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Warfarin

Pronunciation

Pronunciation

(WAR far in)

Index Terms

  • Warfarin Sodium

Dosage Forms

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

Solution Reconstituted, Intravenous, as sodium:

Coumadin: 5 mg (1 ea [DSC])

Tablet, Oral, as sodium:

Coumadin: 1 mg [scored]

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

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

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

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

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

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

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

Coumadin: 10 mg [scored; dye free]

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

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

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

Jantoven: 3 mg [scored]

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

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

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

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

Jantoven: 10 mg [scored]

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

Brand Names: U.S.

  • Coumadin
  • Jantoven

Pharmacologic Category

  • Anticoagulant
  • Anticoagulant, Vitamin K Antagonist

Pharmacology

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.

Absorption

Oral: Rapid, complete

Distribution

0.14 L/kg

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)

Excretion

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

Onset of Action

Anticoagulation: Oral: 24-72 hours; Peak effect: Full therapeutic effect: 5-7 days; INR may increase in 36-72 hours

Time to Peak

Oral: ~4 hours

Duration of Action

2-5 days

Half-Life Elimination

20-60 hours; Mean: 40 hours; highly variable among individuals

Protein Binding

99%

Special Populations: Renal Function Impairment

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

Special Populations: Hepatic Function Impairment

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

Special Populations: Elderly

Patients 60 y and older appear to exhibit greater than expected INR response to warfarin.

Special Populations: Race

Asian patients may require lower initiation and maintenance doses.

Special Populations Note

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

Use: Labeled Indications

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

Nonvalvular AF or atrial flutter: The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines for the management of AF recommend oral anticoagulation for patients with nonvalvular AF or atrial flutter with prior stroke, TIA, or a CHA2DS2-VASc score ≥2. In patients with AF or atrial flutter of ≥48 hours duration or when the duration is unknown, anticoagulation with warfarin is recommended for at least 3 weeks prior to and 4 weeks after cardioversion regardless of the CHA2DS2-VASc score and method used to restore sinus rhythm (AHA/ACC [January 2014]).

Valvular AF: The 2014 American Heart Association/American Stroke Association (AHA/ASA) guidelines for the primary prevention of stroke recommend chronic oral anticoagulation with warfarin for patients with valvular atrial fibrillation at high risk for stroke, defined as a CHA2DS2-VASc score of ≥2, and acceptably low risk for hemorrhagic complications (AHA/ASA [Meschia 2014]).

Mechanical prosthetic cardiac valves: The 2014 American Heart Association/American Stroke Association (AHA/ASA) guidelines for the primary prevention of stroke recommend warfarin and low-dose aspirin in the patients who have received an aortic mechanical prosthetic valve (with or without risk factors) or any mitral mechanical prosthetic valve. Target INRs vary depending on valve position and/or risk factors (AHA/ASA [Meschia 2014]).

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

According to the American College of Cardiology/American Heart Association (ACCF/AHA) guidelines for the management of patients with ST-elevation myocardial infarction (STEMI), warfarin should be administered to patients with STEMI and AF and a CHADS2 score of 2 or more, mechanical valve, venous thromboembolism, or hypercoagulable disorder. Use is reasonable in patients with STEMI and asymptomatic LV mural thrombi and may be considered in patients with STEMI and anterior apical akinesis or dyskinesis (O'Gara 2013).

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.

Use: Unlabeled

Prevention of recurrent transient ischemic attacks

Contraindications

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

Dosing: Adult

Note: Coumadin injection has been discontinued in the US for more than 1 year.

Note: Labeling identifies genetic factors which may increase patient sensitivity to warfarin. 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. The American College of Chest Physicians recommends against the use of routine pharmacogenomic testing to guide dosing (Guyatt 2012). For management of elevated INRs as a result of warfarin therapy, see Additional Information/Pharmacotherapy Pearls for guidance.

Thromboembolic complications (prophylaxis/treatment) or myocardial infarction (risk reduction):

IV (administer as a slow bolus injection): 2 to 5 mg/day

Oral: Initial dosing must be individualized. Consider the patient (hepatic function, cardiac function, age, nutritional status, concurrent therapy, risk of bleeding) in addition to prior dose response (if available) and the clinical situation. Start 2 to 5 mg once daily or for healthy individuals, 10 mg once daily for 2 days; lower doses (eg, 5 mg once daily) recommended for patients with confirmed HIT once platelet recovery has occurred (Guyatt 2012). In patients with acute venous thromboembolism, initiation may begin on the first or second day of low molecular weight heparin or unfractionated heparin therapy (Guyatt 2012). Adjust dose according to INR results; usual maintenance dose ranges from 2 to 10 mg daily (individual patients may require loading and maintenance doses outside these general guidelines).

Note: Lower starting doses may be required for patients with hepatic impairment, poor nutrition, CHF, elderly, high risk of bleeding, or patients who are debilitated, or those with reduced function genomic variants of the catabolic enzymes CYP2C9 (*2 or *3 alleles) or VKORC1 (-1639 polymorphism); see table. Higher initial doses may be reasonable in selected patients (ie, receiving enzyme-inducing agents and with low risk of bleeding). Overlapping a parenteral anticoagulant and warfarin therapy by at least 5 days is necessary in treatment of DVT/PE even if the INR is therapeutic earlier. Although an elevation in INR (due to factor VII depletion) may be seen early (within the first 24 to 48 hours) in warfarin therapy, it does not represent adequate anticoagulation. Factors II and X must also be depleted which takes considerably longer (ACCP [Guyatt 2012]).

Range1 of Expected Therapeutic Maintenance Dose Based on CYP2C92 and VKORC13 Genotypes

VKORC1

CYP2C9

Note: Must also take into account other patient related factors when determining initial dose (eg, age, body weight, concomitant medications, comorbidities). The American College of Chest Physicians recommends against the use of routine pharmacogenomic testing to guide dosing (Guyatt, 2012).

1Ranges derived from multiple published clinical studies.

2Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 alleles may take up to 4 weeks to achieve maximum INR with a given dose regimen.

3VKORC1 -1639G>A (rs 9923231) variant is used in this table; other VKORC1 variants may also be important determinants of dose.

*1/*1

*1/*2

*1/*3

*2/*2

*2/*3

*3/*3

GG

5-7 mg

5-7 mg

3-4 mg

3-4 mg

3-4 mg

0.5-2 mg

AG

5-7 mg

3-4 mg

3-4 mg

3-4 mg

0.5-2 mg

0.5-2 mg

AA

3-4 mg

3-4 mg

0.5-2 mg

0.5-2 mg

0.5-2 mg

0.5-2 mg

Table has been converted to the following text.

Range1 of Expected Therapeutic Maintenance Dose Based on CYP2C92 and VKORC13 Genotypes:

If VKORC1 GG and CYP2C9 *1/*1, then 5-7 mg.

If VKORC1 AG and CYP2C9 *1/*1, then 5-7 mg.

If VKORC1 AA and CYP2C9 *1/*1, then 3-4 mg.

If VKORC1 GG and CYP2C9 *1/*2, then 5-7 mg.

If VKORC1 AG and CYP2C9 *1/*2, then 3-4 mg.

If VKORC1 AA and CYP2C9 *1/*2, then 3-4 mg.

If VKORC1 GG and CYP2C9 *1/*3, then 3-4 mg.

If VKORC1 AG and CYP2C9 *1/*3, then 3-4 mg.

If VKORC1 AA and CYP2C9 *1/*3, then 0.5-2 mg.

If VKORC1 GG and CYP2C9 *2/*2, then 3-4 mg.

If VKORC1 AG and CYP2C9 *2/*2, then 3-4 mg.

If VKORC1 AA and CYP2C9 *2/*2, then 0.5-2 mg.

If VKORC1 GG and CYP2C9 *2/*3, then 3-4 mg.

If VKORC1 AG and CYP2C9 *2/*3, then 0.5-2 mg.

If VKORC1 AA and CYP2C9 *2/*3, then 0.5-2 mg.

If VKORC1 GG and CYP2C9 *3/*3, then 0.5-2 mg.

If VKORC1 AG and CYP2C9 *3/*3, then 0.5-2 mg.

If VKORC1 AA and CYP2C9 *3/*3, then 0.5-2 mg.

Note: Must also take into account other patient related factors when determining initial dose (eg, age, body weight, concomitant medications, comorbidities). The American College of Chest Physicians recommends against the use of routine pharmacogenomic testing to guide dosing (Guyatt, 2012).

1Ranges derived from multiple published clinical studies.

2Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 alleles may take up to 4 weeks to achieve maximum INR with a given dose regimen.

3VKORC1 -1639G>A (rs 9923231) variant is used in this table; other VKORC1 variants may also be important determinants of dose.

Dosing: Geriatric

Thromboembolic complications (prophylaxis/treatment) or myocardial infarction (risk reduction): Oral: Initial dose ≤5 mg. Usual maintenance dose: 2 to 5 mg/day. 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).

Dosing: Pediatric

Note: Coumadin injection has been discontinued in the US for more than 1 year.

Note: Labeling identifies genetic factors which may increase patient sensitivity to warfarin. 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. The American College of Chest Physicians recommends against the use of routine pharmacogenomic testing to guide dosing (Guyatt 2012). For management of elevated INRs as a result of warfarin therapy, see Additional Information/Pharmacotherapy Pearls for guidance.

Prevention/treatment of thrombosis: Infants and Children (off-label use): Oral: Initial loading dose (if baseline INR is 1-1.3): 0.2 mg/kg (maximum: 10 mg/dose); adjust dose based on INR (reported ranges to maintain INR of 2 to 3: 0.09 to 0.33 mg/kg/day). Infants <12 months of age may require doses at or near the high end of this range; consistent anticoagulation may be difficult to maintain in children <5 years of age (Monagle 2012).

Dosing: Renal Impairment

No dosage adjustment necessary. However, patients with renal failure have an increased risk of bleeding complications; monitor closely.

Dosing: Hepatic Impairment

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.

Reconstitution

Reconstitute with 2.7 mL of sterile water for injection (yields 2 mg/mL solution).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Administration

Oral: Administer with or without food.

IV: Administer as a slow bolus injection over 1 to 2 minutes; avoid all IM injections

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Dietary Considerations

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

Compatibility

Stable in D5LR, D51/2NS, D5NS, D5W, D10W.

Y-site administration: Incompatible with aminophylline, ceftazidime, cimetidine, ciprofloxacin, dobutamine, esmolol, gentamicin, labetalol.

Compatibility in syringe: Incompatible with ceftriaxone, heparin.

Storage

Injection: Prior to reconstitution, store at 15°C to 30°C (59°F to 86°F). Following reconstitution with 2.7 mL of sterile water (yields 2 mg/mL solution), stable for 4 hours at 15°C to 30°C (59°F to 86°F). Single-use vial. Protect from light.

Tablet: Store at 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

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. Monitor therapy

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

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

Allopurinol: May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

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. Consider therapy modification

Androgens: May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

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

Antithyroid Agents: May diminish the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Aprepitant: May decrease the serum concentration of Warfarin. Monitor therapy

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

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

Barbiturates: May increase the metabolism of Vitamin K Antagonists. Management: Monitor INR more closely. An anticoagulant dose increase 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. Consider therapy modification

Benzbromarone: May increase the serum concentration of Warfarin. Monitor therapy

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

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

Bile Acid Sequestrants: May decrease the absorption of Vitamin K Antagonists. Monitor therapy

Boceprevir: May decrease the serum concentration of Warfarin. Boceprevir may increase the serum concentration of Warfarin. Monitor therapy

Bosentan: May increase the metabolism of Vitamin K Antagonists. Monitor therapy

Capecitabine: May increase the serum concentration of Vitamin K Antagonists. 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. Warfarin dose adjustments will likely be required. Consider therapy modification

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

Ceritinib: May increase the serum concentration of CYP2C9 Substrates. Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

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

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

Chloramphenicol: May enhance the anticoagulant effect of Vitamin K Antagonists. Chloramphenicol may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

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

Cimetidine: May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Clopidogrel: May enhance the anticoagulant effect of Warfarin. Consider therapy modification

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

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

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

Contraceptives (Estrogens): May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Consider therapy modification

Contraceptives (Progestins): May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: When possible, concomitant hormonal contraceptives and coumarin derivatives should be avoided in order to eliminate the risk of thromboembolic disorders. Consider using an alternative, nonhormonal contraceptive. Consider therapy modification

Corticosteroids (Systemic): May enhance the anticoagulant effect of Warfarin. Monitor therapy

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

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Darunavir: May decrease the serum concentration of Warfarin. Monitor therapy

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

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

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification

Desvenlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Monitor therapy

Dexmethylphenidate: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

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

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

Dronabinol: May increase the serum concentration of Warfarin. Specifically, dronabinol may displace warfarin from its protein-binding sites, leading to an increased concentration of active, unbound drug. Monitor therapy

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

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

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

Enzalutamide: May decrease the serum concentration of Warfarin. More specifically, enzalutamide may decrease concentrations of the S-warfarin enantiomer. Management: Avoid concurrent use of warfarin and enzalutamide whenever possible. If the combination must be used, conduct additional INR monitoring as serum concentrations may be decreased. Consider therapy modification

Erlotinib: May increase the serum concentration of Warfarin. Monitor therapy

Erythromycin (Ophthalmic): May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

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

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

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

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

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

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

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

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

Fat Emulsion (Fish Oil Based): May diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Fenofibrate and Derivatives: May enhance the anticoagulant effect of Warfarin. Fenofibrate and Derivatives may increase the serum concentration of Warfarin. Consider therapy modification

Fenugreek: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Seek alternatives to fenugreek in patients receiving vitamin K antagonists. Monitor patients receiving these combinations closely for increases in INR and systemic effects of the vitamin K antagonist (particularly easy bruising and bleeding). Consider therapy modification

Fibric Acid Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

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

Fluconazole: May increase the serum concentration of Vitamin K Antagonists. Consider therapy modification

Fluorouracil (Systemic): May increase the serum concentration of Vitamin K Antagonists. Consider therapy modification

Fluorouracil (Topical): May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

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

Fosaprepitant: May decrease the serum concentration of Warfarin. The active metabolite aprepitant is likely responsible for this effect. Monitor therapy

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

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. Consider therapy modification

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

Gemcitabine: May enhance the anticoagulant effect of Warfarin. 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. Consider therapy modification

Ginseng (American): May decrease the serum concentration of Warfarin. Monitor therapy

Glucagon: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

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

Glutethimide: May increase the metabolism of Vitamin K Antagonists. Consider therapy modification

Green Tea: May enhance the adverse/toxic effect of Warfarin. Particularly, the risk of bleeding may be increased due to possible antiplatelet effects of green tea. Green Tea may diminish the anticoagulant effect of Warfarin. Monitor therapy

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

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

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification

HMG-CoA Reductase Inhibitors: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: AtorvaSTATin. Monitor therapy

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

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

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

Imatinib: May enhance the anticoagulant effect of Warfarin. Imatinib may decrease the metabolism of Warfarin. Consider therapy modification

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

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

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

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

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

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

Levomilnacipran: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Monitor therapy

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

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

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

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Vitamin K Antagonists. Exceptions: Fidaxomicin; Roxithromycin; Spiramycin. Monitor therapy

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

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

Metreleptin: May decrease the serum concentration of Warfarin. Metreleptin may increase the serum concentration of Warfarin. 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. Consider therapy modification

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

Miconazole (Topical): May increase the serum concentration of Vitamin K Antagonists. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP2C9 Substrates. Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Milnacipran: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Monitor therapy

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

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

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

Nelfinavir: May decrease the serum concentration of Warfarin. Nelfinavir may increase the serum concentration of Warfarin. Monitor therapy

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

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

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

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

NSAID (COX-2 Inhibitor): May enhance the anticoagulant effect of Vitamin K Antagonists. NSAID (COX-2 Inhibitor) may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

NSAID (Nonselective): May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

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

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. 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. Avoid combination

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

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

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

Orlistat: May enhance the anticoagulant effect of Warfarin. Monitor therapy

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

Penicillins: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Dicloxacillin; Nafcillin. Monitor therapy

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

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

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

Phytonadione: May diminish the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

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

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

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

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

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

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

Quinolone Antibiotics: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

RaNITIdine: May increase the serum concentration of Warfarin. Monitor therapy

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

Rifamycin Derivatives: May increase the metabolism of Vitamin K Antagonists. Monitor therapy

Ritonavir: May decrease the serum concentration of Warfarin. Monitor therapy

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

Roxithromycin: May enhance the anticholinergic effect of Warfarin. Monitor therapy

Salicylates: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Salsalate. Consider therapy modification

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

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

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

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

SORAfenib: May enhance the anticoagulant effect of Warfarin. SORAfenib may increase the serum concentration of Warfarin. Management: Warfarin dose adjustment will likely be necessary. Increase frequency of INR monitoring during sorafenib therapy (particularly when starting or stopping therapy), and increase monitoring for signs and symptoms of bleeding. Consider therapy modification

St John's Wort: May increase the metabolism of Vitamin K Antagonists. Consider therapy modification

Streptokinase: May enhance the anticoagulant effect of Vitamin K Antagonists. 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: Administer vitamin K antagonists at least 2 hours before or at least 6 hours after sucralfate. Consider therapy modification

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

Sulfinpyrazone: May decrease the metabolism of Vitamin K Antagonists. Sulfinpyrazone may decrease the protein binding of Vitamin K Antagonists. Consider therapy modification

Sulfonamide Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

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

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

Tegafur: May increase the serum concentration of Vitamin K Antagonists. Management: Monitor INR and signs/symptoms of bleeding closely when starting or stopping this combination. Anticoagulant dose adjustment will likely be necessary. Consider therapy modification

Telaprevir: May decrease the serum concentration of Warfarin. Telaprevir may increase the serum concentration of Warfarin. Monitor therapy

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

Tetracycline Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

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

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

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

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

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

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

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

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

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

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

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

Tricyclic Antidepressants: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

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

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

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

Venlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Monitor therapy

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

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

Voriconazole: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

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

Zafirlukast: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

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

Adverse Reactions

Frequency not defined. Bleeding is the major adverse effect of warfarin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility.

Cardiovascular: Dark blue or purple toes, vasculitis

Central nervous system: Bleeding complications (signs/symptoms of bleeding, including dizziness, fatigue, fever, headache, lethargy, malaise, pain), paralysis, paresthesia

Dermatologic: Alopecia, bullous rash, dermatitis, gangrene of skin or other tissue, pruritus, skin necrosis, skin rash, urticaria

Gastrointestinal: Abdominal pain, diarrhea, dysgeusia, flatulence, gastrointestinal hemorrhage, nausea, vomiting

Genitourinary: Hematuria

Hematologic & oncologic: Anemia, hemorrhage (unrecognized bleeding sites [eg, colon cancer] may be uncovered by anticoagulation), retroperitoneal hemorrhage

Hepatic: Hepatitis (including cholestatic hepatitis), increased serum transaminases

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Neuromuscular & skeletal: Osteoporosis (potential association with long-term use), weakness

Respiratory: Respiratory tract hemorrhage, tracheobronchial calcification

ALERT: U.S. Boxed Warning

Bleeding risk:

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

Warnings/Precautions

Concerns related to adverse effects:

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

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

• Calciphylaxis (calcific uremic arteriolopathy): Vitamin K antagonists may play a role in the development of calciphylaxis, a rare disorder characterized by extremely painful cutaneous lesions that demonstrate poor healing. If calciphylaxis develops, weigh the risks and benefits of continuing warfarin (Nigwekar 2015).

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

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

Disease-related concerns:

• 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 DVT; 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 active HIT; 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 moderate to severe renal impairment.

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

Special populations:

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

• Patients with genomic variants in CYP2C9 and/or VKORC1: Presence of the CYP2C9*2 or *3 allele and/or polymorphism of the vitamin K oxidoreductase (VKORC1) gene may increase the risk of bleeding. 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 metabolic activity and thus may increase risk of bleeding, but are much less common. Lower doses may be required in these patients; genetic testing may help determine appropriate dosing.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Other warnings/precautions:

• Appropriate use: Surgical patients: When temporary interruption is necessary before surgery, discontinue for approximately 5 days before surgery; when there is adequate hemostasis, may reinstitute warfarin therapy ~12 to 24 hours after surgery (evening of or next morning). 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, respectively. If risk of thromboembolism is elevated, consider bridging warfarin therapy with an alternative anticoagulant (eg, unfractionated heparin, LMWH) (Guyatt 2012).

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

Monitoring Parameters

Prothrombin time, hematocrit; INR (frequency varies depending on INR stability); may consider genotyping of CYP2C9 and VKORC1 prior to initiation of therapy, if available

Pregnancy Risk Factor

D (women with mechanical heart valves)/X (other indications)

Pregnancy Considerations

Warfarin crosses the placenta; concentrations in the fetal plasma are similar to maternal values. Teratogenic effects have been reported following first trimester exposure and may include coumarin embryopathy (nasal hypoplasia and/or stippled epiphyses; limb hypoplasia may also be present). Adverse CNS events to the fetus have also been observed following exposure during any trimester and may include CNS abnormalities (including ventral midline dysplasia, dorsal midline dysplasia). Spontaneous abortion, fetal hemorrhage, and fetal death may also occur. Use is contraindicated during pregnancy (or in women of reproductive potential) except in women with mechanical heart valves who are at high risk for thromboembolism; use is also contraindicated in women with threatened abortion, eclampsia, or preeclampsia. Frequent pregnancy tests are recommended for women who are planning to become pregnant and adjusted-dose heparin or low molecular weight heparin (LMWH) should be substituted as soon as pregnancy is confirmed or adjusted-dose heparin or LMWH should be used instead of warfarin prior to conception.

In pregnant women with high-risk mechanical heart valves, the benefits of warfarin therapy should be discussed with the risks of available treatments (ACCP [Bates, 2012]; AHA/ACC [Nishimura, 2014]); when possible avoid warfarin use during the first trimester (ACCP [Bates, 2012]) and close to delivery (ACCP [Bates, 2012]; AHA/ACC [Nishimura, 2014]). Use of warfarin during the first trimester may be considered if the therapeutic INR can be achieved with a dose ≤5 mg/day (AHA/ACC [Nishimura, 2014]). Adjusted-dose LMWH or adjusted-dose heparin may be used throughout pregnancy or until week 13 of gestation when therapy can be changed to warfarin. LMWH or heparin should be resumed close to delivery. In women who are at a very high risk for thromboembolism (older generation mechanical prosthesis in mitral position or history of thromboembolism), warfarin can be used throughout pregnancy and replaced with LMWH or heparin near term; the use of low-dose aspirin is also recommended (ACCP [Bates, 2012] AHA/ACC [Nishimura, 2014]). Women who require long-term anticoagulation with warfarin and who are considering pregnancy, LMWH substitution should be done prior to conception when possible. If anti-Xa monitoring cannot be done, do not use LMWH therapy in pregnant patients with a mechanical prosthetic valve (AHA/ACC [Nishimura, 2014]). When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, VTE, hemorrhage), burden of therapy, and maternal preference should be considered (ACCP [Bates, 2012]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber bleeding, signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that you cannot stop), signs of stroke (strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision), angina, severe dizziness, syncope, edema, signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), severe headache, skin discoloration to black or purple, body temperature change, pain, or loss of strength or energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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