Warfarin

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

Medically reviewed by Drugs.com. Last updated on Oct 13, 2020.

Uses
Dosage
Cautions
Interactions
Pharmacokinetics
Patient advice
Preparations

Warning

Possible major bleeding, sometimes fatal.²¹¹ ³³⁰ More likely to occur during initiation of therapy and with higher dosages, resulting in a higher INR.²¹¹ ³³⁰ (See Hemorrhage under Cautions.)
Risk factors for bleeding include a high intensity of anticoagulation (INR >4), age >65 years, highly variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs that may increase PT/INR, and a long duration of therapy.²¹¹ ³³⁰ (See Cautions.)
Monitor INR regularly.²¹¹ ³³⁰ Patients at high risk for bleeding may benefit from more frequent INR monitoring, careful dosage adjustment to achieve desired INR, and shorter duration of therapy.²¹¹ ³³⁰ (See Laboratory Monitoring of Therapy under Dosage and Administration.)
Instruct patients about preventative measures to minimize risk of bleeding and to immediately report signs and symptoms of bleeding to clinician.²¹¹ ³³⁰ ⁴⁴⁵ ⁴⁵³ (See Advice to Patients.)

Introduction

Anticoagulant; a coumarin derivative.²¹¹ ³³⁰

Uses for Warfarin

DVT and PE

Treatment and secondary prevention of venous thromboembolism (DVT and/or PE).²¹¹ ⁵⁰⁰ ¹⁰⁰⁵

Initiate concomitantly with a parenteral anticoagulant (e.g., a low molecular weight heparin [LMWH], heparin [referring throughout this monograph to unfractionated heparin], fondaparinux).¹⁰⁰⁵ 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.¹⁰⁰⁰ ¹⁰⁰⁵

Anticoagulant therapy generally not recommended for treatment of isolated distal DVT unless symptoms are severe and there is a risk for thrombus extension.¹⁰⁰⁵

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.¹⁰⁰⁰ ¹⁰⁰⁵

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).¹⁰⁰⁵ For most cases of venous thromboembolism, a minimum of 3 months of anticoagulant therapy is recommended.²¹¹ ³³⁰ ¹⁰⁰⁵ 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).¹⁰⁰⁵ (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).¹⁰⁰⁵

Used in select pediatric patients with DVT or PE†.¹⁰¹³ 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).¹⁰¹³

Treatment and secondary prevention of venous thromboembolic events secondary to use of central venous access devices (CVAD) in children†.¹⁰¹³ Remove affected CVAD if no longer functioning or required; however, if CVAD required, ACCP suggests giving anticoagulants until catheter is removed.¹⁰¹³ 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.¹⁰¹³

Orthopedic Surgery

Prevention of postoperative venous thromboembolism in patients undergoing hip- or knee-replacement surgery or hip-fracture surgery.¹⁰⁰³

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).¹⁰⁰³ Continue thromboprophylaxis for at least 10–14 days, and possibly for up to 35 days after surgery.¹⁰⁰³

Several antithrombotic agents (e.g., LMWHs, fondaparinux, low-dose heparin, warfarin, aspirin) recommended by ACCP for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery.¹⁰⁰³ 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).¹⁰⁰³

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, bleeding risk, logistics, and compliance.¹⁰⁰³

Embolism Associated with Atrial Fibrillation

Prevention of stroke and systemic embolism in patients with atrial fibrillation.²²³ ²⁷⁸ ²⁷⁹ ³⁶⁹ ⁴⁵⁶ ⁴⁵⁹ ⁵⁰⁰ ⁹⁹⁰ ⁹⁹⁹ ¹⁰⁰⁷ ¹⁰¹⁷ 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.⁸⁰ ⁸¹ ⁸² ²²³ ²⁷⁸ ²⁷⁹ ³⁶⁹ ⁴⁵⁶ ⁴⁵⁹ ⁹⁹⁰ ⁹⁹² ⁹⁹⁹ ¹⁰⁰⁷ ¹⁰¹⁷

Choice of antithrombotic therapy is based on patient's risk for stroke and bleeding.⁸⁰ ⁸¹ ⁸² ³⁴¹ ³⁴⁵ ³⁶⁹ ⁴⁵⁹ ⁹⁹⁹ ¹⁰⁰⁷ 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.⁸⁰ ⁸¹ ⁸² ²¹¹ ³³⁰ ³³⁵ ³⁴¹ ³⁴⁴ ³⁴⁵ ³⁴⁹ ⁴⁵⁶ ⁹⁹⁰ ⁹⁹⁹ ¹⁰⁰⁷ ¹⁰¹⁷ 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.⁸⁰ ⁸¹ ⁸² ⁵⁰⁰ ⁹⁹⁹ ¹⁰⁰⁷ 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.¹⁰¹⁷

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.¹⁰¹⁷

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.⁹⁹⁸ ¹⁰⁰⁷

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).¹⁰⁰⁷

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),¹⁰³⁸ lower body weight (<50 kg), or advanced liver disease (impaired baseline clotting function).¹⁰¹⁷ 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.⁸⁶

Experts suggest managing antithrombotic therapy in patients with atrial flutter in the same manner as in patients with atrial fibrillation.⁹⁹⁹ ¹⁰⁰⁷

Cardioversion of Atrial Fibrillation

Prevention of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation.³⁴¹ ⁹⁹⁹ ¹⁰⁰⁷

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.⁹⁹⁹ ¹⁰⁰⁷ After successful cardioversion, all patients should receive therapeutic anticoagulation for ≥4 weeks.⁹⁹⁹ ¹⁰⁰⁷

Experts suggest the same approach to thromboprophylaxis in patients undergoing cardioversion for atrial flutter as that used in patients with atrial fibrillation.⁹⁹⁹ ¹⁰⁰⁷

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.³⁴⁴ ⁴⁵⁹ ¹⁰⁰⁸

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.¹⁰⁰⁷ ¹⁰⁰⁸

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.¹⁰⁰⁸

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.⁹⁹⁶

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.¹⁰⁰⁸ 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.¹⁰⁰⁸

Used in a limited number of patients undergoing percutaneous balloon mitral valvotomy† to prevent left atrial embolism.¹⁰⁰⁸

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.²¹¹ ³³⁰ ³⁴¹ ³⁴² ³⁴³ ³⁷⁰ ¹⁰⁰⁸

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.³⁴¹ ³⁴² ³⁴³ ³⁷⁰ ¹⁰⁰⁸

Long-term warfarin therapy required in all patients with mechanical heart valves because of associated high risk of thromboembolism.²¹¹ ³³⁰ ³⁷⁰ ⁴⁵⁹ ⁹⁹⁶ ¹⁰⁰⁸

Warfarin anticoagulation also suggested in patients with mitral bioprosthetic valves, at least for the first 3 months after valve insertion.¹⁰⁰⁸ 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.⁹⁹⁶ ¹⁰⁰⁸ 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).⁹⁹⁶

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.⁵⁰⁰ ¹⁰⁰⁸ ⁹⁹⁶ A higher intensity of warfarin anticoagulation also may be considered in patients with both aortic and mitral mechanical valves.¹⁰⁰⁸

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.¹⁰⁰⁸ Combination therapy also may be warranted in some patients with bioprosthetic valves (e.g., those with additional risk factors for thrombosis).⁹⁹⁶

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.⁵⁰⁰ ⁵²⁷ ⁹⁹² ¹⁰¹⁰

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).⁹⁹² ¹⁰¹⁰

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).⁵⁰⁰ ¹⁰¹⁰ 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).¹⁰¹⁰

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.³³⁵ ³³⁸ ³⁴⁹ ³⁵² ⁹⁹⁹ ¹⁰⁰⁹ ¹⁰¹⁷

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).¹⁰⁰⁸ ¹⁰¹⁰

Antiplatelet agents generally preferred over oral anticoagulation for secondary prevention of noncardioembolic stroke in patients with a history of ischemic stroke or TIA.¹⁰⁰⁹

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†.¹⁰⁰⁹ ¹⁰¹⁷ 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†.¹⁰¹⁷ 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.¹⁰¹³ Warfarin also has been used in children with cerebral venous sinus thrombosis† who do not have substantial intracranial hemorrhage.¹⁰¹³

Arterial Occlusive Disease

Has been used in certain patients with peripheral arterial occlusive disease†.¹⁰¹¹ 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.¹⁰¹¹

Indefinite anticoagulation with warfarin recommended by ACCP in all patients with chronic thromboembolic pulmonary hypertension†.¹⁰⁰⁵

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.¹⁰⁰⁶ Overlap therapy with warfarin and nonheparin anticoagulant for ≥5 days and until desired INR has been achieved.¹⁰⁰⁶

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.¹⁰⁰⁶ (See Necrosis under Cautions.)

Warfarin Dosage and Administration

General

Carefully individualize dosage based on clinical and laboratory findings (i.e., INR).²¹¹ ³³⁰ Determine optimum dosage and duration of therapy by the condition being treated.⁵⁰⁰
Adjust dosage in small increments and carefully monitor patient response.²¹¹ ³³⁰
Dosage of warfarin does not vary with the route of administration.²¹¹
Administration of large loading doses (i.e., >10 mg) not recommended;²¹¹ ³³⁰ possible increased risk of hemorrhage or necrosis.²¹¹ ³³⁰ (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.²¹¹ ³³⁰ ⁴⁶² ⁴⁶³ ⁴⁶⁴ ⁴⁶⁵ ⁴⁶⁸ ⁴⁷² ⁴⁷⁴ (See Factors Influencing Response under Cautions and see Interactions.)

Laboratory Monitoring of Therapy

Determine INR regularly in all patients receiving warfarin.²¹¹ ³³⁰ Monitor INR daily following initiation of therapy until it stabilizes in the therapeutic range.²¹¹ ³³⁰ Frequency of subsequent INR determinations based on clinical judgment and patient response, but generally every 1–4 weeks.⁵⁰⁰
In patients with consistently stable INRs, ACCP has suggested an INR testing interval of up to 12 weeks.¹⁰⁰⁰
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.²¹¹ ³³⁰
Safety and efficacy may be improved by increasing the quality of laboratory control.²¹¹ ³³⁰ 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.²¹¹ ³³⁰ ⁴⁵² ⁴⁶²
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.¹⁰⁰⁰

Pharmacogenomics

Variations in genes responsible for warfarin metabolism or pharmacodynamic response may affect dosage requirements.²¹¹ ³³⁰ ³⁷⁸ ⁴⁶² ⁴⁶³ ⁴⁶⁴ ⁴⁶⁵ ⁴⁶⁶ ⁴⁶⁷ ⁴⁶⁸ ⁴⁶⁹ ⁴⁷⁰ ⁴⁷¹
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).²¹¹ ³³⁰ ⁴⁶² ⁴⁶⁴ ⁴⁶⁵ ⁴⁶⁶ ⁴⁶⁷ ⁴⁶⁹ ⁴⁷⁰ ⁴⁷⁴
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.¹⁰⁰⁰

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.¹⁰⁰⁰ ¹⁰⁰⁵
Manufacturers recommend that heparin and warfarin be used concurrently for ≥4–5 days until the desired INR has been achieved.²¹¹ ³³⁰ ⁵⁰⁰
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.¹⁰⁰⁵
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.¹⁰¹³
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.¹⁰⁰⁶ Initiate warfarin therapy only after substantial recovery from acute HIT has occurred (i.e., platelet counts ≥150,000/mm³).¹⁰⁰⁶
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.³⁹² Consult manufacturer's prescribing information for specific guidelines for conversion.³⁹² Monitor INR daily during concurrent argatroban and warfarin therapy.³⁹²

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.¹⁰⁰⁴
Assess risk of thromboembolism versus risk of perioperative bleeding to determine whether interruption of therapy is necessary.¹⁰⁰⁴ 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).¹⁰⁰⁴
If temporary interruption of warfarin necessary prior to surgery, discontinue approximately 5 days prior to procedure.¹⁰⁰⁴ May resume approximately 12–24 hours postoperatively when adequate hemostasis is achieved.¹⁰⁰⁴
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.¹⁰⁰⁴ 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).¹⁰⁰⁴

Administration

Administer orally.²¹¹ ³³⁰ Administer by IV injection when therapy with a coumarin derivative is indicated and oral therapy is not feasible.²¹¹

IM administration not recommended.²¹¹

Oral Administration

Administer in a single daily dose.²¹¹ ³³⁰ Administer at the same time each day, with food or on an empty stomach.⁴⁵³

If a dose is missed, contact clinician.⁴⁴⁵ ⁴⁵³ 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.⁴⁴⁵ ⁴⁵³

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.²¹¹

Rate of Administration

Inject slowly (over 1–2 minutes) into a peripheral vein.²¹¹

Dosage

Available as warfarin sodium; dosage expressed in terms of warfarin sodium.²¹¹ ³³⁰

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.⁵⁰⁰

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.¹⁰⁰⁰

The manufacturers state that usual initial dosage is 2–5 mg daily in patients whose CYP2C9 and VKORC1 genotypes are not known.²¹¹ ⁵⁰⁰ 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.²¹¹ ⁵⁰⁰ (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.

Table 1. Expected Daily Maintenance Dosages of Warfarin Sodium Based on CYP2C9 and VKORC1 Genotypes211500
	CYP2C9
VKORC1	1/1	1/2	1/3	2/2	2/3	3/3
GG	5–7 mg	5–7 mg	3–4 mg	3–4 mg	3–4 mg	0.5–2 mg
AG	5–7 mg	3–4 mg	3–4 mg	3–4 mg	0.5–2 mg	0.5–2 mg
AA	3–4 mg	3–4 mg	0.5–2 mg	0.5–2 mg	0.5–2 mg	0.5–2 mg

Routine use of warfarin loading doses not recommended by manufacturer;²¹¹ ⁵⁰⁰ however, some evidence suggests that use of a 10-mg loading dose may reduce time to therapeutic INR.¹⁰⁰⁰

Pediatric Patients

Warfarin dosage in pediatric patients varies based on age; infants generally have the highest, and adolescents have the lowest dosage requirements.²¹¹ ⁵⁰⁰ 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.¹⁰¹³

Adults

Treatment of DVT and PE

Oral or IV

Adjust dosage to achieve and maintain target INR of 2.5 (range 2–3).³³² ⁵⁰⁰ ¹⁰⁰⁵

Patients with a proximal DVT or PE provoked by surgery or other transient risk factor: ACCP states that 3 months of anticoagulation usually sufficient.¹⁰⁰⁵

Patients with an unprovoked (idiopathic) thromboembolic event: Continue anticoagulant therapy for ≥3 months; after 3 months, evaluate risks and benefits of extended therapy.¹⁰⁰⁵ In general, extended anticoagulant therapy is recommended in patients with low risk of bleeding.¹⁰⁰⁵

Cancer patients with acute venous thromboembolism: Extended anticoagulant therapy recommended.¹⁰⁰⁵

Patients with acute upper-extremity DVT involving the axillary or more proximal veins: Continue anticoagulant therapy ≥3 months.¹⁰⁰⁵ 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.¹⁰⁰⁵

Prevention of DVT and PE

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

Oral or IV

Adjust dosage to INR range of 2–3.⁵⁰⁰ ¹⁰⁰⁰

ACCP recommends continuing thromboprophylaxis for at least 10–14 days, and possibly for up to 35 days after surgery.¹⁰⁰³

Embolism Associated with Atrial Fibrillation

Oral or IV

Maintain target INR of 2.5 (range 2–3) long term.²¹¹ ³³⁰ ³³⁵ ³⁴⁴ ³⁴⁵ ³⁴⁹ ³⁶⁹ ⁹⁹⁰ ⁹⁹⁹ ¹⁰⁰⁷ Manage atrial flutter in a similar manner as atrial fibrillation.⁹⁹⁹ ¹⁰⁰⁷

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.⁹⁹⁹ ¹⁰⁰⁷ Manage atrial flutter in a similar manner as atrial fibrillation.⁹⁹⁹ ¹⁰⁰⁷

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).¹⁰⁰⁸

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.¹⁰⁰⁸

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.¹⁰⁰⁸

Thromboembolism Associated with Prosthetic Heart Valves

Prophylaxis

Oral or IV

Base intensity of anticoagulation on the type of valve prosthesis.²¹¹ ³³⁰ ⁹⁹⁶ ¹⁰⁰⁸ 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.⁵⁰⁰ ¹⁰⁰⁸ ⁹⁹⁶ Higher intensity of anticoagulation also may be considered in patients with mechanical heart valves in both aortic and mitral positions.¹⁰⁰⁸

Patients with mechanical heart valves in any position: Long-term oral anticoagulation required.⁹⁹⁶ ¹⁰⁰⁸ 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.¹⁰⁰⁸

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.¹⁰⁰⁸

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.⁹⁹⁶

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.⁵⁰⁰ ¹⁰¹⁰

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.³³⁵ ³³⁸ ³⁴⁹ ³⁵² ⁹⁹⁰ ¹⁰⁰⁹

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.¹⁰¹⁰

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,¹⁰⁰⁹ ¹⁰¹⁷ with dosage adjusted to maintain a target INR of 2–3.¹⁰¹⁷

Patients with unprovoked cerebral venous sinus thrombosis†: AHA and ASA suggest continuing warfarin therapy for 6–12 months (target INR of 2–3).¹⁰¹⁷

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†.¹⁰⁰⁹ ¹⁰¹⁷

Patients with a patent foramen ovale and cryptogenic stroke† who have evidence of DVT: Target INR 2.5 (range 2–3) recommended.¹⁰⁰⁸

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).³⁹² ⁴⁴² ⁴⁴³ ⁴⁴⁴ ¹⁰⁰⁶

Overlap therapy with a nonheparin anticoagulant for ≥5 days until desired INR is achieved.³⁸⁷ ³⁹² ³⁹³ ¹⁰⁰⁶

Special Populations

Hepatic Impairment

Possible increased anticoagulant effect.²¹¹ ³³⁰ May require lower initial and maintenance dosages.²¹¹ ³³⁰

Renal Impairment

Possible increased anticoagulant effect in moderate to severe renal impairment.^a No dosage adjustments required.²¹¹ ³³⁰

Geriatric Patients

Possible increased anticoagulant effect.²¹¹ ³³⁰ Consider low initial dosages.⁵⁰⁰ Adjust dosage to maintain INR at the lower end of the range of 2–3.²¹¹ ³³⁰ ³⁴⁴

Debilitated Patients

Possible increased anticoagulant effect.²¹¹ ³³⁰ Consider low initial dosages.⁵⁰⁰

Asian Patients

Possible increased anticoagulant effect.²¹¹ ³³⁰ ³⁷⁸ May require lower initial and maintenance dosages.²¹¹ ³³⁰ ³⁷⁸ (See Pharmacogenomics under Dosage and Administration.)

Cautions for Warfarin

Contraindications

Pregnancy.²¹¹ ³³⁰
Hemorrhagic tendencies or blood dyscrasias.²¹¹ ³³⁰
Recent or contemplated eye, brain, or spinal cord surgery.²¹¹ ³³⁰
Recent or contemplated traumatic surgery resulting in open surgical wounds.²¹¹ ³³⁰
Active ulceration or bleeding of the GI, respiratory, or GU tracts.²¹¹ ³³⁰
Cerebrovascular hemorrhage.²¹¹ ³³⁰
Aneurysms (cerebral, dissecting aorta).²¹¹ ³³⁰
Pericarditis and pericardial effusions.²¹¹ ³³⁰
Bacterial endocarditis.²¹¹ ³³⁰
Eclampsia, preeclampsia, or threatened abortion.²¹¹ ³³⁰
Spinal puncture or other diagnostic or therapeutic procedures with potential for uncontrolled bleeding.²¹¹ ³³⁰
Major regional or lumbar block anesthesia.²¹¹ ³³⁰
Severe, uncontrolled, or malignant hypertension.²¹¹ ³³⁰
Unsupervised patients with senility, alcoholism, or psychosis or other lack of patient cooperation.²¹¹ ³³⁰
Inadequate laboratory facilities for monitoring anticoagulation.²¹¹ ³³⁰
Known hypersensitivity to warfarin or any ingredient in the formulation.²¹¹ ³³⁰

Warnings/Precautions

Warnings

Hemorrhage

Possible massive hemorrhage involving the GI tract, spinal cord, GU, cerebral, pericardial, pulmonary, adrenal, or hepatic sites.^a (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.²¹¹ ³³⁰ 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.^a ²¹¹ ³³⁰ More likely to occur during the initiation of therapy and with higher dosages, resulting in higher INRs.²¹¹ ³³⁰

Increased risk of postoperative hemorrhage associated with an aPTT >50 seconds even if PT/INR in desired range.²¹¹ ³³⁰ ^a

Careful clinical management, including frequent PT/INR determinations, is required.²¹¹ ³³⁰ (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).^a ²¹¹ ³³⁰

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.¹⁰⁰⁰

Adrenal hemorrhage resulting in acute adrenal insufficiency reported with anticoagulant therapy.⁴⁰⁹ ⁴¹⁰ ⁴¹¹ ⁴¹⁷ 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.^a

Tissue Necrosis

Rarely, possible potentially fatal necrosis and/or gangrene of skin or other tissues.²⁰³ ²¹¹ ²¹⁵ ²⁹⁰ ²⁹¹ ²⁹² ²⁹³ ²⁹⁸ ³³⁰ Appears early (e.g., 1–10 days) after initiation of therapy principally at sites of fat tissue (e.g., abdomen, breasts, buttocks, thighs).²⁹⁰ ²⁹³ ²⁹⁸ Increased risk in patients with hereditary, familial, or clinical deficiencies of protein C or its cofactor, protein S.²¹¹ ²¹³ ²⁹⁰ ³³⁰

Discontinue therapy if warfarin-induced necrosis is suspected²¹¹ ²¹³ ²¹⁵ ²⁹⁰ ³³⁰ ³⁵⁴ and administer vitamin K (phytonadione) or fresh frozen plasma.²¹³ ²¹⁵ ²⁹⁰ ²⁹¹ Consider heparin or LMWH therapy to treat the underlying thromboembolic disease and possibly prevent additional microvascular thrombosis.²¹¹ ²¹³ ²¹⁵ ²⁹⁰ ²⁹⁸ ³³⁰ In severe cases, surgical debridement, skin grafting, or amputation may be necessary.²⁰³ ²¹¹ ²¹⁵ ²⁹⁰ ²⁹² ²⁹³ ³³⁰

Possible limb ischemia, necrosis, and gangrene may occur in patients with HIT when warfarin is substituted for or continued after heparin or LMWH treatment.³⁸⁷ ³⁸⁸ ³⁸⁹ ³⁹⁵ Use with caution.²¹¹ ³³⁰ ³⁹¹ 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).³⁵⁴ ⁴⁴² ⁴⁴³ ⁴⁴⁴ ¹⁰⁰⁶

Initiation of anticoagulant therapy with heparin for 4–5 days before initiation of warfarin²¹¹ ³³⁰ or overlapping therapy with the 2 drugs for 5–6 days²⁰³ ²⁹¹ ²⁹² may minimize the risk of warfarin-induced necrosis.²⁰³ ²¹¹ ³³⁰

Purple Toes Syndrome and Cholesterol Microembolization

Purple toes syndrome may result from possible increased release of atheromatous plaque fragments from systemic cholesterol microemboli.²¹¹ ²¹⁶ ²²¹ ²⁸⁴ ²⁸⁵ ²⁸⁶ ²⁸⁷ ²⁸⁸ ³³⁰ May occur 3–10 weeks or later following initiation of warfarin therapy.²⁰³ ²¹¹ ²¹⁶ ²⁸⁴ ²⁸⁹ ³³⁰

Discontinuance of warfarin therapy is recommended; some cases of purple toes syndrome have progressed to gangrene or necrosis, requiring debridement and/or amputation.²¹¹ ²⁸⁴ ²⁸⁸ ³³⁰

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.²¹¹ ²¹⁶ ²²¹ ²⁸⁵ ²⁸⁷ ²⁸⁸ ³³⁰

Fetal/Neonatal Morbidity and Mortality

Possible teratogenicity, fetal or neonatal hemorrhage, and intrauterine death.²¹¹ ³³⁰ ¹⁰¹² ^a Detectable in fetal plasma at concentrations approaching maternal concentrations.²¹¹ ³³⁰ Generally contraindicated during pregnancy, except in certain pregnant women (e.g., those with mechanical heart valves) considered to be at high risk for thrombosis.²¹¹ ³³⁰ ³⁴¹ ³⁴² ³⁴³ ³⁸⁶ ⁵⁰⁰ ¹⁰¹²

ACCP, ACC, and AHA suggest that warfarin might not be fetopathic when administered during the first 6 weeks of pregnancy.³⁴¹ ¹⁰¹² 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).¹⁰¹²

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.²¹¹ ³³⁰

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.²¹¹ ³³⁰ ⁴⁶² ⁴⁶³ ⁴⁶⁴ ⁴⁶⁵ ⁴⁶⁶ ⁴⁶⁷ ⁴⁶⁸ ⁴⁶⁹ ⁴⁷⁰ ⁴⁷³ (See Pharmacogenomics under Dosage and Administration.)

Possible increased sensitivity to anticoagulant effect in Asian patients.²¹¹ ³⁷⁸ ⁴⁶⁵ ⁴⁶⁹ (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.²¹¹ ^a

Rarely, inherited familial coumarin resistance due to variations in the anticoagulant-vitamin K receptor site.^a May require 10–20 times the usual dosage to achieve therapeutic effects.^a Resistance also may result from an increased rate of drug metabolism and excretion.^a Consider acquired or inherited warfarin resistance if large daily doses are required to maintain the PT ratio/INR within a normal therapeutic range.²¹¹ ³³⁰

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.²¹¹

Limit the operative site sufficiently to permit effective use of local procedures for hemostasis (e.g., absorbable hemostatic agents, sutures, pressure dressings) if necessary.²¹¹ Maintain meticulous surgical hemostasis (e.g., absorbable hemostatic agents, sutures, pressure dressings) if minor dental and surgical procedures are performed.²¹¹ ^a

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.²¹¹

Specific Populations

Pregnancy

Category X.²¹¹ (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.²¹¹ ³³⁰ ⁴¹⁴ ⁴²⁰ ⁴²¹ ⁴²² ⁴²³ ⁴²⁴ Although the manufacturer states to exercise caution,⁵⁰⁰ experts generally consider warfarin therapy compatible with breast-feeding.³⁴¹ ⁴¹⁴ ⁴²⁰ ⁴²¹ ⁴²² ⁴²³ ⁴²⁴ ¹⁰¹²

Neonates are particularly sensitive to the effects of warfarin as a result of vitamin K deficiency.^a Monitor infants at risk for bleeding with coagulation tests and evaluate their vitamin K status before breast-feeding.²¹¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.²¹¹ ³³⁰ Has been used in pediatric patients for prevention and treatment of thromboembolic events.²¹¹ ³³⁰ More frequent determinations of INR are recommended in pediatric patients.²¹¹ ³³⁰ ¹⁰¹³

ACCP states experience with warfarin in the pediatric population is mostly based on use in children >3 months of age.¹⁰¹³

Geriatric Use

Increased anticoagulant response.^a ²¹¹ Less warfarin required to produce a therapeutic level of anticoagulation.^a Cautious use recommended, particularly when the risk of hemorrhage is present.²¹¹ ³³⁰ ³³⁵ Increased risk for hemorrhage in patients ≥75 years with atrial fibrillation who are at high risk for thromboembolism.³³⁵ Close monitoring of INR recommended.³³⁵

Hepatic Impairment

Increased anticoagulant response due to decreased synthesis of coagulation factors and decreased metabolism of warfarin.²¹¹ Weigh risks versus benefits of anticoagulant therapy in patients with moderate to severe hepatic impairment.²¹¹

Renal Impairment

Increased anticoagulant response in patients with moderate or severe renal impairment.^a Weigh risks versus benefits of anticoagulant therapy in patients with moderate to severe renal impairment.²¹¹

Common Adverse Effects

Hemorrhage.²¹¹

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).²¹¹ ^a Such interactions may increase or decrease response to coumarin derivatives. (See Tables 2 and 3.)

concurrent use probably should be avoided, if possible

Table 2. Drugs That May Increase Response to Coumarin Derivatives (e.g., Warfarin)211a
acetaminophen	ezetimibe	pantoprazole
*alcohol (acute intoxication)	fenofibrate	*pentoxifylline
allopurinol	fenoprofen calcium	phenylbutazone
aminosalicylic acid	fluoroquinolone anti-infectives	pravastatin
*amiodarone	fluoxetine	propafenone
anabolic steroids	flutamide	propoxyphene
argatroban	fluvastatin	propylthiouracil
aspirin	fluvoxamine	quinidine
atenolol	gefitinib	quinine
atorvastatin	gemfibrozil	*rabeprazole
azithromycin	glucagon	salicylates
bivalirudin	ibuprofen	sertraline
capecitabine	indomethacin	streptokinase
cefixime	influenza virus vaccine	sulfinpyrazone
celecoxib	isoniazid	sulfonamides
chloral hydrate	ketoprofen	sulindac
chloramphenicol	lansoprazole	tamoxifen
cimetidine	lepirudin	tetracycline
cisapride	lovastatin	thiazides
co-trimoxazole	meclofenamate	thyroid drugs
danazol	mefenamic acid	tramadol
diazoxide	methylthiouracil	tricyclic antidepressants
diflunisal	*metronidazole	*urokinase
*disulfiram	miconazole	valdecoxib
erythromycin	nalidixic acid	vitamin E
esomeprazole	neomycin (oral)	zafirlukast
ethacrynic acid	oxandrolone	zileuton

concurrent use probably should be avoided, if possible

Table 3. Drugs that May Decrease Response to Coumarin Derivatives (e.g., Warfarin)
*alcohol (chronic alcoholism)	ethchlorvynol	raloxifene
aminoglutethimide	glutethimide	rifampin
atorvastatin	griseofulvin	spironolactone
*barbiturates	mercaptopurine	sucralfate
carbamazepine	methaqualone	trazodone
clozapine	nafcillin	vitamin K
corticosteroids	*oral contraceptives containing estrogen
corticotropin	pravastatin

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).²¹¹ (See Table 4.) Closely monitor INR in patients who initiate, discontinue, or change dosages of these concomitant drugs.²¹¹

list of drugs is not all-inclusive

Table 4. CYP Interactions with Warfarin211
Enzyme	Inhibitors*	Inducers*
CYP2C9	amiodarone	aprepitant
	capecitabine	bosentan
	co-trimoxazole	carbamazepine
	etravirine	phenobarbital
	fluconazole	rifampin
	fluvastatin
	fluvoxamine
	metronidazole
	miconazole
	oxandrolone
	sulfinpyrazone
	tigecycline
	voriconazole
	zafirlukast
CYP1A2	acyclovir	montelukast
	allopurinol	moricizine
	caffeine	omeprazole
	cimetidine	phenobarbital
	ciprofloxacin	phenytoin
	disulfiram	cigarette smoking
	enoxacin
	famotidine
	fluvoxamine
	methoxsalen
	mexiletine
	norfloxacin
	oral contraceptives
	phenylpropanolamine
	propafenone
	propranolol
	terbinafine
	thiabendazole
	ticlopidine
	verapamil
	zileuton
CYP3A4	alprazolam	armodafinil
	amiodarone	amprenavir
	amlodipine	aprepitant
	amprenavir	bosentan
	aprepitant	carbamazepine
	atorvastatin	efavirenz
	atazanavir	etravirine
	bicalutamide	modafinil
	cilostazol	nafcillin
	cimetidine	phenytoin
	ciprofloxacin	pioglitazone
	clarithromycin	prednisone
	conivaptan	rifampin
	cyclosporine	rufinamide
	darunavir/ritonavir
	diltiazem
	erythromycin
	fluconazole
	fluoxetine
	fluvoxamine
	fosamprenavir
	imatinib
	indinavir
	isoniazid
	itraconazole
	ketoconazole
	lopinavir/ritonavir
	nefazodone
	nelfinavir
	nilotinib
	oral contraceptives
	posaconazole
	ranitidine
	ranolazine
	ritonavir
	saquinavir
	telithromycin
	tipranavir
	voriconazole
	zileuton

Drugs that Increase Risk of Bleeding

Possible increased risk of bleeding with concomitant use of antiplatelet agents, NSAIAs, SSRIs, and anticoagulants other than warfarin.²¹¹ (See Table 5.)

Monitor closely.²¹¹ 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,²¹¹ ⁵⁰⁰ some experts (ACCP) suggest that such concomitant therapy be avoided.¹⁰⁰⁰

Table 5. Drugs that Can Increase Bleeding Risk
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
NSAIAs	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin-reuptake inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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.²¹¹

Monitor INR closely when initiating or discontinuing any antibiotic or antifungal agent in patients receiving warfarin.²¹¹

Dietary or Herbal Supplements

Concomitant therapy with dietary or herbal (botanical) supplements may alter an individual’s response to warfarin therapy.²¹¹ (See Tables 6 and 7.) Limited information is available regarding the interaction potential of dietary and herbal products.²¹¹ Exercise caution and perform additional PT/INR determinations whenever these products are added or discontinued.²¹¹

Table 6. Dietary or Herbal Supplements that May Increase Response to Coumarin Derivatives (e.g., Warfarin)211a
agrimony	chamomile (German and Roman)	parsley
alfalfa	clove	passion flower
aloe gel	*cranberry	pau d’arco
Angelica sinensis (dong quai)	dandelion	policosanol
aniseed	fenugreek	poplar
arnica	feverfew	prickly ash (Northern)
asa foetida	garlic	quassia
aspen	German sarsaparilla	red clover
black cohosh	ginger	senega
black haw	Ginkgo biloba	sweet clover
bladder wrack (Fucus)	ginseng (Panax)	sweet woodruff
bogbean	horse chestnut	tamarind
boldo	horseradish	tonka beans
bromelains	inositol nicotinate	wild carrot
buchu	licorice	wild lettuce
capsicum	meadowsweet	willow
cassia	nettle	wintergreen
celery	onion

Table 7. Dietary or Herbal Supplements that May Decrease Response to Coumarin Derivatives (e.g., Warfarin)211a
agrimony	goldenseal	St. John’s wort
coenzyme Q₁₀ (ubidecarenone)	mistletoe	yarrow
ginseng (Panax)

Some botanical products (e.g., garlic, Gingko biloba) increase risk of bleeding when used alone; additive anticoagulant effects are possible when used concomitantly.²¹¹

Possible interaction between warfarin and cranberry juice (i.e., increased effect and possible increased risk of bleeding).⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ⁵⁰⁵ ⁵⁰⁶ ⁵¹⁰ However, evidence mostly from case reports; prospective controlled studies generally have not been able to confirm this interaction.⁵⁰¹ ⁵⁰² ⁵⁰⁴ ⁵⁰⁵ ⁵⁰⁷ ⁵⁰⁸ ⁵⁰⁹ ⁵¹⁰ ⁵¹¹ Although clinically important interaction not likely, monitor closely for changes in INR and bleeding.⁵⁰¹ ⁵⁰² ⁵⁰⁷ ⁵⁰⁸ ⁵⁰⁹ ⁵¹⁰

Specific Drugs

Drug	Interaction	Comments
Acetaminophen	Potential for increased anticoagulant effects;³⁰⁷ ³¹⁰ ³¹² ³¹³ ¹⁰¹⁴ however, conflicting data exist regarding clinical importance⁹⁰ ³⁰⁴ ³⁰⁵ ³⁰⁶ ³⁰⁸ ³⁰⁹ ³¹¹	Monitoring of INR recommended following initiation of, and during sustained therapy with large (>1.5 g daily) acetaminophen doses²¹¹ ³¹⁸ ³¹⁹ ³²⁰ ³²² ³³⁰ ¹⁰¹⁴
Alcohol	Moderate amounts (300–600 mL wine daily) did not alter warfarin plasma concentrations or hypoprothrombinemic effect in healthy young men;⁴⁹² ⁴⁹³ effects of moderate consumption (e.g., 1–2 drinks daily)⁴⁸⁶ in patients receiving long-term therapeutic anticoagulation not well studied⁴⁸⁶ ⁴⁹⁰ ⁴⁹¹ ⁴⁹⁵ Acute ingestion of alcohol may enhance warfarin hypoprothrombinemia;⁴⁸⁶ ⁴⁹⁰ ⁴⁹⁴ ⁴⁹⁵ long-term alcohol use (e.g., chronic alcoholism) associated with reduced warfarin effect through increased metabolism⁴⁸⁶ ⁴⁹⁰ ⁴⁹⁴ Antiplatelet effect of alcohol may increase bleeding risk without effects on INR⁴⁸⁷	Some clinicians recommend avoidance of concomitant alcohol ingestion⁴⁸⁵ ⁴⁸⁶ Other clinicians suggest limiting alcohol consumption to small amounts (e.g., 1–2 drinks occasionally)⁴⁸⁷ during warfarin therapy⁴⁸⁷ ⁴⁸⁸ and recommend against chronic heavy consumption (e.g., >720 mL beer, >300 mL wine, >60 mL liquor daily)⁴⁸⁹
Antiplatelet agents	Increased risk of bleeding¹⁰⁰⁰	ACCP suggests avoiding concomitant use unless benefit is known or is highly likely to exceed potential harm from bleeding¹⁰⁰⁰
Capecitabine	Inhibits CYP2C9 isoenzyme and decreases warfarin metabolism³⁸³ ³⁸⁴ Possible increased anticoagulant response, increased PT/INR, and/or potentially fatal bleeding episodes, especially in patients >60 years of age with cancer³⁸² ³⁸³	Use concomitantly with caution³⁸² ³⁸³ Frequent monitoring of PT/INR recommended to facilitate anticoagulant dosage adjustments³⁸² ³⁸³ ³⁸⁴
Cholestyramine	Potential for decreased warfarin absorption and decreased warfarin half-life^a Potential decreased vitamin K absorption^a	Concurrent use of cholestyramine and warfarin probably should be avoided, if possible^a
Lomitapide	Increased exposure to warfarin and increased INR¹⁰¹⁵	Manufacturer of lomitapide suggests monitoring INR regularly, particularly following adjustments in lomitapide dosage, and adjusting warfarin dosage as clinically indicated¹⁰¹⁵
Miconazole (vaginal)	Potential for increased PT/INR and/or bleeding²¹¹ ³³⁰ ³⁶² ³⁶³ ³⁶⁴	Monitoring PT/INR and appropriate dosage adjustments recommended with concomitant intravaginal miconazole therapy³⁶³ ³⁶⁴
NSAIAs	Potential for platelet aggregation inhibition, GI bleeding and peptic ulceration and/or perforation, altered PT/INR²¹¹ ³³⁰	Manufacturer recommends cautious use;⁵⁰⁰ ACCP suggests avoidance¹⁰⁰⁰
Oxandrolone	Potential for increased warfarin half-life and AUC⁴¹⁸ ⁴¹⁹ Potential increased PT/INR and bleeding⁴¹⁸ ⁴¹⁹	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 risk⁴¹⁹

Warfarin Pharmacokinetics

Absorption

Bioavailability

Essentially completely absorbed after oral administration; peak plasma concentration usually attained within 4 hours.²¹¹

Onset

Synthesis of vitamin K-dependent coagulation factors is affected soon after absorption (e.g., within 24 hours).²¹¹ ^a Depletion of circulating functional coagulation factors must occur before therapeutic effects of the drug become apparent.^a

Duration

2–5 days after a single dose.²¹¹

Food

Decreased rate, but not extent, of absorption in the presence of food.²¹¹

Distribution

Extent

The apparent volume of distribution is about 0.14 L/kg.²¹¹

Crosses the placental barrier; however, the drug has not been detected in human breast milk.²¹¹

Plasma Protein Binding

Approximately 99%.²¹¹

Elimination

Metabolism

Almost entirely in the liver.²¹¹ Principally by CYP2C9; CYP2C19, 2C8, 2C18, 1A2, and 3A4 involved to a lesser degree.²¹¹

Elimination Route

Excreted principally in urine as metabolites and to a lesser extent in bile.²¹¹

Half-life

Effective half-life averages 40 hours (range: 20–60 hours).²¹¹

Special Populations

Slightly decreased clearance of R-warfarin in geriatric patients compared with that in younger individuals.²¹¹ ³³⁰ However, similar pharmacokinetics of racemic warfarin and S-warfarin in geriatric and younger individuals.²¹¹

Decreased metabolism in patients with hepatic dysfunction.²¹¹

Stability

Storage

Oral

Tablets

15–30°C.²¹¹

Parenteral

Powder for Injection

15–30°C.²¹¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

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

Y-Site CompatibilityHID
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

A coumarin-derivative anticoagulant; a synthetic 3-substituted derivative of 4-hydroxycoumarin.²¹¹ ³³⁰ ^a
A racemic mixture of the 2 optical isomers of the drug.²¹¹ ³³⁰ ^a
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).²¹¹ ³³⁰ ^a Also inhibits the anticoagulant proteins C and S.²¹¹ ³³⁰
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.²¹¹ ³³⁰ Inhibits clotting factor synthesis by inhibiting the regeneration of reduced vitamin K from vitamin K epoxide via inhibition of vitamin K epoxide reductase.⁴⁶⁴
Sequential depletion of circulating functional coagulation factor VII , protein C, factor IX, protein S, factor X, and finally factor II.²¹¹ ³³⁰ ^a
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.⁴⁹⁶ ⁴⁹⁷ ¹⁰¹³
Antithrombogenic effects generally occur only after functional coagulation factors IX and X are diminished (usually 2–7 days following initiation of therapy).^a
Does not alter catabolism of blood coagulation factors.^a
Inhibits thrombus formation when stasis is induced; may prevent extension of existing thrombi.²¹¹ ³³⁰ ^a No direct effect on established thrombi.^a Little if any effect on platelet-rich arterial thrombi adhering to an abnormal vessel wall.^a
Prolongs PT/INR and aPTT.²¹¹ ³³⁰ ^a
Phytonadione (vitamin K₁) reverses the anticoagulant effect.²¹¹ ³³⁰ ^a

Advice to Patients

Importance of providing patient a copy of manufacturer’s patient medication guide.²¹¹ ³³⁰ ⁴⁴⁵ ⁴⁵³
Importance of strict adherence to prescribed dosage and schedule.²¹¹ ³³⁰ Importance of taking tablets at the same time each day.⁴⁵³ 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.⁴⁵³
Importance of informing clinician if a dose is missed or an extra dose is taken.⁴⁵³
Importance of close laboratory monitoring to determine INR and regular visits to clinician.²¹¹ ³³⁰
Importance of informing clinician of coexisting conditions such as hepatic or renal dysfunction, high BP, CHF, diabetes mellitus, propensity for falling, and alcohol abuse.⁴⁵³
Importance of informing clinician if diarrhea, infections, or fever occurs during therapy.⁴⁵³
Importance of patients carrying a notice stating that they are undergoing anticoagulant therapy.²¹¹ ³³⁰
Importance of avoiding alcohol²¹¹ ³³⁰ ⁴⁴⁵ ⁴⁵³ ⁴⁸⁵ ⁴⁸⁶ or limiting use to small amounts; consult and inform clinician about alcohol use and abuse.²¹¹ ³³⁰ ⁴⁴⁵ ⁴⁵³ (See Interactions.)
Importance of avoiding drastic changes in diet and of eating a balanced diet with a constant amount of vitamin K.²¹¹ ³³⁰ Avoid ingestion of large quantities of foods that contain a large amount of vitamin K (e.g., leafy green vegetables, certain vegetable oils).⁴⁵³ Importance of informing clinician before attempting to diet during warfarin therapy.⁴⁵³
Importance of avoiding²¹¹ ³³⁰ ⁴⁴⁵ ⁴⁵³ or using only small amounts⁴⁸⁸ of cranberry products and of informing clinician if these products are part of the diet.²¹¹ ³³⁰ ⁴⁴⁵ ⁴⁵³
Importance of avoiding activities or sports that could cause traumatic injury.²¹¹ ³³⁰ Importance of informing clinician about falls or injuries, especially head injuries, during therapy.⁴⁵³
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.²¹¹ ³³⁰ ⁴¹⁸
Importance of patients reporting symptoms of blood clots (e.g., pain, color, or temperature changes to any area of the body).⁴⁵³ Importance of reporting symptoms of purple toes syndrome (e.g., pain in toes, purple or dark toes) to clinician immediately.⁴⁵³
Importance of patients informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements.²¹¹ ³³⁰ ⁴¹⁸ Importance of not taking OTC drugs or drugs prescribed by other clinicians without first informing primary clinician or pharmacist.²¹¹ ³³⁰
Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.²¹¹ ³³⁰
Importance of informing patients of other important precautionary information.²¹¹ ³³⁰ (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.

Warfarin Sodium
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	1 mg	Coumadin (scored)	Bristol-Myers Squibb
			Jantoven (scored)	USL
			Warfarin Sodium Tablets (scored)
		2 mg	Coumadin (scored)	Bristol-Myers Squibb
			Jantoven (scored)	USL
			Warfarin Sodium Tablets (scored)
		2.5 mg	Coumadin (scored)	Bristol-Myers Squibb
			Jantoven (scored)	USL
			Warfarin Sodium Tablets (scored)
		3 mg	Coumadin (scored)	Bristol-Myers Squibb
			Jantoven (scored)	USL
			Warfarin Sodium Tablets (scored)
		4 mg	Coumadin (scored)	Bristol-Myers Squibb
			Jantoven (scored)	USL
			Warfarin Sodium Tablets (scored)
		5 mg	Coumadin (scored)	Bristol-Myers Squibb
			Jantoven (scored)	USL
			Warfarin Sodium Tablets (scored)
		6 mg	Coumadin (scored)	Bristol-Myers Squibb
			Jantoven (scored)	USL
			Warfarin Sodium Tablets (scored)
		7.5 mg	Coumadin (scored)	Bristol-Myers Squibb
			Jantoven (scored)	USL
			Warfarin Sodium Tablets (scored)
		10 mg	Coumadin (scored)	Bristol-Myers Squibb
			Jantoven (scored)	USL
			Warfarin Sodium Tablets (scored)
Parenteral	For injection, for IV use only	5 mg	Coumadin	Bristol-Myers Squibb

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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