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Coumadin

Pronunciation

Generic Name: Warfarin Sodium
Class: Coumarin Derivatives
CAS Number: 129-06-6

Warning(s)

  • 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 Coumadin

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/Atrial Flutter

Prevention of stroke and systemic embolism in patients with atrial fibrillation.223 278 279 369 456 459 500 990 999 1007 ACCP, the American College of Cardiology (ACC), American Heart Association (AHA), and other experts recommend antithrombotic therapy (e.g., warfarin, aspirin) in patients with persistent, permanent, or paroxysmal atrial fibrillation who are considered to be at increased risk of stroke.223 278 279 369 456 459 990 992 999 1007

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Choice of antithrombotic therapy is based on patient's risk for stroke.341 345 369 459 999 1007 In general, oral anticoagulant therapy is recommended in patients with high risk for stroke; aspirin is recommended in low-risk patients and those with contraindications to oral anticoagulant therapy.211 330 335 341 344 345 349 456 990 999 1007 Patients at increased risk of stroke generally include those with a history of stroke, TIA, or systemic embolism, and those with ≥2 of the following risk factors: advanced age (e.g., ≥75 years), history of hypertension, diabetes mellitus, or severely impaired left ventricular systolic function and/or heart failure.500 999 1007

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

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/Atrial Flutter

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

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 as adjunctive therapy with antiplatelet agents (e.g., aspirin, clopidogrel) during and after successful coronary artery reperfusion for the prevention of early reocclusion and death in patients with acute STEMI.211 226 242 243 244 245 246 247 248 249 250 251 252 330 350 432 482 500 992 1010

In general, antiplatelet therapy is preferred to anticoagulants for secondary prevention and risk reduction in patients with atherosclerosis, including those with acute MI; 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 MI 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).350 500 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).1010

Cerebral Embolism

Oral anticoagulation (e.g., warfarin) is recommended for secondary prevention of cerebral embolism in patients with TIAs or ischemic stroke and concurrent atrial fibrillation.335 338 349 352 432 999 1009

Warfarin also is used for prevention of recurrent stroke in patients at high risk for recurring cerebral embolism from other cardiac sources (e.g., prosthetic mechanical heart valves, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis, extensive wall-motion abnormalities).335 338 349 432 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

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.)

Coumadin 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/Atrial Flutter
Oral or IV

Maintain target INR of 2.5 (range 2–3) long term.211 330 335 344 345 349 369 990 999 1007

Cardioversion of Atrial Fibrillation/Atrial Flutter
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

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
Treatment and Secondary Prevention
Oral or IV

Patients at high risk of systemic or pulmonary embolism (e.g., large anterior MI, 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 MI.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.335 338 349 352 432 990 1009

Patients with risk of recurrent stroke from other cardiac sources (e.g., mechanical prosthetic heart valves, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis, extensive wall-motion abnormalities): Maintain target INR of 2.5 (range 2–3) with concomitant low-dose aspirin.335 338 349 432

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 Coumadin

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 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

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 Coumadin

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-lifea

Potential decreased vitamin K absorptiona

Concurrent use of cholestyramine and warfarin probably should be avoided, if possiblea

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

Coumadin 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.

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Coumadin 1MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$46.99 or 90/$116.97

Coumadin 10MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$65.99 or 90/$175.97

Coumadin 2MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$50.99 or 90/$124.97

Coumadin 2.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$52.99 or 90/$130.97

Coumadin 3MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$49.99 or 90/$127.97

Coumadin 4MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$49.99 or 90/$128.97

Coumadin 5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$49.99 or 90/$129.97

Coumadin 6MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$56.99 or 90/$165.97

Coumadin 7.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$62.99 or 90/$165.98

Jantoven 2MG Tablets (UPSHER-SMITH): 30/$17.99 or 90/$39.97

Jantoven 4MG Tablets (UPSHER-SMITH): 30/$17.99 or 90/$39.97

Jantoven 5MG Tablets (UPSHER-SMITH): 30/$17.99 or 90/$42.97

Warfarin Sodium 1MG Tablets (TARO): 30/$13.99 or 90/$30.99

Warfarin Sodium 10MG Tablets (TEVA PHARMACEUTICALS USA): 30/$24.99 or 90/$63.97

Warfarin Sodium 2MG Tablets (TARO): 30/$14.99 or 90/$33.97

Warfarin Sodium 2.5MG Tablets (TARO): 30/$14.99 or 90/$33.97

Warfarin Sodium 3MG Tablets (TARO): 30/$15.99 or 90/$40.97

Warfarin Sodium 4MG Tablets (TARO): 30/$14.99 or 90/$33.98

Warfarin Sodium 5MG Tablets (TARO): 30/$13.99 or 60/$16.98

Warfarin Sodium 7.5MG Tablets (TARO): 30/$23.99 or 90/$61.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 4, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

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

90. Koch-Weser J, Sellers EM. Drug interactions with coumarin anticoagulants (Second of two parts). New Engl J Med. 1971; 285:547-558. [PubMed 4397794]

200. National Institutes of Health Consensus Development Conference. Prevention of venous thrombosis and pulmonary embolism. JAMA. 1986; 256:744-9. [PubMed 3723773]

201. Hirsch J. Therapeutic range for the control of oral anticoagulant therapy. Arch Intern Med. 1985; 145:1187-8. [IDIS 201237] [PubMed 4015265]

202. Suchman AL, Griner PF. Diagnostic uses of the activated partial thromboplastin time and prothrombin time. Ann Intern Med. 1986; 104:810-6. [PubMed 3706933]

203. Peterson CE, Kwaan HC. Current concepts of warfarin therapy. Arch Intern Med. 1986; 146:581-4. [IDIS 213429] [PubMed 3513725]

204. Kaplan K. Prophylactic anticoagulation following acute myocardial infarction. Arch Intern Med. 1986; 146:593-7. [IDIS 213431] [PubMed 3513727]

205. Goldberg RJ, Gore JM, Dalen JE et al. Long-term anticoagulant therapy after acute myocardial infarction. Am Heart J. 1985; 109(3 Part 1):616-22. [IDIS 197327] [PubMed 3919548]

206. Petitti DB, Strom BL, Melmon KL. Duration of warfarin anticoagulant therapy with the probabilities of recurrent thromboembolism and hemorrhage. Am J Med. 1986; 81:255-9. [IDIS 220903] [PubMed 3740082]

207. Hirsh J, Deykin D, Poller L. American College of Chest Physicians and the National Heart, Lung, and Blood Institute National Conference on Antithrombotic Therapy. “Therapeutic range” for oral anticoagulant therapy: summary and recommendations. Arch Intern Med. 1986; 146:466.

208. Hyers TM, Hull RD, Weg JG. American College of Chest Physicians and the National Heart, Lung, and Blood Institute National Conference on Antithrombotic Therapy. Antithrombotic therapy for venous thromboembolic disease: summary and recommendations. Arch Intern Med. 1986; 146:467.

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