Warfarin Therapy

Copyright 1978-2018 Lexicomp, Inc. All rights reserved.
(For additional information see "Warfarin: Patient drug information" and see "Warfarin: Pediatric
drug information")
For abbreviations and symbols that may be used in Lexicomp (show table)
ALERT: US Boxed Warning
Bleeding risk:
Warfarin can cause major or fatal bleeding. Perform regular monitoring of international
normalized ratio (INR) on all treated patients. Drugs, dietary changes, and other factors affect
INR levels achieved with warfarin therapy. Instruct patients about prevention measures to
minimize the risk of bleeding and to report immediately to their health care provider signs and
symptoms of bleeding.
Brand Names: US Coumadin; Jantoven

Brand Names: Canada Apo-Warfarin; Coumadin; Mylan-Warfarin; Novo-Warfarin; Taro-Warfarin
Pharmacologic Category Anticoagulant; Anticoagulant, Vitamin K Antagonist
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
Duration of therapy:
Warfarin Duration of Therapy by Indication

Indication
Duration of therapy
1Extended therapy is defined as after first 3 months of treatment and with no scheduled stop
date. All patients receiving extended or indefinite therapy should be reassessed at periodic
intervals for continuing use of therapy.
LV = left ventricular; DVT = deep vein thrombosis, AF = atrial flutter, VTE = venous
thromboembolism, PE = pulmonary embolism, LMWH = low molecular weight heparin, MI =
myocardial infarction
AF (including AF and mitral stenosis, AF and stable coronary artery disease) (January 2014)
Indefinite1
Bioprosthetic valves in the mitral position (Whitlock 2012)
3 months after valve insertion
Mechanical prosthetic cardiac valves (Whitlock 2012)
Indefinite1
Anterior MI with LV thrombus or at high risk for LV thrombus (Vandvik 2012)
3 months after MI
VTE (Kearon 2012; Kearon 2016)
First episode, provoked or unprovoked DVT of the leg or PE (without cancer)
3 months minimum or extended therapy1 may be considered in patients who do not have a
high risk of bleeding
Unprovoked second DVT of the leg or PE
Extended therapy1 is recommended in patients who do not have a high risk of bleeding
In patients with DVT of the leg or PE and with cancer
Note: LMWH is preferred over oral anticoagulation for treatment of patients with cancer
Extended therapy1 is recommended, although high bleeding risk confers a lower grade of
recommendation.
Dosing: Renal Impairment (Adult)

No dosage adjustment necessary. However, patients with renal impairment have an increased
risk for bleeding diathesis; monitor INR closely.
Hemodialysis: Not dialyzable (NCS/SCCM [Frontera 2016])
Dosing: Hepatic Impairment (Adult) There are no dosage adjustments provided in the
manufacturer's labeling. However, the response to oral anticoagulants may be markedly
enhanced in obstructive jaundice, hepatitis, and cirrhosis. INR should be closely monitored.
Dosing: Pediatric
(For additional information see "Warfarin: Pediatric drug information")
Note: 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 (Pediatric) No adjustment required; however, patients with renal
failure have an increased risk of bleeding complications. Monitor closely.
Dosing: Hepatic Impairment (Pediatric) There are no dosage adjustments provided in the
manufacturer’s labeling. However, the response to oral anticoagulants may be markedly
enhanced in obstructive jaundice (due to reduced vitamin K absorption) and also in hepatitis
and cirrhosis (due to decreased production of vitamin K-dependent clotting factors); INR should
be closely monitored.
Dosing: 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).
Dosage Forms Excipient information presented when available (limited, particularly for
generics); consult specific product labeling.
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
Generic Equivalent Available (US) Yes

Product Availability Coumadin injection has been discontinued in the US for more than 1 year.
Medication Guide and/or Vaccine Information Statement (VIS) An FDA-approved patient
medication guide, which is available with the product information and at
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009218s017lbl.pdf#page=31
(Coumadin), must be dispensed with this medication.
Administration
Oral: Administer with or without food.
IV: Administer as a slow bolus injection over 1 to 2 minutes; avoid all IM injections
Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves
(single) should be worn during receiving, unpacking, and placing in storage. NIOSH
recommends single gloving for administration of intact tablets or capsules (NIOSH 2016).
Assess risk to determine appropriate containment strategy (USP-NF 2017).
Use
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]).
Venous thromboembolism (VTE): The American College of Chest Physicians (ACCP)

recommends dabigatran, rivaroxaban, apixaban, or edoxaban over warfarin for the initial and
long-term treatment of VTE in patients without cancer. For the treatment of VTE in patients with
cancer, ACCP recommends LMWH over oral anticoagulants (warfarin or dabigatran,
rivaroxaban, apixaban, or edoxaban) for initial and long-term treatment (Kearon 2012; Kearon
2016).
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: Off-Label
Recurrent stroke/Transient ischemic attacks (secondary prevention)
Medication Safety Issues

Sound-alike/look-alike issues:
Coumadin may be confused with Cardura, Compazine, Kemadrin
Jantoven may be confused with Janumet, Januvia
High alert medication:

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

The Joint Commission on Accreditation of Healthcare Organizations requires healthcare
organizations that provide anticoagulant therapy to have a process in place to reduce the risk of
anticoagulant-associated patient harm. Patients receiving anticoagulants should receive
individualized care through a defined process that includes standardized ordering, dispensing,
administration, monitoring and education. This does not apply to routine short-term use of
anticoagulants for prevention of venous thromboembolism when the expectation is that the
patient’s laboratory values will remain within or close to normal values (NPSG.03.05.01).
Adverse Reactions Bleeding is the major adverse effect of warfarin. Hemorrhage may occur at
virtually any site. Risk is dependent on multiple variables, including the intensity of
anticoagulation and patient susceptibility.
1% to 10%:
Hematologic & oncologic: Major hemorrhage (≤5%; INR 2.5 to 4.0 generally associated with
more bleeding)
Frequency not defined:
Cardiovascular: Purple-toe syndrome, systemic cholesterol micro-embolism, vasculitis
Central nervous system: Chills
Dermatologic: Alopecia, bullous rash, dermatitis, pruritus, skin necrosis, urticaria
Gastrointestinal: Abdominal pain, bloating, diarrhea, dysgeusia, flatulence, nausea, vomiting
Hematologic & oncologic: Minor hemorrhage
Hepatic: Hepatitis
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Renal: Acute renal failure (in patients with altered glomerular integrity or with a history of kidney
disease)
Respiratory: Tracheobronchial calcification
<1%, postmarketing, and/or case reports: Gangrene of skin or other tissue, skin necrosis,
vascular calcification (calcium uremic arteriolopathy and calciphylaxis)
Contraindications Hypersensitivity to warfarin or any component of the formulation;

hemorrhagic tendencies (eg, active GI ulceration, patients bleeding from the GI, respiratory, or
GU tract; cerebral aneurysm; CNS hemorrhage; dissecting aortic aneurysm; spinal puncture
and other diagnostic or therapeutic procedures with potential for significant bleeding); recent or
potential surgery of the eye or CNS; major regional lumbar block anesthesia or traumatic
surgery resulting in large, open surfaces; blood dyscrasias; malignant hypertension; pericarditis
or pericardial effusion; bacterial endocarditis; unsupervised patients with conditions associated
with a high potential for noncompliance; eclampsia/preeclampsia, threatened abortion,
pregnancy (except in women with mechanical heart valves at high risk for thromboembolism)
Warnings/Precautions
Concerns related to adverse effects:
• Acute kidney injury: Acute kidney injury, possibly as a result of episodes of excessive
anticoagulation and hematuria, may occur in patients with a history of kidney disease or in
patients with altered glomerular integrity.
• Anaphylaxis/hypersensitivity: May cause hypersensitivity reactions, including anaphylaxis; use

with caution in patients with anaphylactic disorders.
• Bleeding: [US Boxed Warning]: May cause major or fatal bleeding. Perform regular INR
monitoring in all treated patients. INR levels achieved with warfarin therapy may be affected by
concomitant medication, dietary modifications and/or other factors (eg, smoking). Risk factors
for bleeding include high intensity anticoagulation (INR >4), age (≥65 years), variable INRs,
history of GI bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia,
severe diabetes, malignancy, trauma, renal insufficiency, polycythemia vera, vasculitis, open
wound, history of PUD, indwelling catheters, menstruating and postpartum women, drug-drug
interactions, long duration of therapy, or known genetic deficiency in CYP2C9 activity. Patient
must be instructed to report bleeding, accidents, or falls as well as any new or discontinued
medications, herbal or alternative products used, or significant changes in smoking or dietary
habits. Unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulation.
• Calciphylaxis: Fatal and serious calciphylaxis (calcium uremic arteriolopathy) has been
reported in patients with and without end-stage renal disease. If calciphylaxis is diagnosed,
discontinue therapy and treat calciphylaxis as appropriate. Consider alternative anticoagulation
therapy.
• Skin necrosis/gangrene: Necrosis or gangrene of the skin and other tissue can occur (rarely,
<0.1%) due to paradoxical local thrombosis; onset is usually within the first few days of therapy
and is frequently localized to the limbs, breast, or penis. The risk of this effect is increased in
patients with protein C or S deficiency. Consider alternative therapies if anticoagulation is
necessary.
• Atheroemboli/cholesterol microemboli: Warfarin therapy may release atheromatous plaque

emboli; symptoms depend on site of embolization, most commonly kidneys, pancreas, liver,
and spleen. In some cases may lead to necrosis or death. “Purple toe” syndrome, due to
cholesterol microembolization, has been rarely described with coumarin-type anticoagulants.
Typically, this occurs after several weeks of therapy, and may present as a dark, purplish,
mottled discoloration of the plantar and lateral surfaces. Other manifestations of cholesterol
microembolization may include rash; livedo reticularis; gangrene; abrupt and intense pain in
lower extremities; abdominal, flank, or back pain; hematuria, renal insufficiency; hypertension;
cerebral ischemia; spinal cord infarction; or other symptoms of vascular compromise.
Disease-related concerns:
• 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 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 (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.
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.
Metabolism/Transport Effects Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C9

(major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically
relevant drug interaction potential
Drug Interactions
(For additional information: Launch drug interactions program)

Acetaminophen: May enhance the anticoagulant effect of Vitamin K Antagonists. This appears
most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive
days. Risk C: Monitor therapy
Adalimumab: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance
the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Alcohol (Ethyl): May decrease the serum concentration of Vitamin K Antagonists. More
specifically, this effect has been described in heavy drinking alcoholic patients (over 250 g
alcohol daily for over 3 months). The role of alcohol itself is unclear. Risk C: Monitor therapy
Allopurinol: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: 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. Risk D: Consider therapy modification
Androgens: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider
Anticoagulants: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Antihepaciviral NS5B RNA Polymerase Inhibitors: May diminish the anticoagulant effect of
Vitamin K Antagonists. Risk C: Monitor therapy
Antithyroid Agents: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk D:
Consider therapy modification
Apalutamide: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy
Aprepitant: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy
Atazanavir: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
AzaTHIOprine: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Barbiturates: May increase the metabolism of Vitamin K Antagonists. Management: Monitor

INR more closely. 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. Risk D: Consider therapy modification
Benzbromarone: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
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
Bile Acid Sequestrants: May decrease the absorption of Vitamin K Antagonists. Risk C: Monitor
therapy
Boceprevir: May decrease the serum concentration of Warfarin. Boceprevir may increase the
serum concentration of Warfarin. Risk C: Monitor therapy
Bosentan: May increase the metabolism of Vitamin K Antagonists. Risk C: Monitor therapy
Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Capecitabine: May increase the serum concentration of Vitamin K Antagonists. Risk D:

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. Risk D: Consider therapy
modification
Cephalosporins: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C:

Monitor therapy
Ceritinib: May increase the serum concentration of CYP2C9 Substrates (High risk with
Inhibitors). Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a
narrow therapeutic index (eg, warfarin, phenytoin) should be avoided when possible. 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
Chloramphenicol (Systemic): May enhance the anticoagulant effect of Vitamin K Antagonists.

Chloramphenicol (Systemic) may increase the serum concentration of Vitamin K Antagonists.
Risk C: Monitor therapy
Chondroitin Sulfate: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Cimetidine: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider
Clopidogrel: May enhance the anticoagulant effect of Warfarin. Risk D: Consider therapy
modification
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
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.
Corticosteroids (Systemic): May enhance the anticoagulant effect of Warfarin. Risk C: Monitor
therapy
Cranberry: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
CYP2C9 Inducers (Moderate): May decrease the serum concentration of CYP2C9 Substrates
(High risk with Inducers). Risk C: Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates (High risk with
Inducers). 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). Risk D: Consider therapy modification
Daclatasvir: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Darunavir: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically,
the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid.
Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C:
Monitor therapy
Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Risk D: Consider
Desvenlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically,

the risk for bleeding may be increased. Risk C: Monitor therapy
Dexmethylphenidate: 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
Disulfiram: May increase the serum concentration of Vitamin K Antagonists. Risk C: 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. 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
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. Risk D:
Erlotinib: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
Erythromycin (Ophthalmic): May increase the serum concentration of Vitamin K Antagonists.

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
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. Risk D: Consider
Estrogen Derivatives (Contraceptive): May diminish the anticoagulant effect of Vitamin K

Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some
products. Risk D: Consider therapy modification
Ethacrynic Acid: May increase the serum concentration of Vitamin K Antagonists. Risk C:
Monitor therapy
Ethotoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists
may increase the serum concentration of Ethotoin. Management: Anticoagulant dose
adjustment will likely be necessary when ethotoin is initiated or discontinued. Monitor patients
extra closely (INR and signs/symptoms of bleeding) when using this combination. Risk D:
Etoposide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Etoposide Phosphate: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C:
Monitor therapy
Exenatide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Fat Emulsion (Fish Oil and Plant Based): May diminish the anticoagulant effect of Vitamin K
Antagonists. Risk C: Monitor therapy
Fenofibrate and Derivatives: May enhance the anticoagulant effect of Warfarin. Fenofibrate and
Derivatives may increase the serum concentration of Warfarin. Risk D: 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). Risk D: Consider therapy modification
Fibric Acid Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D:
Floxuridine: May increase the serum concentration of Vitamin K Antagonists. Management:

Monitor INR and signs/symptoms of bleeding closely when starting or stopping floxuridine in a
patient receiving a vitamin K antagonist. Anticoagulant dose adjustment will likely be necessary.
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. Risk D: Consider
Fluorouracil (Systemic): May increase the serum concentration of Vitamin K Antagonists. Risk
D: Consider therapy modification
Fluorouracil (Topical): May increase the serum concentration of Vitamin K Antagonists. Risk C:
Monitor therapy
Fosamprenavir: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
Fosaprepitant: May decrease the serum concentration of Warfarin. The active metabolite
aprepitant is likely responsible for this effect. Risk C: Monitor therapy
Fosphenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K

Antagonists may increase the serum concentration of Fosphenytoin. Management:
Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or
discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using
this combination. Risk D: Consider therapy modification
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
Ginseng (American): May decrease the serum concentration of Warfarin. Risk C: Monitor
therapy
Glucagon: 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
Glutethimide: May increase the metabolism of Vitamin K Antagonists. Risk D: Consider therapy
modification
Grazoprevir: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
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. 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
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the
adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk D: Consider therapy
modification
HMG-CoA Reductase Inhibitors (Statins): May enhance the anticoagulant effect of Vitamin K
Antagonists. Exceptions: AtorvaSTATin. 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
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. Risk D: Consider therapy modification
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
Ketoconazole (Systemic): May increase the serum concentration of Vitamin K Antagonists. Risk
C: Monitor therapy
Lansoprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor
therapy
Leflunomide: May enhance the anticoagulant effect of Vitamin K Antagonists. Leflunomide may
diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Letermovir: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy
LevOCARNitine: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C:

Monitor therapy
Levomilnacipran: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically,

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may
be increased. 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
Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with
Inhibitors or Inducers). Lumacaftor may increase the serum concentration of CYP2C9
Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy
Macrolide Antibiotics: May increase the serum concentration of Vitamin K Antagonists.

Exceptions: Fidaxomicin; Roxithromycin; Spiramycin. 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. Risk D:

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

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

Monitor therapy
Metreleptin: May decrease the serum concentration of Warfarin. Metreleptin may increase the
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. Risk D:
MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of
bleeding may be increased. Risk X: Avoid combination
Milnacipran: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the
risk for bleeding may be increased. Risk C: Monitor therapy
Mirtazapine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Multivitamins/Fluoride (with ADE): May enhance the anticoagulant effect of Vitamin K

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
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
Nelfinavir: May decrease the serum concentration of Warfarin. Nelfinavir may increase the
Neomycin: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Nevirapine: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically,

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of

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

effect of Vitamin K Antagonists. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may
increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Nonselective): May enhance the anticoagulant effect of

Vitamin K Antagonists. Risk D: Consider therapy modification
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
Ombitasvir, Paritaprevir, and Ritonavir: May diminish the anticoagulant effect of Warfarin. Risk
C: Monitor therapy
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
Oritavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, oritavancin 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
Orlistat: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Oxatomide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk X: Avoid
combination
Penicillins: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions:

Dicloxacillin; Nafcillin. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C:
Monitor therapy
Pentoxifylline: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Phenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K

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

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

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. Risk D: Consider therapy modification
Progestins (Contraceptive): 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. Risk D: Consider therapy modification
Proguanil: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Propacetamol: May enhance the anticoagulant effect of Vitamin K Antagonists. This appears
most likely with higher doses (equivalent to acetaminophen doses exceeding 1.3 to 2 g/day) for
multiple consecutive days. Risk C: Monitor therapy
Propafenone: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor
therapy
Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically,

the antiplatelet effects of these agents may lead to an increased risk of bleeding with the
combination. Risk C: Monitor therapy
QuiNIDine: May enhance the anticoagulant effect of Vitamin K Antagonists. Note that the
INR/PT might be unchanged in the face of increased bleeding. Risk C: Monitor therapy
QuiNINE: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Quinolones: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
RaNITIdine: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
Regorafenib: Warfarin may enhance the adverse/toxic effect of Regorafenib. Specifically, the
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 increase the metabolism of Vitamin K Antagonists. Risk C: Monitor
therapy
Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with
Inducers). Risk C: Monitor therapy
Ritonavir: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy
RomiDEPsin: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Roxithromycin: May enhance the anticholinergic effect of Warfarin. Risk C: Monitor therapy
Rucaparib: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
Salicylates: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions:

Salsalate. 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
Simeprevir: May enhance the anticoagulant effect of Warfarin. Risk C: 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. Risk
St John's Wort: May increase the metabolism of Vitamin K Antagonists. Risk D: Consider
Streptokinase: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk X: Avoid
combination
Sucralfate: May diminish the anticoagulant effect of Vitamin K Antagonists. Sucralfate may
decrease the serum concentration of Vitamin K Antagonists. Specifically, sucralfate may
decrease the absorption of Vitamin K Antagonists. Management: Administer vitamin K
antagonists at least 2 hours before or at least 6 hours after sucralfate. Risk D: Consider therapy
modification
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 D: Consider therapy modification
Sulfonamide Antibiotics: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk
Sulfonylureas: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K

Antagonists may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tamoxifen: May increase the serum concentration of Vitamin K Antagonists. Risk X: Avoid
combination
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. Risk D: Consider therapy modification
Telaprevir: May decrease the serum concentration of Warfarin. Telaprevir may increase the
Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may
artificially increase the results of laboratory tests commonly used to monitor anticoagulant
effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C:
Monitor therapy
Teriflunomide: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy
Tetracyclines: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
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. 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
Tolterodine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Toremifene: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Torsemide: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
TraMADol: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Tranilast (Systemic): May enhance the adverse/toxic effect of Warfarin. Tranilast (Systemic)
may diminish the therapeutic effect of Warfarin. Risk C: Monitor therapy
TraZODone: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Tricyclic Antidepressants: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk
C: Monitor therapy
Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Vemurafenib: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
Venetoclax: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
Venlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the
Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor
therapy
Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this
combination is expected to increase the risk of bleeding. Risk X: Avoid combination
Voriconazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor
therapy
Vorinostat: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Zafirlukast: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor
therapy
Zileuton: May increase the serum concentration of Warfarin. Risk C: Monitor therapy
Food Interactions
Ethanol: Acute ethanol ingestion (binge drinking) decreases the metabolism of oral
anticoagulants and increases PT/INR. Chronic daily ethanol use increases the metabolism of
oral anticoagulants and decreases PT/INR. Management: Avoid ethanol.
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.
Pregnancy Implications
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]).
Breast-Feeding Considerations
Based on available data, warfarin is not present in breast milk.
Breastfeeding women may be treated with warfarin. According to the American College of
Chest Physicians (ACCP), warfarin may be used in lactating women who wish to breastfeed
their infants (ACCP [Bates 2012]). The manufacturer recommends monitoring of breastfeeding
infants for bruising or bleeding.
Dietary Considerations Foods high in vitamin K (eg, leafy green vegetables) inhibit
anticoagulant effect. The list of usual foods with high vitamin K content is well known, however,
some unique ones include green tea (Camellia sinensis), chewing tobacco, a variety of oils
(canola, corn, olive, peanut, safflower, sesame seed, soybean, and sunflower) (Booth, 1999;
Kuykendall, 2004; Nutescu, 2011). Snack foods containing Olestra have 80 mcg of vitamin K
added to each ounce (Harrell, 1999). Some natural products may contain hidden sources of
vitamin K (Nutescu, 2006). Avoid drastic changes in diet (eg, intake of large amounts of alfalfa,
asparagus, broccoli, Brussels sprouts, cabbage, cauliflower, green teas, kale, lettuce, spinach,
turnip greens, watercress) which decrease efficacy of warfarin. A balanced diet with a
consistent intake of vitamin K is essential. The recommended dietary allowance for vitamin K in
adults is 75 to 120 mcg/day (USDA Dietary Reference Intake).
Monitoring Parameters Prothrombin time, hematocrit; INR (frequency varies depending on INR
stability); may consider genotyping of CYP2C9 and VKORC1 prior to initiation of therapy, if
available
Reference Range
INR = patient prothrombin time/mean normal prothrombin time
ISI = international sensitivity index
INR should be increased by 2 to 3.5 times depending upon indication. An INR >4 does not
generally add additional therapeutic benefit and is associated with increased risk of bleeding.
Note: To prevent gastrointestinal bleeding events in patients receiving the combination of
warfarin, aspirin, and clopidogrel, an INR of 2 to 2.5 is recommended unless condition requires
a higher INR target (eg, certain mechanical heart valves) (Bhatt 2008).
Adult Target INR Ranges Based Upon Indication

Indication
Targeted INR
Targeted INR Range
Note: Unless otherwise noted, all recommendations derived from “Antithrombotic Therapy for
VTE Disease”, (Kearon 2012; Kearon 2016).
1If coronary stent placed, triple therapy (warfarin, low-dose aspirin, and clopidogrel) is
recommended for 1 month (bare-metal stent) or 3-6 months (drug-eluting stent) followed by
discontinuation of warfarin and use of dual antiplatelet therapy (eg, aspirin and clopidogrel) for
up to 12 months.
2If coronary stent not placed, maintain anticoagulation (in combination with low-dose aspirin)
for 3 months followed by discontinuation of warfarin and use of dual antiplatelet therapy (eg,
aspirin and clopidogrel) for up to 12 months.
3The ACCF/AHA guidelines for the management of STEMI, suggest that a lower INR range of
2-2.5 might be considered in patients with STEMI receiving dual antiplatelet therapy (O’Gara
2013).
4Recommended for those patients with nonvalvular AF or atrial flutter with prior stroke, TIA, or
a CHA2DS2-VASc score ≥2 (AHA/ACC/HRS [January, 2014]).
5Recommendation from Stein, 2001.
6If at low risk of bleeding, combine with aspirin 81 mg/day.
7The AHA/ASA recommends use in patients with bileaflet mechanical or current-generation,

single-tilting-disk prostheses (AHA/ASA [Meschia 2014]).
8The On-X prosthetic aortic valve requires an initial INR of 2 to 3 for 3 months after valve
insertion followed by an INR of 1.5 to 2 indefinitely. Unless contraindicated, continuous use of
concurrent aspirin 75 to 100 mg daily is also recommended.
9Risk factors defined by the AHA/ASA include atrial fibrillation, previous thromboembolism, left
ventricular dysfunction, and hypercoagulable condition (AHA/ASA [Meschia 2014]).
10Maintain anticoagulation for 3 months after valve insertion then switch to aspirin 81 mg/day if
no other indications for warfarin exist or clinically reassess need for warfarin in patients with
prior history of systemic embolism.
11Recommendation from the ACCF/AHA 2009 Expert Consensus Document on Pulmonary

Hypertension (McLaughlin 2009)
12Continue for at least 10 to 14 days; up to 35 days after surgery is suggested.
13Instead of adjusted dose warfarin, the use of dabigatran has been suggested. In either case,
oral anticoagulation should be initiated within 1 to 2 weeks after stroke onset or earlier in
patients at low bleeding risk; bridging with aspirin may be required.
Cardiac
Anterior myocardial infarction with LV thrombus or high risk for LV thrombus (EF<40%,
anteroapical wall motion abnormality)1,2,3
2.5
2-3
Atrial fibrillation (nonvalvular)4 or atrial flutter
2.5
2-3
LV systolic dysfunction (without established CAD) (eg, Takotsubo cardiomyopathy) with an LV

thrombus
2.5
2-3
Valvular
Carbomedics or St. Jude Medical bileaflet or Medtronic Hall tilting disk mechanical aortic valve
in normal sinus rhythm and normal LA size5
2.5
2-3
Bileaflet or tilting disk mechanical mitral valve5
2.5-3.5
Caged ball or caged disk mechanical valve5
2.5-3.5
Mechanical aortic valve6,7,8
2.5
2-3
Mechanical aortic valve (with risk factors6,9), mechanical mitral valve6, or mechanical valves in
both the aortic and mitral positions6
2.5-3.5
Bioprosthetic mitral valve10
2.5
2-3
Rheumatic mitral valve disease (particularly mitral stenosis) and normal sinus rhythm (LA
diameter >5.5 cm), AF, previous systemic embolism, or LA thrombus
2.5
2-3
Thromboembolism Treatment
Venous thromboembolism
2.5
2-3
Thromboprophylaxis
Idiopathic pulmonary artery hypertension (IPAH)11
1.5-2.5
Antiphospholipid syndrome (no other risk factors)
2.5
2-3
Antiphospholipid syndrome and recurrent thromboembolism
2.5
2-3
Total hip or knee replacement or hip fracture surgery12
2.5
2-3
Other Indications
Ischemic stroke due to AF13
2.5
2-3
Cryptogenic stroke (recurrent) and either patent foramen ovale (PFO) or atrial septal aneurysm
2.5
2-3
Warfarin levels are not used for monitoring degree of anticoagulation. They may be useful if a
patient with unexplained coagulopathy is using the drug surreptitiously or if it is unclear whether
clinical resistance is due to true drug resistance or lack of drug intake.
Normal prothrombin time (PT): 10.9 to 12.9 seconds. Healthy premature newborns have
prolonged coagulation test screening results (eg, PT, aPTT, TT) which return to normal adult
values at approximately 6 months of age. Healthy prematures, however, do not develop
spontaneous hemorrhage or thrombotic complications because of a balance between
procoagulants and inhibitors.
Mechanism of Action Hepatic synthesis of coagulation factors II (half-life 42 to 72 hours), VII

(half-life 4 to 6 hours), IX, and X (half-life 27 to 48 hours), as well as proteins C and S, requires
the presence of vitamin K. These clotting factors are biologically activated by the addition of
carboxyl groups to key glutamic acid residues within the proteins’ structure. In the process,
“active” vitamin K is oxidatively converted to an “inactive” form, which is then subsequently
reactivated by vitamin K epoxide reductase complex 1 (VKORC1). Warfarin competitively
inhibits the subunit 1 of the multi-unit VKOR complex, thus depleting functional vitamin K
reserves and hence reduces synthesis of active clotting factors.
Pharmacodynamics/Kinetics
Onset of action: Anticoagulation: Oral: 24-72 hours
Peak effect: Full therapeutic effect: 5-7 days; INR may increase in 36-72 hours
Duration: 2-5 days
Absorption: Oral: 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: 20-60 hours; Mean: 40 hours; highly variable among individuals
Time to peak, plasma: Oral: ~4 hours
Excretion: Urine (92%, primarily as metabolites; minimal as unchanged drug)
Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Renal Cl is a minor determinant of anticoagulant response to
warfarin.
Hepatic function impairment: Hepatic impairment can potentiate the response to warfarin
through impaired synthesis of clotting factors and decreased metabolism of warfarin.
Geriatric: Patients 60 years and older appear to exhibit greater than expected INR response to
warfarin.
Race: Asian patients may require lower initiation and maintenance doses.
Pharmacogenetics: Vitamin K epoxide reductase (VKORC1) and CYP2C9 gene variants

generally explain the largest proportion of known variability in warfarin dose requirements.
Pricing: US
Tablets (Coumadin Oral)
1 mg (100): $247.43
2 mg (100): $258.13
2.5 mg (100): $266.35
3 mg (100): $267.38
4 mg (100): $268.10
5 mg (100): $277.61
6 mg (100): $357.65
7.5 mg (100): $370.04
10 mg (100): $383.81
Tablets (Jantoven Oral)
1 mg (100): $61.49
2 mg (100): $64.20
2.5 mg (100): $66.01
3 mg (100): $66.01
4 mg (100): $66.01
5 mg (100): $68.73
6 mg (100): $88.61
7.5 mg (100): $92.24
10 mg (100): $94.95
Tablets (Warfarin Sodium Oral)
1 mg (100): $58.34
2 mg (100): $63.40
2.5 mg (100): $62.84
3 mg (100): $64.50
4 mg (100): $65.50
5 mg (100): $66.80
6 mg (100): $92.30
7.5 mg (100): $94.69
10 mg (100): $98.56
Disclaimer: The pricing data provide a representative AWP and/or AAWP price from a single
manufacturer of the brand and/or generic product, respectively. The pricing data should be
used for benchmarking purposes only, and as such should not be used to set or adjudicate any
prices for reimbursement or purchasing functions. Pricing data is updated monthly.
Brand Names: International Aldocumar (ES); Azwar (LK); Befarin (TH); Circuvit (AR); Cofarin
(TW); Coumadan (AR); Coumadin (AE, AU, BB, BF, BH, BJ, CI, CL, CY, DE, EC, EG, ET, GH,
GM, GN, IL, IQ, IR, IT, JO, KE, KR, KW, LB, LR, LY, MA, ML, MR, MU, MW, MX, NE, NG, NZ,
OM, PH, PK, QA, SA, SC, SD, SL, SN, SY, TN, TR, TZ, UG, VE, YE, ZM, ZW); Coumadine
(FR, VN); Dagonal (UY); Farin (BD); Lawarin (CZ); Lennon-Warfarin (ZA); Mafarin (TW);
Maforan (TH); Marevan (AE, AU, BE, BR, CN, DK, EE, FI, GB, IE, LU, MT, NO, NZ, SG);
Marfarin (HN); Marivarin (HR); Martefarin (HR); Morfarin (TH); Oldin (PY); Orfarin (JO, LV, MY,
TH, TW); Panwarfin (GR); Rilaquin (PY); Simarc-2 (ID); UniWarfin (IN); Varfareks (UA); Varfarin
(HR); Varfine (PT); Waran (SE); Warf (LK); Warfant (IE, TR); Warfar (CO, KR); Warfarina (PE);
Warfil 5 (DO); Warfin (PL); Warik (PH); Warin (BD); Win (BD); Zofarin (LK); Zydarin (TH)
REFERENCES
<800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and
National Formulary (USP 40-NF 35). Rockville, MD: United States Pharmacopeia Convention;
2017:83-102.
Ageno W, Gallus AS, Wittkowsky A, et al, “Oral Anticoagulant Therapy: Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines,” Chest, 2012, 141(2 Suppl):e44-88. [PubMed 22315269]
Anand SS, Yusuf S, Pogue J, et al, “Long-Term Oral Anticoagulant Therapy in Patients With
Unstable Angina or Suspected Non-Q-Wave Myocardial Infarction: Organization to Assess
Strategies for Ischemic Syndromes (OASIS) Pilot Study Results,” Circulation, 1998,
98(11):1064-70. [PubMed 9736592]
Arepally GM and Ortel TL, “Heparin-Induced Thrombocytopenia,” N Engl J Med, 2006, 355
(8):809-17. [PubMed 16928996]
Armstrong MJ, Gronseth G, Anderson DC, et al. Summary of evidence-based guideline:
Periprocedural management of antithrombotic medications in patients with ischemic
cerebrovascular disease: Report of the Guideline Development Subcommittee of the American
Academy of Neurology. Neurology. 2013;80(22):2065-9. [PubMed 23713086]
Baillargeon J, Holmes HM, Lin YL, et al, "Concurrent Use of Warfarin and Antibiotics and the
Risk of Bleeding in Older Adults," Am J Med, 2012, 125(2):183-9. [PubMed 22269622]
Bates SM, Greer IA, Middeldorp S, et al. “VTE, Thrombophilia, Antithrombotic Therapy, and
Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest, 2012, 141(2
Suppl):e691-736. [PubMed 22315276]
Bell AD, Roussin A, Cartier R, et al, “The Use of Antiplatelet Therapy in the Outpatient Setting:
Canadian Cardiovascular Society Guidelines,” Can J Cardiol, 2011, 27(Suppl A):1-59. [PubMed
21640290]
Bhatt DL, Scheiman J, Abraham NS, et al, “ACCF/ACG/AHA 2008 Expert Consensus
Document on Reducing the Gastrointestinal Risk of Antiplatelet Therapy and NSAID Use. A
Report of the American College of Cardiology Foundation Task Force on Clinical Expert
Consensus Documents,” J Am Coll Cardiol, 2008, 52(18):1502-17. [PubMed 19017521]
Booth SL, Centurelli MA. Vitamin K: a practical guide to the dietary management of patients on
warfarin. Nutr Rev.1999;57(9):288-296. [PubMed 10568341]
Carabello PJ, Heit JA, Atkinson EJ, et al, “Long-Term Use of Oral Anticoagulants and the Risk
of Fracture,” Arch Intern Med, 1999, 159(15):1750-6. [PubMed 10448778]
Chimowitz MI, Lynn MJ, Howlett-Smith H, et al, "Comparison of Warfarin and Aspirin for
Symptomatic Intracranial Arterial Stenosis," N Engl J Med, 2005, 352(13):1305-16. [PubMed
15800226]
Coumadin (warfarin) [prescribing information]. Princeton, NJ: Bristol-Meyers Squibb; August
2017.
Culebras A, Messe SR, Chaturvedi S, et al. Summary of evidence-based guideline update:
Prevention of stroke in nonvalvular atrial fibrillation. Neurology. 2014;82:716-724. [PubMed
24566225]
Dager WE and White RH, “Pharmacotherapy of Heparin-Induced Thrombocytopenia,” Expert
Opin Pharmacother, 2003, 4(6):919-40. [PubMed 12783589]
Dager WE, King JF, Regalia RC, et al, “Reversal of Elevated International Normalized Ratios
and Bleeding With Low-Dose Recombinant Activated Factor VII in Patients Receiving
Warfarin,” Pharmacotherapy, 2006, 26(8):1091-8. [PubMed 16863486]
“Effect of Long-Term Oral Anticoagulant Treatment on Mortality and Cardiovascular Morbidity
After Myocardial Infarction. Anticoagulants in the Secondary Prevention of Events in Coronary
Thrombosis (ASPECT) Research Group,” Lancet, 1994, 343(8896):499-503. [PubMed
7906757]
Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al; Guideline for reversal of antithrombotics in
intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care
Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46. [PubMed
26714677]
Gage BF, Birman-Deych E, Radford MJ, et al, “Risk of Osteoporotic Fracture in Elderly Patients
Taking Warfarin. Results From the National Registry of Atrial Fibrillation 2,” Arch Intern Med,
2006, 166(2):241-6. [PubMed 16432096]
Grand’Maison A, Charest AF, and Geerts WH, “Anticoagulant Use in Patients With Chronic
Renal Impairment,” Am J Cardiovasc Drugs, 2005, 5(5):291-305. [PubMed 16156685]
Guyatt GH, Akl EA, Crowther M, et al, “Executive Summary: Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines,” Chest, 2012, 141(2 Suppl):7-47. [PubMed 22315257]
Harrell CC, Kline SS. Vitamin K-supplemented snacks containing olestra: implication for
patients taking warfarin. JAMA. 1999; 282(12):1133-1134. [PubMed 10501114]
Healthcare Environmental Resource Center (HERC), "Pharmaceutical Wastes in Healthcare
Facilities." Available at http://www.hercenter.org/hazmat/pharma.cfm#listed. Last accessed April
8, 2013.
Jaff MR, McMurtry MS, Archer SL, et al, “Management of Massive and Submassive Pulmonary
Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary
Hypertension: A Scientific Statement from the American Heart Association,” Circulation, 2011,
123(16):1788-830. [PubMed 21422387]
Jamal SA, Browner WS, Bauer DC, et al, “Warfarin Use and Risk for Osteoporosis in Elderly
Women. Study of Osteoporotic Fractures Research Group,” Ann Intern Med, 1998,
128(10):829-32. [PubMed 9599195]
January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of
Patients With Atrial Fibrillation: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines and the Heart Rhythm Society [published online
March 28, 2014]. Circulation. doi:10.1161/CIR.0000000000000041. [PubMed
24682347]10.1161/CIR.0000000000000041
Jeske AH, Suchko GD, ADA Council on Scientific Affairs and Division of Science, et al, “Lack of
a Scientific Basis for Routine Discontinuation of Oral Anticoagulation Therapy Before Dental
Treatment,” J Am Dent Assoc, 2003, 134(11):1492-7. [PubMed 14664269 ]
Karsli ED, Erdogan Ö, Esen E, et al, "Comparison of the Effects of Warfarin and Heparin on
Bleeding Caused by Dental Extraction: A Clinical Study," J Oral Maxillofac Surg, 2011,
69(10):2500-7. [PubMed 21764203]
Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
evidence-based clinical practice guidelines [published correction appears in Chest.
2012;142(6):1698-1704]. Chest. 2012;141(2)(suppl):e419S-e496S. doi: 10.1378/chest.11-2301.
[PubMed 22315268]
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE disease: CHEST guideline
and expert panel report. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11.026.
[PubMed 26867832]
Kernan WN, Ovbiagele B, Black HR, et al; American Heart Association Stroke Council; Council
on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Peripheral
Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient
ischemic attack: a guideline for healthcare professionals from the American Heart
Association/American Stroke Association [published correction appears in Stroke.
2015;46(2):e54]. Stroke. 2014;45(7):2160-2236. doi: 10.1161/STR.0000000000000024.
[PubMed 24788967]
Kovacs MJ, Rodger M, Anderson DR, et al, “Comparison of 10-mg and 5-mg Warfarin Initiation
Nomograms Together With Low-Molecular-Weight Heparin for Outpatient Treatment of Acute
Venous Thromboembolism. A Randomized, Double-Blind, Controlled Trial,” Ann Intern Med,

2003, 138(9):714-9. [PubMed 12729425]
Kuykendall JR , Houle MD, Rhodes RS. Possible warfarin failure due to interaction with
smokeless tobacco. Ann Pharmacother. 2004;38(4):595-597. [PubMed 14766993]
Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice
Guideline,” J Card Fail, 2010, 16(6):e1-194. [PubMed 20610207]
Little JW, Miller CS, Henry RG, et al, “Antithrombotic Agents: Implications in Dentistry,” Oral
Surg Oral Med Oral Pathol Oral Radiol Endod, 2002, 93(5):544-51. [PubMed 12075203 ]
McLaughlin VV, Archer SL, Badesch DB, et al, “ACCF/AHA 2009 Expert Consensus Document
on Pulmonary Hypertension. A Report of the American College of Cardiology Foundation Task
Force on Expert Consensus Documents and the American Heart Association,” Circulation,
2009, 119(16):2250-94. [PubMed 19332472]
McMahan DA, Smith DM, Carey MA, et al, “Risk of Major Hemorrhage for Outpatients Treated
With Warfarin,” J Gen Intern Med, 1998, 13(5):311-6. [PubMed 9613886]
Meschia JF, Bushnell C, Boden-Albala B, et al; American Heart Association Stroke Council;
Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on
Functional Genomics and Translational Biology; Council on Hypertension. Guidelines for the
primary prevention of stroke: a statement for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke. 2014;45(12):3754-3832. [PubMed 25355838]
Monagle P, Chan A, Goldenberg NA, et al, "Antithrombotic Therapy in Neonates and Children:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th
Edition)," Chest, 2012, 141(2 Suppl):e737-801. [PubMed 22315277]
Nigwekar SU, Kroshinsky D, Nazarian RM, et al. Calciphylaxis: risk factors, diagnosis, and
treatment. Am J Kidney Dis. 2015;66(1):133-146. [PubMed 25960299]
Nishimura RA, Otto CM, Bonow RO, et al, 2014 AHA/ACC Guideline for the Management of
Patients with Valvular Heart Disease: executive summary: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation.
2014;129(23):2440-92. doi: 10.1161/CIR.0000000000000029. [PubMed 24589852]
Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral
anticoagulants: an update. J Thromb Thrombolysis. 2011;31:326-343. [PubMed 21359645]
Nutescu E, Shapiro NL, Ibrahim S, West P. Warfarin and its interactions with foods, herbs and
other dietary supplements. Expert Opin Drug Saf. 2006;5(3):433-451. [PubMed 16610971]
O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of
ST-elevation myocardial infarction: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines [published
correction appears in Circulation. 2013;128(25):e481.] Circulation. 2013;127(4):e362-e425.
[PubMed 23247304]
Patriquin C and Crowther M, “Treatment of Warfarin-associated Coagulopathy With Vitamin K,”
Expert Rev Hematol, 2011, 4(6):657-67.
Puskas J, Gerdisch M, Nichols D, et al; PROACT Investigators. Reduced anticoagulation after
mechanical aortic valve replacement: Interim results from the Prospective Randomized On-X
Valve Anticoagulation Clinical Trial randomized Food and Drug Administration investigational
device exemption trial. J Thorac Cardiovasc Surg. 2014;147(4):1202-1211. [PubMed 24512654
]
“Randomised Double-Blind Trial of Fixed Low-Dose Warfarin With Aspirin After Myocardial
Infarction. Coumadin Aspirin Reinfarction Study (CARS) Investigators,” Lancet, 1997,
350(9075):389-96. [PubMed 9259652]
Sacco RL, Adams R, Albers G, et al, “Guidelines for Prevention of Stroke in Patients With
Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From
the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored
by the Council on Cardiovascular Radiology and Intervention: The American Academy of
Neurology Affirms the Value of this Guideline,” Stroke, 2006, 37(2):577-617. [PubMed
16432246]
Scully C and Wolff A, “Oral Surgery in Patients on Anticoagulant Therapy,” Oral Surg Oral Med
Oral Pathol Oral Radiol Endod, 2002, 94(1):57-64. [PubMed 12193895 ]
Singer DE, Albers GW, Dalen JE, et al, “Antithrombotic Therapy in Atrial Fibrillation: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest,
2008, 133(6 Suppl):546-92. [PubMed 18574273]
Skanes AC, Healey JS, Cairns JA, et al, “Focused 2012 Update of the Canadian
Cardiovascular Society Atrial Fibrillation Guidelines: Recommendations for Stroke Prevention
and Rate/Rhythm Control,” Can J Cardiol, 2012, 28(2):125-36. [PubMed 22433576]
Smith P, Arnesen H, and Holme I, “The Effect of Warfarin on Mortality and Reinfarction After
Myocardial Infarction,” N Engl J Med, 1990, 323(3):147-52. [PubMed 2194126]
Smith SC Jr, Benjamin EJ, Bonow RO, et al, “AHA/ACCF Secondary Prevention and Risk
Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease:
2011 Update: A Guideline From the American Heart Association and American College of
Cardiology Foundation,” Circulation, 2011, 124(22):2458-73. [PubMed 22052934]
Smythe MA, Warkentin TE, Stephens JL, et al, “Venous Limb Gangrene During Overlapping
Therapy With Warfarin and a Direct Thrombin Inhibitor for Immune Heparin-Induced
Thrombocytopenia,” Am J Hematol, 2002, 71(1):50-2. [PubMed 12221676]
Stein PD, Alpert JS, Bussey HI, et al, “Antithrombotic Therapy in Patients With Mechanical and
Biological Prosthetic Heart Valves,” Chest, 2001, 119(1 Suppl):220-7. [PubMed 11157651]
Suvarna R, Pirmohamed M, and Henderson L, “Possible Interaction Between Warfarin and
Cranberry Juice,” BMJ, 2003, 327(7429):1454. [PubMed 14684645]
US Department of Health and Human Services; Centers for Disease Control and Prevention;
National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other
hazardous drugs in healthcare settings 2016.
http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated
September 2016. Accessed October 5, 2016.
United States Department of Agriculture (USDA), National Agricultural Library (NAL) Dietary
Reference Intake. Available at http://fnic.nal.usda.gov/dietary-guidance/dietary-reference-
intakes/dri-tables. Accessed January 8, 2015.
Whitlock RC, Sun JC, Fremes, SE, et al. Antithrombotic and thrombolytic therapy for valvular
disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
suppl):e576S-e600S. doi: 10.1378/chest.11-2305. [PubMed 22315272]
Vandvik PO, Lincoff AM, Gore JM, et al.. Primary and secondary prevention of cardiovascular
disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
suppl):e637S-e668S. doi: 10.1378/chest.11-2306. [PubMed 22315274]
Yung D, Kapral MK, Asllani E, et al, Reinitiation of anticoagulation after warfarin-associated
intracranial hemorrhage and mortality risk: the best practice for reinitiating anticoagulation
therapy after intracranial bleeding (BRAIN) study. Can J Cardiol. 2012;28:33-39. [PubMed
22153256]
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Copyright 1978-2018 Lexicomp, Inc. All rights reserved.

Brand Names: US Coumadin; Jantoven

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

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

Range1 of Expected Therapeutic Maintenance Dose Based on CYP2C92 and VKORC13

1Ranges derived from multiple published clinical studies.

Warfarin Duration of Therapy by Indication

3 months after valve insertion

Mechanical prosthetic cardiac valves (Whitlock 2012)

Anterior MI with LV thrombus or at high risk for LV thrombus (Vandvik 2012)

VTE (Kearon 2012; Kearon 2016)

First episode, provoked or unprovoked DVT of the leg or PE (without cancer)

Unprovoked second DVT of the leg or PE

In patients with DVT of the leg or PE and with cancer

Dosing: Renal Impairment (Adult)

Hemodialysis: Not dialyzable (NCS/SCCM [Frontera 2016])

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

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

Coumadin: 10 mg [scored; dye free]

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

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]

Generic Equivalent Available (US) Yes

Hazardous Drugs Handling Considerations

Nonvalvular AF or atrial flutter: The 2014 American Heart Association/American College of

Venous thromboembolism (VTE): The American College of Chest Physicians (ACCP)

According to the American College of Cardiology/American Heart Association (ACCF/AHA)

Medication Safety Issues

Jantoven may be confused with Janumet, Januvia

High alert medication:

National Patient Safety Goals:

Frequency not defined:

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

Central nervous system: Chills

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

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

Hematologic & oncologic: Minor hemorrhage

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Respiratory: Tracheobronchial calcification

Contraindications Hypersensitivity to warfarin or any component of the formulation;

• Anaphylaxis/hypersensitivity: May cause hypersensitivity reactions, including anaphylaxis; use

• Atheroemboli/cholesterol microemboli: Warfarin therapy may release atheromatous plaque

• Heparin-induced thrombocytopenia: Use with caution in patients with heparin-induced

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

Metabolism/Transport Effects Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C9

(For additional information: Launch drug interactions program)

Barbiturates: May increase the metabolism of Vitamin K Antagonists. Management: Monitor

Capecitabine: May increase the serum concentration of Vitamin K Antagonists. Risk D:

CarBAMazepine: May decrease the serum concentration of Vitamin K Antagonists.

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

Chloramphenicol (Systemic): May enhance the anticoagulant effect of Vitamin K Antagonists.

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase

Desvenlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically,

Dexmethylphenidate: May increase the serum concentration of Vitamin K Antagonists. Risk C:

Enzalutamide: May decrease the serum concentration of Warfarin. More specifically,

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

Eslicarbazepine: May decrease the serum concentration of Warfarin. Specifically, S-warfarin

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

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More

Estrogen Derivatives (Contraceptive): May diminish the anticoagulant effect of Vitamin K

Fenugreek: May enhance the anticoagulant effect of Vitamin K Antagonists. Management:

Floxuridine: May increase the serum concentration of Vitamin K Antagonists. Management: