbar block anesthesia
Malignant hypertension
Warnings
WARNING: BLEEDING RISK
See full prescribing information for complete Boxed Warning.
* Coumadin can cause major or fatal bleeding.
Perform regular monitoring of INR in all treated patients.
Drugs, dietary changes, and other factors affect INR levels achieved with Coumadin therapy.
Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding.
Hemorrhage
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 [see Clinical Pharmacology (12.5) ], certain concomitant drugs [see Drug Interactions (7) ], and long duration of warfarin therapy.
Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.
Drugs, dietary changes, and other factors affect INR levels achieved with COUMADIN therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7) ].
Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ].
Tissue Necrosis
Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of COUMADIN therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.
Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue COUMADIN therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.
Systemic Atheroemboli and Cholesterol Microemboli
Anticoagulation therapy with COUMADIN may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue COUMADIN therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.
Heparin-Induced Thrombocytopenia
Do not use COUMADIN as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with COUMADIN may be considered after the platelet count has normalized.
Use in Pregnant Women with Mechanical Heart Valves
COUMADIN can cause fetal harm when administered to a pregnant woman. While COUMADIN is contraindicated during pregnancy, the potential benefits of using COUMADIN may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue COUMADIN should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines. 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 this drug 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 [seeUse in Specific Populations (8.1) ].
Females of Reproductive Potential
COUMADIN exposure during pregnancy can cause pregnancy loss, birth defects, or fetal death. Discuss pregnancy planning with females of reproductive potential who are on COUMADIN therapy [see Contraindications (4) and Use in Specific Populations (8.8) ].
Other Clinical Settings with Increased Risks
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: COUMADIN reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. 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: In cataract surgery, COUMADIN use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications. As COUMADIN cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue COUMADIN before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.
Polycythemia vera
Vasculitis
Diabetes mellitus
Endogenous Factors Affecting INR
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.
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Warfarin (oral) in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Warfarin (oral) in the drug label.
↑"Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework". Lancet. 351 (9098): 233–241. 1998-01-24. ISSN0140-6736. PMID9457092.
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