Warfarin (Monograph)

Brand name: Jantoven
Drug class: Coumarin Derivatives
CAS number: 129-06-6

Medically reviewed by Drugs.com on Mar 24, 2023. Written by ASHP.

Warning

Possible major bleeding, sometimes fatal.³³⁰ More likely to occur during initiation of therapy and with higher dosages, resulting in a higher INR.³³⁰
Monitor INR regularly.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.³³⁰
Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy.³³⁰
Instruct patients about preventative measures to minimize risk of bleeding and to immediately report signs and symptoms of bleeding to clinician.³³⁰

Introduction

Anticoagulant; a coumarin derivative.³³⁰

Uses for Warfarin

Treatment of Venous Thromboembolism

Treatment of acute deep-vein thrombosis (DVT) or pulmonary embolism (PE) (i.e., venous thromboembolism [VTE]) in adults.³³⁰ ¹²⁰⁰

Initiate concomitantly with a parenteral anticoagulant (e.g., low molecular weight heparin [LMWH], heparin, fondaparinux).³³⁰ ¹²⁰⁰ 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 ¹²⁰⁰

The American College of Chest Physicians (ACCP) recommends a moderate intensity of anticoagulation (target INR 2.5, range 2–3) for most patients with VTE.¹⁰⁰⁰ ¹²⁰⁰

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).¹¹⁰⁶ ¹²⁰⁰ For most cases of VTE, a minimum of 3 months of anticoagulant therapy is recommended.³³⁰ ¹²⁰⁰ Long-term anticoagulation (>3 months) may be considered in selected patients (e.g., those with idiopathic [unprovoked] VTE who are at low risk of bleeding, cancer patients with VTE).¹¹⁰⁶ ¹²⁰⁰

Warfarin remains an option for treatment of VTE; however, direct oral anticoagulants (DOACs; e.g., dabigatran, rivaroxaban, apixaban, edoxaban) are preferred in most cases by experts such as ACCP, American Society of Hematology (ASH), and the Anticoagulation Forum.¹⁰⁰⁶ ¹¹⁰⁶ ¹²⁰⁰ DOACs have similar efficacy to warfarin, but reduced bleeding (particularly intracranial hemorrhage) and greater convenience for patients and healthcare providers.¹⁰⁰⁶ ¹¹⁰⁶ ¹²⁰⁰

In patients with cancer and established VTE, LMWH or oral factor Xa inhibitors are generally recommended over warfarin for long-term anticoagulation.¹¹⁰² ¹¹⁰³

Used in select pediatric patients with DVT or PE^{† [off-label]}.¹⁰¹³ ¹¹¹⁸ LMWHs or heparin generally recommended for both initial and ongoing treatment of VTE in children; however, warfarin may be indicated in some situations (e.g., recurrent idiopathic VTE).¹⁰¹³

Prophylaxis of Venous Thromboembolism

Prevention of VTE in adults undergoing major orthopedic surgery (hip- or knee-replacement surgery or hip-fracture surgery).³³⁰ 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, DOACs, low-dose heparin, warfarin, aspirin) recommended by experts for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery.¹⁰⁰³ ¹¹⁰⁹

Although LMWHs and DOACs generally preferred, alternative agents (e.g., warfarin) may be considered.¹⁰⁰³ ¹¹⁰⁹ Drug selection and duration of therapy should be individualized based on type of surgery, patient risk factors for embolism and bleeding, as well as costs, patient compliance, preference, tolerance, and comorbidities; and other clinical factors such as renal function.¹⁰⁰³ ¹¹⁰⁸

Used for primary thromboprophylaxis in children with ventricular assist devices^{† [off-label]} or with an arteriovenous fistula undergoing hemodialysis^{† [off-label]} and in children with certain medical conditions associated with a high risk of thrombosis (e.g., large or giant coronary aneurysms following Kawasaki disease^{† [off-label]}, primary pulmonary hypertension^{† [off-label]})¹⁰¹³ ¹¹⁶⁵ ¹¹⁶⁶ ¹¹⁶⁷

Embolism Associated with Atrial Fibrillation

Prevention of stroke and systemic embolism in patients with atrial fibrillation.²²³ ²⁷⁸ ²⁷⁹ ³⁶⁹ ⁴⁵⁶ ⁴⁵⁹ ⁹⁹⁰ ⁹⁹⁹ ¹²⁰¹ ¹⁰¹⁷

ACCP, American College of Cardiology (ACC), American Heart Association (AHA), the American Stroke Association (ASA), and other experts recommend antithrombotic therapy 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 at increased risk of stroke, unless such therapy is contraindicated.⁸¹ ⁸² ⁸⁷ ⁹⁸⁹ ⁹⁹⁰ ⁹⁹⁹ ¹²⁰¹ ¹⁰¹⁷

Current guidelines recommend use of the CHA₂DS₂-VASc risk stratification tool for assessing a patient’s risk of stroke and need for anticoagulant therapy.⁸² ⁹⁸⁹ ¹²⁰¹

In patients with nonvalvular atrial fibrillation who are eligible for oral anticoagulant therapy, DOACs are recommended over warfarin based on improved safety and similar or improved efficacy.⁸² ⁸⁷ ⁹⁸⁹ ¹²⁰¹

Anticoagulant selection should be individualized based on the absolute and relative risks of stroke and bleeding; costs; patient compliance, preference, tolerance, and comorbidities; and other clinical factors such as renal function and degree of INR control if the patient has been taking warfarin.⁸¹ ⁸² ⁸³ ⁸⁷ ⁹⁸⁹ ¹²⁰¹

Experts suggest managing antithrombotic therapy in patients with atrial flutter in the same manner as in patients with atrial fibrillation.⁹⁹⁹ ¹²⁰¹

Cardioversion of Atrial Fibrillation†

Prevention of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation.³⁴¹ ⁹⁹⁹ ¹²⁰¹

ACCP and other experts recommend that patients with atrial fibrillation of unknown or ≥48 hours' duration who are to undergo elective cardioversion receive therapeutic anticoagulation (e.g., warfarin, apixaban, dabigatran, edoxaban, rivaroxaban) for ≥3 weeks prior to cardioversion; alternatively, a transesophageal echocardiography (TEE)-guided approach may be used.⁹⁹⁹ ¹²⁰¹ After successful cardioversion, all patients should receive therapeutic anticoagulation for ≥4 weeks.⁹⁹⁹ ¹²⁰¹

Experts suggest the same approach to thromboprophylaxis in patients undergoing cardioversion for atrial flutter as that used in patients with atrial fibrillation.⁹⁹⁹ ¹²⁰¹

Embolism Associated with Valvular Heart Disease

Prevention of thromboembolic complications in patients with valvular heart disease, including those with mechanical and bioprosthetic heart valves.³³⁰ ³⁴¹ ³⁴² ³⁴³ ³⁷⁰ ¹¹⁴³ ¹²⁰²

Assess risk of thromboembolism versus risk of bleeding when determining choice of antithrombotic therapy.³⁴⁴ ⁴⁵⁹ ¹²⁰²

Among the common types of valvular heart disease, rheumatic mitral valve disease is associated with greatest risk of systemic thromboembolism; risk is further increased in patients with concurrent atrial fibrillation, left atrial thrombus, or history of systemic embolism.¹²⁰¹ ¹²⁰²

The 2020 AHA/ACC guideline for management of valvular heart disease states that patients with valvular heart disease and atrial fibrillation should be evaluated for risk of thromboembolic events and treated with oral anticoagulation if at high risk.¹¹⁴³ Vitamin K antagonists are the anticoagulants of choice for patients with rheumatic mitral stenosis and mechanical heart valves.¹¹⁴³

All patients with mechanical heart valves require long-term warfarin therapy because of the high risk of thromboembolism.³³⁰ ³⁷⁰ ⁴⁵⁹ ⁹⁹⁶ ¹¹⁴³ ¹²⁰² Risk is higher with mechanical than with bioprosthetic heart valves, higher with first-generation mechanical (e.g., caged ball, caged disk) valves than with newer mechanical (e.g., bileaflet, Medtronic Hall tilting disk) valves, higher with more than one prosthetic valve, and higher with prosthetic mitral than with aortic valves; risk also is higher in the first few days and months after valve insertion and increases in the presence of atrial fibrillation.³⁴¹ ³⁴² ³⁴³ ³⁷⁰ ¹¹⁴³ ¹²⁰²

In patients with mechanical aortic valve replacement who have additional risk factors (e.g., older generation valve, atrial fibrillation, previous thromboembolism, hypercoagulable state, left ventricular systolic dysfunction), a target INR of 3 (range 2.5–3.5) is recommended; in the absence of these risk factors, a target INR of 2.5 (range 2–3) is recommended.³³⁰ ¹¹⁴³

In patients with mechanical mitral valve replacement, a target INR of 3 (range 2.5–3.5) is recommended.³³⁰ ¹¹⁴³

Due to increased risk of major bleeding, addition of aspirin 75–100 mg is no longer routinely recommended in patients with mechanical valve replacement; the decision to add aspirin should be based on thromboembolism risk, bleeding risk, and presence of an indication for antiplatelet therapy.⁸² ¹¹⁴³

Warfarin is recommended during the initial 3–6 months following surgical bioprosthetic valve replacement, regardless of position (aortic or mitral).⁸² ³³⁰ ¹¹⁴³ Following transcatheter aortic valve implantation, the decision to select antiplatelet therapy or warfarin during the first 3–6 months should be individualized.¹¹⁴³ The target INR is 2.5 (range 2–3) following either valve replacement approach.¹¹⁴³ Following the initial period of warfarin prophylaxis, patients may be switched to aspirin 75–100 mg provided they are in normal sinus rhythm and have no other indication for therapeutic anticoagulation (e.g., atrial fibrillation, previous thromboembolism, hypercoagulable state, left ventricular dysfunction).³³⁰ ¹¹⁴³

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.¹²⁰² In patients with a prosthetic valve who are already receiving warfarin, ACCP suggests temporary discontinuance of the drug if infective endocarditis develops.¹¹⁴³ ¹²⁰²

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 ST-segment-elevation MI (STEMI).³³⁰ ⁵²⁷ ⁹⁹² ¹⁰¹⁰

Manufacturer states that following an acute STEMI in high-risk patients (e.g., those with a large anterior STEMI, substantial heart failure, intracardiac thrombus visible on transthoracic echocardiography, atrial fibrillation, history of previous thromboembolic event), use of warfarin (target INR 2–3) in conjunction with low-dose aspirin (not exceeding 100 mg daily) for at least 3 months is recommended.³³⁰

Antiplatelet therapy preferred over warfarin for secondary prevention and risk reduction in patients with atherosclerosis, including those with acute STEMI unless there is a separate indication for use (e.g., atrial fibrillation, prosthetic heart valve, left ventricular thrombus or high risk for such thrombi, or concomitant venous thromboembolic disease).⁹⁹² ¹⁰¹⁰ ¹¹⁷²

Due to the lack of data supporting routine anticoagulation in the current era of reperfusion, coronary stenting, and dual antiplatelet therapy (DAPT), experts state prophylactic anticoagulation to prevent left ventricular thrombus post-STEMI is not routinely recommended for all patients.¹¹⁹⁹

Therapeutic anticoagulation (e.g., with warfarin, DOACs) for the treatment of left ventricular thrombus after acute MI is appropriate.¹¹⁹⁹

Cerebral Embolism

Antiplatelet agents generally preferred over oral anticoagulation for secondary prevention of noncardioembolic stroke in patients with a history of ischemic stroke or transient ischemic attack (TIA).⁸² ¹⁰⁰⁹

Oral anticoagulation with warfarin or DOAC (e.g., apixaban, dabigatran, rivaroxaban, edoxaban) is recommended for secondary prevention of cerebral embolism in patients with TIAs or ischemic stroke and concurrent atrial fibrillation, provided no contraindications exist.⁸² ³³⁵ ³³⁸ ³⁴⁹ ³⁵² ⁹⁹⁹ ¹⁰⁰⁹ ¹⁰¹⁷

Warfarin anticoagulation also is recommended for 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).⁸² ¹⁰¹⁰ ¹¹⁹⁹ ¹²⁰²

American Heart Association Stroke Council recommends warfarin following initial therapy with heparin or LMWH in patients with acute cerebral venous sinus thrombosis^†.¹¹⁷⁵

Heparin-Induced Thrombocytopenia

ACCP and ASH state that warfarin may be used as follow-up therapy after initial parenteral treatment with a nonheparin anticoagulant (e.g., argatroban, bivalirudin, fondaparinux) in patients with heparin-induced thrombocytopenia (HIT).¹¹⁶⁸ ¹²⁰³ Overlap therapy with warfarin and the nonheparin anticoagulant for ≥5 days and until desired INR has been achieved.¹²⁰³

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, experts recommend administration of vitamin K.¹¹⁶⁸ ¹²⁰³

Thrombotic Antiphospholipid Syndrome†

The International Society on Thrombosis and Haemostasis (ISTH) recommends use of warfarin over DOACs in patients with high-risk antiphospholipid syndrome (APS), including those with triple-positive APS and patients non-adherent to warfarin or with recurrent thrombosis while on therapeutic intensity warfarin.¹¹⁶³

Warfarin Dosage and Administration

General

Pretreatment Screening

Obtain baseline INR.³³⁰ ¹¹⁷⁶ ¹¹⁷⁷
Obtain baseline CBC.³³⁰ ¹¹⁷⁶ ¹¹⁷⁷
Verify pregnancy status in females of reproductive potential.³³⁰
Perform other relevant baseline laboratory tests as needed based upon the patient’s clinical condition (e.g., liver function tests [LFTs]).³³⁰ ¹¹⁷⁶ ¹¹⁷⁷
Assess patient for active bleeding and bleeding risk.³³⁰ ¹¹⁷⁶
Assess patient for comorbid conditions (e.g., heart failure, diarrhea) and drug-drug interactions (e.g., amiodarone, metronidazole) that may influence warfarin dose selection.³³⁰ ¹¹⁷⁶ ¹¹⁷⁷
Pharmacogenomic testing for CYP2C9 and vitamin K epoxide reductase (VKORC)1 genotypes is available and recommended, but not required.³³⁰ ¹¹⁷⁸

Patient Monitoring

Perform INR assessments regularly during therapy.³³⁰ ¹¹⁷⁶
Perform an INR assessment daily after warfarin initiation until the INR stabilizes in the therapeutic range.³³⁰ ¹¹⁷⁶ ¹¹⁷⁷
ACCP states that INR assessments usually are performed daily in hospitalized patients until the INR is in the therapeutic range for at least 2 consecutive days; in nonhospitalized patients, initial INR assessments may be reduced from daily to every few days until a stable response has been achieved.¹⁰¹⁴ ¹¹⁷⁶ ¹¹⁷⁷
The frequency of INR assessments should be based on clinical judgment and patient response, but generally are performed every 1–4 weeks.³³⁰ In patients with consistently stable INRs, ACCP has suggested an INR testing interval of up to 12 weeks.¹⁰⁰⁰ ¹¹⁷⁶ ¹¹⁷⁷
Monitor for signs and symptoms of bleeding (e.g., bruising, gum or nose bleeding, blood in stool).³³⁰ ¹¹⁷⁶
Monitor for signs and symptoms of thrombosis (e.g., leg swelling).³³⁰ ¹¹⁷⁶
Monitor CBC regularly and other laboratory tests based upon the patient’s clinical condition.³³⁰ ¹¹⁷⁶
Monitor comorbid conditions (e.g., heart failure, diarrhea) for clinical changes that may influence the patient’s INR response to warfarin (e.g., diarrhea, resolved or decompensated heart failure).³³⁰ ¹¹⁷⁶ ¹¹⁷⁷
Monitor for drug-drug interactions and drug therapy that is added, discontinued, or taken irregularly, that may influence the patient’s INR response.³³⁰ ¹¹⁷⁶ ¹¹⁷⁷
Perform additional INR assessments when differing warfarin preparations (e.g., proprietary versus nonproprietary [generic]) are interchanged.³³⁰ ¹¹⁷⁷

Dispensing and Administration Precautions

Personnel who are pregnant should avoid exposure to crushed or broken tablets. ³³⁰
Procedures for proper handling and disposal of potentially hazardous drugs should be considered.¹²⁰⁶
Per the Institute for Safe Medication Practices (ISMP), warfarin is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.¹²⁰⁵

Other General Considerations

In patients managed by anticoagulation clinics, compared with patients receiving usual monitoring by their primary care clinician, available data indicate that the proportion of time in the therapeutic INR range and patient satisfaction is increased, but clinical outcomes such as bleeding, thrombosis, and mortality are not significantly different.¹¹⁸⁰
Self-testing with or without self-monitoring may be an option for some patients.¹¹⁷⁹ A Cochrane systematic review with meta-analysis reported no difference in bleeding or mortality, and reduced thromboembolic events, when patient self-testing or self-monitoring was compared to standard therapy; however, the risk of bias downgraded the quality of evidence.¹¹⁷⁹
Self-management of warfarin therapy is suggested by ACCP as an alternative to outpatient INR monitoring in patients who are motivated and can demonstrate competency in self-management strategies, including the use of self-testing equipment.¹⁰⁰⁰

Administration

Oral Tablets

Administer orally without regard to food.³³⁰

Administer as a single daily dose at the same time each day.³³⁰

If a dose is missed, take the dose as soon as possible on the same day.³³⁰ A double dose should not be taken the next day to make up for the missed dose.³³⁰

Dosage

Dosage expressed in terms of warfarin sodium.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.³³⁰ ¹¹⁷⁶ ¹¹⁷⁷

Routine use of warfarin loading doses not recommended by manufacturer.³³⁰ Some evidence suggests that use of a 10-mg loading dose may reduce time to therapeutic INR and the ACCP suggests that in sufficiently healthy, nonhospitalized patients, an initial dosage of 10 mg daily for the first 2 days may be administered, with subsequent dosing based on INR determinations.¹⁰⁰⁰

In patients whose CYP2C9 and VKORC1 genotypes are not known, the manufacturer states that usual initial dosage is 2–5 mg daily or the expected maintenance dose.³³⁰

For patients with known CYP2C9 and VKORC1 genotypes, the manufacturer suggests that initial dosage may be determined by expected maintenance dosages observed in clinical studies of patients with various combinations of these gene variants.³³⁰ (See Table 1.)

Manufacturer suggests using these expected maintenance dosage ranges to estimate initial daily dosage in patients with known CYP2C9 and VKORC1 genotypes.³³⁰ Dosage ranges derived from multiple published clinical studies.³³⁰ VKORC1-1639G > A (rs9923231) variant is used in this table; other co-inherited VKORC1 variants also may be important determinants of warfarin sodium dosage.³³⁰

Table 1. Expected Daily Maintenance Dosages of Warfarin Sodium Based on CYP2C9 and VKORC1 Genotypes
			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

Adjust maintenance 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 ¹¹⁷⁶ ¹¹⁷⁷ If an unexpected result that does not fit the patient’s clinical picture occurs, consider repeating the INR.¹¹⁷⁶ ¹¹⁷⁷

The 2017 update of the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for pharmacogenetics-guided warfarin dosing suggests pharmacogenetic algorithm-based warfarin dosing over the genetics-based dosing table (Table 1) found in the FDA-approved warfarin label.³³⁰ ¹¹⁷⁸

The recommended algorithms (Gage or International Warfarin Pharmacogenetics Consortium [IWPC]) consider age, sex, race or self-identified ancestry, weight, height, smoking status, warfarin indication, target INR, interacting drugs (e.g., amiodarone, phenytoin) and genetic variables (e.g., CYP2C9, VKORC1 genotypes).¹¹⁷⁸ CPIC recommends the Gage over IWPC algorithm because it can adjust for CYP4F2, CYP2C9*5 and *6, if those genotypes are known.¹¹⁷⁸

Pediatric Patients

Warfarin dosage in pediatric patients varies based on age; infants generally have the highest, and adolescents have the lowest dosage requirements.³³⁰ 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 ¹¹⁴³

Adults

Treatment of DVT and PE

Oral

Adjust dosage to achieve and maintain target INR of 2.5 (range 2–3).³³⁰ ¹²⁰⁰

Patients with proximal DVT or PE provoked by surgery or other transient risk factor: ACCP states that 3 months of anticoagulation usually sufficient.³³⁰ ¹¹⁰⁶ ¹²⁰⁰

Consider continuing anticoagulant therapy beyond 3 months depending on the individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors, presence of cancer, patient's risk of bleeding).³³⁰ ¹¹⁰⁶ ¹²⁰⁰

Prevention of DVT and PE

Major Orthopedic Surgery

Oral

Adjust dosage to INR range of 2–3.¹⁰⁰³

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

Maintain target INR of 2.5 (range 2–3) long term.³³⁰ ⁹⁸⁹ ¹²⁰¹

Manage atrial flutter in a similar manner as atrial fibrillation.⁹⁸⁹ ¹²⁰¹

Cardioversion of Atrial Fibrillation

Oral

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 ¹²⁰¹

Manage atrial flutter in a similar manner as atrial fibrillation.⁹⁹⁹ ¹²⁰¹

Embolism Associated with Valvular Heart Disease

Oral

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).⁸² ¹²⁰¹ ¹²⁰²

Thromboembolism Associated with Prosthetic Heart Valves

Prophylaxis

Oral

Base intensity of anticoagulation on type of valve prosthesis.⁸² ³³⁰ ¹¹⁴³ ¹²⁰² 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.⁸² ³³⁰ ¹¹⁴³ ¹²⁰²

Patients with mechanical heart valves in any position: Long-term oral anticoagulation required.³³⁰ ¹¹⁴³ The addition of low-dose aspirin (e.g., 50–100 mg daily) is no longer routine; the decision to use aspirin should be based on thromboembolism risk, bleeding risk, and presence of an indication for antiplatelet therapy.⁸² ¹¹⁴³

Patients with bioprosthetic mitral or aortic valves: 3–6 months of warfarin therapy suggested after valve insertion; after 3 months, may switch to aspirin therapy, provided patient is in normal sinus rhythm and has no other indication for therapeutic anticoagulation (e.g., atrial fibrillation, previous thromboembolism, hypercoagulable state, left ventricular dysfunction).⁸² ³³⁰ ¹¹⁴³

Following transcatheter aortic valve implantation, the decision to select dual antiplatelet therapy or warfarin during the first 3–6 months, if the patient has a low risk of bleeding, should be individualized.¹¹⁴³

STEMI

Secondary Prevention

Oral

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): Warfarin (INR 2–3) and aspirin therapy (≤100 mg daily) following acute STEMI is an option.³³⁰ ¹¹⁹⁹

Cerebral Thromboembolism

Secondary Prevention

Oral

Patients with TIA or ischemic stroke and concurrent atrial fibrillation: Maintain target INR of 2.5 (range 2–3) long term, provided no contraindications to therapy exist.⁸² ¹¹⁹⁹ ¹²⁰²

Warfarin is recommended 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).⁸² ¹⁰¹⁰ ¹¹⁹⁹ ¹²⁰²

Patients with acute cerebral venous sinus thrombosis^†: Target INR is 2–3 and recommended duration of therapy is based on known or unknown provocation and the presence or absence of thrombophilia.¹¹⁷⁵

HIT†

Conversion to Warfarin Therapy†

Oral

Initiate warfarin only after substantial recovery from acute HIT has occurred (i.e., platelet counts ≥150,000/mm³).¹¹⁶⁸ ¹²⁰³

Overlap therapy with a nonheparin anticoagulant for ≥5 days until desired INR is achieved.¹¹⁶⁸ ¹²⁰³

Maintain target INR of 2.5 (range 2–3).¹¹⁶⁸ ¹²⁰³

Pharmacogenomic Considerationg in Dosing

Variations in genes responsible for warfarin metabolism or pharmacodynamic response may affect dosage requirements. ³³⁰ ³⁷⁸ ⁴⁶² ⁴⁶³ ⁴⁶⁴ ⁴⁶⁵ ⁴⁶⁶ ⁴⁶⁷ ⁴⁶⁹ ¹¹⁷⁸

Lower dosages may be required to avoid excessive anticoagulation (e.g., INR >3) and bleeding in patients with variations in CYP2C9 and VKORC1.³³⁰ ⁴⁶² ⁴⁶⁴ ⁴⁶⁵ ⁴⁶⁶ ⁴⁶⁷ ⁴⁶⁹ ⁴⁷⁴ ¹¹⁷⁸

Genetic information does not replace regular INR monitoring and results of genetic testing should not delay initiation of warfarin therapy.⁴⁷³

Additional information about pharmacogenetic testing can be found at the Genetic Testing Registry ([Web]).¹¹⁷⁸

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, fondaparinux), overlap therapy until adequate warfarin response obtained as indicated by INR monitoring.³³⁰ ¹⁰⁰⁰ ¹²⁰⁰

Manufacturers recommend that heparin and warfarin be used concurrently for ≥4–5 days until the desired INR has been achieved.³³⁰

In adults with acute DVT or PE, ACCP and ASH recommend that heparin, LMWH, or fondaparinux be used concurrently with warfarin for ≥5 days and until INR is ≥2 for ≥24 hours.¹⁰⁰⁶ ¹²⁰⁰

In children with VTE^† in whom long-term warfarin therapy is being considered, ACCP recommends that warfarin be initiated on the same day as heparin or 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, bivalirudin, fondaparinux) in patients with HIT^†, overlap therapy for ≥5 days until adequate warfarin response is obtained as indicated by INR.¹²⁰³ Initiate warfarin therapy only after substantial recovery from acute HIT has occurred (i.e., stable platelet counts ≥150,000/mm³ or platelet recovery >50% of baseline).¹²⁰³ Do not use a warfarin loading dose in HIT patients.³⁹² ¹¹⁶⁸ ¹²⁰³

Conversion from argatroban to warfarin is more complex than with other nonheparin anticoagulants since combined therapy with argatroban and warfarin prolongs the 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

Transferring from Other Anticoagulants to Warfarin

The manufacturer suggests consulting the labeling of other anticoagulants for instructions on conversion to warfarin.³³⁰

Managing Anticoagulation in Patients Requiring Invasive Procedures

Temporary interruption of warfarin therapy may be required in patients undergoing surgery or other invasive procedures to minimize risk of perioperative bleeding.³³⁰ 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 at least 5 days prior to procedure.¹⁰⁰⁴ Elderly patients with comorbidities, patients with low dose warfarin requirements, and those with a higher target INR range are among those who may require >5 days of warfarin interruption prior to surgery.¹⁰⁰⁴

Determine the INR immediately prior to any invasive procedure.³³⁰

May resume warfarin therapy within 24 hours postoperatively, usually on the evening of the surgery or procedure, when adequate hemostasis is achieved.¹⁰⁰⁴ Resume at the patient’s established maintenance dosage; loading doses (e.g., double the established maintenance dose) are not recommended.¹⁰⁰⁴

Heparin bridging is defined as administration of an LMWH or IV heparin during the period of warfarin interruption.¹⁰⁰⁴ ACCP recommends against heparin bridging in patients with mechanical heart valves, atrial fibrillation, or VTE who are not considered to be high-risk for thromboembolism when warfarin is interrupted for an elective surgery or procedure.¹⁰⁰⁴ ACCP states that heparin bridging is recommended for patients at the highest risk for thromboembolism (e.g., patients with older-generation [e.g., tilting-disc] mechanical heart valves, any mechanical mitral valve, thromboembolic event within the last 3 months, atrial fibrillation patients with a CHA₂DS₂VASc score ≥7 or CHADS₂ score ≥5).¹⁰⁰⁴

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations; monitor more frequently for bleeding.³³⁰

Renal Impairment

The manufacturer makes no specific dosage recommendations; more frequent INR monitoring may be required.³³⁰

Geriatric Use

In patients >60 years of age, consider lower initial and maintenance dosages.³³⁰ More frequent monitoring may be necessary.³³⁰

Debilitated Patients

Consider lower initial and maintenance dosages.³³⁰

Asian Patients

May require lower initial and maintenance dosages.³³⁰

Black Patients

The CYP2C9 *5, *6, *8, and *11 alleles associated with reduced enzymatic activity and warfarin metabolism occur in 45–50% of patients with self-reported African ancestry.³³⁰ ¹¹⁷⁸

The 2017 update of the CPIC guideline for pharmacogenetics-guided warfarin dosing suggests a 15–30% warfarin dosage reduction when CYP2C9 *5, *6, *8, and *11 variant alleles are detected, regardless of self-reported ancestry.¹¹⁷⁸

Cautions for Warfarin

Contraindications

Pregnancy, except in patients with mechanical heart valves.³³⁰
Patients with hemorrhagic tendencies or blood dyscrasias.³³⁰
Recent or contemplated surgery of the eye or CNS and in those undergoing traumatic surgery resulting in large open surfaces.³³⁰
Bleeding tendencies associated with active ulceration or overt bleeding of the GI, respiratory, or genitourinary tract; CNS hemorrhage; aneurysms (cerebral, dissecting aorta); pericarditis and pericardial effusions; bacterial endocarditis.³³⁰
Threatened abortion, eclampsia, and preeclampsia.³³⁰
Unsupervised patients with conditions associated with a potential high level of non-compliance with therapy (e.g., dementia/senility).³³⁰
Known hypersensitivity (e.g., anaphylaxis).³³⁰
Spinal puncture and other diagnostic or therapeutic procedures associated with the potential for uncontrollable bleeding.³³⁰
Major regional or lumbar block anesthesia.³³⁰
Malignant hypertension.³³⁰

Warnings/Precautions

Warnings

Bleeding Risk

Risk of serious, potentially fatal, bleeding.³³⁰ (See Boxed Warning.)

Promptly evaluate if any manifestations of blood loss occur during therapy.³³⁰

More likely to occur during the initiation of therapy and with higher dosages, resulting in higher INRs.³³⁰

Risk factors for bleeding include higher dosages, high intensity of anticoagulation (INR >4), age ≥65 years, highly variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal or liver impairment, alcohol abuse, prior stroke, certain genetic factors, concomitant drugs that may increase INR response, and a long duration of warfarin therapy.³³⁰ ⁴⁶² ⁴⁶⁶ ⁴⁷⁴ ¹⁰¹⁴

Bleeding may still occur when the INR is in the usual therapeutic range.³³⁰

GI or urinary tract bleeding may warrant investigation of underlying malignancy or other correctable lesions.¹⁰¹⁴

In patients with major bleeding requiring urgent warfarin reversal, ACCP and the ACC Expert Consensus Decision Pathway suggest the use of 4-factor prothrombin complex concentrate (INR-based dose [e.g., 25, 35 or 50 units/kg] or fixed dose [e.g., 1000 units, 1500 units]) rather than fresh frozen plasma (FFP); additional use of vitamin K (5–10 mg by slow IV infusion) recommended.¹⁰⁰⁰ ¹¹⁸²

Other Warnings and Precautions

Tissue Necrosis

Tissue necrosis and/or gangrene of skin or other tissues reported rarely.²⁰³ ²¹⁵ ²⁹⁰ ²⁹¹ ²⁹² ²⁹³ ²⁹⁸ ³³⁰ ¹¹⁸³

Appears early within 1–10 days after initiation of therapy principally at sites of fat tissue (e.g., abdomen, breasts, buttocks, hips, thighs); reported more frequently in women.²⁰³ ²⁹⁰ ²⁹³ ²⁹⁸ ³³⁰ ¹¹⁸³

Increased risk in patients with hereditary, familial, or clinical deficiencies of protein C or its cofactor, protein S.²⁹⁰ ³³⁰ ¹¹⁸³

Careful clinical evaluation is required to determine whether necrosis is caused by underlying disease.³³⁰

Discontinue warfarin if tissue necrosis occurs; suggested treatments include supportive care, surgical debridement, aggressive wound care, and topical bactericidal agents.³³⁰ ¹¹⁸³ Consider alternative anticoagulants.³³⁰

Systemic Atheroemboli and Cholesterol Microemboli

May result from possible increased release of atheromatous plaque emboli; some cases have progressed to necrosis and death.²¹⁶ ²²¹ ²⁸⁴ ²⁸⁵ ²⁸⁶ ²⁸⁷ ²⁸⁸ ³³⁰ May occur 3–10 weeks or later following initiation of warfarin therapy.²⁰³ ²¹⁶ ²⁸⁴ ²⁸⁹ ³³⁰

The most common visceral organs involved are the kidneys, followed by the pancreas, spleen, and liver. ³³⁰ Signs and symptoms vary depending on the site of embolization.³³⁰

A distinct syndrome resulting from microemboli to the feet is known as ”purple toes syndrome.”³³⁰

If signs and symptoms are observed, discontinue warfarin and consider an alternative anticoagulant.³³⁰

Calciphylaxis

Calciphylaxis or calcium uremic arteriolopathy in patients with and without end stage renal disease reported; may be serious and/or fatal.³³⁰ ¹¹⁸⁴

Occurs after a prolonged duration of therapy compared to warfarin-induced necrosis, which occurs typically within the first 10 days.¹¹⁸⁴

Discontinue warfarin, treat calciphylaxis as appropriate, and consider alternative anticoagulants.³³⁰ ¹¹⁸⁴

Acute Kidney Injury

May occur in patients with altered glomerular integrity or with a history of kidney disease, possibly in relation to episodes of excessive anticoagulation and hematuria.³³⁰

Monitor patients with compromised renal function more frequently.³³⁰

Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS

Do not use warfarin as initial therapy for heparin-induced thrombocytopenia (HIT) or HIT with thrombosis syndrome (HITTS).³³⁰ ¹¹⁶⁸ ¹²⁰³

Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when warfarin was initiated or continued after heparin discontinuance.³³⁰ ³⁸⁷ ³⁸⁸ ³⁸⁹ ³⁹⁵ ¹¹⁶⁸

Amputation of the involved area and/or death have occurred.³³⁰ ¹¹⁶⁸

Delay warfarin initiation until thrombin generation is adequately controlled and thrombocytopenia has resolved (i.e., platelet counts ≥150,000/mm³ and stable).³³⁰ ³⁵⁴ ⁴⁴² ⁴⁴⁴ ¹¹⁶⁸ ¹²⁰³

Use in Pregnant Women with Mechanical Heart Valves

Possible teratogenicity, fetal or neonatal hemorrhage, and intrauterine death.³³⁰

Warfarin is generally contraindicated during pregnancy, but in women with mechanical heart valves at high risk of thromboembolism, manufacturer states the potential benefits of using warfarin may outweigh fetal risks.³³⁰

If used during pregnancy, or if the patient becomes pregnant while taking warfarin, apprise patient of the potential fetal hazard.³³⁰

Other Clinical Settings with Increased Risks

Utilize clinical judgment after weighing risks versus benefits of warfarin in the following situations: moderate to severe hepatic or renal impairment, infectious diseases (e.g., patients receiving antibiotic therapy) or disturbances of intestinal flora (e.g., sprue), patients with indwelling catheters, moderate to severe hypertension, acquired or hereditary protein C or protein S deficiencies, polycythemia vera, diabetes mellitus, eye surgery, and vasculitis.³³⁰

Although diabetes mellitus is listed, this should be interpreted with caution because diabetes is a prominent factor in stroke scoring tools (e.g., CHA₂DS₂VASc, ATRIA), but it is a less consistent risk factor for bleeding.³³⁰ ¹¹⁸⁶ ¹¹⁸⁷ ¹¹⁹⁰

The manufacturer states cataract surgery in patients taking warfarin has resulted in minor complications of sharp needle and local anesthesia block but has not been associated with potentially sight-threatening operative hemorrhagic complications.³³⁰ ¹⁰⁰⁴ The decision to discontinue or reduce the warfarin dosage prior to less invasive or less complex eye surgery should be based on the patient’s risk of thromboembolism.³³⁰ ¹⁰⁰⁴

Endogenous Factors Affecting INR

Endogenous factors associated with increased INR response include diarrhea, hepatic disorders, poor nutritional state, steatorrhea, and vitamin K deficiency.³³⁰ Other factors have been reported in the literature (e.g., decompensated heart failure, non-euthyroid hyperthyroidism).¹⁰¹⁴

Endogenous factors associated with decreased INR response include increased vitamin K intake or hereditary warfarin resistance.³³⁰ Other factors have been reported in the literature (e.g., alcoholism following chronic ingestion, non-euthyroid hypothyroidism).¹⁰¹⁴

Specific Populations

Pregnancy

May cause fetal harm.³³⁰

Contraindicated during pregnancy, but in women with mechanical heart valves at high risk of thromboembolism, the manufacturer states the potential benefits of using warfarin may outweigh fetal risks.³³⁰

Multiple strategies to reduce and balance the maternal (e.g., valve thrombosis, death) and fetal risks (e.g., fetal loss, teratogenicity) are based on factors such as daily warfarin dosage, ability to utilize heparin or LMWH, ability to conduct frequent laboratory monitoring, and the patient's values and priorities.¹¹⁴³ ¹¹⁸⁵

No single anticoagulation strategy is optimally safe for both the mother and the fetus; maternal and fetal risks can be reduced, but not eliminated.¹¹⁴³

Consult ACC/AHA guidelines for recommendations on the management of women with mechanical heart valves who are pregnant or planning to become pregnant.¹¹⁴³

Consult other guidance documents (e.g., American College of Obstetricians and Gynecologists [ACOG], American Society of Hematology [ASH]) for management of other warfarin indications in the context of pregnancy.¹¹²⁵ ¹¹²⁶ ¹¹⁸⁸

Lactation

Not significantly distributed into human breast milk or detectable in plasma of nursing infants; prolonged PT/INRs reported in some infants, but substantial coagulation abnormalities not observed.³³⁰ ⁴¹⁴ ¹¹²⁵ ¹¹²⁶ ¹¹⁸⁸ ¹¹⁸⁹

ACOG, ASH, American Academy of Pediatrics (AAP), ACCP, and other experts consider warfarin therapy to be compatible with breast-feeding.⁴¹⁴ ¹⁰¹² ¹¹²⁵ ¹¹²⁶ ¹¹⁸⁸

Neonates are particularly sensitive to the effects of warfarin as a result of vitamin K deficiency.³³⁰ Monitor infants receiving human milk for bruising and bleeding.³³⁰

Females and Males of Reproductive Potential

Counsel females of reproductive potential on potential risks to fetus and use of effective contraception.³³⁰

Such patients should use effective contraception during treatment and for at least 1 month after the final dose.³³⁰

Pediatric Use

Lack of adequate, well-controlled studies to inform optimum dosing, safety, and efficacy in pediatric patients.³³⁰

Use based on adult data and recommendations, as well as limited pediatric data from observational studies and patient registries.³³⁰ ¹⁰¹³ ¹¹¹⁸

Has been used in pediatric patients for prevention and treatment of thromboembolic events.¹⁰¹³ ¹¹¹⁸ More frequent determinations of INR are recommended in pediatric patients.³³⁰ ¹⁰¹³

Variable bleeding rates observed; pediatric patients should avoid activities or sports that may result in traumatic injury.³³⁰ ¹⁰¹³

Geriatric Use

Increased sensitivity and anticoagulant response.³³⁰

Increasing age confers increasing bleeding outcomes.¹¹⁸⁶ ¹¹⁸⁷ ¹¹⁹⁰ ¹¹⁹¹

Consider lower initial and maintenance doses for elderly and/or debilitated patients.³³⁰ Conduct more frequent monitoring.³³⁰

Hepatic Impairment

Increased anticoagulant response due to decreased synthesis of coagulation factors and decreased metabolism of warfarin.³³⁰ ³³⁰

Conduct more frequent monitoring for bleeding.³³⁰

Renal Impairment

Renal clearance considered a minor determinant of anticoagulant response.³³⁰

No dosage adjustment necessary.³³⁰

The manufacturer suggests increased INR monitoring.³³⁰

Common Adverse Effects

Most common adverse effects: fatal and nonfatal hemorrhage from any tissue or organ.³³⁰

Drug Interactions

Drug interactions 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).³³⁰ Such interactions may increase or decrease response to warfarin.³³⁰

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).³³⁰ (See Table 2.) Closely monitor INR in patients who initiate, discontinue, or change dosages of these concomitant drugs.³³⁰

list of drugs is not all-inclusive

Table 2. CYP Interactions with Warfarin330
Enzyme	Inhibitors*	Inducers*
CYP2C9	amiodarone	aprepitant
	capecitabine	bosentan
	co-trimoxazole	carbamazepine
	etravirine	phenobarbital
	fluconazole	rifampin
	fluvastatin
	fluvoxamine
	metronidazole
	miconazole
	oxandrolone
	tigecycline
	voriconazole
	zafirlukast
CYP1A2	acyclovir	montelukast
	allopurinol	moricizine
	caffeine	omeprazole
	cimetidine	phenobarbital
	ciprofloxacin	phenytoin
	disulfiram	cigarette smoking
	enoxacin
	famotidine
	fluvoxamine
	methoxsalen
	mexiletine
	oral contraceptives
	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
	tipranavir
	voriconazole
	zileuton

Protein-bound Drugs

Drugs may competitively or noncompetitively interfere with protein binding and unbound warfarin may increase temporarily due to concomitant plasma half-life and renal clearance changes.¹¹⁹² ¹¹⁹³

Marginal change in INR is transient.¹¹⁹²

Drugs that Increase Risk of Bleeding

Possible increased risk of bleeding with concomitant use of antiplatelet agents, NSAIAs, SSRIs, and anticoagulants other than warfarin.³³⁰ (See Table 3.)

Monitor closely.³³⁰ While the manufacturers of warfarin suggest close monitoring in those receiving NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors, and others recommend gastroprotective agents when the combination cannot be avoided, some experts (ACCP) suggest that such concomitant therapy be avoided.¹⁰⁰⁰ ¹¹⁹² ¹¹⁹³

list of drugs is not all-inclusive

Table 3. Drugs that Can Increase Bleeding Risk
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, heparin, fondaparinux, apixaban, dabigatran, edoxaban, rivaroxaban, enoxaparin
Antiplatelet agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine, ticagrelor, vorapaxar
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.³³⁰ ¹¹⁹²

Monitor INR closely when initiating or discontinuing any antibiotic or antifungal agent in patients receiving warfarin.³³⁰ ¹¹⁹² ¹¹⁹³

Dietary or Herbal Supplements

Concomitant therapy with dietary or herbal (botanical) supplements may alter an individual’s response to warfarin therapy.³³⁰ ¹¹⁹² ¹¹⁹⁷ (See Tables 4 and 5.) Limited information is available regarding the interaction potential of dietary and herbal products.³³⁰ ¹¹⁹² ¹¹⁹⁷ Exercise caution and perform additional PT/INR determinations whenever these products¹¹⁹² are added or discontinued.³³⁰ ¹¹⁹⁷

Table 4. Dietary or Herbal Supplements that May Increase Response to Coumarin Derivatives (e.g., Warfarin)33011921197
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 5. Dietary or Herbal Supplements that May Decrease Response to Coumarin Derivatives (e.g., Warfarin)33011921197
agrimony	goldenseal	St. John’s wort
coenzyme Q₁₀ (ubidecarenone)	mistletoe	yarrow
ginseng (Panax)

Possible interaction between warfarin and cranberry juice (i.e., increased effect and possible increased risk of bleeding).⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ⁵⁰⁵ ⁵⁰⁶ ⁵¹⁰ ¹¹⁹⁷ ¹¹⁹⁸ Available data do not appear to support a clinically important interaction between warfarin and moderate cranberry juice (240–480 mL) or cranberry extract (≤1,350 mg/day) consumption; monitor closely for changes in INR and manifestations of bleeding.⁵⁰¹ ⁵⁰² ⁵⁰⁷ ⁵⁰⁹ ⁵¹⁰ ¹¹⁹⁸

Specific Drugs

Drug	Interaction	Comments
Acetaminophen	Potential for increased anticoagulant effects;³⁰⁷ ³¹⁰ ³¹² ³¹³ ¹⁰¹⁴ however, conflicting data exist regarding clinical importance⁹⁰ ³⁰⁴ ³⁰⁵ ³⁰⁶ ³⁰⁸ ³¹¹ ¹¹⁹⁶	Monitoring of INR recommended following initiation of, and during sustained therapy with large (>1.5 g daily) acetaminophen doses³²² ¹⁰¹⁴ ¹¹⁹² ¹¹⁹⁶
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 ⁴⁹⁰ ⁴⁹⁴ ⁴⁹⁵ ¹¹⁹⁷ Acute ingestion of alcohol may enhance warfarin hypoprothrombinemc effect;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 and recommend against chronic heavy consumption (e.g., >720 mL beer, >300 mL wine, >60 mL liquor daily)
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 ¹¹⁹² ¹¹⁹³
Capecitabine	Inhibits CYP2C9 isoenzyme and decreases warfarin metabolism Possible increased anticoagulant response, increased PT/INR, and/or potentially fatal bleeding episodes, especially in patients >60 years of age with cancer	Use concomitantly with caution Frequent monitoring of PT/INR recommended to facilitate anticoagulant dosage adjustments
Cholestyramine	Potential for decreased warfarin absorption and decreased warfarin half-life³²² ¹¹⁹² ¹¹⁹⁴ Potential decreased vitamin K absorption¹¹⁹⁵ ¹¹⁹⁴	If concurrent use of cholestyramine and warfarin cannot be avoided, administer warfarin 1 hour before or ≥4 to 6 hours after cholestyramine¹¹⁹⁴
Lomitapide	Increased exposure to warfarin and increased INR	Manufacturer of lomitapide suggests monitoring INR regularly, particularly following adjustments in lomitapide dosage, and adjusting warfarin dosage as clinically indicated
Miconazole (vaginal)	Potential for increased PT/INR and/or bleeding³³⁰ ³⁶² ³⁶³ ³⁶⁴ ¹¹⁹²	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/INR³³⁰	Manufacturer recommends close monitoring;³³⁰ ACCP suggests avoiding concomitant use unless benefit is known or is highly likely to exceed potential harm from bleeding¹⁰⁰⁰ ¹¹⁹² ¹¹⁹³
Oxandrolone	Potential for increased warfarin half-life and AUC Potential increased PT/INR and bleeding; necessary warfarin dosage reduction may be as high as 80%	When oxandrolone therapy is initiated, changed, or discontinued, close monitoring of PT/INR and clinical response recommended to facilitate warfarin dosage adjustments and reduce bleeding risk

Warfarin Pharmacokinetics

Absorption

Bioavailability

Essentially completely absorbed after oral administration; peak plasma concentration usually attained within 4 hours.³³⁰

Onset

Synthesis of vitamin K-dependent coagulation factors is affected soon after absorption (e.g., within 24 hours).³³⁰ Depletion of circulating functional coagulation factors must occur before therapeutic effects of the drug become apparent.³³⁰

Duration

2–5 days after a single dose.³³⁰

Distribution

Extent

The apparent volume of distribution is about 0.14 L/kg.³³⁰

Crosses the placental barrier; however, the drug has not been detected in human breast milk.³³⁰

Plasma Protein Binding

Approximately 99%.³³⁰

Elimination

Metabolism

Almost entirely in the liver.³³⁰ Principally by CYP2C9; CYP2C19, 2C8, 2C18, 1A2, and 3A4 involved to a lesser degree.³³⁰

Elimination Route

Excreted principally in urine as metabolites.³³⁰

Half-life

Effective half-life averages 40 hours (range: 20–60 hours).³³⁰

Special Populations

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

Decreased metabolism in patients with hepatic dysfunction.³³⁰

Stability

Storage

Oral

Tablets

20–25°C.³³⁰

Protect from light.³³⁰

Actions

A coumarin-derivative anticoagulant.³³⁰
A racemic mixture of the 2 optical isomers of the drug.³³⁰
An indirect-acting anticoagulant; interferes with the hepatic synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X.³³⁰ Also inhibits the anticoagulant proteins C and S.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.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 ¹¹⁷⁶
Sequential depletion of circulating functional coagulation factor VII, protein C, factor IX, protein S, factor X, and finally factor II.³³⁰
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 5–10 days following initiation of therapy).¹¹⁷⁶ ¹¹⁷⁷
Does not alter catabolism of blood coagulation factors.¹¹⁷⁶
Inhibits thrombus formation when stasis is induced; may prevent extension of existing thrombi.³³⁰ ¹¹⁷⁶ No direct effect on established thrombi.³³⁰
Prolongs PT/INR and aPTT.³³⁰ ¹¹⁷⁶
Phytonadione (vitamin K₁) reverses the anticoagulant effect.³³⁰

Advice to Patients

Inform patients to strictly adhere to the prescribed dosage schedule and to not discontinue therapy without first consulting a healthcare provider.³³⁰
Inform patients that if a dose is missed, it should be taken as soon as possible on the same day; resume the regular dosing schedule the following day.³³⁰ Do not double a dose to make up for a missed dose.³³⁰
Inform patients that INR tests must be obtained based on their healthcare provider’s recommendations and regular visits are necessary.³³⁰ Instruct patients that their healthcare provider will decide what INR goal is appropriate and adjust the warfarin dosage based on the INR results.³³⁰
Advise patients that if warfarin is discontinued, the anticoagulant effects may persist for 2–5 days.³³⁰
Inform patients that they may bruise and/or bleed more easily and that a longer than normal time may be required to stop bleeding when taking warfarin.³³⁰ Instruct patients to tell their healthcare provider about any unusual bleeding (e.g., nose bleeds, bleeding gums, heavier than normal menstrual bleeding, unexpected vaginal bleeding, pink or brown urine, red or black stools, coughing up blood, vomiting blood or material that looks like coffee grounds) or bruising during therapy.³³⁰
Advise patients to avoid any activity or sport that may result in traumatic injury and to tell their healthcare provider if they fall often as this may increase their risk for complications.³³⁰
Advise patients to eat a normal, balanced diet to maintain a consistent intake of vitamin K.³³⁰ Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables.³³⁰
Advise patients to report any serious illness, such as severe diarrhea, infection, or fever to their healthcare provider.³³⁰
Advise patients to inform all healthcare providers, including dentists, about their warfarin therapy including before scheduling any medical, surgical, dental, or other invasive procedure.³³⁰
Advise patients to carry identification notifying others of their current warfarin therapy.³³⁰
Advise patients to immediately contact their healthcare provider if they experience pain and discoloration of the skin (a purple bruise-like rash) that primarily occurs on areas of the body with high fat content, such as breasts, thighs, buttocks, hips, and abdomen.³³⁰
Advise patients to immediately contact a healthcare provider if they experience any unusual symptoms or pain since warfarin may cause small cholesterol or atheroemboli.³³⁰ When this occurs in the feet, symptoms may include sudden cool, painful, purple discoloration of the toe(s) or forefoot.³³⁰
Advise patients to immediately contact a healthcare provider if any of the following occur: pain, swelling, discomfort, headache, dizziness, weakness, and fall or injury, especially if they hit their head.³³⁰
Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.³³⁰ Effective measures to avoid pregnancy should be used while taking warfarin and for 1 month after the last dose.³³⁰
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses. Instruct patients not to take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other OTC drugs, and botanical (herbal) products except on advice of a healthcare provider.³³⁰
Advise patients of other important precautionary information.³³⁰

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Warfarin Sodium
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	1 mg*	Jantoven (scored)	Upsher-Smith Laboratories
			Warfarin Sodium Tablets (scored)
		2 mg*	Jantoven (scored)	Upsher-Smith Laboratories
			Warfarin Sodium Tablets (scored)
		2.5 mg*	Jantoven (scored)	Upsher-Smith Laboratories
			Warfarin Sodium Tablets (scored)
		3 mg*	Jantoven (scored)	Upsher-Smith Laboratories
			Warfarin Sodium Tablets (scored)
		4 mg*	Jantoven (scored)	Upsher-Smith Laboratories
			Warfarin Sodium Tablets (scored)
		5 mg*	Jantoven (scored)	Upsher-Smith Laboratories
			Warfarin Sodium Tablets (scored)
		6 mg*	Jantoven (scored)	Upsher-Smith Laboratories
			Warfarin Sodium Tablets (scored)
		7.5 mg*	Jantoven (scored)	Upsher-Smith Laboratories
			Warfarin Sodium Tablets (scored)
		10 mg*	Jantoven (scored)	Upsher-Smith Laboratories
			Warfarin Sodium Tablets (scored)

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

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Pregnancy & Lactation Risk data available

CSA Schedule* Not a controlled drug N/A

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