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| Drug | Interaction | Comments |
|---|---|---|
| Acetaminophen | Potential for increased anticoagulant effects | Monitoring of PT/INR recommended for sustained therapy with large acetaminophen doses |
| Capecitabine |
Inhibits CYP2C9 isoenzyme and decreases warfarin metabolism Possible increased anticoagulant response, increased PT/INR, and/or potentially fatal bleeding episodes, especially in patients >60 years of age with cancer |
Use concomitantly with caution Frequent monitoring of PT/INR recommended to facilitate anticoagulant dosage adjustments |
| Cholestyramine |
Potential for decreased warfarin absorption and decreased warfarin half-life Potential decreased vitamin K absorption |
Concurrent use of cholestyramine and warfarin probably should be avoided, if possible |
| Miconazole (Vaginal) | Potential for increased PT/INR and/or bleeding | Monitoring PT/INR and appropriate dosage adjustments recommended with concomitant intravaginal miconazole therapy |
| NSAIAs | Potential for platelet aggregation inhibition, GI bleeding and peptic ulceration and/or perforation, altered PT | Cautious use recommended |
| Oxandrolone |
Potential for increased warfarin half-life and AUC) Potential increased PT/INR and bleeding |
When oxandrolone therapy is initiated, changed, or discontinued, close monitoring of PT/INR and clinical response recommended to facilitate anticoagulant dosage adjustments and reduce bleeding risk |
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Home : Drugs A - Z : Warfarin
Special Alerts:
[Posted 08/16/2007] FDA approved updated labeling to include pharmacogenomics information to the CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for the widely used blood-thinning drug, warfarin (Coumadin). This new information explains that people’s genetic makeup may influence how they respond to the drug. Specifically, people with variations in two genes may need lower warfarin doses than people without these genetic variations. The two genes are called CYP2C9 and VKORC1. The CYP2C9 gene is involved in the breakdown (metabolism) of warfarin and the VKORC1 gene helps regulate the ability of warfarin to prevent blood from clotting.
The dosage and administration of warfarin must be individualized for each patient according to the particular patient’s prothrombin time (PT) / International Normalized Ratio (INR) response to the drug. The specific dose recommendations are described in the warfarin product labeling, along with the new information regarding the impact of genetic information upon the initial dose and the response to warfarin. Ongoing warfarin therapy should be guided by continued INR monitoring. For more information visit the FDA website at: [Web].
[Posted 10/06/2006] FDA and Bristol-Myers Squibb notified pharmacists and physicians of revisions to the labeling for warfarin (Coumadin), to include a new patient Medication Guide as well as a reorganization and highlighting of the current safety information to better inform providers and patients.
The FDA regulation 21CFR 208 requires a Medication Guide to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. Information about all currently approved Medication Guides is available at: [Web]. For more information visit the FDA website at: [Web], and [Web].
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Warfarin Clinical Information
a coumarins and indandione
Generic Name: warfarin
Brand Names: Coumadin, Jantoven
Uses
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Treatment/Secondary Prevention of Venous Thrombosis and Pulmonary Embolism
Used as follow-up to initial heparin anticoagulation for treatment of proximal DVT or nonmassive acute pulmonary embolism; initiate concomitantly with full-dose IV or adjusted-dose sub-Q unfractionated heparin or a weight-based dosage of sub-Q low molecular weight (LMW) heparin. May consider thrombolytic therapy in those with massive pulmonary embolism with hemodynamic instability or severe ileofemoral thrombosis.
LMW heparin or sub-Q unfractionated heparin used as alternative therapy for secondary prevention of DVT and pulmonary embolism when warfarin is contraindicated or inconvenient.
Secondary prevention of DVT and pulmonary embolism in patients with concurrent cancer; LMW heparin preferred in such patients.
Secondary prevention of venous thromboembolism or pulmonary embolism associated with reversible or time-limited risk factors (e.g., transient immobilization, trauma, surgery, pharmacologic doses of estrogen, central venous catheter).
Secondary prevention of venous thromboembolism associated with thrombophilic conditions (e.g., combined factor V Leiden and prothrombin 20210 gene mutations).
Secondary prevention of venous thromboembolism in children with ongoing risk factors such as active nephrotic syndrome, ongoing asparaginase therapy, or lupus anticoagulant.
Prophylaxis in General Surgery
American College of Chest Physicians (ACCP) prefers other drug therapies (LMW heparin or low-dose unfractionated heparin) or non-drug therapies (intermittent pneumatic compression, elastic stockings) in most moderate- to high-risk general surgery patients†.
Prophylaxis in Hip-Replacement Surgery
Short-term prophylaxis in patients undergoing hip-replacement surgery as one of several therapeutic options (fondaparinux, LMW heparin).
Consider extended prophylaxis (≤28–35 days) in patients undergoing hip-replacement surgery who have ongoing risk factors for venous thromboembolism (e.g., obesity, delayed mobilization, cancer, history of venous thromboembolism).
Prophylaxis in Hip-fracture Surgery
Short-term prophylaxis in patients undergoing hip-fracture surgery†, as one of several therapeutic options (fondaparinux, LMW heparin).
Consider extended prophylaxis (≤28–35 days) in patients undergoing hip-fracture surgery who have ongoing risk factors for venous thromboembolism (e.g., obesity, delayed mobilization, cancer, history of venous thromboembolism).
Prophylaxis in Knee-replacement Surgery
Short-term prophylaxis in patients undergoing knee-replacement surgery† as one of several therapeutic options (LMW heparin, fondaparinux, intermittent pneumatic compression).
Prophylaxis in Trauma
Prevention of thromboembolism in the rehabilitation phase of acute spinal cord injury†, as an alternative to continued therapy with an LMW heparin.
Prevention of thromboembolism in other types of trauma† after initial treatment with an LMW heparin in patients with an ongoing risk of venous thromboembolism requiring extended hospital stays.
Continued prophylaxis with warfarin or an LMW heparin after hospital discharge suggested by ACCP in selected patients with impaired mobility.
Embolism Associated with Atrial Fibrillation/Flutter
Prophylaxis of thromboembolic episodes in patients with persistent or paroxysmal atrial fibrillation who are at high risk for stroke (e.g., history of stroke, TIA, or systemic embolism; poor left ventricular systolic function and/or CHF; hypertension; diabetes mellitus; >75 years of age) or as alternative to aspirin in patients with persistent or paroxysmal atrial fibrillation and no other high-risk factors.
Prevention of thromboembolism in patients with atrial flutter† with or without mitral valve stenosis. Use alone or in combination with aspirin in patients with atrial flutter and prosthetic heart valves.
Patients with “lone” atrial fibrillation should be offered aspirin rather than warfarin because of their relatively low risk of stroke. ACCP, ACC, and AHA state that patients who decline therapy with warfarin or who are extremely poor candidates for oral anticoagulation also should be offered aspirin, except when contraindicated.
Short-term prevention of thromboembolism in patients with atrial fibrillation (>48 hours) who are at high risk for stroke after open-heart surgery.
Thromboprophylaxis during Cardioversion of Atrial Fibrillation/Flutter
Prevention of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation/flutter†.
Embolism Associated with Valvular Heart Disease
Prevention of thromboembolism associated with various types of valvular heart disease†, in combination with or as alternative to low-dose aspirin; choice of antithrombotic therapy depends on risks of thromboembolism versus hemorrhagic complications from such therapy.
Many experts recommend long-term oral anticoagulation with warfarin therapy in patients with rheumatic mitral valve disease† and atrial fibrillation or a history of systemic embolism (e.g., stroke). Add low-dose aspirin therapy in patients with atrial fibrillation or history of systemic embolism who have a breakthrough embolic event despite prophylactic anticoagulation; may use another oral platelet-aggregation inhibitor (e.g., dipyridamole, clopidogrel) if aspirin not tolerated.
Consider long-term anticoagulation in patients with rheumatic mitral valve disease† and normal sinus rhythm who have a left atrial diameter >5.5 cm (high risk of atrial fibrillation).
Prophylaxis with warfarin (target INR 2.5, range 2–3) recommended by ACC/AHA in selected high-risk patients with mitral valve prolapse† and atrial fibrillation (i.e., those ≥65 years of age or those with mitral valve regurgitation, hypertension, or a history of heart failure). Patients <65 years of age with mitral valve prolapse and atrial fibrillation who do not have these risk factors for thromboembolism and those with mitral valve prolapse and unexplained TIAs should be considered for low-dose aspirin therapy. Also consider long-term warfarin prophylaxis in patients with mitral valve prolapse who have atrial fibrillation, a history of systemic embolism (e.g., stroke), or recurrent TIAs despite aspirin therapy.
Adjusted-dose warfarin also recommended by some clinicians for prevention of thromboembolic events in patients with mitral valve regurgitation and concomitant atrial fibrillation or a history of systemic embolism.
Long-term antithrombotic therapy generally not recommended in patients with mitral annular calcification who lack a history of thromboembolism or atrial fibrillation. However, ACCP suggests that long-term warfarin therapy be given to patients with mitral annular calcification complicated by systemic embolism not documented to be calcific embolism or in those who have atrial fibrillation.
Generally should not initiate anticoagulant therapy in patients with uncomplicated infective endocarditis involving a native valve because of the risk of hemorrhage and lack of documented efficacy.
Oral anticoagulant therapy recommended in patients undergoing mitral valvuloplasty beginning 3 weeks prior to the procedure and continuing for 4 weeks following the procedure.
Generally should not initiate long-term anticoagulant therapy in patients with aortic arch valve disease unless warranted by a coexisting condition. However, ACCP states that patients with mobile aortic atheromas and aortic plaques >4 mm (as measured by transesophageal echocardiography) should receive long-term anticoagulation with warfarin.
Thromboembolism Associated with Prosthetic Heart Valves
Follow-up anticoagulation after unfractionated heparin or an LMW heparin for prevention of thromboembolic complications associated with heart valve replacement.
Risk of systemic embolism is higher with prosthetic mechanical than with bioprosthetic heart valves, higher with first-generation mechanical (e.g., caged ball, caged disk) valves than with newer mechanical (e.g., bileaflet, Medtronic Hall tilting disk) heart valves, higher with more than one prosthetic valve, and higher with prosthetic mitral than with aortic valves; risk also increases in the presence of atrial fibrillation. Lifelong prophylaxis required in all patients with mechanical heart valves because of associated high risk of thromboembolism.
Combination therapy with aspirin recommended in patients with mechanical heart valves and additional risk factors (e.g., atrial fibrillation, left atrial enlargement, endocardial damage, low ejection fraction).
Combination therapy with aspirin recommended in patients with first-generation mechanical heart valves.
Short-term (3 months) prophylaxis in patients with a bioprosthetic valve in the mitral position; follow-up with long-term aspirin therapy in patients with no continuing risk factors who are in normal sinus rhythm.
Short-term (3 months) prophylaxis with warfarin or aspirin in patients with a bioprosthetic valve in the aortic position; follow-up with aspirin in patients with no continuing risk factors who are in normal sinus rhythm.
Short-term prophylaxis in patients with a bioprosthetic valve and evidence of a left atrial thrombus.
Long-term prophylaxis in patients with a bioprosthetic valve and other risk factors (e.g., atrial fibrillation, prior thromboembolism, left ventricular dysfunction, hypercoagulable states).
Generally should not initiate anticoagulant therapy in patients with uncomplicated infective endocarditis involving a bioprosthetic heart valve because of the risk of hemorrhage and lack of documented efficacy. However, ACCP states that patients with mechanical prosthetic valves receiving long-term anticoagulation who develop infective endocarditis generally should remain on anticoagulant therapy unless there are specific contraindications, keeping in mind the substantial risk of intracranial hemorrhage.
Treatment of “breakthrough” thromboembolic events in patients with prosthetic heart valves receiving thromboprophylaxis. Combination therapy with aspirin recommended in patients with breakthrough embolic event despite warfarin therapy.
Thromboembolism Following ST-Segment Elevation MI
Used as adjunctive therapy with platelet-aggregation inhibitors (e.g., aspirin, clopidogrel) after coronary artery reperfusion for the prevention of early reocclusion and death.
Used short-term with an LMW heparin in the treatment of DVT or pulmonary embolism following MI in hospitalized patients.
Used in selected patients to reduce the incidence of thromboembolic events such as stroke or systemic embolization following MI. ACC and AHA recommend follow-up anticoagulation (3 months) at hospital discharge and adjunctive aspirin after initiation of unfractionated heparin or an LMW heparin in patients at high risk for systemic emboli. ACCP suggests oral anticoagulation and aspirin following MI for 3 months in those at high risk for embolism.
ACC and AHA recommend long-term anticoagulation alone or with aspirin at hospital discharge in patients without stent implantation who have coexisting conditions (i.e., atrial fibrillation, left ventricular thrombus, cerebral emboli, extensive wall motion abnormality) that warrant such therapy.
Used as an alternative to clopidogrel in patients who are unable to take daily aspirin therapy and who do not have a stent implanted.
Primary Prevention of Thromboembolic Events in CAD
Used to reduce the incidence of cardiovascular events and mortality† in patients at high risk for CAD.
Thromboembolism Associated with Other Cardiovascular Diseases
Used in conjunction with aspirin to prevent thrombi and infarction in children with Kawasaki disease†.
Used as primary prophylaxis for thrombotic complications in children with dilated cardiomyopathy† awaiting a cardiac transplant.
May be used as primary prevention of thromboembolic events in children undergoing Fontan surgery for congenital univentricular heart lesions†; use with aspirin (5 mg/kg daily) as follow-up to heparin therapy.
Cerebral Thromboembolism
Secondary prevention in patients with TIAs† or mild ischemic stroke and concurrent atrial fibrillation, provided no contraindications to therapy exist.
Used in conjunction with aspirin for prevention of recurrent stroke in patients at high risk for recurring cerebral embolism from other cardiac sources (e.g., mechanical prosthetic heart valves, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis, extensive wall-motion abnormalities). Follow-up anticoagulation after heparin or an LMW heparin in patients with recent MI and acute ischemic stroke and cardiac sources of embolism.
Has been used as follow-up anticoagulation after heparin therapy for the prevention of embolism in paralyzed or immobile patients with progressive stroke† (when the suspected mechanism is thromboembolic) or stroke-in-evolution†. However, use of heparin or an LMW heparin not recommended by ACCP in patients with a stroke-in-evolution because of lack of conclusive data on efficacy and safety.
Short-term (3–6 months) follow-up anticoagulation with warfarin or an LMW heparin after heparin or an LMW heparin in children with arterial ischemic stroke from cardiac sources† or vascular dissection. May initiate aspirin following completion of anticoagulation.
Long-term antithrombotic therapy generally not recommended in asymptomatic patients with a patent foramen ovale or atrial septal aneurysm unless such patients have unexplained system embolism or TIAs and demonstrable venous thrombosis or pulmonary embolism. Treatment of suspected DVT in patients with cryptogenic stroke and patent foramen ovale†. ACCP suggests use of antiplatelet agents over warfarin in patients with cryptogenic stroke and patent foramen ovale without DVT.
ACCP suggests either oral anticoagulation or antiplatelet agents for secondary prophylaxis in patients with cryptogenic stroke and mobile arch thrombi†.
Oral anticoagulation (3–6 months) recommended by ACCP as follow-up to unfractionated heparin or an LMW heparin in patients with acute cerebral venous sinus thrombosis†.
Thrombosis Associated with CABG
Prevention of saphenous vein or internal mammary artery graft occlusion following CABG†. ACCP recommends use in combination with aspirin when other coexisting conditions (e.g., heart valve replacement) warrant such therapy.
Prevention of Stent Thrombosis and Restenosis Following PCI
Has been used short-term for prevention of stent thrombosis after stent placement† or long-term (1–6 months) for prevention of restenosis following PCI†. Since warfarin has no apparent advantages over antiplatelet therapy, not routinely recommended by ACCP after PCI if no other indications for anticoagulation exist.
Arterial Occlusive Disease
Has been used in selected patients with peripheral arterial occlusive disease†, but ACCP currently recommends against use of anticoagulants for intermittent claudication.
Treatment/Secondary Prevention in Arterial Vascular Surgery
ACCP recommends long-term follow-up oral anticoagulation after initial heparin treatment in patients undergoing embolectomy†.
ACCP recommends long-term oral anticoagulation in postsurgical patients following pulmonary thromboendarterectomy† and in patients ineligible for such a procedure.
Prevention (combined with aspirin therapy) of embolism in selected (high risk for graft thrombosis and limb loss) patients after infrainguinal femoropopliteal or distal vein bypass†.
Heparin-Induced Thrombocytopenia
Has been administered as follow-up treatment of heparin-induced thrombocytopenia† when substantial recovery has occurred (i.e., platelet counts ≥ 100,000–150,000/mm3 and are stable) after therapy with a direct thrombin inhibitor (e.g., lepirudin, bivalirudin, argatroban). Overlap therapy for approximately 5 days until an adequate response to warfarin is obtained.
Dosage and Administration
General
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
- Carefully individualize dosage based on clinical and laboratory findings (i.e., determination of INR and/or PT ratios). Adjust dosage in small increments and carefully monitor patient response. Determine optimum duration of therapy by the condition being treated and its severity.
- Determine PT prior to and 24 hours after initiation of therapy. Determine PT daily until the PT/INR is in the therapeutic range. Intervals between subsequent PT determinations based on clinician’s judgment and patient’s response. Determine PT/INR generally every 1–4 weeks after a stable dosage has been determined.
- Determine PT when different warfarin preparations (e.g., proprietary versus generic) are interchanged. Determine PT when concomitant drug therapy is added, discontinued, or taken irregularly.
- Dosage does not vary with the route of administration.
- Administration of large loading doses (i.e., >20 mg) not recommended. Possible increased risk of hemorrhage or necrosis. (See Hemorrhage under Cautions.)
- For follow-up therapy after heparin, the manufacturer recommends that therapy with heparin and warfarin be used concurrently for at least 4–5 days or until the desired PT/INR has been achieved. Some clinicians recommend that unfractionated heparin or an LMW heparin be used concurrently with warfarin for about 5–7 days or until the desired INR has been achieved for 2 consecutive days.
- Increased risk of thrombosis or rebound thromboembolism has been suggested following abrupt discontinuance of warfarin therapy; some manufacturers recommend gradually decreasing dosage (e.g., over 3–4 weeks) when withdrawing therapy.
Transferring from Anticoagulation with Direct Thrombin Inhibitors
- For follow-up therapy after most direct thrombin inhibitors, overlap therapy with direct thrombin inhibitors for ≥5 days until desired INR has been achieved for 2 consecutive days.
- Combined therapy with argatroban and warfarin prolongs the PT and INR beyond that produced by warfarin alone. Determine PT and INR daily during concurrent argatroban and warfarin therapy. Continue to monitor the effects of argatroban using aPTT during conversion to warfarin.
- For an argatroban infusion rate ≤2 mcg/kg per minute, discontinue argatroban therapy when INR on combined therapy >4. Avoid overshooting target INR, as supratherapeutic INRs during concomitant therapy with direct thrombin inhibitors and warfarin have been associated with necrosis or gangrene of the skin or limbs.
- Determine INR 4–6 hours after discontinuance of argatroban infusion during warfarin monotherapy. If INR is below the desired therapeutic range, resume argatroban infusion. Repeat attempts to discontinue argatroban daily and until INR (4–6 hours after discontinuance of argatroban) on warfarin alone is in therapeutic range.
- For argatroban infusion rates >2 mcg/kg per minute, reduce infusion rate temporarily to 2 mcg/kg per minute, and reinstitute the procedure just described for conversion to oral therapy. Repeat INR determination 4–6 hours after reduction of the argatroban infusion and reinstitute procedure just described for conversion to oral therapy.
Administration
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Administer orally. Administer by IV injection when a coumarin derivative is indicated and oral therapy is not feasible.
IM administration not recommended.
Oral Administration
Administer orally in a single, daily dose.
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
Reconstitution
Reconstitute powder for injection with 2.7 mL of sterile water for injection to a final concentration of 2 mg/mL.
Rate of Administration
Inject slowly (over 1–2 minutes) into a peripheral vein.
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Available as warfarin sodium; dosage expressed in terms of the salt.
Pediatric Patients
Venous Thrombosis and Pulmonary Embolism
Treatment or Secondary Prevention
Oral
Neonates with homozygous protein C deficiency and associated purpura fulminans: Maintenance of an INR of 2.5–4.5 long-term suggested.
Children >2 months of age with first episode idiopathic thromboembolic event: Follow-up anticoagulation after heparin or an LMW heparin with dosage adjusted to maintain a target INR of 2.5 (range 2–3) for at least 6 months.
Children >2 months of age with first episode thromboembolic event secondary to precipitating factors: Maintenance of a target INR of 2.5 (range 2–3) is suggested for 3 months or until resolution of such factors. Such factors include cancer, trauma/surgery, congenital heart disease, or systemic lupus erythematosus.
Children >2 months of age with recurrent thromboembolic events secondary to precipitating factors after previous 3 months of oral anticoagulation: Continued maintenance of a target INR of 2.5 (range 2–3) is suggested for another 3 months or until resolution of such factors.
Children with recurrent idiopathic thromboembolic events: Indefinite oral anticoagulation at low (INR of 1.3–1.8) to moderate intensity (INR of 2–3) suggested.
Children >2 months of age with central venous catheter-associated venous thromboembolic events: Adjust dosage to maintain target INR of 2.5 (range 2–3) for 3 months.
Children >2 months of age with first DVT associated with a central venous catheter after previous 3 months of oral anticoagulation for catheter-related thrombosis: Continue anticoagulation at a lower intensity (INR 1.5–1.8) until the central venous catheter is removed.
Children >2 months of age with recurrent thrombosis associated with a central venous catheter after previous 3 months of oral anticoagulation: Continue anticoagulation at a lower intensity (INR 1.5–1.8) until the central venous catheter is removed.
Children >2 months of age with breakthrough thrombosis associated with central venous catheters despite low-intensity oral anticoagulation: Increase of the anticoagulation to an INR of 2–3 until the catheter is removed or for a minimum of 3 months.
Children >2 months of age receiving long-term total parenteral nutrition via a central venous catheter: Continuous dosage at INR 2–2.5 suggested or alternatively, for the first 3 months after each central venous catheter is inserted.
Cardiovascular Conditions
Oral
Giant coronary aneurysms following Kawasaki disease†: Adjustment of dosage to maintain an INR of 2–3 with aspirin (3–5 mg/kg daily) is suggested to reduce subsequent thrombosis and infarction.†
Neonates and children with dilated cardiomyopathy†: Primary prophylaxis at INR of 2–3 suggested while the child is awaiting a cardiac transplant.†
Fontan surgery for congenital univentricular heart lesions†: Maintenance of an INR of 2–3 following full-dose heparin suggested for primary prevention of thromboembolic events; the optimal duration of therapy unknown.†
Cerebral Thromboembolism
Acute Cerebral Venous Sinus Thrombosis
Oral
Secondary prevention†: Follow-up oral anticoagulation at a target INR of 2.5 (range 2–3) for 3–6 months after therapy with unfractionated heparin or an LMW heparin.†
Adults
Venous Thrombosis and Pulmonary Embolism
Treatment or Secondary Prevention
Oral
As follow-up to therapy with heparin or an LMW heparin, initial dose is 5–10 mg daily. Adjust subsequent daily dosage to achieve and maintain a target INR of 2.5 (range 2–3) for ≥3 months.
Individualize length of treatment of DVT or pulmonary embolism based on age, comorbid conditions, and the likelihood of recurrence.
DVT or pulmonary embolism with reversible or time-limited risk factors for venous thromboembolism: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for at least 3 months.
First episode of idiopathic DVT: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for at least 6–12 months.
First episode of DVT or pulmonary embolism and continuing risk factors: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for at least 6–12 months. Such factors include cancer, antithrombin III or protein C or S deficiencies, antiphospholipid antibody syndrome, factor V Leiden or prothrombin 20210A gene mutations, homocysteinemia, and high levels of factor VII.
First episode of DVT or pulmonary embolism with antiphospholipid antibodies or ≥2 thrombophilic conditions: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for 12 months. Indefinite anticoagulation suggested in these patients.
Consider long-term therapy in patients with risk factors for recurrent thromboembolism, including venous insufficiency, idiopathic venous thromboembolism, and history of thrombotic events (≥2 episodes).
Prophylaxis in Hip-replacement Surgery
Oral
Initially, 5–10 mg daily with dosage adjusted to achieve a target INR of 2.5 (range 2–3) for ≥10 days.
Initiate prophylaxis for venous thromboembolism perioperatively (the evening before or after surgery).
Extended prophylaxis for ≤28–35 days with warfarin, fondaparinux, or LMW heparin recommended.
Prophylaxis in Hip-fracture Surgery
Oral
Initially, 5–10 mg daily with dosage adjusted to achieve a target INR of 2.5 (range 2–3) for ≥10 days.
Initiate prophylaxis for venous thromboembolism preoperatively with heparin or a LMW heparin if surgery is delayed or after surgery once hemostasis has been demonstrated. Continue prophylactic anticoagulant therapy with warfarin, a LMW heparin, or fondaparinux following surgery for 28–35 days.
Prophylaxis in Knee-replacement Surgery
Oral
Initially, 5–10 mg daily with dosage adjusted to achieve a target INR of 2.5 (range 2–3) for 10 days.
Initiate prophylaxis for venous thromboembolism perioperatively (the evening before or after surgery).
Prophylaxis in Trauma
Oral
Acute spinal cord injury: Following initial therapy with an LMW heparin, adjust warfarin sodium dosage to a target INR of 2.5 (range 2–3) in the rehabilitation phase. Continue prophylactic anticoagulant therapy following trauma for a minimum of 3 months or until completion of the inpatient phase of rehabilitation.
Trauma patients with impaired mobility: Adjust dosage to a target INR of 2.5 (range 2–3) after hospital discharge.
Embolism Associated with Atrial Fibrillation/Flutter
Oral
Adjust dosage for long-term oral anticoagulation to a target INR of 2.5 (range 2–3) in patients who are at high risk for stroke.
For atrial fibrillation persisting for >48 hours after open-heart surgery: Maintain a target INR of 2.5 (range 2–3) in patients at high risk for stroke for several weeks following reversion to normal sinus rhythm.
Atrial flutter and mitral stenosis: Adjust dosage to maintain a target INR of 2.5 (range 2–3).
Thromboprophylaxis during Cardioversion of Atrial Fibrillation/Flutter
Oral
Initiate at least 3–4 weeks prior to cardioversion (target INR of 2.5, range 2–3) and continue after the procedure until normal sinus rhythm has been maintained for 3–4 weeks. For emergency cardioversion, administer for ≥4 weeks as follow-up anticoagulation after initiating periprocedural IV heparin.
Embolism Associated with Valvular Heart Disease
Oral
Mitral valve disease associated with rheumatic fever or mitral valve regurgitation: Adjust dosage to prolong the INR to a target of 2.5 (range 2–3) in patients who have either concurrent paroxysmal or chronic persistent atrial fibrillation or a history of systemic embolism (e.g., stroke). Add aspirin (75–100 mg daily) to therapy in patients who have a breakthrough embolic event.
Rheumatic mitral valve disease with left atrial hypertrophy (left atrial diameter exceeding 5.5 cm) and normal sinus rhythm: Long-term anticoagulation at a target INR of 2.5 (range 2–3).
Mitral valve prolapse and a history of systemic embolism (e.g., stroke), or recurrent TIAs despite aspirin therapy: Maintain a target INR of 2.5 (range 2–3).
Mitral annular calcification complicated by systemic embolism (noncalcific systemic embolism): Long-term prophylaxis at a target INR of 2.5 (range 2–3) suggested.
Patients undergoing percutaneous mitral valvuloplasty: Maintain a target INR of 2.5 (range 2–3) for 3 weeks prior to the procedure and for 4 weeks after the procedure.
Thromboembolism Associated with Prosthetic Heart Valves
Prophylaxis
Oral
Bioprosthetic valve in the aortic position: Adjust dosage to maintain a target INR of 2.5 (range 2–3) during the first 3 months.
Bioprosthetic valve in the mitral position: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for the first 3 months.
Mitral bioprosthetic heart valve and additional risk factors (atrial fibrillation, left ventricular dysfunction, prior thromboembolism, hypercoagulable states): Maintenance of a target INR of 3 (range 2.5–3.5) for ≥3 months recommended by ACC and AHA.
Bioprosthetic valves with evidence of a left atrial thrombus at valve replacement surgery: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for the first 3 months.
Patients with bioprosthetic valves who have a history of systemic embolism: Maintenance of a target INR of 2.5 (range 2–3) for 3–12 months recommended by ACCP.
Patients with newer (e.g., bileaflet, Medtronic disk) mechanical heart valves in the aortic position with no additional risk factors: Adjust dosage to a target INR of 2.5 (range 2–3) long-term.
Tilting disk valves and bileaflet mechanical heart valves in the mitral position: Adjust dosage to maintain a target INR of 3 (range 2.5–3.5) long-term.
Mechanical valves and additional risk factors (atrial fibrillation, left atrial enlargement, endocardial damage, low ejection fraction): Long-term oral anticoagulation at a target INR of 3 (range 2.5–3.5) and low-dose aspirin (75–100 mg daily).
First-generation mechanical valve (e.g., caged ball, caged disk): Combination therapy with warfarin (dosage adjusted to a target INR of 3 [range 2.5–3.5]) and aspirin (75–100 mg daily) is recommended long-term.
Treatment
Oral
Breakthrough embolic event despite dosage adjusted to maintain a target INR of 2.5 (range 2–3): Increase dosage to achieve and maintain a target INR of 3 (range 2.5–3.5) and add aspirin (75–100 mg daily).
Breakthrough embolic event despite target INR of 3 (range 2.5–3.5): Increase dosage to a target INR of 4 (range 3.5–4.5).
Breakthrough embolic event in patients receiving a combination of low-dose aspirin (80–100 mg daily) and warfarin: ACC and AHA suggest increasing the dosage of warfarin first. Increase the aspirin dosage (to 325 mg daily) if the higher warfarin dosage does not prevent embolic events.
Breakthrough embolic event on aspirin therapy alone: Increase the aspirin dosage to 325 mg daily or initiate warfarin to achieve and maintain a target INR of 2.5 (range 2–3).
Patients with large valve thrombosis in whom surgical intervention is not feasible and thrombolytic therapy is successful: Follow-up anticoagulation to IV unfractionated heparin and overlap agents until attainment of a target INR of 3.5 (range 3–4) or 4 (range 3.5–4.5) in patients with aortic or mitral prosthetic valves, respectively.
Patients with some residual valve thrombosis after partially successful thrombolytic therapy: Adjust dosage to achieve a target INR of 3 (range 2.5–3.5) and institute adjusted-dose sub-Q unfractionated heparin twice daily for 3 months.
Patients with small valve thrombus who are in NYHA class I or II heart failure and who are hemodynamically stable with IV unfractionated heparin: May be transferred from IV unfractionated heparin therapy to the combination of sub-Q adjusted-dose unfractionated heparin (to achieve an aPTT of 55–80 seconds) and adjusted-dose warfarin therapy (adjusted to maintain a target INR of 3 [range 2.5–3.5]) for 1–3 months as an alternative to thrombolytic therapy or reoperation. Upon resolution of the small valve thrombus, increase dosage to maintain a target INR of 3.5 (range 3–4) for prosthetic aortic valves or a target INR of 4 (range 3.5–4.5) for prosthetic mitral valves; institute concomitant low-dose aspirin therapy.
ST-Segment Elevation MI
Treatment or Secondary Prevention
Oral
As follow-up after heparin or LMW heparin therapy, initiate warfarin therapy after the initial 2 days of hospitalization to maintain a target INR of 2.5 (range 2–3) for 3 months in patients at increased risk of systemic or pulmonary embolism (e.g., history of previous systemic embolism, ventricular mural thrombus or severe left ventricular dysfunction, venous thromboembolism, or severe heart failure).
Hospitalized patients with DVT or pulmonary embolism: Initiate concurrently with full-dose LMW heparin and continue for a minimum of 5 days until a target INR of 2.5 (range 2–3) is obtained.
Manufacturer recommends initiation of therapy in patients at 2–4 weeks postinfarction with dosage adjusted to maintain a target INR of 3 (range 2.5–3.5). Where meticulous INR monitoring is standard and routinely accessible, ACCP recommends long-term (up to 4 years) anticoagulation with high-intensity warfarin (target INR of 3 [range 2.5–3.5]) or moderate-intensity (target INR of 2.5 [range 2–3]) warfarin and low-dose aspirin in both high- and low-risk patients following MI.
In patients with AMI who are at increased risk for bleeding complications or who are receiving concomitant aspirin therapy, maintain the INR at the lower end of this suggested range.
ACCP recommends oral anticoagulation (target INR 2.5, range 2–3) in addition to low-dose (≤100 mg daily) aspirin for 3 months following MI in high-risk patients (e.g., large anterior MI, substantial heart failure, intracardiac thrombus visible on echocardiography, history of thromboembolism).
ACC and AHA recommend initiation at hospital discharge in patients with documented left ventricular thrombus or extensive wall motion abnormality. Adjust dosage to maintain a target INR of 2.5 (range 2–3) for 3 months or indefinitely in patients without an increased risk for bleeding.
ACC and AHA recommend long-term prophylaxis, initiated at hospital discharge in patients without stent implantation who have other coexisting conditions that warrant anticoagulation (i.e., left ventricular thrombus, cerebral emboli, wall motion abnormality). Adjust dosage to maintain a target INR of 3 (range 2.5–3.5) or a target INR of 2.5 (range 2–3) with concomitant aspirin (75–162 mg daily).
Patients unable to take aspirin who do not undergo stent implantation, as an alternative to clopidogrel: Adjust dosage to maintain a target INR of 3 (range 2.5-3.5).
Recent MI and persistent atrial fibrillation: Adjust dosage to maintain a target INR of 2.5 (range 2–3) indefinitely.
Primary Prevention
Oral
Patients at high risk for CAD, as an alternative to aspirin therapy alone: Adjust dosage to maintain a target INR of 1.5.
Cerebral Thromboembolism
Secondary Prevention
Oral
TIAs or mild ischemic stroke and concurrent atrial fibrillation: Adjust dosage to maintain a target INR of 2.5 (range 2–3) long-term, provided no contraindications to therapy exist.
Patients at high risk for recurrent stroke from other cardiac sources: Maintenance of a target INR of 2.5 (range 2–3) with concomitant aspirin (75–162 mg daily) recommended by ACC and AHA. Cardiac sources of embolism include mechanical prosthetic heart valves, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis, and extensive wall-motion abnormalities.
Recent MI complicated by ischemic stroke and left ventricular thrombus or akinetic segment: Adjust dosage to maintain a target INR of 2.5 (range 2–3) with aspirin (75–162 mg daily) therapy for ≥3 months.
Acute phase of cerebral venous sinus thrombosis†: Follow-up oral anticoagulation (target INR of 2.5 [range 2–3]) for 3–6 months after unfractionated heparin or an LMW heparin.
Treatment/Secondary Prevention in Arterial Vascular Surgery
Oral
Pulmonary thromboendarterectomy: Indefinite oral anticoagulation a target INR of 2.5 (range 2–3).†
Patients who are ineligible for pulmonary endarterectomy: Indefinite oral anticoagulation at a target INR of 2.5 (range 2–3).†
Special Populations
Hepatic Impairment
Possible increased anticoagulant effect. May require lower initial and maintenance dosages.
Renal Impairment
Possible increased anticoagulant effect in moderate to severe renal impairment. No dosage adjustments required.
Geriatric Patients
Possible increased anticoagulant effect. Lower initial (≤5 mg) and maintenance dosages recommended. Adjust dosage to maintain INR at the lower end of the range of 2–3.
In patients >75 years of age who are considered at high risk for bleeding complications but do not have frank contraindications, use a lower target INR of 2 (range: 1.6–2.5) for primary prevention of stroke and systemic embolism.
Asian Patients
Possible increased anticoagulant effect. May require lower initial and maintenance dosages.
Cautions
Contraindications
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
- Pregnancy.
- Bleeding, hemorrhagic blood dyscrasias (e.g., hemophilia, polycythemia vera, purpura, leukemia) or a history of hemorrhagic diathesis or tendencies.
- Recent or contemplated eye, brain, or spinal cord surgery or prostatectomy.
- Open ulcerative, traumatic, or surgical wounds.
- Active ulceration of the GI, respiratory, or GU tracts.
- Cerebrovascular hemorrhage.
- Aneurysms (cerebral, dissecting aorta).
- Pericarditis and pericardial effusions.
- Bacterial endocarditis.
- Eclampsia, preeclampsia, or threatened abortion.
- Spinal puncture or other diagnostic or therapeutic procedures with potential for uncontrolled bleeding.
- Major regional or lumbar block anesthesia.
- Severe, uncontrolled, or malignant hypertension.
- Unsupervised patients with senility, alcoholism, or psychosis.
- Known hypersensitivity to warfarin or any ingredient in the formulation.
Warnings/Precautions
Warnings
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Hemorrhage
Possible massive hemorrhage involving the GI tract, spinal cord, GU, cerebral, pericardial, pulmonary, adrenal, or hepatic sites. Hemorrhagic complications may be manifested by signs or symptoms that do not indicate obvious bleeding, such as paralysis; headache; pain in the chest, abdomen, joints, muscles, or other areas; dizziness; shortness of breath; difficulty breathing or swallowing; unexplained swelling; weakness; hypotension; or unexplained shock. Results principally from overdosage or excessive PT prolongation. Increased risk of postoperative hemorrhage associated with an aPTT >50 seconds even if PT or INR in desired range.
Careful clinical management, including frequent PT or INR determinations, is required. (See General under Dosage and Administration.) Immediate critical evaluation recommended if any unexpected bleeding occurs (e.g., microscopic or gross hematuria, melena, excessive uterine or menstrual bleeding, petechiae, ecchymoses, bleeding from gums or other mucous membranes, oozing from shaving nicks).
Decrease dosage or withhold ≥1 dose to manage minor hemorrhage or an overly prolonged PT or INR (<5). Phytonadione is not recommended in patients with minor hemorrhage in whom anticoagulant therapy must be continued.
If moderate or severe hemorrhage occurs or if the PT or INR is excessively prolonged, immediately discontinue warfarin therapy and administer phytonadione.
If bleeding is severe and immediate restoration of functional vitamin K-dependent blood coagulation factors is necessary, administer fresh plasma or anti-inhibitor coagulant complex (commercial factor IX complex, prothrombin concentrate) with phytonadione. May consider recombinant factor VIIa as an alternative to anti-inhibitor coagulant complex. In patients with manifestations of acute adrenal hemorrhage or insufficiency, discontinue anticoagulant therapy and institute prompt, vigorous therapy with IV corticosteroids; delay in initiating therapy may result in death.
Necrosis
Rarely, possible potentially fatal necrosis and/or gangrene of skin or other tissues. Appears early (e.g., 1–10 days) after initiation of therapy principally at sites of fat tissue (e.g., abdomen, breasts, buttocks, thighs). Increased risk in patients with hereditary, familial, or clinical deficiencies of protein C or its cofactor, protein S.
Discontinue therapy if necrosis is suspected and administer vitamin K (phytonadione) or fresh frozen plasma. Consider heparin therapy to treat the underlying thromboembolic disease and possibly prevent additional microvascular thrombosis. In severe cases, surgical debridement, skin grafting, or amputation may be necessary.
Possible limb ischemia, necrosis, and gangrene may occur in patients with heparin-induced thrombocytopenia when warfarin is substituted for heparin treatment or continued after heparin discontinuance. Cautious use recommended. Consider delaying warfarin therapy until thrombin generation is adequately controlled and thrombocytopenia has resolved (i.e., platelet counts at least 100,000–150,000/mm3 and are stable).
Purple Toes Syndrome and Cholesterol Microembolization
Purple toes syndrome may result from possible increased release of atheromatous plaque fragments from systemic cholesterol microemboli. May occur 3–10 weeks or later following initiation of warfarin therapy.
Discontinuance of warfarin therapy is recommended; some cases of purple toes syndrome have progressed to gangrene or necrosis, requiring debridement and/or amputation.
Other possible manifestations of systemic atheroembolism include livedo reticularis, rash, gangrene, abrupt and intense pain in the leg, foot, or toes, foot ulcers, myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction, pancreatitis, and symptoms simulating polyarteritis.
Sensitivity Reactions
Possible minor or severe allergic/hypersensitivity reactions, including anaphylactic reactions.
General Precautions
Factors Influencing Response
Possible increased anticoagulant response (increased PT and risk of hemorrhage) due to vitamin K deficiency, scurvy, malnutrition or cachexia, small body size, hepatic dysfunction, moderate to severe renal impairment, fever, hyperthyroidism, infectious disease, carcinoma, collagen disease, CHF, diarrhea, biliary obstruction, old age, debility, menstruation and menstrual disorders, radiation therapy, and initial hypoprothrombinemia.
Possible increased sensitivity to anticoagulant effect in Asian patients. (See Asian Patients under Dosage and Administration.)
Possible decreased response (decreased PT) due to increased intake or GI absorption of vitamin K, diabetes mellitus, edema, hyperlipidemia, hypothyroidism, and visceral carcinoma.
Possible inherited familial coumarin resistance due to variations in the anticoagulant-vitamin K receptor site. May require 10–20 times the usual dosage to achieve therapeutic effects. Resistance also may result from an increased rate of drug metabolism and excretion. Consider acquired or inherited warfarin resistance if large daily doses are required to maintain the PT ratio/INR within a normal therapeutic range.
Surgical Procedures
Generally contraindicated in patients with recent or contemplated surgery of the eye or CNS and in those undergoing traumatic surgery resulting in large open surfaces.
Limit the operative site sufficiently to permit effective use of local procedures for hemostasis (e.g., absorbable hemostatic agents, sutures, pressure dressings) if necessary. Maintain meticulous surgical hemostasis (e.g., absorbable hemostatic agents, sutures, pressure dressings) if minor dental and surgical procedures are performed.
In most patients, discontinue warfarin about 4 days prior to surgery. Perform the procedure when the INR has returned to normal or near normal levels, using postoperative anticoagulation with either prophylactic or full doses of IV or sub-Q unfractionated heparin or sub-Q LMW heparin.
In patients with a low risk of thromboembolism, may initiate postoperative prophylaxis with a low dose of sub-Q unfractionated heparin sodium (5000 units) or a prophylactic dose of an LMW heparin (e.g., dalteparin sodium 5000 units daily, enoxaparin sodium 40 mg daily) and reinitiate warfarin simultaneously. Patients at low risk include those with no thromboembolism within the past 3 months, atrial fibrillation without a history of stroke or other risk factors, or bileaflet mechanical prosthetic heart valve in the aortic position.
In patients at intermediate risk of thromboembolism, administer a low dose of sub-Q unfractionated heparin sodium (5000 units) or a prophylactic dose of an LMW heparin (e.g., dalteparin sodium 5000 units daily, enoxaparin sodium 40 mg daily) 2 days preoperatively. Postoperatively, may reinitiate anticoagulation with heparin or an LMW heparin in conjunction with warfarin.
In patients at high risk for thromboembolism, may initiate anticoagulation with a full dose of heparin or an LMW heparin as the INR falls, approximately 2 days preoperatively. Such risk factors include recent [within 3 months] history of thromboembolism, prosthetic heart valve in the mitral position, or ball/cage prosthetic valve. May discontinue anticoagulation prior to surgery (5 hours prior to surgery with IV heparin or 12–24 hours prior to surgery with sub-Q heparin or an LMW heparin). Postoperatively, may reinitiate anticoagulation with full-dose unfractionated heparin or LMW heparin in conjunction with warfarin therapy.
In patients receiving long-term oral antithrombotic therapy (warfarin and/or aspirin) who require additional cardiac surgical procedures associated with a risk of perioperative bleeding, the AHA and ACC recommend discontinuance of warfarin therapy and performance of the procedure when the anticoagulant effects largely have dissipated (as indicated by an INR of ≤1.5). Administer for follow-up treatment after heparin therapy in patients undergoing noncardiac procedures who are at very high risk for thrombosis without oral anticoagulant therapy. Overlap therapy with the 2 drugs for 3–5 days until an INR of 2 or greater is obtained.
In patients with a low risk of bleeding, some clinicians suggest dosage reduction 4–5 days prior to surgery to a dosage that achieves an INR of 1.3–1.5 and then discontinuance prior to surgery. Reinitiate warfarin postoperatively, in conjunction with a low dose of unfractionated heparin sodium (5000 units sub-Q) or a prophylactic dose of an LMW heparin (e.g., dalteparin sodium 5000 units daily, enoxaparin sodium 40 mg daily), if necessary.
When emergency surgery is necessary, administer fresh plasma or phytonadione to normalize blood coagulation.
Ensure availability of close medical supervision and adequate laboratory facilities for monitoring therapy and for treating hemorrhage.
Hepatic Effects
Possible hepatitis, cholestatic hepatic injury, or jaundice.
Specific Populations
Pregnancy
Category X. Possible teratogenicity, fetal or neonatal hemorrhage, and intrauterine death. Generally contraindicated during pregnancy.
Has been used in certain pregnant women (e.g., those with mechanical prosthetic heart valves) considered at high risk for thrombosis. Embryopathy observed when administered between weeks 6–12 of gestation. Avoid administration during such weeks and close to term (to avoid anticoagulation of the fetus). Detectable in fetal plasma at concentrations approaching maternal concentrations.
Lactation
Limited data indicate that warfarin is not distributed into breast milk or detectable in plasma of nursing infants and has not produced substantial coagulation abnormalities in such infants. Manufacturer states that prolonged PTs have been reported in some infants, although not as prolonged as in the mothers. However, based on limited data, maternal warfarin therapy considered unlikely to pose substantial risk to healthy, full-term breast-feeding infants; AAP and other clinicians consider such therapy compatible with breast-feeding. Carefully consider available alternatives and closely monitor women who decide to breast-feed to avoid exceeding the recommended PTs/INRs.
Neonates are particularly sensitive to the effects of warfarin as a result of vitamin K deficiency. Monitor infants at risk for bleeding with coagulation tests and evaluate their vitamin K status before breast-feeding.
Pediatric Use
Safety and efficacy not established in children <18 years of age. Has been used in pediatric patients for prevention and treatment of thromboembolic events. More frequent determinations of PT/INR are recommended.
Geriatric Use
Increased anticoagulant response. Less warfarin required to produce a therapeutic level of anticoagulation. Cautious use recommended, particularly when the risk of hemorrhage is present. Increased risk for hemorrhage in patients ≥75 years with atrial fibrillation who are at high risk for thromboembolism. Close monitoring of INR recommended.
Hepatic Impairment
Increased anticoagulant response. Weigh risks versus benefits of anticoagulant therapy in patients with moderate to severe hepatic impairment.
Renal Impairment
Increased anticoagulant response in patients with moderate or severe renal impairment. Weigh risks versus benefits of anticoagulant therapy in patients with moderate to severe renal impairment.
Common Adverse Effects
Hemorrhage.
Interactions
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Concomitant therapy with drugs or dietary or herbal supplements may alter an individual’s response to warfarin therapy. For adequate anticoagulation control, perform additional PT determinations when concomitant drug therapy is added, discontinued, or taken irregularly.
Drugs or Supplements Increasing Anticoagulant Response
Potential pharmacodynamic interaction (e.g., decreased intestinal synthesis or absorption of vitamin K; altered distribution or metabolism of vitamin K; increased warfarin affinity for receptor sites; decreased synthesis and/or increased catabolism of functional blood coagulation factors II, VII, IX, and X; interference with platelet function or fibrinolysis; ulcerogenic effects). Potential pharmacokinetic interaction (e.g., decreased rate of warfarin metabolism; decreased protein binding).
Drugs or Supplements Decreasing Anticoagulant Response
Potential pharmacodynamic interaction (e.g., increased synthesis of functional blood coagulation factors II, VII, IX, and X). Potential pharmacokinetic interaction (decreased absorption, induction of hepatic microsomal enzymes [e.g., St. John’s wort]). Potential pharmacodynamic interaction (procoagulant effects [e.g., coenzyme Q10]).
Specific Drugs
Pharmacokinetics
Absorption
Bioavailability
Essentially completely absorbed after oral administration.
Onset
Synthesis of vitamin K-dependent coagulation factors is affected soon after absorption (e.g., within 24 hours). Depletion of circulating functional coagulation factors must occur before therapeutic effects of the drug become apparent.
Duration
2–5 days after a single dose.
Food
Decreased rate, but not extent, of absorption in the presence of food.
Distribution
Extent
The apparent volume of distribution is about 0.14 L/kg.
Crosses the placental barrier; however, the drug has not been detected in human breast milk.
Plasma Protein Binding
Approximately 99%.
Elimination
Metabolism
Almost entirely in the liver. Principally by CYP2C9; CYP2C19, 2C8, 2C18, 1A2, and 3A4 involved to a lesser degree.
Elimination Route
Excreted principally in urine as metabolites and to a lesser extent in bile.
Half-life
Effective half-life averages 40 hours (range: 20–60 hours).
Special Populations
Slightly decreased clearance of R-warfarin in geriatric patients compared with that in younger individuals. However, similar pharmacokinetics of racemic warfarin and S-warfarin in geriatric and younger individuals.
Decreased metabolism in patients with hepatic dysfunction.
Stability
Storage
Oral
Tablets
15–30°C.
Parenteral
Powder for Injection
15–30°C.
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Solution Compatibility
| Compatible |
|---|
| Dextrose 5% in Ringer’s injection, lactated |
| Dextrose 5% in sodium chloride 0.45 or 0.9% |
| Dextrose 5 or 10% in water |
| Incompatible |
| Ringer’s injection |
| Variable |
| Ringer’s injection, lactated |
| Sodium chloride 0.9% |
Drug Compatibility
| Compatible |
|---|
| Amikacin sulfate |
| Ascorbic acid injection |
| Cefazolin sodium |
| Ceftriaxone sodium |
| Dopamine HCl |
| Epinephrine HCl |
| Heparin sodium |
| Lidocaine HCl |
| Metaraminol tartrate |
| Morphine sulfate |
| Nitroglycerin |
| Oxytocin |
| Potassium chloride |
| Ranitidine HCl |
| Incompatible |
| Aminophylline |
| Bretylium tosylate |
| Ceftazidime |
| Cimetidine HCl |
| Ciprofloxacin |
| Dobutamine HCl |
| Esmolol HCl |
| Gentamicin sulfate |
| Labetalol HCl |
| Metronidazole HCl |
| Ringer’s injection |
| Variable |
| Ammonium chloride |
| Vancomycin HCl |
Actions
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
- A coumarin-derivative anticoagulant; a synthetic 3-substituted derivative of 4-hydroxycoumarin.
- A racemic mixture of the 2 optical isomers of the drug.
- An indirect-acting anticoagulant; interferes with the hepatic synthesis of vitamin K-dependent coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor or plasma thromboplastin component), and X (Stuart-Prower factor).
- Sequential depletion of circulating functional coagulation factors VII , IX , X, and finally II.
- Antithrombogenic effects generally occur only after functional coagulation factors IX and X are diminished (usually 2–7 days following initiation of therapy).
- Does not alter catabolism of blood coagulation factors.
- Inhibits thrombus formation when stasis is induced; may prevent extension of existing thrombi. No direct effect on established thrombi. Little if any effect on platelet-rich arterial thrombi adhering to an abnormal vessel wall.
- Prolongs PT and aPTT.
- Phytonadione (vitamin K1) reverses the anticoagulant effect.
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
- Importance of strict adherence to prescribed dosage and schedule.
- Importance of close laboratory monitoring to determine PT and regular visits to clinician.
- Importance of patients informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements. Importance of not taking nonprescription drugs or drugs prescribed by other physicians without first informing primary clinician or pharmacist.
- Importance of patients carrying a notice stating that they are undergoing anticoagulant therapy.
- Importance of avoiding alcohol.
- Importance of avoiding drastic changes in diet and eating a balanced diet with a constant amount of vitamin K.
- Importance of avoiding cranberry products and of informing clinician if these products are part of the diet.
- Importance of avoiding activities or sports that could cause traumatic injury.
- Importance of patients reporting any signs of bleeding (e.g., pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness) to clinicians immediately.
- Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.
- Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
| Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
| Oral | Tablets | 1 mg | Coumadin® (scored) | Bristol-Myers Squibb |
Warfarin Sodium Tablets (scored) | Barr, Sandoz, Taro | |||
| 2 mg | Coumadin® (scored) | Bristol-Myers Squibb | ||
Warfarin Sodium Tablets (scored) | Barr, Sandoz, Taro | |||
| 2.5 mg | Coumadin® (scored) | Bristol-Myers Squibb | ||
Warfarin Sodium Tablets (scored) | Barr, Sandoz, Taro | |||
| 3 mg | Coumadin® (scored) | Bristol-Myers Squibb | ||
Warfarin Sodium Tablets (scored) | Barr, Sandoz, Taro | |||
| 4 mg | Coumadin® (scored) | Bristol-Myers Squibb | ||
Warfarin Sodium Tablets (scored) | Barr, Sandoz, Taro | |||
| 5 mg | Coumadin® (scored) | Bristol-Myers Squibb | ||
Warfarin Sodium Tablets (scored) | Barr, Sandoz, Taro | |||
| 6 mg | Coumadin® (scored) | Bristol-Myers Squibb | ||
Warfarin Sodium Tablets (scored) | Barr, Sandoz, Taro | |||
| 7.5 mg | Coumadin® (scored) | Bristol-Myers Squibb | ||
Warfarin Sodium Tablets (scored) | Barr, Sandoz, Taro | |||
| 10 mg | Coumadin® (scored; dye-free) | Bristol-Myers Squibb | ||
Warfarin Sodium Tablets (scored) | Barr, Sandoz, Taro | |||
| Parenteral | For injection, for IV use only | 5 mg | Coumadin® | Bristol-Myers Squibb |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
| Coumadin 1MG Tablets | B-M SQUIBB U.S. (PRIMARY CARE) | 30/$42.29 or 90/$101.01 |
| Coumadin 10MG Tablets | B-M SQUIBB U.S. (PRIMARY CARE) | 30/$58.73 or 90/$142.12 |
| Coumadin 2MG Tablets | B-M SQUIBB U.S. (PRIMARY CARE) | 30/$42.28 or 90/$105.71 |
| Coumadin 2.5MG Tablets | B-M SQUIBB U.S. (PRIMARY CARE) | 30/$44.63 or 90/$109.22 |
| Coumadin 3MG Tablets | B-M SQUIBB U.S. (PRIMARY CARE) | 30/$46.98 or 90/$111.58 |
| Coumadin 4MG Tablets | B-M SQUIBB U.S. (PRIMARY CARE) | 30/$45.8 or 90/$109.22 |
| Coumadin 5MG Tablets | B-M SQUIBB U.S. (PRIMARY CARE) | 30/$45.81 or 90/$115.1 |
| Coumadin 6MG Tablets | B-M SQUIBB U.S. (PRIMARY CARE) | 30/$58.73 or 90/$142.12 |
| Coumadin 7.5MG Tablets | B-M SQUIBB U.S. (PRIMARY CARE) | 30/$58.73 or 90/$146.82 |
| Warfarin Sodium 1MG Tablets | TARO | 30/$13.99 or 90/$30.99 |
| Warfarin Sodium 10MG Tablets | TARO | 30/$24.24 or 90/$63.74 |
| Warfarin Sodium 2MG Tablets | TARO | 30/$14.88 or 90/$32.97 |
| Warfarin Sodium 2.5MG Tablets | TARO | 30/$14.99 or 90/$33.97 |
| Warfarin Sodium 3MG Tablets | TARO | 30/$15.99 or 90/$40.97 |
| Warfarin Sodium 4MG Tablets | TARO | 30/$14.99 or 90/$33.98 |
| Warfarin Sodium 5MG Tablets | TARO | 30/$13.99 or 90/$34.99 |
| Warfarin Sodium 7.5MG Tablets | TARO | 30/$23.21 or 90/$61.05 |
AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions September 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.
Last Updated: September 01, 2007
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Warfarin
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