"On July 1, the U.S. Food and Drug Administration approved Xarelto (rivaroxaban) to reduce the risk of blood clots, deep vein thrombosis (DVT), and pulmonary embolism (PE) following knee or hip replacement surgery.
Xarelto is a pill taken on"...
COUMADIN® (warfarin sodium) is 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.
Limitations of Use
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.
DOSAGE AND ADMINISTRATION
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].
Recommended Target INR Ranges and Durations for Individual Indications
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 (including deep venous thrombosis [DVT] and PE)
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.
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
- 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.
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
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.
Initial and Maintenance Dosing
The appropriate initial dosing of COUMADIN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:
- Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities
- Genetic factors (CYP2C9 and VKORC1 genotypes) [see CLINICAL PHARMACOLOGY]
Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. 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.
Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.
Dosing Recommendations without Consideration of Genotype
If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.
Dosing Recommendations with Consideration of Genotype
Table 1 displays three ranges of expected maintenance COUMADIN doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see CLINICAL PHARMACOLOGY]. If the patient's CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time ( > 2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.
Table 1: Three Ranges of
Expected Maintenance COUMADIN Daily Doses Based on CYP2C9 and VKORC1 Genotypes†
|GG||5-7 mg||5-7 mg||3-4 mg||3-4 mg||3-4 mg||0.5-2 mg|
|AG||5-7 mg||3-4 mg||3-4 mg||3-4 mg||0.5-2 mg||0.5-2 mg|
|AA||3-4 mg||3-4 mg||0.5-2 mg||0.5-2 mg||0.5-2 mg||0.5-2 mg|
|† Ranges are derived from multiple published clinical studies. VKORC1 -1639G > A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose.|
Monitoring to Achieve Optimal Anticoagulation
COUMADIN is a narrow therapeutic range (index) drug, and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during COUMADIN therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with COUMADIN, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR [see DRUG INTERACTIONS].
Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of COUMADIN therapy.
The anticoagulant effect of COUMADIN persists beyond 24 hours. If a patient misses a dose of COUMADIN at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose.
Intravenous Route of Administration
The intravenous dose of COUMADIN is the same as the oral dose. After reconstitution, COUMADIN for injection should be administered as a slow bolus injection into a peripheral vein over 1 to 2 minutes. COUMADIN for injection is not recommended for intramuscular administration.
Reconstitute the vial with 2.7 mL of Sterile Water for Injection. The resulting yield is 2.5 mL of a 2 mg per mL solution (5 mg total). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is noted.
After reconstitution, COUMADIN for injection is 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 for single use only, and any unused solution should be discarded.
Treatment During Dentistry and Surgery
Some dental or surgical procedures may necessitate the interruption or change in the dose of COUMADIN therapy. Consider the benefits and risks when discontinuing COUMADIN even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of COUMADIN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.
Conversion From Other Anticoagulants
Since the full anticoagulant effect of COUMADIN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with COUMADIN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to COUMADIN may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap COUMADIN therapy with heparin for 4 to 5 days and until COUMADIN has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued.
As heparin may affect the INR, patients receiving both heparin and COUMADIN should have INR monitoring at least:
- 5 hours after the last intravenous bolus dose of heparin, or
- 4 hours after cessation of a continuous intravenous infusion of heparin, or
- 24 hours after the last subcutaneous heparin injection.
COUMADIN may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation ( > 50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.
Consult the labeling of other anticoagulants for instructions on conversion to COUMADIN.
Dosage Forms And Strengths
COUMADIN tablets are 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 tablets are supplied in the following strengths:
|10 mg||white (dye-free )|
COUMADIN for injection is available in a vial containing 5 mg of lyophilized powder.
Storage And Handling
COUMADIN tablets are 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:
|Bottles of 100||Bottles of 1000||Hospital Unit-Dose Blister Package of 100|
|1 mg pink||NDC 0056-0169-70||NDC 0056-0169-90||NDC 0056-0169-75|
|2 mg lavender||NDC 0056-0170-70||NDC 0056-0170-90||NDC 0056-0170-75|
|2-1/2 mg green||NDC 0056-0176-70||NDC 0056-0176-90||NDC 0056-0176-75|
|3 mg tan||NDC 0056-0188-70||NDC 0056-0188-90||NDC 0056-0188-75|
|4 mg blue||NDC 0056-0168-70||NDC 0056-0168-90||NDC 0056-0168-75|
|5 mg peach||NDC 0056-0172-70||NDC 0056-0172-90||NDC 0056-0172-75|
|6 mg teal||NDC 0056-0189-70||NDC 0056-0189-90||NDC 0056-0189-75|
|7-1/2 mg yellow||NDC 0056-0173-70||NDC 0056-0173-75|
|10 mg white (dye-free)||NDC 0056-0174-70||NDC 0056-0174-75|
Protect from light and moisture. Store at controlled room temperature (59°-86°F, 15°-30°C). Dispense in a tight, light-resistant container as defined in the USP.
Store the hospital unit-dose blister packages in the carton until contents have been used.
COUMADIN for injection vials yield 5 mg of warfarin after reconstitution with 2.7 mL of Sterile Water for Injection (maximum yield is 2.5 mL of a 2 mg/mL solution). Net content of vial is 5.4 mg lyophilized powder.
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.
Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:160S-198S.
Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:454S-545S.
Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:546S-592S.
Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:776S-814S.
Salem DN, O'Gara PT, Madias C, Pauker SG. Valvular and structural heart disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:593S-629S.
Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:887S-968S.
Distributed by: Bristol-Myers Squibb Company, Princeton, New Jersey 08543 USA. Rev October 2011
Last reviewed on RxList: 10/2/2012
This monograph has been modified to include the generic and brand name in many instances.
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