Class: Coumarin Derivatives
CAS Number: 129-06-6
Brands: Coumadin, Jantoven

Medically reviewed by Drugs.com on Oct 13, 2021. Written by ASHP.

• Uses
• Dosage
• Cautions
• Interactions
• Pharmacokinetics
• Patient advice
• Preparations

Introduction

Anticoagulant; a coumarin derivative.

Uses for Warfarin

DVT and PE

Treatment and secondary prevention of venous thromboembolism (DVT and/or PE).

Initiate concomitantly with a parenteral anticoagulant (e.g., a low molecular weight heparin [LMWH], heparin [referring throughout this monograph to unfractionated heparin], fondaparinux). Overlap parenteral and oral anticoagulant therapy for ≥5 days and until a stable INR of ≥2 has been maintained for ≥24 hours, then discontinue parenteral anticoagulant.

Anticoagulant therapy generally not recommended for treatment of isolated distal DVT unless symptoms are severe and there is a risk for thrombus extension.

The American College of Chest Physicians (ACCP) recommends a moderate intensity of anticoagulation (target INR 2.5, range 2–3) for most patients with DVT or PE.

Appropriate duration of therapy determined by individual factors (e.g., location of thrombi, presence or absence of precipitating factors, presence of cancer, patient's risk of bleeding). For most cases of venous thromboembolism, a minimum of 3 months of anticoagulant therapy is recommended. Long-term anticoagulation (>3 months) may be considered in selected patients (e.g., those with idiopathic [unprovoked] DVT or PE who are at low risk of bleeding, cancer patients with DVT or PE). (See Dosage under Dosage and Administration.)

Warfarin generally is the preferred anticoagulant for long-term treatment of venous thromboembolism in patients without cancer; however, in patients with cancer, ACCP suggests use of an LMWH over warfarin because of certain factors in such patients that may affect warfarin therapy (e.g., possible reduced response to warfarin, drug interactions, need for invasive procedures that require reversal of anticoagulation).

Used in select pediatric patients with DVT or PE†. LMWHs or heparin generally recommended for both initial and ongoing treatment of venous thromboembolism in children; however, warfarin may be indicated in some situations (e.g., recurrent idiopathic venous thromboembolism).

Treatment and secondary prevention of venous thromboembolic events secondary to use of central venous access devices (CVAD) in children†. Remove affected CVAD if no longer functioning or required; however, if CVAD required, ACCP suggests giving anticoagulants until catheter is removed. After initial 3 months of therapy, may consider use of prophylactic-dose warfarin (target INR 1.5–1.9); however, therapeutic dosages may be required if recurrent thromboembolism occurs.

Orthopedic Surgery

Prevention of postoperative venous thromboembolism in patients undergoing hip- or knee-replacement surgery or hip-fracture surgery.

ACCP recommends routine thromboprophylaxis (with a pharmacologic and/or mechanical method) in all patients undergoing major orthopedic surgery (hip- or knee-replacement surgery, hip-fracture surgery). Continue thromboprophylaxis for at least 10–14 days, and possibly for up to 35 days after surgery.

Several antithrombotic agents (e.g., LMWHs, fondaparinux, low-dose heparin, warfarin, aspirin) recommended by ACCP for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery. Although LMWHs generally preferred, alternative agents (e.g., warfarin) may be considered if an LMWH is not available or cannot be used (e.g., in patients with heparin-induced thrombocytopenia [HIT] or in those who refuse or are uncooperative with sub-Q injections).

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, bleeding risk, logistics, and compliance.

Embolism Associated with Atrial Fibrillation

Prevention of stroke and systemic embolism in patients with atrial fibrillation. ACCP, ACC, AHA, the American Stroke Association (ASA), and other experts recommend antithrombotic therapy (e.g., warfarin, aspirin) in all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless such therapy is contraindicated.

Choice of antithrombotic therapy is based on patient's risk for stroke and bleeding. In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients who have a moderate to high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke. Patients considered to be at increased risk of stroke generally include those with advanced age (e.g., ≥75 years), history of hypertension, diabetes mellitus, or congestive heart failure. In addition, population-based studies suggest that female sex is an important risk factor for stroke in patients with atrial fibrillation, particularly in patients ≥75 years of age.

AHA and ASA state that oral anticoagulation is not recommended in women ≤65 years of age with atrial fibrillation and no other risk factors; instead, antiplatelet therapy is a reasonable option in selected low-risk women.

In patients with atrial fibrillation at increased risk of stroke who cannot take or choose not to take oral anticoagulants for reasons other than concerns about major bleeding (e.g., those with difficulty maintaining stable INRs, compliance issues, dietary restrictions, cost limitations), combination therapy with clopidogrel and aspirin rather than aspirin alone is recommended.

Antiplatelet agents may be used in combination with warfarin therapy in selected patients who have coexisting conditions that warrant use of antiplatelet therapy (e.g., those with recent placement of an intracoronary stent, those with acute coronary syndrome).

AHA and ASA state that apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in selected women with paroxysmal or permanent atrial fibrillation and certain risk factors who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (creatinine clearance <15 mL/minute), lower body weight (<50 kg), or advanced liver disease (impaired baseline clotting function). Warfarin generally should remain the treatment of choice in patients with severe renal impairment pending clinical outcomes data with the non-vitamin K antagonist oral anticoagulants in such patients.

Experts suggest managing antithrombotic therapy in patients with atrial flutter in the same manner as in patients with atrial fibrillation.

Cardioversion of Atrial Fibrillation

Prevention of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation.

ACCP and other experts recommend that patients with atrial fibrillation lasting >48 hours or of unknown duration who are to undergo elective cardioversion receive therapeutic anticoagulation (e.g., usually with warfarin) for ≥3 weeks prior to cardioversion; alternatively, a transesophageal echocardiography (TEE)-guided approach may be used. After successful cardioversion, all patients should receive therapeutic anticoagulation for ≥4 weeks.

Experts suggest the same approach to thromboprophylaxis in patients undergoing cardioversion for atrial flutter as that used in patients with atrial fibrillation.

Embolism Associated with Valvular Heart Disease

Prevention of thromboembolism associated with various types of valvular heart disease, in combination with or as an alternative to low-dose aspirin; assess risk of thromboembolism versus risk of bleeding when determining choice of antithrombotic therapy.

Warfarin anticoagulation (INR 2–3) is recommended in patients with rheumatic mitral valve disease and concurrent atrial fibrillation, left atrial thrombus, or a history of systemic embolism.

ACCP suggests warfarin anticoagulation in patients with rheumatic mitral valve disease and normal sinus rhythm who have a left atrial diameter >5.5 cm† because of their high risk of developing atrial fibrillation.

Warfarin also recommended by ACC and AHA for prevention of thromboembolic events in selected patients with mitral valve prolapse and a history of stroke who have concomitant atrial fibrillation, mitral valve regurgitation, or left atrial thrombus.

Generally should not initiate antithrombotic therapy in patients with infective endocarditis involving a native valve because of the risk of serious (e.g., intracerebral) hemorrhage and lack of documented efficacy. In patients with a prosthetic valve who are already receiving warfarin, ACCP suggests temporary discontinuance of the drug if infective endocarditis develops and reinitiation of therapy once invasive procedures no longer required and patient is stabilized without signs of neurologic complications.

Used in a limited number of patients undergoing percutaneous balloon mitral valvotomy† to prevent left atrial embolism.

Thromboembolism Associated with Prosthetic Heart Valves

Used to reduce the incidence of thromboembolism (e.g., stroke) in patients with prosthetic mechanical or biological heart valves.

Risk of systemic embolism higher with mechanical versus bioprosthetic valves, higher with first-generation mechanical (e.g., caged ball, caged disk) valves versus newer mechanical (e.g., bileaflet, Medtronic Hall tilting disk) valves, higher with >1 prosthetic valve, and higher with prosthetic mitral versus aortic valves; risk also increases in the presence of atrial fibrillation.

Long-term warfarin therapy required in all patients with mechanical heart valves because of associated high risk of thromboembolism.

Warfarin anticoagulation also suggested in patients with mitral bioprosthetic valves, at least for the first 3 months after valve insertion. In patients with aortic bioprosthetic valves who are in sinus rhythm and have no other indications for warfarin therapy, aspirin generally suggested for initial (e.g., first 3 months after valve insertion) and long-term antithrombotic therapy. However, long-term warfarin therapy (INR 2.5, range 2–3) may be indicated in some patients with bioprosthetic heart valves who have additional risk factors for thromboembolism (e.g., atrial fibrillation, prior thromboembolism, left ventricular dysfunction, hypercoagulable states).

In general, target INR of 2.5 (range 2–3) is suggested in patients with an aortic mechanical valve, while target INR of 3 (range 2.5–3.5) is recommended in those with a mitral mechanical valve. A higher intensity of warfarin anticoagulation also may be considered in patients with both aortic and mitral mechanical valves.

ACCP recommends adding low-dose aspirin (e.g., 50–100 mg daily) to warfarin therapy in all patients with mechanical heart valves who are at low risk of bleeding. Combination therapy also may be warranted in some patients with bioprosthetic valves (e.g., those with additional risk factors for thrombosis).

ST-Segment-Elevation MI (STEMI)

Used for secondary prevention to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after acute STEMI.

In general, antiplatelet therapy is preferred to anticoagulants for secondary prevention and risk reduction in patients with atherosclerosis, including those with acute STEMI; however, warfarin (in combination with low-dose aspirin) may be indicated in selected patients (e.g., those with atrial fibrillation, prosthetic heart valve, left ventricular thrombus, or concomitant venous thromboembolic disease).

The manufacturer and other experts recommend warfarin therapy (target INR 2–3) in conjunction with low-dose aspirin (≤100 mg daily) for ≥3 months following acute STEMI in high-risk patients (e.g., those with large anterior MI, substantial heart failure, intracardiac thrombus visible on transthoracic echocardiography, atrial fibrillation, history of previous thromboembolic event). Triple therapy with warfarin, low-dose aspirin, and clopidogrel is suggested in some patients (e.g., those with anterior MI and left ventricular thrombus who undergo coronary artery stent placement).

Cerebral Embolism

Oral anticoagulation with warfarin or one of the non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran, rivaroxaban) is recommended for secondary prevention of cerebral embolism in patients with TIAs or ischemic stroke and concurrent atrial fibrillation, provided no contraindications exist.

Warfarin anticoagulation also is recommended for the prevention of recurrent stroke in patients at high risk for recurring cerebral embolism from other cardiac sources (e.g., prosthetic mechanical heart valves, anterior MI and left ventricular thrombus).

Antiplatelet agents generally preferred over oral anticoagulation for secondary prevention of noncardioembolic stroke in patients with a history of ischemic stroke or TIA.

ACCP, AHA, and ASA generally recommend oral anticoagulation with warfarin following initial therapy with heparin or an LMWH in patients with acute cerebral venous sinus thrombosis†. AHA and ASA recommend postpartum anticoagulation with warfarin (target INR of 2–3) as an alternative to LMWH for at least 6 weeks (for a total minimum duration of 6 months of anticoagulant therapy) following LMWH therapy during pregnancy in women with cerebral venous sinus thrombosis†. Warfarin is suggested by ACCP as an option for long-term anticoagulation in children with arterial ischemic stroke† associated with dissection or a cardioembolic cause. Warfarin also has been used in children with cerebral venous sinus thrombosis† who do not have substantial intracranial hemorrhage.

Arterial Occlusive Disease

Has been used in certain patients with peripheral arterial occlusive disease†. However, ACCP generally recommends use of antiplatelet agents (aspirin or clopidogrel) for primary or secondary prevention of cardiovascular events in patients with peripheral arterial disease.

Indefinite anticoagulation with warfarin recommended by ACCP in all patients with chronic thromboembolic pulmonary hypertension†.

Heparin-Induced Thrombocytopenia

May be used as follow-up therapy after initial treatment with a nonheparin anticoagulant (e.g., lepirudin, argatroban) in patients with HIT. Overlap therapy with warfarin and nonheparin anticoagulant for ≥5 days and until desired INR has been achieved.

Do not initiate warfarin in patients with HIT until substantial platelet recovery occurs (e.g., platelet count ≥150,000/mm³); in patients already receiving warfarin at the time of HIT diagnosis, ACCP suggests administration of vitamin K. (See Necrosis under Cautions.)

Warfarin Dosage and Administration

General

• Carefully individualize dosage based on clinical and laboratory findings (i.e., INR). Determine optimum dosage and duration of therapy by the condition being treated.

• Adjust dosage in small increments and carefully monitor patient response.

• Dosage of warfarin does not vary with the route of administration.

• Administration of large loading doses (i.e., >10 mg) not recommended; possible increased risk of hemorrhage or necrosis. (See Hemorrhage under Cautions.)

• Factors such as concomitant therapy with drugs or dietary or herbal supplements, changes in diet, environment (prolonged hot weather), physical state, and genetic variations in warfarin metabolism and/or sensitivity may alter an individual’s response to warfarin therapy. (See Factors Influencing Response under Cautions and see Interactions.)

Laboratory Monitoring of Therapy

• Determine INR regularly in all patients receiving warfarin. Monitor INR daily following initiation of therapy until it stabilizes in the therapeutic range. Frequency of subsequent INR determinations based on clinical judgment and patient response, but generally every 1–4 weeks.

• In patients with consistently stable INRs, ACCP has suggested an INR testing interval of up to 12 weeks.

• Perform additional INR testing when different warfarin preparations (e.g., proprietary versus generic) are interchanged, and when concomitant drug therapy is added, discontinued, or taken irregularly.

• Safety and efficacy may be improved by increasing the quality of laboratory control. Proportion of time in the therapeutic INR range is increased in patients managed by anticoagulation clinics and in patients managed with the assistance of computer programs.

• ACCP suggests that self-management be considered as an alternative to outpatient monitoring in appropriately selected, motivated patients who can demonstrate competency in self-management strategies and techniques.

Pharmacogenomics

• Variations in genes responsible for warfarin metabolism or pharmacodynamic response may affect dosage requirements.

• Lower dosages may be required to avoid excessive anticoagulation (e.g., INR >3) and bleeding in patients with variations in 2 genes (CYP2C9 and VKORC1).

• Current lack of evidence to support benefit of routine genetic testing; ACCP currently recommends against routine use of genetic testing to guide initial dosage selection.

Transferring from Parenteral Anticoagulants to Warfarin

• When warfarin is indicated for follow-up therapy after initial therapy with a parenteral anticoagulant (e.g., heparin, LMWH), overlap therapy with parenteral anticoagulant and warfarin until adequate oral anticoagulation obtained as indicated by INR monitoring.

• Manufacturers recommend that heparin and warfarin be used concurrently for ≥4–5 days until the desired INR has been achieved.

• In adults with acute DVT or PE, ACCP recommends that heparin, an LMWH, or fondaparinux be used concurrently with warfarin for ≥5 days and until INR is ≥2 for ≥24 hours.

• In children with venous thromboembolism† in whom long-term warfarin therapy is being considered, ACCP recommends that warfarin be initiated on the same day as heparin or an LMWH; overlap such therapy for ≥5 days and until the INR is therapeutic.

• When warfarin is used for follow-up therapy after a nonheparin anticoagulant (e.g., argatroban, lepirudin) in patients with HIT, overlap therapy with warfarin and the nonheparin anticoagulant for ≥5 days until an adequate response to warfarin is obtained as indicated by INR. Initiate warfarin therapy only after substantial recovery from acute HIT has occurred (i.e., platelet counts ≥150,000/mm³).

• Conversion from argatroban to warfarin is more complex than with other nonheparin anticoagulants since combined therapy with argatroban and warfarin prolongs the PT/INR beyond that produced by warfarin alone. Consult manufacturer's prescribing information for specific guidelines for conversion. Monitor INR daily during concurrent argatroban and warfarin therapy.

Interruption of Therapy for Invasive Procedures

• Temporary interruption of warfarin therapy may be required in patients undergoing surgery or other invasive procedures to minimize risk of perioperative bleeding.

• Assess risk of thromboembolism versus risk of perioperative bleeding to determine whether interruption of therapy is necessary. Temporary interruption of therapy usually required for major surgical or invasive procedures, but may not be necessary for minor procedures associated with a low bleeding risk (e.g., minor dental procedures, minor dermatologic procedures, cataract surgery).

• If temporary interruption of warfarin necessary prior to surgery, discontinue approximately 5 days prior to procedure. May resume approximately 12–24 hours postoperatively when adequate hemostasis is achieved.

• May consider bridging anticoagulation (administration of an LMWH or IV heparin during the period of warfarin interruption) in patients at particularly high risk of thromboembolism. ACCP states that bridging therapy generally unnecessary for patients other than those at highest risk for stroke and/or venous thromboembolism (e.g., patients with mechanical heart valves, atrial fibrillation, or a venous thromboembolic event with additional risk factors for venous thromboembolism).

Administration

Administer orally. Administer by IV injection when therapy with a coumarin derivative is indicated and oral therapy is not feasible.

IM administration not recommended.

Oral Administration

Administer in a single daily dose. Administer at the same time each day, with food or on an empty stomach.

If a dose is missed, contact clinician. Administer dose as soon as remembered on the same day; do not take a double dose the next day to make up for the missed dose.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute lyophilized 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

Available as warfarin sodium; dosage expressed in terms of warfarin sodium.

Initial dosage varies widely among patients; individualize dosage based on factors such as age, race, body weight, sex, genotype, concomitant drugs, and the specific indication being treated.

Adjust dosage based on INR; if a previously stable patient presents with a single subtherapeutic or supratherapeutic INR (≤0.5 above or below the therapeutic range), ACCP suggests that current dosage be continued and INR retested within 1–2 weeks.

The manufacturers state that usual initial dosage is 2–5 mg daily in patients whose CYP2C9 and VKORC1 genotypes are not known. For patients with known CYP2C9 and VKORC1 genotypes, the manufacturers suggest that initial dosage may be determined by expected maintenance dosages observed in clinical studies of patients with various combinations of these gene variants. (See Table.)

Manufacturers suggest using these expected maintenance dosage ranges to estimate initial daily dosage in patients with known CYP2C9 and VKORC1 genotypes. Dosage ranges derived from multiple published clinical studies. VKORC1-1639G > A (rs9923231) variant is used in this table; other co-inherited VKORC1 variants also may be important determinants of warfarin sodium dosage.

Routine use of warfarin loading doses not recommended by manufacturer; however, some evidence suggests that use of a 10-mg loading dose may reduce time to therapeutic INR.

Pediatric Patients

Warfarin dosage in pediatric patients varies based on age; infants generally have the highest, and adolescents have the lowest dosage requirements. ACCP generally suggests a target INR range of 2–3 for most indications in children except in the setting of prosthetic cardiac valves where adherence to adult recommendations is suggested.

Adults

Treatment of DVT and PE

Oral or IV

Adjust dosage to achieve and maintain target INR of 2.5 (range 2–3).

Patients with a proximal DVT or PE provoked by surgery or other transient risk factor: ACCP states that 3 months of anticoagulation usually sufficient.

Patients with an unprovoked (idiopathic) thromboembolic event: Continue anticoagulant therapy for ≥3 months; after 3 months, evaluate risks and benefits of extended therapy. In general, extended anticoagulant therapy is recommended in patients with low risk of bleeding.

Cancer patients with acute venous thromboembolism: Extended anticoagulant therapy recommended.

Patients with acute upper-extremity DVT involving the axillary or more proximal veins: Continue anticoagulant therapy ≥3 months. If upper-extremity DVT associated with a central venous catheter, continue anticoagulation as long as the catheter remains in place; if catheter is removed, 3 months of anticoagulation is sufficient.

Prevention of DVT and PE

Hip-Replacement, Knee-Replacement, or Hip-fracture Surgery

Oral or IV

Adjust dosage to INR range of 2–3.

ACCP recommends continuing thromboprophylaxis for at least 10–14 days, and possibly for up to 35 days after surgery.

Embolism Associated with Atrial Fibrillation

Oral or IV

Maintain target INR of 2.5 (range 2–3) long term. Manage atrial flutter in a similar manner as atrial fibrillation.

Cardioversion of Atrial Fibrillation

Oral or IV

Patients with atrial fibrillation lasting >48 hours or of unknown duration: Initiate warfarin ≥3 weeks prior to cardioversion (target INR 2–3) and continue after the procedure until normal sinus rhythm maintained for ≥4 weeks. Manage atrial flutter in a similar manner as atrial fibrillation.

Embolism Associated with Valvular Heart Disease

Oral or IV

Patients with rheumatic mitral valve disease and concurrent atrial fibrillation, left atrial thrombus, or a history of systemic embolism: Maintain target INR of 2.5 (range 2–3).

Patients with rheumatic mitral valve disease in normal sinus rhythm, but with left atrial hypertrophy (left atrial diameter >5.5 cm)†: Target INR of 2.5 (range 2–3) suggested by ACCP.

Patients being considered for percutaneous mitral valvotomy with evidence of left atrial thrombus (confirmed by TEE)†: Treat with warfarin (target INR of 3; range 2.5–3.5) and postpone procedure until thrombus resolution.

Thromboembolism Associated with Prosthetic Heart Valves

Prophylaxis

Oral or IV

Base intensity of anticoagulation on the type of valve prosthesis. In general, target INR of 2.5 (range 2–3) suggested in patients with a mechanical aortic valve; target INR of 3 (range 2.5–3.5) recommended in those with a mechanical mitral valve. Higher intensity of anticoagulation also may be considered in patients with mechanical heart valves in both aortic and mitral positions.

Patients with mechanical heart valves in any position: Long-term oral anticoagulation required. ACCP recommends adding an antiplatelet agent such as low-dose aspirin (e.g., 50–100 mg daily) to warfarin therapy in patients at low risk of bleeding.

Patients with bioprosthetic mitral valves: ≥3 months of warfarin therapy suggested after valve insertion; after 3 months, may switch to aspirin therapy, provided patient is in normal sinus rhythm.

Patients with bioprosthetic heart valves and additional risk factors for thromboembolism (e.g., atrial fibrillation, prior thromboembolism, left ventricular dysfunction, hypercoagulable states): Long-term warfarin therapy may be warranted; may consider adding aspirin therapy.

STEMI

Secondary Prevention

Oral or IV

Patients at high risk of systemic or pulmonary embolism (e.g., large anterior STEMI, a history of previous thromboembolism, intracardiac thrombus, atrial fibrillation, or substantial heart failure): Long-term (≥3 months) warfarin (INR 2–3) and aspirin therapy (≤100 mg daily) recommended following acute STEMI.

Cerebral Thromboembolism

Secondary Prevention

Oral or IV

Patients with TIAs or ischemic stroke and concurrent atrial fibrillation: Maintain target INR of 2.5 (range 2–3) long term, provided no contraindications to therapy exist.

Patients with risk of recurrent stroke from other cardiac sources (e.g., anterior MI and left ventricular thrombus): ACCP recommends warfarin anticoagulation to maintain an INR of 2–3 with concomitant low-dose aspirin; the addition of clopidogrel is recommended in selected patients.

Patients with acute cerebral venous sinus thrombosis† provoked by a transient risk factor: AHA, ASA, and other experts suggest continuation of anticoagulation with warfarin (after initial heparin or low molecular weight heparin therapy) for 3–6 months, with dosage adjusted to maintain a target INR of 2–3.

Patients with unprovoked cerebral venous sinus thrombosis†: AHA and ASA suggest continuing warfarin therapy for 6–12 months (target INR of 2–3).

Patients with severe thrombophilia, recurrent cerebral venous sinus thrombosis†, venous thrombosis occurring after acute cerebral venous sinus thrombosis†, or other permanent risk factors for recurrent thrombosis: Consider indefinite anticoagulation with warfarin (target INR of 2–3) following an initial episode of cerebral venous sinus thrombosis†.

Patients with a patent foramen ovale and cryptogenic stroke† who have evidence of DVT: Target INR 2.5 (range 2–3) recommended.

HIT†

Conversion to Warfarin Therapy†

Oral or IV

Initiate warfarin only after substantial recovery from acute HIT has occurred (i.e., platelet counts ≥150,000/mm³).

Overlap therapy with a nonheparin anticoagulant for ≥5 days until desired INR is achieved.

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. Consider low initial dosages. Adjust dosage to maintain INR at the lower end of the range of 2–3.

Debilitated Patients

Possible increased anticoagulant effect. Consider low initial dosages.

Asian Patients

Possible increased anticoagulant effect. May require lower initial and maintenance dosages. (See Pharmacogenomics under Dosage and Administration.)

Cautions for Warfarin

Contraindications

• Pregnancy.

• Hemorrhagic tendencies or blood dyscrasias.

• Recent or contemplated eye, brain, or spinal cord surgery.

• Recent or contemplated traumatic surgery resulting in open surgical wounds.

• Active ulceration or bleeding 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 or other lack of patient cooperation.

• Inadequate laboratory facilities for monitoring anticoagulation.

• Known hypersensitivity to warfarin or any ingredient in the formulation.

Warnings/Precautions

Warnings

Hemorrhage

Possible massive hemorrhage involving the GI tract, spinal cord, GU, cerebral, pericardial, pulmonary, adrenal, or hepatic sites. (See Boxed Warning.) 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/INR prolongation; however, may occur when the PT/INR is in the usual therapeutic range and frequently results from the presence of occult lesions. More likely to occur during the initiation of therapy and with higher dosages, resulting in higher INRs.

Increased risk of postoperative hemorrhage associated with an aPTT >50 seconds even if PT/INR in desired range.

Careful clinical management, including frequent PT/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).

In patients with major bleeding associated with warfarin therapy, ACCP suggests the use of 4-factor prothrombin complex concentrate rather than fresh frozen plasma for rapid reversal of anticoagulation; additional use of phytonadione (5–10 mg by slow IV infusion) recommended.

Adrenal hemorrhage resulting in acute adrenal insufficiency reported with anticoagulant therapy. In patients with manifestations of acute adrenal hemorrhage or insufficiency, discontinue anticoagulant therapy, measure plasma cortisol concentrations immediately, and institute prompt, vigorous therapy with IV corticosteroids; delay in initiating therapy may result in death.

Tissue 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 warfarin-induced necrosis is suspected and administer vitamin K (phytonadione) or fresh frozen plasma. Consider heparin or LMWH 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 HIT when warfarin is substituted for or continued after heparin or LMWH treatment. Use with caution. If warfarin use necessary, delay initiation of therapy until thrombin generation is adequately controlled and thrombocytopenia has resolved (i.e., platelet counts ≥150,000/mm³).

Initiation of anticoagulant therapy with heparin for 4–5 days before initiation of warfarin or overlapping therapy with the 2 drugs for 5–6 days may minimize the risk of warfarin-induced necrosis.

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.

Fetal/Neonatal Morbidity and Mortality

Possible teratogenicity, fetal or neonatal hemorrhage, and intrauterine death. Detectable in fetal plasma at concentrations approaching maternal concentrations. Generally contraindicated during pregnancy, except in certain pregnant women (e.g., those with mechanical heart valves) considered to be at high risk for thrombosis.

ACCP, ACC, and AHA suggest that warfarin might not be fetopathic when administered during the first 6 weeks of pregnancy. If decision made to use warfarin during pregnancy, ACCP recommends avoiding administration during weeks 6–12 of gestation and close to term (to avoid anticoagulation of the fetus).

General Precautions

Adequate Patient Evaluation and Monitoring

Closely supervise all patients medically and ensure availability of adequate laboratory facilities for monitoring therapy (e.g., using PT/INR) and treating hemorrhage.

Factors Influencing Response

Possible increased anticoagulant response (increased PT/INR 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, initial hypoprothrombinemia, and decreased clearance of warfarin as a result of variations in genes responsible for warfarin metabolism. (See Pharmacogenomics under Dosage and Administration.)

Possible increased sensitivity to anticoagulant effect in Asian patients. (See Asian Patients under Dosage and Administration.)

Possible decreased response (decreased PT/INR) due to increased intake or GI absorption of vitamin K, diabetes mellitus, edema, hyperlipidemia, hypothyroidism, and visceral carcinoma.

Rarely, 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.

Surgery or Other Invasive 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.

Administer IM injections of concomitantly administered therapy in an upper extremity to permit easy access for manual compression, inspection for bleeding, and/or use of pressure bandages.

Specific Populations

Pregnancy

Category X. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Limited data indicate that warfarin is not distributed into breast milk or detectable in plasma of nursing infants; prolonged PT/INRs reported in some infants, but substantial coagulation abnormalities not observed. Although the manufacturer states to exercise caution, experts generally consider warfarin therapy compatible with breast-feeding.

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 INR are recommended in pediatric patients.

ACCP states experience with warfarin in the pediatric population is mostly based on use in children >3 months of age.

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 due to decreased synthesis of coagulation factors and decreased metabolism of warfarin. 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 for Warfarin

Drug interactions with warfarin and other coumarin derivatives can occur via pharmacodynamic interactions (e.g., impaired hemostasis; increased or 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) or pharmacokinetic interactions (e.g., increased or decreased rate of warfarin metabolism; increased or decreased protein binding). Such interactions may increase or decrease response to coumarin derivatives. (See Tables 2 and 3.)

concurrent use probably should be avoided, if possible

concurrent use probably should be avoided, if possible

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with inhibitors or inducers of CYP2C9, 1A2, or 3A4 (increased warfarin exposure with concomitant inhibitors, decreased warfarin exposure with concomitant inducers). (See Table 4.) Closely monitor INR in patients who initiate, discontinue, or change dosages of these concomitant drugs.

list of drugs is not all-inclusive

Drugs that Increase Risk of Bleeding

Possible increased risk of bleeding with concomitant use of antiplatelet agents, NSAIAs, SSRIs, and anticoagulants other than warfarin. (See Table 5.)

Monitor closely. While the manufacturers of warfarin state that NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors, may be used with close monitoring in patients receiving warfarin, some experts (ACCP) suggest that such concomitant therapy be avoided.

Antibiotics or Antifungal Agents

Potential alteration in INR with concomitant use of certain antibiotics or antifungal agents; however, studies have not shown consistent effects on plasma warfarin concentrations.

Monitor INR closely when initiating or discontinuing any antibiotic or antifungal agent in patients receiving warfarin.

Dietary or Herbal Supplements

Concomitant therapy with dietary or herbal (botanical) supplements may alter an individual’s response to warfarin therapy. (See Tables 6 and 7.) Limited information is available regarding the interaction potential of dietary and herbal products. Exercise caution and perform additional PT/INR determinations whenever these products are added or discontinued.

Some botanical products (e.g., garlic, Gingko biloba) increase risk of bleeding when used alone; additive anticoagulant effects are possible when used concomitantly.

Possible interaction between warfarin and cranberry juice (i.e., increased effect and possible increased risk of bleeding). However, evidence mostly from case reports; prospective controlled studies generally have not been able to confirm this interaction. Although clinically important interaction not likely, monitor closely for changes in INR and bleeding.

Specific Drugs

Warfarin Pharmacokinetics

Absorption

Bioavailability

Essentially completely absorbed after oral administration; peak plasma concentration usually attained within 4 hours.

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 CompatibilityHID

Drug Compatibility

Actions

• 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). Also inhibits the anticoagulant proteins C and S.

• Interferes with the action of reduced vitamin K, which is necessary for the γ-carboxylation of several glutamic acid residues in the precursor proteins of these coagulation factors. Inhibits clotting factor synthesis by inhibiting the regeneration of reduced vitamin K from vitamin K epoxide via inhibition of vitamin K epoxide reductase.

• Sequential depletion of circulating functional coagulation factor VII , protein C, factor IX, protein S, factor X, and finally factor II.

• Vitamin K-dependent coagulation factors physiologically decreased in neonates compared with adults; thrombin generation after warfarin therapy delayed and reduced in children compared with adults.

• 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/INR and aPTT.

• Phytonadione (vitamin K₁) reverses the anticoagulant effect.

Advice to Patients

• Importance of providing patient a copy of manufacturer’s patient medication guide.

• Importance of strict adherence to prescribed dosage and schedule. Importance of taking tablets at the same time each day. If a dose is missed, take as soon as possible on the same day; do not take a double dose the next day to make up for the missed dose.

• Importance of informing clinician if a dose is missed or an extra dose is taken.

• Importance of close laboratory monitoring to determine INR and regular visits to clinician.

• Importance of informing clinician of coexisting conditions such as hepatic or renal dysfunction, high BP, CHF, diabetes mellitus, propensity for falling, and alcohol abuse.

• Importance of informing clinician if diarrhea, infections, or fever occurs during therapy.

• Importance of patients carrying a notice stating that they are undergoing anticoagulant therapy.

• Importance of avoiding alcohol or limiting use to small amounts; consult and inform clinician about alcohol use and abuse. (See Interactions.)

• Importance of avoiding drastic changes in diet and of eating a balanced diet with a constant amount of vitamin K. Avoid ingestion of large quantities of foods that contain a large amount of vitamin K (e.g., leafy green vegetables, certain vegetable oils). Importance of informing clinician before attempting to diet during warfarin therapy.

• Importance of avoiding or using only small amounts of 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 informing clinician about falls or injuries, especially head injuries, during therapy.

• 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 patients reporting symptoms of blood clots (e.g., pain, color, or temperature changes to any area of the body). Importance of reporting symptoms of purple toes syndrome (e.g., pain in toes, purple or dark toes) to clinician immediately.

• 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 OTC drugs or drugs prescribed by other clinicians without first informing primary clinician or pharmacist.

• 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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