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Warfarin: Drug information

Warfarin: Drug information
(For additional information see "Warfarin: Patient drug information" and see "Warfarin: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Bleeding risk:

Warfarin can cause major or fatal bleeding. Perform regular monitoring of international normalized ratio (INR) on all treated patients. Drugs, dietary changes, and other factors affect INR levels achieved with warfarin therapy. Instruct patients about prevention measures to minimize the risk of bleeding and to report immediately to their health care provider signs and symptoms of bleeding.

Brand Names: US
  • Coumadin [DSC];
  • Jantoven
Brand Names: Canada
  • APO-Warfarin;
  • Coumadin [DSC];
  • TARO-Warfarin
Pharmacologic Category
  • Anticoagulant;
  • Anticoagulant, Vitamin K Antagonist
Dosing: Adult

The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP.

Note: Dosing must be individualized and use of an institutional protocol is recommended (ACCP [Holbrook 2012]; Nutescu 2013). Response to warfarin is influenced by numerous factors (eg, age, organ function) as described below. Genetic variations in metabolism (eg, CYP2C9 and/or VKORC1 genes) can impact warfarin sensitivity; however, routine genetic testing is not recommended (ACCP [Holbrook 2012]; CPIC [Johnson 2017]).

Anticoagulation

Anticoagulation: Oral:

Initial: 5 mg once daily for most patients. A lower or higher starting dose may be used depending upon patient-specific factors (see example warfarin initiation nomogram below). Although an elevation in INR can be seen as soon as 24 to 48 hours after the first dose due to depletion of factor VII, this does not represent therapeutic anticoagulation because other vitamin K–dependent clotting factors with longer half-lives (eg, factors II, IX, and X) must also be depleted. Accordingly, in patients at high risk for thromboembolism, overlap ("bridging") with a parenteral anticoagulant may be necessary during initiation of warfarin until a stable therapeutic INR is attained (Wittkowsky 2018).

Example Warfarin Initiation Nomogram Targeting an INR Range of 2 to 3 (for Outpatients or Clinically Stable Inpatients) (Adapted From Wittkowsky 2018)a

Standard dosing for patients who are not expected to be sensitive to warfarinb

Reduced dosing for patients expected to be more sensitive to warfarinc

aDosing nomograms offer a reasonable starting point for estimating an initial warfarin dose and subsequent adjustments but should not serve as a substitute for clinical judgment. If the patient received warfarin previously, history of prior dose requirement is useful for guiding reinitiation of therapy.
bPatients who are generally started using “standard dosing” include otherwise healthy adults who are not receiving interacting medications.
cPatients expected to be more sensitive to warfarin include adults who are frail, elderly, or undernourished; have liver disease, kidney disease, heart failure, or acute illness; or are receiving a medication known to decrease warfarin metabolism.
dSome experts suggest starting select younger, otherwise healthy patients at 7.5 or 10 mg for the first 2 days (ACCP [Holbrook 2012]). A higher initial dose may also be appropriate in a patient who was previously treated with warfarin and required high doses or is receiving a medication that increases warfarin metabolism. However, this nomogram has not been validated for starting doses >5 mg/day.

Initial dose

5 mg daily for 3 daysd

2.5 mg daily for 3 days

Check INR the morning of day 4

<1.5

7.5 to 10 mg daily for 2 to 3 days

5 to 7.5 mg daily for 2 to 3 days

1.5 to 1.9

5 mg daily for 2 to 3 days

2.5 mg daily for 2 to 3 days

2 to 3

2.5 mg daily for 2 to 3 days

1.25 mg daily for 2 to 3 days

3.1 to 4

1.25 mg daily for 2 to 3 days

0.5 mg daily for 2 to 3 days

>4

Hold until INR <3

Hold until INR <3

Maintenance: Usual maintenance dose: 2 to 10 mg once daily. Once INR is therapeutic and stable following initiation, subsequent dosage requirements may be guided with the use of a maintenance dosing nomogram (see example warfarin maintenance dosing nomogram below). INR should be checked at least weekly when it is out of range and approximately every 4 weeks once therapeutic and stable. In chronic therapy, INR values are most affected by the doses administered 2 to 3 days prior to INR measurement.

Example Warfarin Maintenance Dosing Nomograma (Adapted From Hadlock 2018)

Regular-intensity anticoagulation: INR goal 2 to 3

High-intensity anticoagulation: INR goal 2.5 to 3.5

Suggested adjustment(s) to warfarin dose

aAs with initiation therapy nomograms, maintenance therapy nomograms must be used in conjunction with clinical judgment.
bAs an example, a patient with an INR goal of 2 to 3 and receiving 30 mg of warfarin per week (eg, administered as 5 mg on 5 days and 2.5 mg on 2 days) has an INR result of 1.4. The weekly dose should be increased by 10% to 20% (eg, increase to 35 mg per week by administering 5 mg once daily). A one-time supplemental dose of 7.5 mg may be considered on the day INR was checked, then start new maintenance dose (eg, 5 mg daily) the following day.

Adjustment(s) for subtherapeutic (low) INR – Note: If the factor causing subtherapeutic INR is transient (eg, missed warfarin dose or temporary change in vitamin K intake), consider resumption of prior maintenance dose following a one-time supplemental dose, if indicated.

INR <1.5

INR <2

• Increase weekly maintenance dose by 10% to 20%b

• Consider a one-time supplemental dose of 1.5 to 2 times the daily maintenance doseb

INR 1.5 to 1.7

INR 2 to 2.2

• Increase weekly maintenance dose by 5% to 15%

• Consider a one-time supplemental dose of 1.5 to 2 times the daily maintenance dose

INR 1.8 to 1.9

INR 2.3 to 2.4

• No dosage adjustment may be necessary if the last 2 INRs were in range, if there is no clear explanation for the INR to be out of range, and, if in the judgment of the clinician, the INR does not represent an increased risk of thromboembolism for the patient; additional monitoring may be warranted

• If dosage adjustment needed, increase weekly maintenance dose by 5% to 10%

• Consider a one-time supplemental dose of 1.5 to 2 times the daily maintenance dose

INR within therapeutic range

INR 2 to 3

INR 2.5 to 3.5

Desired range; no adjustment needed

Adjustment(s) for supratherapeutic (high) INR – Note: If the factor causing elevated INR is transient (eg, temporary change in vitamin K intake, acute illness, acute alcohol ingestion), consider resumption of prior maintenance dose following dose(s) held and low-dose oral vitamin K, if indicated.

INR 3.1 to 3.2

INR 3.6 to 3.7

• No dosage adjustment may be necessary if the last 2 INRs were in range, if there is no clear explanation for the INR to be out of range, and, if in the judgment of the clinician, the INR does not represent an increased risk of hemorrhage to patient; additional monitoring may be warranted

• If dosage adjustment needed, decrease weekly maintenance dose by 5% to 10%

INR 3.3 to 3.4

INR 3.8 to 3.9

• Decrease weekly maintenance dose by 5% to 10%

INR 3.5 to 3.9

INR 4 to 4.4

• Consider holding 1 dose

• Decrease weekly maintenance dose by 5% to 15%

INR >4 but ≤10 and no bleeding

INR >4.5 but ≤10 and no bleeding

• Hold until INR below upper limit of therapeutic range

• Decrease weekly maintenance dose by 5% to 20%

• If patient considered to be at significant risk for bleeding, consider low-dose oral vitamin K

INR >10 and no bleeding

INR >10 and no bleeding

• Hold until INR below upper limit of therapeutic range

• Administer vitamin K orally

• Decrease weekly maintenance dose by 5% to 20%

Warfarin: Adult Target INR Ranges Based Upon Indication

Indication

Targeted INR range

Treatment duration

Cardiac

Myocardial infarction with left ventricular thrombus or high risk for left ventricular thrombus (eg, ejection fraction <40% and severe anteroapical wall motion abnormality on imaging 48 hours after reperfusion) (ACCF/AHA [O’Gara 2013]; ACCP [Vandvik 2012]).

Note: Antiplatelet selection and duration of therapy for treatment of myocardial infarction may vary when used in combination with anticoagulation; consider risks of bleeding and thrombotic events when choosing antithrombotic therapy (ACC [Kumbhani 2021]; ACCP [Vandvik 2012]).

2 to 3

3 months after myocardial infarction

Atrial fibrillation or atrial flutter (AHA/ACC/HRS [January 2014, January 2019]).

Note: For eligible patients with nonvalvular atrial fibrillation, a direct oral anticoagulant is recommended over warfarin (AHA/ACC/HRS [January 2014, January 2019]).

2 to 3

Indefinite

Stress (takotsubo) cardiomyopathy with acute left ventricular thrombus (ACCP [Vandvik 2012])

2 to 3

3 months

Stroke or transient ischemic attack and left ventricular thrombus (AHA/ASA [Kleindorfer 2021])

2 to 3

3 months after stroke or transient ischemic attack

Valvular – Note: For mechanical valves, combination therapy with aspirin is not routinely required, except for patients who receive an On-X mechanical aortic valve. For surgically placed bioprosthetic valves in patients at low risk of bleeding, warfarin is suggested for the first 3 to 6 months after surgery followed by aspirin monotherapy; for patients at elevated risk of bleeding, initiating aspirin monotherapy after surgery and continuing long term may be appropriate (ie, no initial use of warfarin after surgery). When choosing antithrombotic therapy, additional risk factors for thromboembolism (eg, atrial fibrillation, previous thromboembolism, left ventricular systolic dysfunction, hypercoagulable conditions) should be considered. The goal INR is generally the central value in the indicated acceptable range, especially for patients with a mechanical valve (ACC/AHA [Otto 2021]; Puskas 2014).

On-X mechanical bileaflet aortic valve without additional risk factors for thromboembolism (ACC/AHA [Otto 2021]; Puskas 2014)

Months 1 to 3:

2 to 3

Month 4 and after:

1.5 to 2

Indefinite

Mechanical bileaflet aortic valve (other than On-X) without additional risk factors for thromboembolism

or

Current-generation single-tilting disc aortic valve without additional risk factors for thromboembolism

or

On-X mechanical bileaflet aortic valve with additional risk factors for thromboembolism (ACC/AHA [Otto 2021]; Puskas 2014)

2 to 3

Indefinite

Current-generation mechanical aortic valve with additional risk factors for thromboembolism

or

Older-generation mechanical aortic valve (eg, ball-in-cage) without additional risk factors for thromboembolism

or

Current-generation mechanical mitral valve with or without additional risk factors for thromboembolism (ACC/AHA [Otto 2021])

2.5 to 3.5

Indefinite

Older-generation mechanical aortic valve (eg, ball-in-cage) with additional risk factors for thromboembolism

or

Older-generation mechanical mitral valve (eg, ball-in-cage) with or without additional risk factors for thromboembolism (Gaasch 2021)

3 to 4

Indefinite

Surgically placed bioprosthetic aortic or mitral valve at low risk of bleeding (ACC/AHA [Otto 2021])

2 to 3

3 to 6 months

Rheumatic mitral stenosis with atrial fibrillation, previous systemic embolism, or left atrial thrombus (ACC/AHA [Otto 2021])

2 to 3

Indefinite

Thrombosis of bioprosthetic valve, nonurgent management

Note: Some experts limit use to left-sided (aortic or mitral) bioprosthetic valve thrombosis and favor fibrinolysis for right-sided bioprosthetic valve thrombosis (Pislaru 2021). Target INR and duration of therapy may vary depending on antithrombotic regimen at the time of thrombosis. Regularly assess (ie, every 30 days) for improvement in signs and symptoms (AHA/ACC [Otto 2021]; Butnaru 2013; Chakravarty 2017; Jose 2017; Latib 2015; Makkar 2015; Pislaru 2015; Pislaru 2021).

2 to 3

≥6 months after thrombus resolution

Acute venous thromboembolism treatment – Note: For eligible patients, a direct oral anticoagulant is recommended over warfarin. When warfarin is selected for long-term treatment, a parenteral anticoagulant must be used initially as a bridge until INR measurements are therapeutic and stable. Start warfarin on the first or second day of parenteral anticoagulation and overlap until INR is ≥2 for at least 2 days. Duration of overlap is usually 4 to 5 days (ACCP [Ageno 2012]). The optimal duration of warfarin therapy is dependent on several factors, such as presence of provoking events, patient risk factors for recurrence or bleeding, and patient preferences. If indefinite treatment is suggested, reassess need for anticoagulation at periodic intervals (ACCP [Kearon 2012, Kearon 2016]).

Venous thromboembolism, provoked (ACCP [Kearon 2012, Kearon 2016])

2 to 3

Minimum of 3 months

Venous thromboembolism, unprovoked (ACCP [Kearon 2012, Kearon 2016]; ISTH [Baglin 2012])

2 to 3

Minimum of 3 months and up to indefinite

Thromboprophylaxis

Idiopathic or inherited pulmonary artery hypertension (ACCF/AHA [McLaughlin 2009]; ACCP [Klinger 2019]; ESC/ERS [Galiè 2016]; Olsson 2014)

Note: Anticoagulation should be considered on an individual basis for patients with idiopathic or inherited pulmonary arterial hypertension after considering risks and benefits. Avoid anticoagulation in patients with scleroderma-associated pulmonary arterial hypertension (Hopkins 2019; Khan 2018; Olsson 2014).

1.5 to 2.5

Indefinite

Chronic thromboembolic pulmonary arterial hypertension (ACCF/AHA [McLaughlin 2009]; ESC/ERS [Galiè 2016])

2 to 3

Indefinite

Antiphospholipid syndrome (ACCP [Holbrook 2012]; Erkan 2019)

Note: Antiphospholipid syndrome is an autoimmune syndrome characterized by venous or arterial thrombosis and/or pregnancy loss in the presence of persistent antiphospholipid antibodies. Patients with antiphospholipid antibodies alone, without a history of thromboembolism, should not receive anticoagulation unless another indication exists. The PT/INR may be prolonged at baseline, in the absence of anticoagulation, in a small percentage of patients due to the presence of antiphospholipid antibodies. This should not be considered a therapeutic effect. An alternative method for monitoring warfarin may be necessary (Erkan 2019).

2 to 3

Indefinite

Total hip arthroplasty or hip fracture surgery

Note: May be used as an alternative to low-molecular-weight heparin or low-dose SubQ heparin (ACCP [Falck-Ytter 2012]).

2 to 3

Minimum of 10 to 14 days and up to 35 days

Total knee arthroplasty

Note: May be used as an alternative to low-molecular-weight heparin or low-dose SubQ heparin (ACCP [Falck-Ytter 2012]).

2 to 3

Typically, 10 to 14 days, but consider up to 35 days if there are multiple or persistent risk factors

Heparin-induced thrombocytopenia – Note: If a patient is taking warfarin at the time of diagnosis, it should be discontinued, and vitamin K should be administered to reverse its effect. Initial therapy should be with a parenteral nonheparin anticoagulant. Warfarin may be initiated after the patient has been stably anticoagulated with a parenteral nonheparin anticoagulant and the platelet count has recovered (eg, ≥150 × 109/L or at the patient's baseline). Starting dose should be ≤5 mg once daily. Overlap the parenteral nonheparin anticoagulant with warfarin for ≥5 days and until INR is therapeutic. Some nonheparin anticoagulants may elevate INR, complicating interpretation. Recheck INR after effects of the nonheparin anticoagulant have worn off to ensure INR remains therapeutic (ACCP [Linkins 2012]; ASH [Cuker 2018]).

Heparin-induced thrombocytopenia without thrombosis (ACCP [Linkins 2012]; ASH [Cuker 2018])

2 to 3

4 weeks to 3 months (ACCP [Linkins 2012]). Some experts allow for discontinuation of anticoagulation after platelet count recovery, potentially resulting in a shorter duration (ASH [Cuker 2018]).

Heparin-induced thrombocytopenia with thrombosis (ACCP [Linkins 2012]; ASH [Cuker 2018])

2 to 3

Optimal duration not well established. Typically, 3 to 6 months (ACCP [Linkins 2012]; ASH [Cuker 2018]).

Transitioning between anticoagulants:

Transitioning from another anticoagulant to warfarin: Note: Apixaban, dabigatran, edoxaban, and rivaroxaban can elevate INR, complicating interpretation if overlapped with warfarin. To minimize interference, check INR near end of direct oral anticoagulant dosing interval.

Transitioning from apixaban to warfarin: Some experts suggest overlapping apixaban with warfarin for ≥2 days until INR is therapeutic. An alternative is to stop apixaban, start warfarin the same day, and bridge with a parenteral anticoagulant until the desired INR is reached (Leung 2019).

Transitioning from dabigatran to warfarin: One option is to stop dabigatran, start warfarin the same day, and bridge with a parenteral anticoagulant until the desired INR is reached (Leung 2019). An alternative option is to overlap the 2 agents. If this is done, the timing of warfarin initiation is based on CrCl as outlined below:

CrCl >50 mL/minute: Initiate warfarin 3 days before discontinuing dabigatran.

CrCl 30 to 50 mL/minute: Initiate warfarin 2 days before discontinuing dabigatran.

CrCl 15 to 30 mL/minute: Initiate warfarin 1 day before discontinuing dabigatran.

CrCl <15 mL/minute: Dosing recommendations cannot be provided. Dabigatran is not recommended for use in patients with severe renal impairment.

Transitioning from edoxaban to warfarin:

Oral option: For patients taking edoxaban 60 mg once daily, reduce the dose to 30 mg once daily and begin warfarin concomitantly. For patients taking edoxaban 30 mg once daily, reduce the dose to 15 mg once daily and begin warfarin concomitantly. Discontinue edoxaban once a stable INR ≥2 is achieved; continue warfarin (Leung 2019).

Parenteral option: Discontinue edoxaban and initiate a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose. Discontinue the parenteral anticoagulant once a stable INR ≥2 is achieved; continue warfarin.

Transitioning from rivaroxaban to warfarin: Some experts suggest overlapping rivaroxaban with warfarin for ≥2 days until INR is therapeutic. An alternative is to stop rivaroxaban, start warfarin the same day, and bridge with a parenteral anticoagulant until the desired INR is reached (Leung 2019).

Transitioning from therapeutic-dose parenteral anticoagulant to warfarin: Start warfarin and continue parenteral anticoagulant until INR is within therapeutic range (Hull 2022a; Wittkowsky 2018). Note: Overlap parenteral anticoagulant with warfarin until INR is ≥2 for at least 2 days (duration of overlap is usually 4 to 5 days) (ACCP [Ageno 2012]; Hull 2022b).

Transitioning from warfarin to another anticoagulant:

Note: In general, it is reasonable to discontinue warfarin and initiate another anticoagulant as soon as INR is ≤2 depending on the indication and risks of thrombosis and bleeding (Leung 2019). Specific recommendations from manufacturers include:

Transitioning from warfarin to apixaban: Discontinue warfarin and initiate apixaban as soon as INR falls to <2 (US labeling).

Transitioning from warfarin to dabigatran: Discontinue warfarin and initiate dabigatran as soon as INR falls to <2 (US labeling).

Transitioning from warfarin to edoxaban: Discontinue warfarin and initiate edoxaban as soon as INR falls to ≤2.5 (US labeling).

Transitioning from warfarin to rivaroxaban: Discontinue warfarin and initiate rivaroxaban as soon as INR falls to <3 (US labeling) or ≤ 2.5 (Canadian labeling).

Transitioning from warfarin to parenteral anticoagulation: Stop warfarin and start the parenteral anticoagulant when INR is as close as possible to the lower end of the targeted INR range (Wittkowsky 2018).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function: There are no specific dosage adjustments recommended for any degree of kidney impairment. However, compared to patients with normal kidney function, retrospective data suggest patients with eGFR <60 mL/minute/1.73 m2 tend to require ~10% to 20% lower warfarin doses and are at higher risk of overanticoagulation and bleeding. Consider starting with lower initial doses in these patients and more frequent INR monitoring, especially if the patient has additional risk factors for warfarin sensitivity (eg, elderly, eGFR <30 mL/minute/1.73 m2) (Limdi 2009; Limdi 2010; Sakaan 2014; expert opinion).

Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (highly protein bound): Patients with end-stage kidney disease (ESKD) tend to require ~20% lower doses compared to patients with normal kidney function (Sakaan 2014) and have a significant risk of bleeding (Elliott 2007). Use lower initial doses and monitor INR frequently (Limdi 2009; Sakaan 2014).

Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound): Patients with ESKD tend to require ~20% lower doses compared to patients with normal kidney function (Sakaan 2014) and have a significant risk of bleeding (Elliott 2007). Use lower initial doses and monitor INR frequently (Limdi 2009; Sakaan 2014).

CRRT: Avoid use (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Avoid use (expert opinion).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling. However, the response to oral anticoagulants may be markedly enhanced in obstructive jaundice, hepatitis, and cirrhosis. INR should be closely monitored.

Dosing: Pediatric

(For additional information see "Warfarin: Pediatric drug information")

Note: Labeling identifies genetic factors which may increase patient sensitivity to warfarin based on experience in adult patients. Specifically, genetic variations in the proteins CYP2C9 and VKORC1, responsible for warfarin's primary metabolism and pharmacodynamic activity, respectively, have been identified as predisposing factors associated with decreased dose requirement and increased bleeding risk. Genotyping tests are available and may provide guidance on initiation of anticoagulant therapy. Routine genetic testing is not recommended (ACCP [Holbrook 2012]; CPIC [Johnson 2017]). For management of elevated INRs as a result of warfarin therapy, see Phytonadione monograph or ACCP Guidelines for additional information (ACCP [Monagle 2012]).

Thromboembolic complications; prophylaxis and treatment: Limited data available: Individualize dose to achieve target INR based on indication; INRs are primarily extrapolated from adult experience; although there may be some exceptions, for most indications the therapeutic target INR is 2.5 (range: 2 to 3), and for low-dose prophylaxis, a target INR is 1.7 (range: 1.5 to 1.9) (ACCP [Monagle 2012]); see "Reference Range" for more information and consult expert guidelines.

Infants, Children, and Adolescents:

Target INR between 2 to 3 (eg, treatment) :

Day 1: Initial loading dose (if baseline INR is 1 to 1.3): Oral: 0.2 mg/kg/day once daily; maximum dose: 10 mg/dose; use a reduced initial loading dose of 0.1 mg/kg if patient has undergone a Fontan procedure or has liver dysfunction (ACCP [Monagle 2012]; AHA [Giglia 2013]; Streif 1999).

Days 2 to 4: Additional loading doses are dependent upon patient's INR (ACCP [Monagle 2012]): Oral:

INR 1.1 to 1.3: Repeat the initial loading dose.

INR 1.4 to 1.9: Dose is 50% of the initial loading dose.

INR 2 to 3: Dose is 50% of the initial loading dose.

INR 3.1 to 3.5: Dose is 25% of the initial loading dose.

INR >3.5: Hold the drug until INR <3.5, then restart at 50% of previous dose.

Days ≥5: Maintenance doses are dependent upon patient's INR (ACCP [Monagle 2012]): Oral:

INR 1.1 to 1.4: Increase previous dose by 20%.

INR 1.5 to 1.9: Increase previous dose by 10%.

INR 2 to 3: No change in dose.

INR 3.1 to 3.5: Decrease previous dose by 10%.

INR >3.5: Hold the drug until INR <3.5, then restart at 20% less than the previous dose.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

No adjustment required; however, patients with renal failure have an increased risk of bleeding complications. Monitor closely.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling. However, the response to oral anticoagulants may be markedly enhanced in obstructive jaundice (due to reduced vitamin K absorption) and also in hepatitis and cirrhosis (due to decreased production of vitamin K-dependent clotting factors); INR should be closely monitored.

Dosing: Older Adult

Patients >60 years of age tend to require lower dosages to produce a therapeutic level of anticoagulation (due to changes in the pattern of warfarin metabolism).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as sodium:

Coumadin: 1 mg [DSC] [scored]

Coumadin: 2 mg [DSC] [scored; contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake]

Coumadin: 2.5 mg [DSC] [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake]

Coumadin: 3 mg [DSC] [scored; contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #6 aluminum lake]

Coumadin: 4 mg [DSC] [scored; contains fd&c blue #1 aluminum lake]

Coumadin: 5 mg [DSC] [scored; contains fd&c yellow #6 aluminum lake]

Coumadin: 6 mg [DSC] [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #6 aluminum lake]

Coumadin: 7.5 mg [DSC] [scored; contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Coumadin: 10 mg [DSC] [scored; dye free]

Jantoven: 1 mg [scored; contains fd&c red #40 aluminum lake]

Jantoven: 2 mg [scored; contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake]

Jantoven: 2.5 mg [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake]

Jantoven: 3 mg [scored]

Jantoven: 4 mg [scored; contains fd&c blue #1 aluminum lake]

Jantoven: 5 mg [scored; contains fd&c yellow #6 aluminum lake]

Jantoven: 6 mg [scored; contains fd&c blue #1 aluminum lake]

Jantoven: 7.5 mg [scored; contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Jantoven: 10 mg [scored]

Generic: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as sodium:

Coumadin: 1 mg [DSC]

Coumadin: 2 mg [DSC] [contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake]

Coumadin: 2.5 mg [DSC] [contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake]

Coumadin: 3 mg [DSC] [contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #6 aluminum lake]

Coumadin: 4 mg [DSC] [contains fd&c blue #1 aluminum lake]

Coumadin: 5 mg [DSC] [contains fd&c yellow #6 aluminum lake]

Coumadin: 6 mg [DSC], 10 mg [DSC]

Generic: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009218s017lbl.pdf#page=31 (Coumadin), must be dispensed with this medication.

Administration: Adult

Oral: Administer with or without food. Warfarin should be administered orally once a day at approximately the same time. In clinical practice, patients are often encouraged to take their dose later in the day to facilitate implementation of needed dose changes identified at daytime monitoring visits (Wittkowsky 2018).

Administration: Pediatric

Oral: Administer with or without food. Take at the same time each day.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 3]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).

Use: Labeled Indications

Myocardial infarction: Adjunct to reduce risk of systemic embolism (eg, recurrent myocardial infarction, stroke) after myocardial infarction.

Thromboembolic complications: Prophylaxis and treatment of thromboembolic disorders (eg, venous, pulmonary) and embolic complications arising from atrial fibrillation or cardiac valve replacement.

Limitations of use: Warfarin has no direct effect on an established thrombus and does not reverse ischemic tissue damage. The goal of anticoagulant therapy is to prevent further extension of an already formed thrombus and to prevent secondary thromboembolic complications that may result in serious and potentially fatal sequelae.

Medication Safety Issues
Sound-alike/look-alike issues:

Coumadin may be confused with Cardura, Compazine, Kemadrin

Jantoven may be confused with Janumet, Januvia

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

National Patient Safety Goals:

The Joint Commission (TJC) requires healthcare organizations that provide anticoagulant therapy to have approved protocols and evidence-based practice guidelines in place to reduce the risk of anticoagulant-associated patient harm. Patients receiving anticoagulants should receive individualized care through a defined process that includes medication selection, dosing (including adjustments for age, renal function, or liver function), drug-drug interactions, drug-food interactions, other applicable risk factors, monitoring, patient and family education, proper administration, reversal of anticoagulation, management of bleeding events, and perioperative management. This does not apply to routine short-term use of anticoagulants for prevention of venous thromboembolism during procedures or hospitalizations (NPSG.03.05.01).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Bleeding is the major adverse effect of warfarin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility.

1% to 10%:

Hematologic & oncologic: Major hemorrhage (≤5%; INR 2.5 to 4.0 generally associated with more bleeding)

Frequency not defined:

Cardiovascular: Purple-toe syndrome, systemic cholesterol micro-embolism, vasculitis

Central nervous system: Chills

Dermatologic: Alopecia, bullous rash, dermatitis, pruritus, skin necrosis, urticaria

Gastrointestinal: Abdominal pain, bloating, diarrhea, dysgeusia, flatulence, nausea, vomiting

Hematologic & oncologic: Minor hemorrhage

Hepatic: Hepatitis

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Renal: Acute renal failure (in patients with altered glomerular integrity or with a history of kidney disease)

Respiratory: Tracheobronchial calcification

<1%, postmarketing, and/or case reports: Gangrene of skin or other tissue, skin necrosis, vascular calcification (calcium uremic arteriolopathy and calciphylaxis)

Contraindications

Hypersensitivity to warfarin or any component of the formulation; hemorrhagic tendencies (eg, active GI ulceration, patients bleeding from the GI, respiratory, or GU tract; cerebral aneurysm; CNS hemorrhage; dissecting aortic aneurysm; spinal puncture and other diagnostic or therapeutic procedures with potential for significant bleeding); recent or potential surgery of the eye or CNS; major regional lumbar block anesthesia or traumatic surgery resulting in large, open surfaces; blood dyscrasias; malignant hypertension; pericarditis or pericardial effusion; bacterial endocarditis; unsupervised patients with conditions associated with a high potential for noncompliance; eclampsia/preeclampsia, threatened abortion, pregnancy (except in women with mechanical heart valves at high risk for thromboembolism)

Warnings/Precautions

Concerns related to adverse effects:

• Acute kidney injury: Acute kidney injury, possibly as a result of episodes of excessive anticoagulation and hematuria, may occur in patients with a history of kidney disease or in patients with altered glomerular integrity.

• Anaphylaxis/hypersensitivity: May cause hypersensitivity reactions, including anaphylaxis; use with caution in patients with anaphylactic disorders.

• Bleeding: [US Boxed Warning]: May cause major or fatal bleeding. Perform regular INR monitoring in all treated patients. INR levels achieved with warfarin therapy may be affected by concomitant medication, dietary modifications and/or other factors (eg, smoking). Risk factors for bleeding include high intensity anticoagulation (INR >4), age (≥65 years), variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, severe diabetes, malignancy, trauma, renal insufficiency, polycythemia vera, vasculitis, open wound, history of PUD, indwelling catheters, menstruating and postpartum women, drug-drug interactions, long duration of therapy, or known genetic deficiency in CYP2C9 activity. Patient must be instructed to report bleeding, accidents, or falls as well as any new or discontinued medications, herbal or alternative products used, or significant changes in smoking or dietary habits. Unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulation.

• Calciphylaxis: Fatal and serious calciphylaxis (calcium uremic arteriolopathy) has been reported in patients with and without end-stage renal disease. If calciphylaxis is diagnosed, discontinue therapy and treat calciphylaxis as appropriate. Consider alternative anticoagulation therapy.

• Skin necrosis/gangrene: Necrosis or gangrene of the skin and other tissue can occur (rarely, <0.1%) due to paradoxical local thrombosis; onset is usually within the first few days of therapy and is frequently localized to the limbs, breast, or penis. The risk of this effect is increased in patients with protein C or S deficiency. Consider alternative therapies if anticoagulation is necessary.

• Atheroemboli/cholesterol microemboli: Warfarin therapy may release atheromatous plaque emboli; symptoms depend on site of embolization, most commonly kidneys, pancreas, liver, and spleen. In some cases may lead to necrosis or death. “Purple toe” syndrome, due to cholesterol microembolization, has been rarely described with coumarin-type anticoagulants. Typically, this occurs after several weeks of therapy, and may present as a dark, purplish, mottled discoloration of the plantar and lateral surfaces. Other manifestations of cholesterol microembolization may include rash; livedo reticularis; gangrene; abrupt and intense pain in lower extremities; abdominal, flank, or back pain; hematuria, renal insufficiency; hypertension; cerebral ischemia; spinal cord infarction; or other symptoms of vascular compromise.

Disease-related concerns:

• Bariatric surgery: High risk for hemorrhage postsurgery: Avoid warfarin if possible immediately after gastric bypass and sleeve gastrectomy; significant risk for hemorrhage, readmission, and mortality (Bechtel 2013). Several studies have observed warfarin dose reduction postoperatively with a subsequent return to preoperative doses 6 to 12 months after surgery (Irwan 2013; Schullo-Feulner 2014; Steffen 2015; Strong 2018). The change in dose requirement may be multifactorial but is most likely due to attributable variation in the time to resuming full solid intake and the consequent alteration in the intake of vitamin K-containing foods. Monitor INR closely in the early postoperative period and up to 1 year after surgery or when significant nutritional or supplementation changes occur.

• Dietary insufficiency: Use with caution in patients with prolonged dietary insufficiencies (vitamin K deficiency).

• Heparin-induced thrombocytopenia: Use with caution in patients with heparin-induced thrombocytopenia and venous thromboembolism; limb ischemia, necrosis, and gangrene have occurred when warfarin was started or continued after heparin was stopped. Warfarin monotherapy is contraindicated in the initial treatment of heparin-induced thrombocytopenia; warfarin initially inhibits the synthesis of protein C, potentially accelerating the underlying active thrombotic process.

• Hepatic impairment: Reduced liver function, regardless of etiology, may impair synthesis of coagulation factors leading to increased warfarin sensitivity.

• Infection: Use with caution in patients with acute infection or active TB or any disruption of normal GI flora; antibiotics and fever may alter response to warfarin.

• Renal impairment: Use with caution in patients with renal impairment. Patients with renal impairment are at increased risk for bleeding diathesis; frequent INR monitoring is recommended.

• Thyroid disease: Use with caution in patients with thyroid disease; warfarin responsiveness may increase (ACCP [Ageno 2012]).

Special populations:

• Elderly: The elderly may be more sensitive to anticoagulant therapy.

• Patients with genomic variants in CYP2C9 and/or VKORC1: Presence of the CYP2C9*2 or *3 allele and/or polymorphism of the vitamin K oxidoreductase (VKORC1) gene may have increased sensitivity to warfarin (eg, lower doses needed to achieve therapeutic anticoagulation). The *2 allele is reported to occur with a frequency of 4% to 11% in African-Americans and Caucasians, respectively, while the *3 allele frequencies are 2% to 7% respectively. Other variant 2C9 alleles (eg, *5, *6, *9, and *11) are also associated with reduced warfarin metabolism and thus may increase sensitivity to warfarin, but are much less common. Lower doses may be required in these patients. Genetic testing may help determine appropriate dosing.

Other warnings/precautions:

• Appropriate use: Surgical patients: When temporary interruption is necessary before surgery, discontinue for approximately 5 days before surgery; when there is adequate hemostasis, may reinstitute warfarin therapy ~12 to 24 hours after surgery. Decision to safely continue warfarin therapy through the procedure and whether or not bridging of anticoagulation is necessary is dependent upon risk of perioperative bleeding and risk of thromboembolism. If risk of thromboembolism is elevated, consider bridging warfarin therapy with an alternative anticoagulant (eg, unfractionated heparin or low-molecular-weight heparin) (ACCP [Ageno 2012]).

• Patient selection: Use care in the selection of patients appropriate for this treatment; ensure patient cooperation especially from the alcoholic, illicit drug user, demented, or psychotic patient; ability to comply with routine laboratory monitoring is essential.

Warnings: Additional Pediatric Considerations

Vitamin K-antagonist (VKA) (eg, warfarin) therapy is usually avoided in neonates and infants <4 months due to pharmacodynamic and administration issues which result in a greater risk of bleeding and necessitate more frequent monitoring and dose adjustment in these patients. Pharmacodynamic issues which create problematic dosing and monitoring include: Physiologically decreased neonatal plasma levels of vitamin K-dependent clotting factors (comparable to an adult with an INR 2 to 3 on VKA therapy), and a lower concentration of vitamin K in breast milk relative to infant formula (which is supplemented) making breast-fed infants very sensitive to VKA therapy (eg, much lower doses required to achieve target INR). Administration is problematic since no oral liquid formulation of warfarin is available; although some centers dissolve the appropriate tablet/dose in water, data which verifies stability and full assessment of practice is lacking (ACCP [Monagle 2012]; Hepponstall 2017).

Rare hair loss has been reported with warfarin use (ACCP [Monagle 2012]); pediatric cases include 2 case reports occurring with accidental ingestions in a 2 year old and 6 year old (Watras 2016). Tracheal calcification has been reported in young children and initially was considered a rare observation (ACCP [Monagle 2012]). However, newer data suggests it occurs more frequently; an incidence of 35% (6 out of 17 subjects) was reported in a retrospective analysis evaluating patients ≤10 years of age who underwent cardiac valve replacement and were receiving long-term anticoagulation with warfarin (Golding 2013).

Decreased bone mineral density (BMD) has been reported in children and adolescents receiving long-term warfarin therapy; a case control study reported a significant reduction in lumbar spinal bone mineral apparent density (BMAD) scores in pediatric patients on warfarin therapy (n=17) compared to age-matched controls (n=321); the mean age of the 17 case subjects was 14.7 years (range: 8 to 18 years) and the mean duration of warfarin treatment was 8.2 years (range: 1 to 14 years) (Barnes 2005; Hepponstall 2017). Another cohort study evaluated BMD in 26 subjects with single ventricle physiology (age range: 5 to 12 years; treatment group [warfarin], n=16) and reported significant reductions of spinal BMD z-score than controls; they also reported lower total body less head BMD z-score (Bendaly 2015). Some centers include bone density monitoring (eg, dual energy X-ray absorptiometry [DXA] scan) as part of routine management for long-term warfarin therapy (Barnes 2005).

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C9 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

5-Aminosalicylic Acid Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. 5-Aminosalicylic Acid Derivatives may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Acetaminophen: May enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive days. Risk C: Monitor therapy

Adalimumab: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Alcohol (Ethyl): May decrease the serum concentration of Vitamin K Antagonists. More specifically, this effect has been described in heavy drinking alcoholic patients (over 250 g alcohol daily for over 3 months). The role of alcohol itself is unclear. Risk C: Monitor therapy

Alemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Allopurinol: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Monitor for increased prothrombin times (PT)/therapeutic effects of oral anticoagulants if allopurinol is initiated/dose increased, or decreased effects if allopurinol is discontinued/dose decreased. Reductions in coumarin dosage will likely be needed. Risk D: Consider therapy modification

Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy

Amiodarone: May enhance the anticoagulant effect of Vitamin K Antagonists. Amiodarone may increase the serum concentration of Vitamin K Antagonists. Management: Monitor patients extra closely for evidence of increased anticoagulant effects if amiodarone is started. Consider empiric reduction of 30% to 50% in warfarin dose, though no specific guidelines on dose adjustment have been published. Risk D: Consider therapy modification

Amitriptyline: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Androgens: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Monitor for increased effects of vitamin K antagonists if an androgen is initiated/dose increased, or decreased effects if androgen is discontinued/dose decreased. Significant reductions in vitamin K antagonist dose are likely required. Risk D: Consider therapy modification

Anticoagulants: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Antithyroid Agents: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Aprepitant: May decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Atazanavir: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

AzaTHIOprine: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Vitamin K Antagonists. Management: Monitor INR more closely. Anticoagulant dose increases of 30% to 60% may be needed after a barbiturate is initiated or given at an increased dose. Anticoagulant dose decreases may be needed following barbiturate discontinuation or dose reduction. Risk D: Consider therapy modification

Bicalutamide: May increase the serum concentration of Vitamin K Antagonists. Specifically, free concentrations of the vitamin K antagonists may be increased. Risk C: Monitor therapy

Bifonazole: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Bosentan: May decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Caffeine and Caffeine Containing Products: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Cannabinoid-Containing Products: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

CarBAMazepine: May decrease the serum concentration of Vitamin K Antagonists. Management: Monitor for decreased INR and effects of vitamin K antagonists if carbamazepine is initiated/dose increased, or increased INR and effects if carbamazepine is discontinued/dose decreased. Vitamin K antagonist dose adjustments will likely be required. Risk D: Consider therapy modification

Carbimazole: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Cephalosporins: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Chenodiol: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Chloral Betaine: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Chloral Hydrate: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the serum concentration of Vitamin K Antagonists. Management: Separate the administration of vitamin K antagonists and cholestyramine by at least 3 to 4 hours. Monitor patients closely for reduced vitamin K antagonist effects (eg, decreased INR, thrombosis) when these agents are combined. Risk D: Consider therapy modification

Chondroitin Sulfate: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Cimetidine: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Avoid coadministration of cimetidine and vitamin K antagonists. If unavoidable, monitor for increased effects of vitamin K antagonists when cimetidine is initiated/dose increased, or decreased effects if cimetidine is discontinued/dose decreased. Risk D: Consider therapy modification

Clopidogrel: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Cloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Cloxacillin may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Cobicistat: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Coenzyme Q-10: May diminish the anticoagulant effect of Vitamin K Antagonists. Coenzyme Q-10 may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Colesevelam: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy

Corticosteroids (Systemic): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Cranberry: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

CYP2C9 Inducers (Weak): May decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

CYP2C9 Inhibitors (Weak): May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Darunavir: May decrease the serum concentration of Warfarin. Darunavir may increase the serum concentration of Warfarin. Risk C: Monitor therapy

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with other anticoagulants prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: Consider therapy modification

Dicloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Direct Acting Antiviral Agents (HCV): May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Disulfiram: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Dronedarone: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Econazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Efavirenz: May decrease the serum concentration of Vitamin K Antagonists. Efavirenz may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Elexacaftor, Tezacaftor, and Ivacaftor: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Enzalutamide: May decrease the serum concentration of Vitamin K Antagonists. Management: Avoid concurrent use of vitamin K antagonists and enzalutamide when possible. If combined, monitor for reduced vitamin K antagonist effects (ie, decreased INR, thrombosis) and increase vitamin K antagonist doses as needed. Risk D: Consider therapy modification

Erlotinib: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Eslicarbazepine: May decrease the serum concentration of Warfarin. Specifically, S-warfarin serum concentrations may be decreased. Risk C: Monitor therapy

Esomeprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Ethacrynic Acid: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Ethotoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Ethotoin. Management: Anticoagulant dose adjustment will likely be necessary when ethotoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Risk D: Consider therapy modification

Etoposide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Etoposide Phosphate: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Exenatide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Fenofibrate and Derivatives: May enhance the anticoagulant effect of Warfarin. Fenofibrate and Derivatives may increase the serum concentration of Warfarin. Management: Monitor for signs and symptoms of bleeding, and increase INR monitoring in patients taking warfarin who are initiated on fenofibrate derivatives. Warfarin dose reductions will likely be required. Risk D: Consider therapy modification

Fibric Acid Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider reducing the oral anticoagulant dose by 25% to 33% when initiating a fibric acid derivative. Monitor for toxic or reduced anticoagulant effects if a fibric acid derivative is initiated/dose increased, or discontinued/dose decreased, respectively. Risk D: Consider therapy modification

Flucloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Flucloxacillin may decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Fluconazole: May increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives when possible. If combined, consider reducing the vitamin K antagonist dose by 10% to 20% if combined with fluconazole. Monitor for increased anticoagulant effects (ie, increased INR, bleeding) to guide further dose adjustments. Risk D: Consider therapy modification

Fluorouracil Products: May increase the serum concentration of Vitamin K Antagonists. Management: Monitor INR and for signs/symptoms of bleeding closely when a fluorouracil product is combined with a vitamin K antagonist (eg, warfarin). Anticoagulant dose adjustment will likely be necessary. Risk D: Consider therapy modification

Fosamprenavir: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Fosaprepitant: May decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Fosphenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Fosphenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Risk D: Consider therapy modification

Frankincense, Indian: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of Vitamin K Antagonists. Management: Vitamin K antagonist dose adjustments may be required when used with systemic fusidic acid. Patients using this combination should be monitored extra closely for evidence of bleeding and to determine appropriate dose. Risk D: Consider therapy modification

Gefitinib: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Gemcitabine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Ginkgo Biloba: May enhance the adverse/toxic effect of Vitamin K Antagonists. Management: Consider avoiding the use of this combination of agents. Monitor for signs and symptoms of bleeding if vitamin K antagonists and Ginkgo biloba are used concomitantly. Risk D: Consider therapy modification

Glucagon and Glucagon Analogs: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Glucosamine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Griseofulvin: May decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapy

HMG-CoA Reductase Inhibitors (Statins): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Hormonal Contraceptives: May increase the serum concentration of Vitamin K Antagonists. Hormonal Contraceptives may decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Ifosfamide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Imatinib: May enhance the anticoagulant effect of Warfarin. Imatinib may decrease the metabolism of Warfarin. Management: Consider using low-molecular-weight heparin or heparin instead of warfarin. If warfarin and imatinib must be coadministrered, increase monitoring of INR and for signs/symptoms of bleeding. Risk D: Consider therapy modification

Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Interferons (Alfa): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Interleukin-6 (IL-6) Inhibiting Therapies: May decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy

Itraconazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Ivermectin (Systemic): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Kanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Lactulose: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Lansoprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Leflunomide: May enhance the anticoagulant effect of Vitamin K Antagonists. Leflunomide may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Letermovir: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

LevOCARNitine: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy

Lipid Emulsion (Fish Oil and Plant Based): May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Lomitapide: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Lopinavir: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Lornoxicam: May enhance the anticoagulant effect of Vitamin K Antagonists. Lornoxicam may increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising. Risk D: Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Maitake: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Megestrol: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Menadiol Diphosphate: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Menatetrenone: May diminish the anticoagulant effect of Vitamin K Antagonists. Management: Coadministration is not recommended. If concomitant use of menatetrenone and vitamin K antagonists cannot be avoided, monitor coagulation parameters, such as PT/INR. Risk D: Consider therapy modification

Menthol: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Mercaptopurine: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

MetFORMIN: May diminish the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of MetFORMIN. Risk C: Monitor therapy

Methylphenidate: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

MetroNIDAZOLE (Systemic): May increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to concomitant therapy with these agents. If concomitant therapy cannot be avoided, consider reducing the dose of the vitamin K antagonist and monitor for increased INR/bleeding. Risk D: Consider therapy modification

Miconazole (Oral): May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Miconazole (Topical): May increase the serum concentration of Vitamin K Antagonists. Management: Avoid using any miconazole-containing preparation in patients who are taking warfarin. If coadministration is unavoidable, consider reducing warfarin dose 10% to 20% and monitor for increased warfarin effects (eg, INR, bleeding). Risk D: Consider therapy modification

MiFEPRIStone: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk of bleeding may be increased. MiFEPRIStone may increase the serum concentration of Vitamin K Antagonists. Risk X: Avoid combination

Mirtazapine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Mitapivat: May decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy

Mitotane: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the anticoagulant effect of Vitamin K Antagonists. Multivitamins/Minerals (with ADEK, Folate, Iron) may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Nafcillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Management: Consider choosing an alternative antibiotic. Monitor for decreased therapeutic effects and need for dose adjustments of oral anticoagulants if nafcillin is initiated/dose increased, or increased effects if nafcillin is discontinued/dose decreased. Risk D: Consider therapy modification

Neomycin: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Nevirapine: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Nonselective): May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Obeticholic Acid: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Omeprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Oritavancin: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Orlistat: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Oxatomide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk X: Avoid combination

Penicillins: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Pentoxifylline: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Phenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Phenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Risk D: Consider therapy modification

Phytonadione: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Posaconazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Proguanil: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Propacetamol: May enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with higher doses (equivalent to acetaminophen doses exceeding 1.3 to 2 g/day) for multiple consecutive days. Risk C: Monitor therapy

Propafenone: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy

QuiNIDine: May enhance the anticoagulant effect of Vitamin K Antagonists. Note that the INR/PT might be unchanged in the face of increased bleeding. Risk C: Monitor therapy

QuiNINE: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Quinolones: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

RaNITIdine (Withdrawn from US Market): May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Regorafenib: Warfarin may enhance the adverse/toxic effect of Regorafenib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Revaprazan: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Ribavirin (Systemic): May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Vitamin K Antagonists. Management: Consider alternatives if possible. If combined, monitor for reduced anticoagulant effects if a rifamycin derivative is initiated in a vitamin K antagonist treated patient. Vitamin K antagonist dose adjustments will likely be required. Risk D: Consider therapy modification

Ritonavir: May decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Rolapitant: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

RomiDEPsin: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Roxithromycin: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Salicylates: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Avoid as needed use of salicylates in patients taking vitamin K antagonists. Aspirin (80 to 325 mg/day) may be used with warfarin for prevention of cardiovascular events. If coadministering salicylates and vitamin K antagonists, monitor for bledding. Risk D: Consider therapy modification

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Salicylates (Topical): May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Saquinavir: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Selumetinib: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Sodium Zirconium Cyclosilicate: May increase the serum concentration of Warfarin. Management: Separate the administration of sodium zirconium cyclosilicate and warfarin by at least 2 hours. If simultaneous administration is required, monitor for signs and symptoms of warfarin toxicity (eg, elevated INR, bleeding). Risk D: Consider therapy modification

SORAfenib: May enhance the anticoagulant effect of Warfarin. SORAfenib may increase the serum concentration of Warfarin. Risk C: Monitor therapy

St John's Wort: May increase the metabolism of Vitamin K Antagonists. Management: Consider avoiding coadministration of St John's Wort and vitamin K antagonists. If combined, monitor for decreased anticoagulant therapeutic effects (eg, decreased INR, thromboembolic events) if St John's Wort is initiated/dose increased. Risk D: Consider therapy modification

Streptokinase: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk X: Avoid combination

Sucralfate: May diminish the anticoagulant effect of Vitamin K Antagonists. Sucralfate may decrease the serum concentration of Vitamin K Antagonists. Specifically, sucralfate may decrease the absorption of Vitamin K Antagonists. Management: Monitor for decreased vitamin K antagonist effects (eg, decreased INR, thrombosis) when these agents are combined and consider administering vitamin K antagonists at least 2 hours before sucralfate to minimize this interaction. Risk C: Monitor therapy

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Sulfinpyrazone: May decrease the metabolism of Vitamin K Antagonists. Sulfinpyrazone may decrease the protein binding of Vitamin K Antagonists. Risk C: Monitor therapy

Sulfonamide Antibiotics: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider reducing the vitamin K antagonist dose by 10% to 20% prior to starting the sulfonamide antibiotic. Monitor INR closely to further guide dosing. Risk D: Consider therapy modification

Sulfonylureas: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Tamoxifen: May increase the serum concentration of Vitamin K Antagonists. Risk X: Avoid combination

Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy

Teriflunomide: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Tetracyclines: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Tezacaftor and Ivacaftor: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: Monitor for signs and symptoms of bleeding if these agents are combined. For the treatment of acute ischemic stroke, avoidance with anticoagulants is often recommended, see full Lexicomp or drug interaction monograph for details. Risk C: Monitor therapy

Thyroid Products: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Tigecycline: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Tobacco (Smoked): May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Tolterodine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Toremifene: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Torsemide: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

TraMADol: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Tranilast (Systemic): May enhance the adverse/toxic effect of Warfarin. Tranilast (Systemic) may diminish the therapeutic effect of Warfarin. Risk C: Monitor therapy

TraZODone: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Valproate Products: May decrease the protein binding of Warfarin. Risk C: Monitor therapy

Vemurafenib: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Venetoclax: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination

Vorinostat: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Zileuton: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Food Interactions

Ethanol: Acute ethanol ingestion (binge drinking) decreases the metabolism of oral anticoagulants and increases PT/INR. Chronic daily ethanol use increases the metabolism of oral anticoagulants and decreases PT/INR. Management: Limit alcohol consumption; monitor INR closely.

Food: The anticoagulant effects of warfarin may be decreased if taken with foods rich in vitamin K. Vitamin E may increase warfarin effect. Cranberry juice may increase warfarin effect. Management: Maintain a consistent diet; consult prescriber before making changes in diet. Take warfarin at the same time each day.

Reproductive Considerations

Evaluate pregnancy status prior to use in patients who may become pregnant. Patients who may become pregnant should use effective contraception during therapy and for 1 month after the last dose.

Patients with mechanical heart valves who are planning a pregnancy may be able to continue therapy depending on the warfarin dose (ACC/AHA [Otto 2021]). Consult current recommendations for appropriate use during pregnancy.

Pregnancy Considerations

Warfarin crosses the placenta; concentrations in the fetal plasma are similar to maternal values.

Teratogenic effects have been reported following first trimester exposure and may include coumarin embryopathy (nasal hypoplasia and/or stippled epiphyses; limb hypoplasia may also be present). Adverse CNS events to the fetus have also been observed following exposure during any trimester and may include CNS abnormalities (including ventral midline dysplasia, dorsal midline dysplasia). Spontaneous abortion, fetal hemorrhage, and fetal death may also occur. The teratogenic effects of warfarin may be dose dependent (ACC/AHA [Otto 2021]).

Use is contraindicated during pregnancy except in patients with mechanical heart valves who are at high risk for thromboembolism; use is also contraindicated in patients with threatened abortion, eclampsia, or preeclampsia.

Patients with mechanical heart valves have an increased risk of adverse maternal and fetal outcomes and these risks are greater without appropriate anticoagulation. When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, venous thromboembolism, hemorrhage), burden of therapy, and maternal preference should be considered. Use of warfarin during the first trimester may be considered if the therapeutic INR can be achieved with a dose ≤5 mg/day. Alternately, adjusted-dose low molecular weight heparin or adjusted-dose heparin may be used until after the first trimester, when therapy can be changed to warfarin, if required. Warfarin should be discontinued and changed to heparin at least 1 week prior to delivery (ACC/AHA [Otto 2021]). Consult current recommendations for appropriate use in pregnancy.

Breastfeeding Considerations

Based on available data, warfarin is not present in breast milk.

Warfarin is considered compatible with breastfeeding (ACOG 2018). The manufacturer recommends monitoring of breastfeeding infants for bruising or bleeding.

Dietary Considerations

Foods high in vitamin K (eg, leafy green vegetables) inhibit anticoagulant effect. The list of usual foods with high vitamin K content is well known, however, some unique ones include green tea (Camellia sinensis), chewing tobacco, a variety of oils (canola, corn, olive, peanut, safflower, sesame seed, soybean, and sunflower) (Booth 1999; Kuykendall 2004; Nutescu 2011). Snack foods containing Olestra have 80 mcg of vitamin K added to each ounce (Harrell 1999). Some natural products may contain hidden sources of vitamin K (Nutescu 2006). Avoid drastic changes in diet (eg, intake of large amounts of alfalfa, asparagus, broccoli, Brussels sprouts, cabbage, cauliflower, green teas, kale, lettuce, spinach, turnip greens, watercress) which decrease efficacy of warfarin. A balanced diet with a consistent intake of vitamin K is essential. The recommended dietary allowance for vitamin K in adults is 75 to 120 mcg/day (USDA Dietary Reference Intake).

Monitoring Parameters

Adults:

Prothrombin time, INR; hematocrit; may consider genotyping of CYP2C9 and VKORC1 prior to initiation of therapy; however, routine genetic testing is not recommended (ACCP [Holbrook 2012]; CPIC [Johnson 2017]).

Frequency of INR monitoring: During warfarin initiation, monitor INR daily for hospitalized patients and every 1 to 3 days for nonhospitalized patients. After initiating warfarin therapy, INR should be monitored every 2 to 3 days during the first week of therapy. Once a stable response to therapy is achieved, INR monitoring may be performed less frequently: once a week for the first 1 to 2 weeks, then every 2 weeks, and eventually monthly thereafter. Very stable and reliable patients may have their monitoring extended up to every 12 weeks (Wittkowsky 2018).

Example Frequency of Monitoring by Clinical Setting (Adapted From Wittkowsky 2018)a

aThese example suggestions should not replace clinical judgment; more frequent monitoring may be necessary.

Initiation of therapy

Frequency of monitoring

Inpatient initiation

Daily.

After hospital discharge

If stable, within 3 to 5 days. If unstable, within 1 to 3 days.

Outpatient flexible initiation

Daily through day 4, then within 3 to 5 days.

Outpatient average daily dosing method

Every 3 to 5 days until INR reaches lower limit of therapeutic range, then within 1 week.

First month of therapy

At least weekly.

Maintenance therapy

Frequency of monitoring

Medically stable inpatients

Every 1 to 3 days.

Medically unstable inpatients

Daily.

After hospital discharge

If stable, within 3 to 5 days. If unstable, within 1 to 3 days.

Routine follow-up in medically stable and reliable patients

Every 4 to 12 weeks.

Routine follow-up in medically unstable or unreliable patients

Every 1 to 2 weeks.

Dose held today for significant over-anticoagulation

Recheck in 1 to 2 days.

Dosage adjustment today

Recheck within 1 to 2 weeks.

Dosage adjustment ≤2 weeks ago

Recheck within 2 to 4 weeks.

Mechanism of Action

Hepatic synthesis of coagulation factors II (half-life 42 to 72 hours), VII (half-life 4 to 6 hours), IX, and X (half-life 27 to 48 hours), as well as proteins C and S, requires the presence of vitamin K. These clotting factors are biologically activated by the addition of carboxyl groups to key glutamic acid residues within the proteins’ structure. In the process, “active” vitamin K is oxidatively converted to an “inactive” form, which is then subsequently reactivated by vitamin K epoxide reductase complex 1 (VKORC1). Warfarin competitively inhibits the subunit 1 of the multi-unit VKOR complex, thus depleting functional vitamin K reserves and hence reduces synthesis of active clotting factors.

Pharmacokinetics

Onset of action: Initial anticoagulant effect on INR may be seen as soon as 24 to 72 hours (Harrison 1997; O’Reilly 1968).

Note: Full therapeutic effect generally seen between 5 and 7 days after initiation; dependent on reduction in vitamin K-dependent coagulation factors, especially prothrombin (factor II), which has a half-life of 60 to 72 hours (ACCP [Ageno 2012]; Crowther 1999; Kovacs 2003; manufacturer's labeling).

Duration: 2 to 5 days

Absorption: Rapid, complete

Distribution: 0.14 L/kg

Protein binding: 99%

Metabolism: Hepatic, primarily via CYP2C9; minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4

Genomic variants: Approximately 37% reduced clearance of S-warfarin in patients heterozygous for 2C9 (*1/*2 or *1/*3), and ~70% reduced in patients homozygous for reduced function alleles (*2/*2, *2/*3, or *3/*3)

Half-life elimination: 20 to 60 hours; Mean: 40 hours; highly variable among individuals

Time to peak, plasma: ~4 hours

Excretion: Urine (92%, primarily as metabolites; minimal as unchanged drug)

Pharmacokinetics: Additional Considerations

Renal function impairment: Renal Cl is a minor determinant of anticoagulant response to warfarin.

Hepatic function impairment: Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.

Geriatric: Patients 60 years and older appear to exhibit greater than expected INR response to warfarin.

Race: Asian patients may require lower initiation and maintenance doses.

Pharmacogenetics: Vitamin K epoxide reductase (VKORC1) and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements.

Pricing: US

Tablets (Jantoven Oral)

1 mg (per each): $0.61

2 mg (per each): $0.64

2.5 mg (per each): $0.66

3 mg (per each): $0.66

4 mg (per each): $0.66

5 mg (per each): $0.69

6 mg (per each): $0.89

7.5 mg (per each): $0.92

10 mg (per each): $0.95

Tablets (Warfarin Sodium Oral)

1 mg (per each): $0.29 - $0.61

2 mg (per each): $0.29 - $0.64

2.5 mg (per each): $0.29 - $0.66

3 mg (per each): $0.29 - $0.66

4 mg (per each): $0.29 - $0.66

5 mg (per each): $0.29 - $0.67

6 mg (per each): $0.36 - $0.95

7.5 mg (per each): $0.36 - $0.98

10 mg (per each): $0.36 - $1.02

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Aldocumar (ES);
  • Anasmol (VE);
  • Apo-Warfarin (QA);
  • Azwar (LK);
  • Befarin (TH);
  • Cavamed (CL);
  • Circuvit (AR);
  • Cofarin (TW);
  • Coumadan (AR);
  • Coumadin (AE, AU, BB, BF, BH, BJ, CI, CL, CY, DE, EC, ET, GH, GM, GN, IL, IQ, IR, IT, KE, KR, KW, LB, LR, LY, MA, ML, MR, MU, MW, MX, NE, NG, NZ, OM, PH, PK, SC, SD, SL, SN, SY, TN, TR, TZ, UG, VE, YE, ZM, ZW);
  • Coumadine (VN);
  • Cumar (VE);
  • Dagonal (UY);
  • Farin (BD);
  • Haemofarin (EG);
  • Mafarin (TW);
  • Maforan (TH);
  • Marevan (AE, AU, BE, BR, CN, DK, EE, EG, FI, GB, GR, IE, LU, MT, NO, NZ, SG);
  • Marfarin (HN);
  • Marivarin (HR);
  • Martefarin (HR);
  • Morfarin (TH);
  • Oldin (PY);
  • Orfarin (HK, JO, LV, MY, TH, TW);
  • Rilaquin (PY);
  • Simarc-2 (ID);
  • UniWarfin (IN);
  • Varfarin (HR);
  • Varfine (PT);
  • Waran (SE);
  • Warf (LK);
  • Warfant (IE, TR);
  • Warfar (CO, KR);
  • Warfarin (SA);
  • Warfarina (PE);
  • Warfil 5 (DO);
  • Warfin (KW, PL);
  • Warik (PH);
  • Warin (BD);
  • Win (BD);
  • Zofarin (LK);
  • Zydarin (TH)


For country abbreviations used in Lexicomp (show table)

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