COUMADIN is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.

COUMADIN is indicated for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.

COUMADIN is indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

The dosage and administration of COUMADIN must be individualized for each patient according to the particular patient's PT/INR response to the drug. The dosage should be adjusted based upon the patient's PT/INR. ^{15,16,17,18,19} The best available information supports the following recommendations for dosing of Coumadin.

Venous Thromboembolism (including deep venous thrombosis [DVT] and pulmonary embolism [PE])

For patients with a first episode of DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with a first episode of idiopathic DVT or PE, warfarin is recommended for at least 6 to 12 months. For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is suggested. For patients with a first episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT or PE who have documented deficiency of antithrombin, deficiency of protein C or protein S, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels (> 90th percentile of normal), treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis. The risk-benefit should be reassessed periodically in patients who receive indefinite anticoagulant treatment.^12,20 The dose of warfarin should be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations. These recommendations are supported by the 7th ACCP guidelines.^{15,17, 21,22}

Atrial Fibrillation

Five clinical trials evaluated the effects of warfarin in patients with non-valvular atrial fibrillation (AF). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. There are no adequate and well-controlled studies in populations with atrial fibrillation and valvular heart disease. Similar data from clinical studies in valvular atrial fibrillation patients are not available. The trials in non-valvular atrial fibrillation support the American College of Chest Physicians' (7th ACCP) recommendation that an INR of 2.0-3.0 be used for warfarin therapy in appropriate AF patients.¹⁷

Oral anticoagulation therapy with warfarin is recommended in patients with persistent or paroxysmal AF (PAF) (intermittent AF) at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, age > 75 years, moderately or severely impaired left ventricular systolic function and/or congestive heart failure, history of hypertension, or diabetes mellitus). In patients with persistent AF or PAF, age 65 to 75 years, in the absence of other risk factors, but who are at intermediate risk of stroke, antithrombotic therapy with either oral warfarin or aspirin, 325 mg/day is recommended. For patients with AF and mitral stenosis, anticoagulation with oral warfarin is recommended (7th ACCP). For patients with AF and prosthetic heart valves, anticoagulation with oral warfarin should be used; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.17

Post-Myocardial Infarction

The results of the WARIS II study and 7th ACCP guidelines suggest that in most healthcare settings, moderate- and low-risk patients with a myocardial infarction should be treated with aspirin alone over oral vitamin-K antagonist (VKA) therapy plus aspirin. In health-care settings in which meticulous INR monitoring is standard and routinely accessible, for both high- and low-risk patients after myocardial infarction (MI), long-term (up to 4 years) high-intensity oral warfarin (target INR, 3.5; range, 3.0 to 4.0) without concomitant aspirin or moderate-intensity oral warfarin (target INR, 2.5; range, 2.0 to 3.0) with aspirin is recommended. For high-risk patients with MI, including those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on echocardiography, and those with a history of a thromboembolic event, therapy with combined moderate-intensity (INR, 2.0 to 3.0) oral warfarin plus low-dose aspirin (≤100 mg/day) for 3 months after the MI is suggested.²³

Mechanical and Bioprosthetic Heart Valves

For all patients with mechanical prosthetic heart valves, warfarin is recommended. For patients with a St. Jude Medical (St. Paul, MN) bileaflet valve in the aortic position, a target INR of 2.5 (range, 2.0 to 3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, the 7th ACCP recommends a target INR of 3.0 (range, 2.5 to 3.5). For patients with caged ball or caged disk valves, a target INR of 3.0 (range, 2.5 to 3.5) in combination with aspirin, 75 to 100 mg/day is recommended. For patients with bioprosthetic valves, warfarin therapy with a target INR of 2.5 (range, 2.0 to 3.0) is recommended for valves in the mitral position and is suggested for valves in the aortic position for the first 3 months after valve insertion. ¹⁵

Recurrent Systemic Embolism and Other Indications

Oral anticoagulation therapy has not been evaluated by properly designed clinical trials in patients with valvular disease associated with atrial fibrillation, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. A moderate dose regimen (INR 2.0 to 3.0) is recommended for these patients.¹⁷

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.

Initial Dosage

The dosing of COUMADIN must be individualized according to patient's sensitivity to the drug as indicated by the PT/INR. Use of a large loading dose may increase the incidence of hemorrhagic and other complications, does not offer more rapid protection against thrombi formation, and is not recommended. It is recommended that COUMADIN therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT/INR determinations.^17,18 The lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes as well as for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR responses to COUMADIN (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

Maintenance

Most patients are satisfactorily maintained at a dose of 2 to 10 mg daily. Flexibility of dosage is provided by breaking scored tablets in half. The individual dose and interval should be gauged by the patient's prothrombin response. Acquired or inherited warfarin resistance is rare, but should be suspected if large daily doses of COUMADIN are required to maintain a patient's PT/INR within a normal therapeutic range. Lower maintenance doses are recommended for elderly and/or debilitated patients and patients with a potential to exhibit greater than expected PT/INR response to COUMADIN (see PRECAUTIONS).

Duration of Therapy

The duration of therapy in each patient should be individualized. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed. ^{14,15,17,18,21,22}

Missed Dose

The anticoagulant effect of COUMADIN persists beyond 24 hours. If the patient forgets to take the prescribed dose of COUMADIN at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not take the missed dose by doubling the daily dose to make up for missed doses, but should refer back to his or her physician.

Intravenous Route of Administration

COUMADIN for Injection provides an alternate administration route for patients who cannot receive oral drugs. The IV dosages would be the same as those that would be used orally if the patient could take the drug by the oral route. COUMADIN for Injection should be administered as a slow bolus injection over 1 to 2 minutes into a peripheral vein. It is not recommended for intramuscular administration. The vial should be reconstituted with 2.7 mL of sterile Water for Injection and inspected for particulate matter and discoloration immediately prior to use. Do not use if either particulate matter and/or discoloration is noted. After reconstitution, COUMADIN for Injection is chemically and physically stable for 4 hours at room temperature. It does not contain any antimicrobial preservative and, thus, care must be taken to assure the sterility of the prepared solution. The vial is not recommended for multiple use and unused solution should be discarded.

Laboratory Control

The PT reflects the depression of vitamin K dependent Factors VII, X and II. A system of standardizing the PT in oral anticoagulant control was introduced by the World Health Organization in 1983. It is based upon the determination of an International Normalized Ratio (INR) which provides a common basis for communication of PT results and interpretations of therapeutic ranges²⁴ The PT should be determined daily after the administration of the initial dose until PT/INR results stabilize in the therapeutic range. Intervals between subsequent PT/INR determinations should be based upon the physician's judgment of the patient's reliability and response to COUMADIN in order to maintain the individual within the therapeutic range. Acceptable intervals for PT/INR determinations are normally within the range of one to four weeks after a stable dosage has been determined. To ensure adequate control, it is recommended that additional PT tests be done when other warfarin products are interchanged with warfarin sodium tablets, USP, as well as whenever other medications are initiated, discontinued, or taken irregularly (see PRECAUTIONS). Safety and efficacy of warfarin therapy can be improved by increasing the quality of laboratory control. Reports suggest that in usual care monitoring, patients are in therapeutic range only 33%-64% of the time. Time in therapeutic range is significantly greater (56%-93%) in patients managed by anticoagulation clinics, among self-testing and self-monitoring patients, and in patients managed with the help of computer programs.²⁵ Self-testing patients had fewer bleeding events than patients in usual care.²⁵

Treatment During Dentistry And Surgery

The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists.^15,19 PT/INR determination is recommended just prior to any dental or surgical procedure. In patients undergoing minimal invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of COUMADIN to maintain the PT/INR at the low end of the therapeutic range may safely allow for continued anticoagulation. The operative site should be sufficiently limited and accessible to permit the effective use of local procedures for hemostasis. Under these conditions, dental and minor surgical procedures may be performed without undue risk of hemorrhage. Some dental or surgical procedures may necessitate the interruption of COUMADIN therapy. When discontinuing COUMADIN even for a short period of time, the benefits and risks should be strongly considered.

Conversion From Heparin Therapy

Since the anticoagulant effect of COUMADIN is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to COUMADIN may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that COUMADIN therapy be overlapped with heparin for 4 to 5 days, until COUMADIN has produced the desired therapeutic response as determined by PT/INR. When COUMADIN has produced the desired PT/INR or prothrombin activity, heparin may be discontinued.

COUMADIN may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (> 50 seconds) in activated partial thromboplastin time (aPTT) with a PT/INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.

During initial therapy with COUMADIN, the interference with heparin anticoagulation is of minimal clinical significance.

As heparin may affect the PT/INR, patients receiving both heparin and COUMADIN should have blood for PT/INR determination drawn at least:

• 5 hours after the last IV bolus dose of heparin, or
• 4 hours after cessation of a continuous IV infusion of heparin, or
• 24 hours after the last subcutaneous heparin injection.

Tablets

For oral use, single scored with one face imprinted numerically with 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2 or 10 superimposed and inscribed with “COUMADIN” and with the opposite face plain. COUMADIN is available in bottles and Hospital Unit-Dose Blister Packages with potencies and colors as follows:

Protect from light. Store at controlled room temperature (59°-86°F, 15°-30°C). Dispense in a tight, light-resistant container as defined in the USP.

Hospital Unit-Dose Blister Packages are to be stored in carton until contents have been used.

Injection

Available for intravenous use only. Not recommended for intramuscular administration. Reconstitute with 2.7 mL of sterile Water for Injection to yield 2 mg/mL. Net contents 5.4 mg lyophilized powder. Maximum yield 2.5 mL.

5 mg vial (box of 6) NDC 0590-0324-35

Protect from light. Keep vial in box until used. Store at controlled room temperature (59°-86°F, 15°-30°C).

After reconstitution, store at controlled room temperature (59°-86°F, 15°-30°C) and use within 4 hours. Do not refrigerate. Discard any unused solution.

REFERENCES

15. Salem DN, Stein PD, Al-Ahmad, et al. Antithrombotic therapy in valvular heart disease-native and prosthetic. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:457S-482S.

16. American Geriatrics Society Clinical Practice Guidelines. The Use of Oral Anticoagulants (Warfarin) in Older People. J Amer Geriat Soc 2000; 48:224-227.

17. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL and Manning WJ. Antithrombotic Therapy in Atrial Fibrillation. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:429S-456S.

18. Jaffer AK and Bragg L. Practical Tips for warfarin dosing and monitoring. Cleveland Clinic J Med 2003; 70:361-371.

19. Jaffer AK, Brotman DJ and Chukwumerije N. When patients on warfarin need surgery. Cleveland Clinic J Med 2003; 70:973-984.

20. Kearon C, Ginsberg JS, Kovacs M, et al, for the Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 349:631-639.

21. Schulman S, Granqvist S, Holmström M, et al. The Duration of Oral Anticoagulant Trial Study Group. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997; 336:393-398.

22. Ridker PM, Goldhaber SZ, Danielson E, et al, for the PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348:1425-1434.

23. Harrington RA, Becker RC, Ezekowitz M, et al. Antithrombotic therapy for coronary artery disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:513S-548S.

24. Ansell J, Hirsh J, Pollen L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:204S-233S.

25. Heneghan C, Alonso-Coello P, Garcia-Alamino JM, Perera R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet. 2006;367:404-411.

Distributed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA. COUMADIN® and the color and configuration of COUMADIN tablets are trademarks of Bristol-Myers Squibb Pharma Company. Rev August 2007. FDA rev date: 8/16/2007

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