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.
The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP.
Dosage guidance:
Dosing: Dosing must be individualized and use of an institutional protocol is recommended (Ref).
Clinical considerations: Response to warfarin is influenced by numerous factors (eg, age, organ function). Genetic variations in metabolism (eg, CYP2C9 and/or VKORC1 genes) can impact warfarin sensitivity; however, routine genetic testing is not recommended (Ref).
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 (Ref).
Standard dosing for patients who are not expected to be sensitive to warfarinb |
Reduced dosing for patients expected to be more sensitive to warfarinc | |
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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.
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bPatients who are generally started using “standard dosing” include otherwise healthy adults who are not receiving interacting medications.
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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.
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d Young, healthy patients may start 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.
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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.
Regular-intensity anticoagulation: INR goal 2 to 3 |
High-intensity anticoagulation: INR goal 2.5 to 3.5 |
Suggested adjustment(s) to warfarin dose |
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aAs with initiation therapy nomograms, maintenance therapy nomograms must be used in conjunction with clinical judgment.
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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.
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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% |
Indication |
Targeted INR range |
Treatment duration |
---|---|---|
LV = left ventricular; MI = myocardial infarction. | ||
Cardiac | ||
Atrial fibrillation or atrial flutter (ACC/AHA [Joglar 2024]). Note: For eligible patients with atrial fibrillation or atrial flutter with no history of moderate to severe mitral stenosis, a direct oral anticoagulant is recommended over warfarin (ACC/AHA [Joglar 2024]). |
2 to 3 |
Indefinite |
LV thrombus, treatment post MI (ACCF/AHA [O’Gara 2013]; ACCP [Vandvik 2012]; AHA [Levine 2022]). Note: When an antiplatelet agent is used in combination with an anticoagulant, selection and duration of antiplatelet therapy for MI may vary; consider risks of bleeding and thrombotic events when choosing antithrombotic therapy combinations (ACC [Kumbhani 2021]; AHA [Levine 2022]). |
2 to 3 |
≥3 to 6 months after MI. Note: For acute MI, ~3 months is reasonable. For more distant MI, 3 to 6 months is reasonable. Duration may vary based on follow-up imaging (eg, assessment of thrombus resolution, LV function) and shared decision making; indefinite therapy may be considered if LV function does not improve (eg, reduced systolic function, persistent apical akinesis or dyskinesis) or in patients with other ongoing thrombotic risk factors. |
LV thrombus, prophylaxis for high-risk patients post MI (eg, ejection fraction <40% and/or anteroapical wall motion abnormality) (ACCF/AHA [O’Gara 2013]; ACCP [Vandvik 2012]; AHA [Levine 2022]). Note: When an antiplatelet agent is used in combination with an anticoagulant, selection and duration of antiplatelet therapy for MI may vary; consider risks of bleeding and thrombotic events when choosing antithrombotic therapy combinations (ACC [Kumbhani 2021]; AHA [Levine 2022]). |
2 to 3 |
1 to 3 months after MI. Note: Duration may vary based on follow-up imaging (eg, assessment of LV function) and shared decision making. |
LV thrombus treatment in patients with nonischemic dilated cardiomyopathy (ACCP [Vandvik 2012]; AHA [Levine 2022]) |
2 to 3 |
≥3 to 6 months. Note: Duration may vary based on follow-up imaging (eg, assessment of thrombus resolution and LV function) and shared decision making; indefinite therapy may be considered even after thrombus resolution if LV function does not improve (eg, reduced systolic function, persistent apical akinesis or dyskinesis) or in patients with other ongoing thrombotic risk factors. |
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 (Konkle 2022) |
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 2022). 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 2022). |
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 ~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 [Stevens 2021]). | ||
Venous thromboembolism, provoked (ACCP [Stevens 2021]) |
2 to 3 |
Minimum of 3 months |
Venous thromboembolism, unprovoked (ACCP [Stevens 2021]; 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 [Humbert 2022]; 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 (ESC/ERS [Humbert 2022]; Khan 2018; Olsson 2014). |
1.5 to 2.5 |
Indefinite |
Chronic thromboembolic pulmonary arterial hypertension (ACCF/AHA [McLaughlin 2009]; ESC/ERS [Humbert 2022]) |
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]). Alternatively, may discontinue 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 (Ref).
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 (Ref). 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 (Ref).
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 (Ref).
Transitioning from therapeutic-dose parenteral anticoagulant to warfarin: Start warfarin and continue parenteral anticoagulant until INR is within therapeutic range (Ref). Note: Overlap parenteral anticoagulant with warfarin until INR is ≥2 for at least 2 days (duration of overlap is ~5 days) (Ref).
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 (Ref). 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 (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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) (Ref).
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 (Ref) and have a significant risk of bleeding (Ref). Use lower initial doses and monitor INR frequently (Ref).
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 (Ref) and have a significant risk of bleeding (Ref). Use lower initial doses and monitor INR frequently (Ref).
CRRT: Avoid use (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Avoid use (Ref).
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.
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). Avoid as initial treatment of venous thromboembolism or atrial fibrillation (unless contraindications or substantial barriers to alternative options). In older adults already on long-term therapy, continued therapy may be reasonable, especially if INRs are well controlled and there are no adverse effects (Ref).
(For additional information see "Warfarin: Pediatric drug information")
Dosage guidance:
Clinical considerations: Labeling identifies genetic factors that 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 (Ref). For management of elevated INRs as a result of warfarin therapy, see Phytonadione monograph or ACCP guidelines for additional information (Ref).
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) (Ref); 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 (Ref).
Days 2 to 4: Additional loading doses are dependent upon patient's INR (Ref): 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 (Ref): 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.
No adjustment required; however, patients with renal failure have an increased risk of bleeding complications. Monitor closely.
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.
Atheromatous embolism/cholesterol embolus syndrome have rarely been reported with warfarin use (Ref). Symptoms depend on the site of embolization, with the most common sites as the kidneys, pancreas, liver, and spleen. In some cases, atheroemboli/cholesterol microemboli may be fatal (Ref). Cholesterol microembolization may lead to “purple toe” syndrome, which presents as a dark, purplish, mottled discoloration of the plantar and lateral surfaces (Ref). Other manifestations of cholesterol microembolization may include skin rash; livedo reticularis; gangrene of skin and/or subcutaneous tissues; abrupt and intense lower extremity pain; abdominal pain, flank pain, or back pain; hematuria; hypertension; cerebral ischemia; spinal cord infarction; or other symptoms of vascular compromise (Ref). Symptoms are typically reversible upon discontinuation (Ref).
Mechanism: Related to the pharmacologic action; anticoagulation with warfarin may induce plaque hemorrhage, subsequently causing the release of cholesterol crystals and particles within the atheromatous plaques, resulting in microemboli, vessel occlusion, and inflammation (Ref).
Onset: Varied; cases have been reported from after 2 weeks to 6 months of use (Ref).
Risk factors:
• Protein C deficiency (Ref)
• Atherosclerotic disease (Ref)
• Hypertension (Ref)
• History of smoking (Ref)
• Elevations in baseline C-reactive protein (Ref)
• Older males (Ref)
Serious and fatal calciphylaxis (calcium uremic arteriolopathy) has rarely been reported in association with warfarin use in patients with and without end-stage kidney disease (Ref). Signs and symptoms may include stellate ulcers with purpuric borders, fixed livedo, retiform purpura, ischemia/necrosis, blistering/ulceration, abdominal pain, and thrombosis (Ref). Symptoms typically resolve upon discontinuation and may require additional treatment (Ref).
Mechanism: Related to the pharmacologic action; inhibits vitamin K–dependent matrix Gla protein, which is responsible for preventing calcium deposition in vessels (Ref). Warfarin paradoxically incites thrombosis and inhibits normal endothelial cell responses to calcification by decreasing proteins C and S synthesis in endothelial cells, which regulate procoagulant and anticoagulant factors (Ref).
Onset: Delayed; duration of warfarin prior to calciphylaxis ranged from 1 month to 14 years with an average of ~2.6 years (Ref).
Risk factors:
• Females (Ref)
• Peripheral vascular disease (Ref)
• Hyperphosphatemia (Ref)
• Hypercalcemia (Ref)
• Hyperparathyroidism (Ref)
• Low serum albumin levels (Ref)
• Hemodialysis (Ref)
Decreased bone mineral density (BMD) has been reported in children and adolescents receiving long-term warfarin therapy (Ref); available data in adult patients are conflicting (Ref). A significant reduction in lumbar spinal bone mineral apparent density (BMAD) scores was reported in a case control study (age range: 8 to 18 years; mean duration of warfarin treatment was 8.2 years [range: 1 to 14 years]) (Ref). Another cohort study (age range: 5 to 12 years) reported significant reductions of spinal BMD z-score and lower total body less head BMD z-score (Ref).
Mechanism: Related to mechanism of action; modulates carboxylation range of glutamic acid residues in osteocalcin. Carboxylated osteocalcin weakly binds to and accumulates in the bone matrix (Ref).
Onset: Delayed; associated with prolonged duration of treatment. Although an exact duration has not been defined, a duration of >1 year has been suggested (Ref).
Risk factors:
• Prolonged duration of treatment; exact duration not defined but >1 year has been suggested (Ref)
Warfarin can cause major (or fatal) hemorrhage in all ages (Ref). Given the prevalence and seriousness of this reaction, the US product labeling includes a boxed warning regarding the risk of major and fatal bleeding (Ref). Upon discontinuation, warfarin-induced bleeding is reversible; however, reversal may be delayed without reversal agents due to the long half-life.
Mechanism: Dose- and duration-related; related to the pharmacologic action. Warfarin inhibits vitamin K epoxide reductase subunit 1, depleting functional vitamin K from activating clotting factors II, VII, IX, and X and proteins C and S (Ref). Of note, decreased plasma levels of vitamin K–dependent coagulation factors in neonates and a continuously changing hemostatic system in infants has been well described and associated with an increased risk of bleeding (Ref).
Onset: Varied; bleeding may occur at any time. However, bleeding risk is highest within the first 30 days of therapy in adults (Ref).
Risk factors:
• Use of loading doses (Ref)
• Long duration of therapy
• Highly variable INRs
• Elevated INR (>3, especially >4) (Ref)
• Pediatric patients, especially neonates, infants, and children (Ref)
• Adult patients ≥65 years of age (Ref)
• Concurrent use of medications that increase bleeding risk (Ref)
• GI bleeding (Ref)
• Hypertension (Ref)
• Cerebrovascular disease (Ref)
• Heart disease (Ref)
• Anemia (Ref)
• Malignancy (Ref)
• Trauma (Ref)
• Kidney impairment (Ref)
• Pediatric specific issues:
- Breastfed neonates and infants (low concentrations of vitamin K in breast milk) (Ref)
- Rapidly changing physiologic values of vitamin K–dependent coagulation proteins in neonates (Ref)
- Frequent dietary changes (Ref)
- Frequent changes in medication regimens (Ref)
- Lack of an oral liquid formulation (Ref)
Warfarin-induced skin necrosis is a very rare condition that may lead to surgery, debridement, or death (Ref). Manifestations include painful purpuric lesions, skin mottling, arterial or venous thrombosis, hemorrhagic bullae, and overt cutaneous necrosis (Ref). Symptoms are reversible upon discontinuation of warfarin and treatment with vitamin K and fresh frozen plasma (Ref).
Mechanism: Dose-related; related to the pharmacologic action; not clearly established; may be due to the paradoxical shift to a hypercoagulable state in the initial days of warfarin therapy secondary to inhibition of proteins C and S synthesis (Ref).
Onset: Varied; typically occurs within the first five days of therapy but has been reported later (Ref).
Risk factors:
• Large loading doses of warfarin, particularly in the presence of no concomitant heparinization (Ref)
• Males (Ref)
• Protein C or S deficiency (Ref)
• Factor V Leiden (Ref)
• Hyperhomocysteinanemia (Ref)
• Antiphospholipid antibodies (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
<1%: Dermatologic: Gangrene of skin and/or subcutaneous tissues, skin necrosis
Frequency not defined:
Cardiovascular: Vasculitis
Dermatologic: Bullous rash, dermatitis, pruritus
Gastrointestinal: Abdominal pain, bloating, diarrhea, dysgeusia, flatulence, nausea, vomiting
Hepatic: Hepatitis, increased liver enzymes
Hypersensitivity: Anaphylaxis
Nervous system: Chills
Postmarketing:
Cardiovascular: Atheromatous embolism (Munawar 2019), cholesterol embolus syndrome (Hyman 1987), livedo reticularis (Cakebread 2014), purple toe syndrome (Varis 2010), vascular calcification (calcium uremic arteriolopathy and calciphylaxis) (Yu 2017)
Dermatologic: Alopecia (Watras 2016), skin rash (Cakebread 2014)
Genitourinary: Hematuria (Munawar 2019)
Hematologic & oncologic: Hemorrhage (including minor and major hemorrhage) (ACCP [Monagle 2012]; Gomes 2013)
Neuromuscular & skeletal: Decreased bone mineral density (Hepponstall 2017), lower extremity pain (Cakebread 2014)
Renal: Acute kidney injury (Munawar 2019)
Respiratory: Tracheobronchial calcification (Eckersley 2014; Golding 2013; Kansara 2019)
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)
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:
• Older adult: 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:
• Elective surgery/procedure: When temporary interruption is necessary before surgery, discontinue for ~5 days before surgery. When there is adequate hemostasis, may reinstitute warfarin within 24 hours after surgery at the patient’s usual maintenance dose. 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 [Douketis 2022]).
• 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.
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).
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: 2.5 mg [DSC] [contains fd&c blue #1 (brill blue) aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Coumadin: 4 mg [DSC] [contains fd&c blue #1 (brill blue) aluminum lake]
Jantoven: 1 mg [scored; contains fd&c red #40(allura red ac)aluminum lake]
Jantoven: 2 mg [scored; contains fd&c blue #2 (indigo carm) aluminum lake, fd&c red #40(allura red ac)aluminum lake]
Jantoven: 2.5 mg [scored; contains fd&c blue #1 (brill blue) aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Jantoven: 3 mg [scored]
Jantoven: 4 mg [scored; contains fd&c blue #1 (brill blue) aluminum lake]
Jantoven: 5 mg [scored; contains fd&c yellow #6(sunset yellow)alumin lake]
Jantoven: 6 mg [scored; contains fd&c blue #1 (brill blue) aluminum lake]
Jantoven: 7.5 mg [scored; contains fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) 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
Yes
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.
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 (indigo carm) aluminum lake, fd&c red #40(allura red ac)aluminum lake]
Coumadin: 2.5 mg [DSC] [contains fd&c blue #1 (brill blue) aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Coumadin: 3 mg [DSC] [contains fd&c blue #2 (indigo carm) aluminum lake, fd&c red #40(allura red ac)aluminum lake, fd&c yellow #6(sunset yellow)alumin lake]
Coumadin: 4 mg [DSC] [contains fd&c blue #1 (brill blue) aluminum lake]
Coumadin: 5 mg [DSC] [contains fd&c yellow #6(sunset yellow)alumin 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
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 (Ref).
Oral: Administer with or without food. Take at the same time each day.
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
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.
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.
Coumadin may be confused with Avandia (DSC), Cardura, Compazine, Kemadrin
Jantoven may be confused with Janumet, Januvia
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (anticoagulants, parenteral and oral; contraindicated in pregnancy [except in patients with mechanical heart valves at high risk for thromboembolism]) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
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).
Beers Criteria: Warfarin is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients ≥65 years of age (independent of diagnosis or condition) for the initial treatment of venous thromboembolism or atrial fibrillation (with no history of moderate to severe mitral stenosis) (unless contraindications or substantial barriers to alternative options) due to high-risk of major bleeding and lower or similar effectiveness compared with direct oral anticoagulants. In older adults already on long-term therapy, continued therapy may be reasonable, especially if INRs are well controlled and there are no adverse effects (Beers Criteria [AGS 2023]).
Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C9 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
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
Abciximab: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk X: Avoid combination
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 CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). 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
Aldesleukin: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). 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
Alteplase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
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
Anacaulase: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Anagrelide: May enhance the anticoagulant effect of Anticoagulants. 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
Avocado: May diminish the anticoagulant effect 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
Bimekizumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). 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. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification
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
Crizotinib: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
CYP2C9 Inducers (Moderate): May decrease the serum concentration of Vitamin K Antagonists. Management: Monitor for decreased effects of vitamin K antagonists (eg, decreased INR, thrombosis) if combined with moderate CYP2C9 inducers. Vitamin K antagonist dose adjustments will likely be required. Risk D: Consider therapy modification
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
Danshen: May enhance the anticoagulant effect of Warfarin. Warfarin may increase the serum concentration of Danshen. 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
Defibrotide: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
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
Dexlansoprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Dicloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Dinutuximab Beta: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). 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
Elranatamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Epcoritamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
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 enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethotoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Ethotoin may diminish the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Ethotoin. Risk C: Monitor therapy
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 Warfarin. Risk C: Monitor therapy
Favipiravir: May enhance the anticoagulant effect of Warfarin. 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-Phenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Fosphenytoin-Phenytoin may diminish the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy
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
Glofitamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
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
Goji Berry: 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
Honeybee Products: May enhance the anticoagulant effect of Warfarin. 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
Isoniazid: May increase the serum concentration of Warfarin. 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
Ivosidenib: May decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Consider alternatives to this combination when possible. If combined, monitor for decreased effectiveness of these CYP2C9 substrates if combined with ivosidenib. Risk D: Consider therapy modification
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
Lecanemab: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor therapy
Leflunomide: May enhance the anticoagulant effect of Warfarin. Leflunomide may diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Lenvatinib: May enhance the anticoagulant effect of Warfarin. 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
Linezolid: May enhance the anticoagulant effect of Vitamin K Antagonists. 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 enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Maitake: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
Mavacamten: May decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Mefloquine: May enhance the anticoagulant effect 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
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
Mosunetuzumab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). 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 (Systemic): 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
Nirmatrelvir and Ritonavir: May decrease the serum concentration of Vitamin K Antagonists. Nirmatrelvir and Ritonavir may increase the serum concentration of Vitamin K Antagonists. 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 (Ophthalmic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
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
Ornidazole: 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
PACLitaxel (Conventional): May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
PACLitaxel (Protein Bound): May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
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
Phytonadione: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Pirtobrutinib: May enhance the anticoagulant effect of Anticoagulants. 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 Vitamin K Antagonists. 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
Protein C Concentrate (Human): May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk of warfarin-induced skin necrosis may be increased. Protein C Concentrate (Human) may diminish the therapeutic effect of Vitamin K Antagonists. This is effect is transient and occurs at the initiation of vitamin K antagonist therapy. Risk C: Monitor therapy
QUEtiapine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
QuiNIDine: May enhance the anticoagulant effect of Vitamin K Antagonists. 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
Raloxifene: May diminish the anticoagulant effect of Vitamin K Antagonists. Raloxifene may increase the serum concentration 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: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
Remdesivir: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Reteplase: May enhance the anticoagulant effect of Anticoagulants. 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
RifAXIMin: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy
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
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
Soybean: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Sparsentan: May decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Spinach: May diminish the therapeutic effect of Vitamin K Antagonists. 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 Anticoagulants. 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
Talquetamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Tamoxifen: May increase the serum concentration of Vitamin K Antagonists. Management: Use of a vitamin K antagonist (VKA) is contraindicated when tamoxifen is used to reduce breast cancer incidence and for ductal carcinoma in situ. Monitor VKA closely when tamoxifen is used to treat metastatic breast cancer or as adjuvant therapy. Risk D: Consider therapy modification
Teclistamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
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
Tenecteplase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Teriflunomide: May enhance the anticoagulant effect of Warfarin. Teriflunomide may diminish the anticoagulant effect 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
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
Tirzepatide: May increase the serum concentration of Warfarin. Tirzepatide may decrease the serum concentration of Warfarin. Risk C: Monitor therapy
Tobacco (Smoked): May decrease the serum concentration of Warfarin. Risk C: Monitor therapy
Tobacco (Smokeless): May diminish the therapeutic effect of Vitamin K Antagonists. Risk C: Monitor therapy
Tolterodine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Toremifene: May increase the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). 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. Management: Consider avoiding this combination due to an increased risk of hemorrhage. If anticoagulants are coadministered with urokinase, monitor patients closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Ustekinumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Valproate Products: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Vedolizumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). 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
Volanesorsen: 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
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.
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.
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.
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.
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).
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. |
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.
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)
Altered kidney function: 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.
Older adult: Patients 60 years and older appear to exhibit greater than expected INR response to warfarin.
Race/ethnicity: 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.
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