Warfarin- Drug Information

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Warfarin: Drug information

Copyright 1978-2012 Lexicomp, Inc. All rights reserved.

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

Special Alerts

Warfarin (Jantoven®): Recall Due to Mislabeled Bottle (Update) February 2011

Upsher-Smith Laboratories has initiated a voluntary recall of Jantoven® warfarin sodiumtablets. The precautionary recall was prompted after a single bottle labeled with 3 mgtablets (tan colored tablets) was found to actually contain the 10 mg strength tablets(white colored tablets). The risk of administering a 10 mg strength tablet in place of theintended 3 mg strength tablet could potentially result in life-threatening hemorrhage.

As an additional precautionary measure, Upsher-Smith Laboratories has expanded itspreviously announced recall to include additional products and lots produced on the sameline during a similar period of time.

For the most recent information, including the products recalled, please refer tohttp://www.upsher-smith.com.

ALERT: U.S. Boxed Warning The FDA-approved labeling includes a boxedwarning. See Warnings/Precautions section for a concise summary of this information. Forverbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Brand Names: U.S. Coumadin®; Jantoven®

Brand Names: Canada Apo-Warfarin®; Coumadin®; Mylan-Warfarin;Novo-Warfarin; Taro-Warfarin

Medication Guide An FDA-approved patient medication guide, which is availablewith the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088578.pdf, must be dispensed with this medication.

Pharmacologic Category Anticoagulant, Coumarin Derivative; Vitamin KAntagonist

Dosing: Adult Note: Labeling identifies genetic factors which may increase patientsensitivity 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 requirementand increased bleeding risk. Genotyping tests are available, and may provide importantguidance on initiation of anticoagulant therapy.

Warfarin: Drug information http://www.uptodate.com/contents/warfarin-drug-information...

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Prevention/treatment of thrombosis/embolism:

I.V. (administer as a slow bolus injection): 2-5 mg/day

Oral: Initial dosing must be individualized. Consider the patient (hepatic function,cardiac function, age, nutritional status, concurrent therapy, risk of bleeding) inaddition to prior dose response (if available) and the clinical situation. Start 2-5 mgdaily for 2 days or 5-10 mg daily for 1-2 days (Ansell, 2008). Adjust doseaccording to INR results; usual maintenance dose ranges from 2-10 mg daily(individual patients may require loading and maintenance doses outside thesegeneral guidelines).

Note: Lower starting doses may be required for patients with hepatic impairment,poor nutrition, CHF, elderly, high risk of bleeding, or patients who aredebilitated, or those with reduced function genomic variants of the catabolicenzymes CYP2C9 (*2 or *3 alleles) or VKORC1 (-1639 polymorphism); seetable. Higher initial doses may be reasonable in selected patients (ie, receivingenzyme-inducing agents and with low risk of bleeding).

Range1 of Expected Therapeutic Maintenance Dose Based onCYP2C92 and VKORC13 Genotypes

VKORC1 CYP2C9

Note: Must also take into account other patient related factors whendetermining initial dose (eg, age, body weight, concomitantmedications, comorbidities).

1Ranges derived from multiple published clinical studies.

2Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 alleles maytake up to 4 weeks to achieve maximum INR with a given doseregimen.

3VKORC1 -1639G>A (rs 9923231) variant is used in this table; otherVKORC1 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

Dosing: Pediatric


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

Prevention/treatment of thrombosis: Oral: Infants and Children (unlabeled use):Initial loading dose (if baseline INR is 1-1.3): 0.2 mg/kg (maximum: 10 mg/dose); adjustdose based on INR (reported ranges to maintain INR of 2-3: 0.09-0.33 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.

Dosing: Geriatric Oral: Initial dose ≤5 mg. Usual maintenance dose: 2-5 mg/day.The elderly tend to require lower dosages to produce a therapeutic level of anticoagulation(due to changes in the pattern of warfarin metabolism).

Dosing: Renal Impairment No adjustment required, however, patients withrenal failure have an increased risk of bleeding complications. Monitor closely.

Dosing: Hepatic Impairment Monitor effect at usual doses. The response tooral anticoagulants may be markedly enhanced in obstructive jaundice, hepatitis, andcirrhosis. INR should be closely monitored.

Dosage Forms: U.S. Excipient information presented when available (limited,particularly for generics); consult specific product labeling.

Injection, powder for reconstitution, as sodium:

Coumadin®: 5 mg

Tablet, oral, as sodium: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg

Coumadin®: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg [scored]

Coumadin®: 10 mg [scored; dye free]

Jantoven®: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg [scored]

Jantoven®: 10 mg [scored; dye free]

Generic Equivalent Available: U.S. Yes: Tablet

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

I.V.: Administer as a slow bolus injection over 1-2 minutes; avoid all I.M. injections

Compatibility Stable in D5LR, D51/2NS, D5NS, D5W, D10W, variable stability

(consult detailed reference) in LR, NS.

Y-site administration: Compatible: Amikacin, ascorbic acid injection, bivalirudin,cefazolin, dopamine, epinephrine, heparin, lidocaine, morphine, nitroglycerin, oxytocin,potassium chloride, ranitidine. Incompatible: Aminophylline, ceftazidime, cimetidine,ciprofloxacin, dobutamine, esmolol, gentamicin, labetalol. Variable (consult detailedreference): Ammonium chloride, ceftriaxone, metronidazole, vancomycin.

Compatibility in syringe: Incompatible: Ceftriaxone, heparin.

Use Prophylaxis and treatment of thromboembolic disorders (eg, venous, pulmonary)


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and embolic complications arising from atrial fibrillation or cardiac valve replacement;adjunct to reduce risk of systemic embolism (eg, recurrent MI, stroke) after myocardialinfarction

Use - Unlabeled/Investigational Prevention of recurrent transient ischemicattacks

Medication Safety Issues

Sound-alike/look-alike issues:

Coumadin® may be confused with Avandia®, Cardura®, Compazine®, Kemadrin®

Jantoven® may be confused with Janumet®, Januvia®

High alert medication:

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

2009 National Patient Safety Goals:

The Joint Commission on Accreditation of Healthcare Organizations requires healthcareorganizations that provide anticoagulant therapy to have a process in place toreduce the risk of anticoagulant-associated patient harm. Patients receivinganticoagulants should receive individualized care through a defined process thatincludes standardized ordering, dispensing, administration, monitoring andeducation. This does not apply to routine short-term use of anticoagulants forprevention of venous thromboembolism when the expectation is that the patient’slaboratory values will remain within or close to normal values (NPSG.03.05.01).

Adverse Reactions Significant 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: Angina, chest pain, edema, hemorrhagic shock, hypotension, pallor,syncope, vasculitis

Central nervous system: Coma, dizziness, fatigue, fever, headache, lethargy, malaise,pain, stroke

Dermatologic: Alopecia, bullous eruptions, dermatitis, rash, pruritus, urticaria

Gastrointestinal: Abdominal cramps, abdominal pain, anorexia, diarrhea, flatulence,gastrointestinal bleeding, mouth ulcers, nausea, taste disturbance, vomiting

Genitourinary: Hematuria, priapism

Hematologic: Agranulocytosis, anemia, leukopenia, retroperitoneal hematoma,unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulation

Hepatic: Cholestatic jaundice, hepatic injury, hepatitis, transaminases increased

Neuromuscular & skeletal: Joint pain, muscle pain, osteoporosis (potential association with


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long-term use), paralysis, paresthesia, weakness

Respiratory: Dyspnea, tracheobronchial calcification

Miscellaneous: Anaphylactic reaction, cold intolerance, hypersensitivity/allergic reactions,skin necrosis, gangrene, “purple toes” syndrome

Contraindications Hypersensitivity to warfarin or any component of theformulation; hemorrhagic tendencies (eg, patients bleeding from the GI, respiratory, or GUtract; aneurysm; cerebrovascular hemorrhage; following spinal puncture and otherdiagnostic or therapeutic procedures with potential for significant bleeding; history ofbleeding diathesis); recent or potential surgery of the eye or CNS; major regional lumbarblock anesthesia or surgery resulting in large, open surfaces; blood dyscrasias; severeuncontrolled or malignant hypertension; pericarditis or pericardial effusion; subacutebacterial endocarditis; history of warfarin-induced necrosis; an unreliable, noncompliantpatient; alcoholism; patient who has a history of falls or is a significant fall risk;unsupervised senile or psychotic patient; eclampsia/pre-eclampsia, threatened abortion,pregnancy

Warnings/PrecautionsBoxed warnings:

• Bleeding: See “Concerns related to adverse effects” below.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects:

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

• Bleeding: [U.S. Boxed Warning]: May cause major or fatal bleeding. Riskfactors for bleeding include high intensity anticoagulation (INR >4), age (≥65years), variable INRs, history of GI bleeding, hypertension, cerebrovasculardisease, serious heart disease, anemia, severe diabetes, malignancy, trauma, renalinsufficiency, polycythemia vera, vasculitis, open wound, history of PUD, indwellingcatheters, menstruating and postpartum women, drug-drug interactions, longduration of therapy, or known genetic deficiency in CYP2C9 activity. Patient mustbe instructed to report bleeding, accidents, or falls as well as any new ordiscontinued medications, herbal or alternative products used, or significantchanges in smoking or dietary habits. Unrecognized bleeding sites (eg, coloncancer) may be uncovered by anticoagulation.

• 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 thefirst 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.

• “Purple toe” syndrome, due to cholesterol microembolization, has been rarelydescribed with coumarin-type anticoagulants. Typically, this occurs after severalweeks of therapy, and may present as a dark, purplish, mottled discoloration of theplantar and lateral surfaces. Other manifestations of cholesterol microembolization


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may include rash; livedo reticularis; gangrene; abrupt and intense pain in lowerextremities; abdominal, flank, or back pain; hematuria, renal insufficiency;hypertension; cerebral ischemia; spinal cord infarction; or other symptoms ofvascular compromise.

Disease-related concerns:

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

• Heparin-induced thrombocytopenia: Use with caution in patients with heparin-induced thrombocytopenia and DVT; limb ischemia, necrosis, and gangrene haveoccurred 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 theunderlying active thrombotic process.

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

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

• Renal impairment: Use with caution in patients with moderate-to-severe renalimpairment.

• Thyroid disease: Use with caution in patients with thyroid disease.

Special populations:

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

• Ovulating women: May be at risk of developing ovarian hemorrhage at the time ofovulation.

• Patients with genomic variants in CYP2C9 and/or VKORC1: Presence of the CYP2C9*2or *3 allele and/or polymorphism of the vitamin K oxidoreductase (VKORC1) genemay increase the risk of bleeding. The *2 allele is reported to occur with afrequency of 4% to 11% in African-Americans and Caucasians, respectively, whilethe *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 thusmay increase risk of bleeding, but are much less common. Lower doses may berequired in these patients; genetic testing may help determine appropriate dosing.

• Pediatrics: Safety and efficacy have not been established in children; monitor closely.

Other warnings/precautions:

• 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 laboratorymonitoring is essential.

Metabolism/Transport Effects Substrate of CYP1A2 (minor), 2C9 (major),2C19 (minor), 3A4 (minor); Inhibits CYP2C9 (moderate), 2C19 (weak)

Drug Interactions


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(For additional information: Launch Lexi-Interact™ Drug Interactions Program )

Acetaminophen: May enhance the anticoagulant effect of Vitamin K Antagonists. Most likelywith daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

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

Aminoglutethimide: May increase the metabolism of Vitamin K Antagonists. Risk D:Consider therapy modification

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

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

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

Antineoplastic Agents: May enhance the anticoagulant effect of Vitamin K Antagonists.Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists.Exceptions: Alitretinoin; Altretamine; Aminoglutethimide; Anastrozole; Asparaginase;AzaCITIDine; Bleomycin; Capecitabine; CARBOplatin; Carmustine; Chlorambucil;CISplatin; Cladribine; Cytarabine; Cytarabine (Liposomal); Dacarbazine;DACTINomycin; DAUNOrubicin Citrate (Liposomal); DAUNOrubicin Hydrochloride;Denileukin Diftitox; DOCEtaxel; DOXOrubicin (Liposomal); Epirubicin; Estramustine;Etoposide Phosphate; Exemestane; Fludarabine; Goserelin; Hydroxyurea; IDArubicin;Irinotecan; Letrozole; Leuprolide; Lomustine; Mechlorethamine; Megestrol; MitoMYcin;MitoXANtrone; Nilutamide; PACLitaxel; Pegaspargase; Pentostatin; Polyestradiol;Porfimer; RiTUXimab; Streptozocin; Tamoxifen; Temozolomide; Teniposide;Thioguanine; Thiotepa; Topotecan; Toremifene; Tretinoin (Systemic); Valrubicin;VinBLAStine; Vinorelbine. Risk C: Monitor therapy

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

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

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. Risk D: Considertherapy modification

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

Bile Acid Sequestrants: May decrease the absorption of Vitamin K Antagonists. Risk C:


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Monitor therapy

Boceprevir: May decrease the serum concentration of Warfarin. Boceprevir may increasethe serum concentration of Warfarin. Risk C: Monitor therapy

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

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

CarBAMazepine: May decrease the serum concentration of Vitamin K Antagonists. Risk D:Consider therapy modification

Cephalosporins: May enhance the anticoagulant effect of Vitamin K Antagonists.Exceptions: Cefaclor; Cefadroxil; Cefdinir; Cefditoren; Cefepime; Cefixime;Cefotaxime; Cefpodoxime; Cefprozil; Ceftaroline Fosamil; CefTAZidime; Ceftibuten;Cefuroxime; Cephalexin. Risk C: Monitor therapy

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

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

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

Clopidogrel: May enhance the anticoagulant effect of Warfarin. Risk D: Consider therapymodification

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

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

Contraceptives (Estrogens): May diminish the anticoagulant effect of Vitamin KAntagonists. In contrast, enhanced anticoagulant effects have also been noted withsome products. Risk D: Consider therapy modification

Contraceptives (Progestins): May diminish the anticoagulant effect of Vitamin KAntagonists. In contrast, enhanced anticoagulant effects have also been noted withsome products. Management: When possible, concomitant hormonal contraceptivesand coumarin derivatives should be avoided in order to eliminate the risk ofthromboembolic disorders. Consider using an alternative, nonhormonal contraceptive.Risk D: Consider therapy modification

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: Monitortherapy

CYP2C9 Inducers (Highly Effective): May increase the metabolism of CYP2C9 Substrates(High risk). Risk C: Monitor therapy


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

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

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitortherapy

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

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. RiskC: 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: Monitortherapy

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

Drotrecogin Alfa: Vitamin K Antagonists may enhance the adverse/toxic effect ofDrotrecogin Alfa. Bleeding may occur. Management: Weigh potential benefits ofdrotrecogin against increased bleeding risk in patients who have received oralanticoagulants within 1 week or have INR 3 or greater. Monitor for bleeding andimmediately stop infusion if clinically important bleeding occurs. Risk D: Considertherapy modification

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

Erythromycin (Ophthalmic): May increase the serum concentration of Vitamin KAntagonists. Risk C: Monitor therapy

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

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

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

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


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

Fenofibrate: May enhance the anticoagulant effect of Warfarin. Fenofibrate may increasethe serum concentration of Warfarin. Risk D: Consider therapy modification

Fenofibric Acid: May enhance the anticoagulant effect of Warfarin. Fenofibric Acid mayincrease the serum concentration of Warfarin. Risk D: Consider therapy modification

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

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

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

Fluorouracil: May increase the serum concentration of Vitamin K Antagonists. Risk D:Consider therapy modification

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. RiskC: Monitor therapy

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

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

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

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

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

Ginseng (American): May decrease the serum concentration of Warfarin. Risk C: Monitortherapy

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

Glutethimide: May increase the metabolism of Vitamin K Antagonists. Risk D: Considertherapy modification

Green Tea: May enhance the adverse/toxic effect of Vitamin K Antagonists. Particularly, therisk of bleeding may be increased due to possible antiplatelet effects of green tea.


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Green Tea may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C:Monitor therapy

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

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhancethe adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk D: Considertherapy modification

HMG-CoA Reductase Inhibitors: May enhance the anticoagulant effect of Vitamin KAntagonists. Exceptions: Atorvastatin. Risk C: Monitor therapy

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

Imatinib: May enhance the anticoagulant effect of Warfarin. Imatinib may decrease themetabolism of Warfarin. Risk D: Consider therapy modification

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

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

Ketoconazole: May increase the serum concentration 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. Risk C:Monitor therapy

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

Macrolide Antibiotics: May increase the serum concentration of Vitamin K Antagonists.Exceptions: Fidaxomicin (Systemic); Spiramycin. Risk C: Monitor therapy

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

MetroNIDAZOLE: May increase the serum concentration of Vitamin K Antagonists.Management: Consider alternatives to concomitant therapy with these agents. Monitorfor increased INR/bleeding risk if metronidazole is initiated/dose increased, ordecreased effects if metronidazole is discontinued/dose decreased. Risk D: Considertherapy modification

MetroNIDAZOLE (Systemic): May decrease the metabolism of Vitamin K Antagonists. RiskD: Consider therapy modification

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


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therapy

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

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

Nafcillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Considertherapy modification

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

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

NSAID (COX-2 Inhibitor): May enhance the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapy

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

Omega-3-Acid Ethyl Esters: May enhance the anticoagulant effect of Warfarin. Risk C:Monitor therapy

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

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

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates (Highrisk). Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. RiskC: 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 KAntagonists may increase the serum concentration of Phenytoin. Management:Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated ordiscontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding)when using this combination. Risk D: Consider therapy modification

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

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

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

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


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

QuiNIDine: May enhance the anticoagulant effect of Vitamin K Antagonists. Note that theINR/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: Monitortherapy

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

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

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

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

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Risk X:Avoid combination

RomiDEPsin: May enhance the therapeutic effect 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: Monitortherapy

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

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

Sitaxentan: May increase the serum concentration of Warfarin. Risk D: Consider therapymodification

SORAfenib: May enhance the anticoagulant effect of Warfarin. SORAfenib may increase theserum concentration of Warfarin. Management: Warfarin dose adjustment will likely benecessary. Increase frequency of INR monitoring during sorafenib therapy (particularlywhen starting or stopping therapy), and increase monitoring for signs and symptoms ofbleeding. Risk D: Consider therapy modification

St Johns Wort: May increase the metabolism of Vitamin K Antagonists. Risk D: Considertherapy modification

Sucralfate: May diminish the anticoagulant effect of Vitamin K Antagonists. Sucralfate maydecrease the serum concentration of Vitamin K Antagonists. Specifically, sucralfatemay decrease the absorption of Vitamin K Antagonists. Management: Administervitamin K antagonists at least 2 hours before or at least 6 hours after sucralfate. RiskD: Consider therapy modification

Sulfinpyrazone [Off Market]: May decrease the metabolism of Vitamin K Antagonists.Sulfinpyrazone [Off Market] may decrease the protein binding of Vitamin KAntagonists. Risk D: Consider therapy modification


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

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

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

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

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

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

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitortherapy

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: Monitortherapy

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

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

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

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: Monitortherapy

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

Ethanol/Nutrition/Herb InteractionsEthanol: Avoid ethanol. Acute ethanol ingestion (binge drinking) decreases the metabolism

of warfarin and increases PT/INR. Chronic daily ethanol use increases the metabolismof warfarin and decreases PT/INR.


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Food: The anticoagulant effects of warfarin may be decreased if taken with foods rich invitamin K. Vitamin E may increase warfarin effect. Cranberry juice may increasewarfarin effect.

Herb/Nutraceutical: Cranberry, fenugreek, ginkgo biloba, glucosamine, may enhancebleeding or increase warfarin's effect. Ginseng (American), coenzyme Q10, and StJohn’s wort may decrease warfarin levels and effects. Avoid alfalfa, anise, bilberry,bladderwrack, bromelain, cat's claw, celery, chamomile, coleus, cordyceps, dong quai,evening primrose oil, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng(American), ginseng (Panax), ginseng (Siberian), grapeseed, green tea, guggul, horsechestnut seed, horseradish, licorice, omega-3-acids, prickly ash, red clover, reishi,SAMe (s-adenosylmethionine), sweet clover, turmeric, and white willow (all haveadditional antiplatelet activity).

Pregnancy Risk Factor X (show table)

Pregnancy Implications Warfarin crosses the placenta; concentrations in thefetal plasma are similar to maternal values. Teratogenic effects have been reportedfollowing first trimester exposure and may include coumarin embryopathy (nasalhypoplasia and/or stippled epiphyses; limb hypoplasia may also be present). Adverseevents to the fetus have also been observed following second and third trimester exposureand may include CNS abnormalities (including ventral midline dysplasia, dorsal midlinedysplasia). Use is contraindicated during pregnancy (or in women of reproductivepotential), threatened abortion, eclampsia, or preeclampsia. Frequent pregnancy tests arerecommended for women who are planning to become pregnant and adjusted dose heparinor low molecular weight heparin should be substituted as soon as pregnancy is confirmed.In pregnant women with high-risk mechanical heart valves, the benefits of warfarintherapy should be discussed with the risks of available treatments; when possible avoidwarfarin use during the first trimester and close to delivery.

Lactation Does not enter breast milk (AAP rates “compatible”; AAP 2001 updatepending)

Breast-Feeding Considerations Breast-feeding women may be treated withwarfarin. Based on limited data, warfarin does not pass into breast milk; however,prolonged PT may occur in some infants (product labeling). Women who are breast-feedingshould be carefully monitored to avoid excessive anticoagulation. ACCP guidelinesrecommend continuation of warfarin in lactating women who wish to breast-feed theirinfants (Bates, 2008). Warfarin was not detected in breast milk in 2 reports of warfarinexposure during breast-feeding in 9 infants. Evaluation of coagulation tests and vitamin Kstatus of breast-feeding infant is considered prudent (product labeling).

Dietary Considerations Foods high in vitamin K (eg, beef liver, pork liver, greentea, and leafy green vegetables) inhibit anticoagulant effect. Do not change dietary habitsonce stabilized on warfarin therapy. A balanced diet with a consistent intake of vitamin K isessential. Avoid large amounts of alfalfa, asparagus, broccoli, Brussels sprouts, cabbage,cauliflower, green teas, kale, lettuce, spinach, turnip greens, and watercress; decreasedefficacy of warfarin. It is recommended that the diet contain a CONSISTENT vitamin Kcontent of 70-140 mcg/day. Check with healthcare provider before changing diet.

Pricing: U.S. (www.drugstore.com)


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Tablets (Coumadin)

1 mg (30): $46.99

2 mg (30): $50.99

2.5 mg (30): $52.99

3 mg (30): $55.99

4 mg (30): $54.99

5 mg (30): $53.99

6 mg (30): $56.99

7.5 mg (30): $58.99

10 mg (30): $62.99

Tablets (Jantoven)

2 mg (30): $17.99

4 mg (30): $17.99

5 mg (30): $17.99

Tablets (Warfarin Sodium)

1 mg (30): $13.99

2 mg (30): $14.99

2.5 mg (30): $14.99

3 mg (30): $15.99

4 mg (30): $14.99

5 mg (30): $13.99

7.5 mg (30): $23.99

10 mg (30): $24.99

Monitoring Parameters Prothrombin time, hematocrit, INR; consider genotypingof CYP2C9 and VKORC1 prior to initiation of therapy, if available

Reference RangeINR = patient prothrombin time/mean normal prothrombin time

ISI = international sensitivity index

INR should be increased by 2-3.5 times depending upon indication. An INR >4 does notgenerally add additional therapeutic benefit and is associated with increased risk ofbleeding. Note: To prevent gastrointestinal bleeding events in patients receiving thecombination of warfarin, aspirin, and clopidogrel, an INR of 2-2.5 is recommendedunless condition requires a higher INR target (eg, certain mechanical heart valves)(Bhatt, 2008).


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Adult Target INR Ranges Based Upon Indication

IndicationTargeted

INR

TargetedINR

Range

Cardiac

Acute myocardial infarction (high risk)1,2,3 2.5 2-3

Atrial fibrillation or atrial flutter 2.5 2-3

Valvular

Bileaflet or Medtronic Hall tilting disk mechanicalaortic valve in normal sinus rhythm and normal LAsize

2.5 2-3

Bileaflet or tilting disk mechanical mitral valve 3 2.5-3.5

Caged ball or caged disk mechanical valve 3 2.5-3.5

Mechanical prosthetic valve with systemicembolism despite adequate anticoagulation4 3 or 3.5

2.5-3.5

or

3-4

Mechanical valve and risk factors forthromboembolism (eg, AF, MI5, LA enlargement,hypercoagulable state, low EF) or history ofatherosclerotic vascular disease6

3 2.5-3.5

Bioprosthetic mitral valve7 2.5 2-3

Bioprosthetic mitral or aortic valve with priorhistory of systemic embolism7 2.5 2-3

Bioprosthetic mitral or aortic valve with evidenceof LA thrombus at surgery8 2.5 2-3

Bioprosthetic mitral or aortic valve with risk factorsfor thromboembolism (eg, AF, hypercoagulablestate or low EF)9

2.5 2-3


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IndicationTargeted

INR

TargetedINR

Range

Prosthetic mitral valve thrombosis (resolved)3 4 3.5-4.5

Prosthetic aortic valve thrombosis (resolved)3 3.5 3-4

Rheumatic mitral valve disease and normal sinusrhythm (LA diameter >5.5 cm), AF, previoussystemic embolism, or LA thrombus

2.5 2-3

Thromboembolism Treatment

Venous thromboembolism10,11 2.5 2-3

Thromboprophylaxis

Chronic thromboembolic pulmonary hypertension(CTPH)

2.5 2-3

Idiopathic pulmonary artery hypertension (IPAH)12 2 1.5-2.5

Lupus inhibitor (no other risk factors) 2.5 2-3

Lupus inhibitor and recurrent thromboembolism 3 2.5-3.5

Major trauma patients with impaired mobilityundergoing rehabilitation

2.5 2-3

Spinal cord injury (acute) undergoingrehabilitation

2.5 2-3

Total hip or knee replacement (elective) or hipfracture surgery13 2.5 2-3

Other Indications

Cerebral venous sinus thrombosis14 2.5 2-3

Ischemic stroke due to AF 2.5 2-3

1High-risk includes large anterior MI, significant heart failure,


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IndicationTargeted

INR

TargetedINR

Range

intracardiac thrombus, atrial fibrillation, history of thromboembolism.

2Maintain anticoagulation for 3 months.

3Combine with aspirin 81 mg/day.

4Combine with aspirin 81 mg/day, if not previously receiving, and/or ifprevious target INR was 2.5, then new target INR should be 3(2.5-3.5). If previous target INR was 3, then new target INR shouldbe 3.5 (3-4).

5MI refers to anterior-apical ST-segment elevation myocardial infarction.

6Combine with aspirin 81 mg/day unless patient is at high risk ofbleeding (eg, history of GI bleed, age >80 years).

7Maintain anticoagulation for 3 months after valve insertion then switchto aspirin 81 mg/day if no other indications for warfarin exist orclinically reassess need for warfarin in patients with prior history ofsystemic embolism.

8Maintain anticoagulation with warfarin until thrombus resolution.

9If patient has history of atherosclerotic vascular disease, combine withaspirin 81 mg/day unless patient is at high risk of bleeding (eg,history of GI bleed, age >80 years).

10Treat for 3 months in patients with VTE due to transient reversible riskfactor. Treat for a minimum of 3 months in patients with unprovokedVTE and evaluate for long term therapy. Other risk groups (eg,cancer) may require >3 months of therapy.

11In patients with unprovoked VTE who prefer less frequent INRmonitoring, low-intensity therapy (INR range: 1.5-1.9) with lessfrequent monitoring is recommended over stopping treatment.

12Recommendation from the ACCF/AHA 2009 Expert ConsensusDocument on Pulmonary Hypertension (McLaughlin, 2009)

13Continue for at least 10 days and up to 35 days after surgery.


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IndicationTargeted

INR

TargetedINR

Range

14Continue for up to 12 months.

Warfarin levels are not used for monitoring degree of anticoagulation. They may be usefulif a patient with unexplained coagulopathy is using the drug surreptitiously or if it isunclear whether clinical resistance is due to true drug resistance or lack of drug intake.

Normal prothrombin time (PT): 10.9-12.9 seconds. Healthy premature newborns haveprolonged coagulation test screening results (eg, PT, aPTT, TT) which return to normaladult values at approximately 6 months of age. Healthy prematures, however, do notdevelop spontaneous hemorrhage or thrombotic complications because of a balancebetween procoagulants and inhibitors.

International Brand Names Aldocumar (ES); Befarin (TH); Circuvit (AR);Cofarin (TW); Coumadan (AR); Coumadin (AE, AU, BF, BH, BJ, CI, CN, CY, DE, EC, EG, ET,GH, GM, GN, IL, IQ, IR, IT, JO, KE, KP, KW, LB, LR, LY, MA, ML, MR, MU, MW, MX, NE, NG,NZ, OM, PE, PH, PK, PY, QA, SA, SC, SD, SL, SN, SY, TN, TR, TZ, UG, VE, YE, ZM, ZW);Coumadine (FR); Dagonal (UY); Fargem (TH); Lawarin (CZ); Lennon-Warfarin (ZA);Mafarin (TW); Maforan (TH); Marevan (AU, BE, BR, DK, EE, FI, GB, IE, LU, NO, NZ, SG);Marfarin (HN); Marivarin (HR); Orfarin (MY, TH, TW); Panwarfin (GR); Simarc-2 (ID);Tedicumar (ES); Tufam (TH); UniWarfin (IN); Varfine (PT); Waran (SE); Warfar (CO, KP);Warfil 5 (DO); Warfin (PL); Warik (PH); Zydarin (TH); Zyfarin (PH)

Mechanism of Action Hepatic synthesis of coagulation factors II, VII, IX, and X, aswell as proteins C and S, requires the presence of vitamin K. These clotting factors arebiologically activated by the addition of carboxyl groups to key glutamic acid residueswithin the proteins’ structure. In the process, “active” vitamin K is oxidatively converted toan “inactive” form, which is then subsequently reactivated by vitamin K epoxide reductasecomplex 1 (VKORC1). Warfarin competitively inhibits the subunit 1 of the multi-unit VKORcomplex, thus depleting functional vitamin K reserves and hence reduces synthesis ofactive clotting factors.

Pharmacodynamics/KineticsOnset 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


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Genomic variants: Approximately 37% reduced clearance of S-warfarin in patientsheterozygous for 2C9 (*1/*2 or *1/*3), and ~70% reduced in patientshomozygous 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)

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