This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or standards of non-Merck sources.

ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Pronunciation

(WAR far in)

Generic Available (U.S.)

Yes: Tablet

Index Terms

• Warfarin Sodium

Medication Guide

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

Brand Names: U.S.

• Coumadin®
• Jantoven®

Brand Names: Canada

• Apo-Warfarin®
• Coumadin®
• Mylan-Warfarin
• Novo-Warfarin
• Taro-Warfarin

Pharmacologic Category

• Anticoagulant, Coumarin Derivative
• Vitamin K Antagonist

Pharmacologic Category Synonyms

• Coumarin Derivative Anticoagulant
• Oral Anticoagulant, Coumarin Derivative

Use: Labeled Indications

Prophylaxis and treatment of thromboembolic disorders (eg, venous, pulmonary) and embolic complications arising from atrial fibrillation or cardiac valve replacement; adjunct to reduce risk of systemic embolism (eg, recurrent MI, stroke) after myocardial infarction

Use: Unlabeled

Prevention of recurrent transient ischemic attacks

Pregnancy Risk Factor

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

Pregnancy Considerations

Warfarin crosses the placenta; concentrations in the fetal plasma are similar to maternal values. Teratogenic effects have been reported following first trimester exposure and may include coumarin embryopathy (nasal hypoplasia and/or stippled epiphyses; limb hypoplasia may also be present). Adverse events to the fetus have also been observed following second and third trimester exposure and may include CNS abnormalities (including ventral midline dysplasia, dorsal midline dysplasia). Spontaneous abortion 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 should be substituted as soon as pregnancy is confirmed. In pregnant women with high-risk mechanical heart valves, the benefits of warfarin therapy should be discussed with the risks of available treatments; when possible avoid warfarin use during the first trimester and close to delivery (Bates, 2008).

Lactation

Does not enter breast milk/use caution (AAP rates “compatible”; AAP 2001 update pending)

Breast-Feeding Considerations

Breast-feeding women may be treated with warfarin. Based on limited data, warfarin does not pass into breast milk. Women who are breast-feeding should be carefully monitored to avoid excessive anticoagulation. ACCP guidelines recommend continuation of warfarin in lactating women who wish to breast-feed their infants (Bates, 2008). Monitor nursing infants for bruising or bleeding (per manufacturer).

Contraindications

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

Warnings/Precautions

Boxed 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, including anaphylaxis; use with caution in patients with anaphylactic disorders.

• Bleeding: [U.S. Boxed Warning]: May cause major or fatal bleeding. 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.

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

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

Disease-related concerns:

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

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

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

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

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

• Thyroid disease: Use with caution in patients with thyroid disease; warfarin responsiveness may increase (Ansell, 2008).

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:

• 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.

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.

Cardiovascular: Vasculitis

Central nervous system: Signs/symptoms of bleeding (eg, dizziness, fatigue, fever, headache, lethargy, malaise, pain)

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

Gastrointestinal: Abdominal pain, diarrhea, flatulence, gastrointestinal bleeding, nausea, taste disturbance, vomiting

Genitourinary: Hematuria

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

Hepatic: Hepatitis (including cholestatic hepatitis), transaminases increased

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

Respiratory: Respiratory tract bleeding, tracheobronchial calcification

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

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; Inhibits CYP2C19 (weak), CYP2C9 (weak)

Drug Interactions

Acetaminophen: May enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with 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 (E. coli); Asparaginase (Erwinia); AzaCITIDine; Bleomycin; Capecitabine; CARBOplatin; Carmustine; Chlorambucil; CISplatin; Cladribine; Cytarabine (Conventional); Cytarabine (Liposomal); Dacarbazine; DACTINomycin; DAUNOrubicin (Conventional); DAUNOrubicin (Liposomal); 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: Consider therapy modification

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

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

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. Risk C: 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 therapy modification

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

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

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

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy

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

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

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

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. Risk C: 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. 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

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

Drotrecogin Alfa (Activated): Vitamin K Antagonists may enhance the adverse/toxic effect of Drotrecogin Alfa (Activated). Bleeding may occur. Management: Weigh potential benefits of drotrecogin against increased bleeding risk in patients who have received oral anticoagulants within 1 week or have INR 3 or greater. Monitor for bleeding and immediately stop infusion if clinically important bleeding occurs. Risk D: Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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. 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

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

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

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

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

Green Tea: May enhance the adverse/toxic effect of Vitamin K Antagonists. Particularly, the risk of bleeding may be increased due to possible antiplatelet effects of green tea. 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 enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk D: Consider therapy modification

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

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; 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. Monitor for increased INR/bleeding risk if metronidazole is initiated/dose increased, or decreased effects if metronidazole is discontinued/dose decreased. Risk D: Consider therapy modification

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

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

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

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. Risk D: 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. Risk C: Monitor therapy

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

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

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

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

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

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

Quinolone Antibiotics: 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

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: Monitor therapy

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

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

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

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 D: Consider therapy modification

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

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

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

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: Avoid combination

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

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: Monitor therapy

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

Ethanol/Nutrition/Herb Interactions

Ethanol: Acute ethanol ingestion (binge drinking) decreases the metabolism of warfarin and increases PT/INR. Chronic daily ethanol use increases the metabolism of warfarin 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.

Herb/Nutraceutical: Some herbal medications (eg, St John's wort) may decrease warfarin levels and effects; many others can add additional antiplatelet activity to warfarin therapy. Management: Avoid ginseng (American), coenzyme Q₁₀, and St John's wort. Avoid cranberry, fenugreek, ginkgo biloba, glucosamine, alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, celery, chamomile, coleus, cordyceps, dong quai, evening primrose oil, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng (Panax), ginseng (Siberian), grapeseed, green tea, guggul, horse chestnut seed, horseradish, licorice, omega-3-acids, prickly ash, red clover, reishi, SAMe (s-adenosylmethionine), sweet clover, turmeric, and white willow.

Storage

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

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

Reconstitution

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

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 detailed reference): Ammonium chloride, ceftriaxone, metronidazole, vancomycin.

Compatibility in syringe: Incompatible: Ceftriaxone, heparin.

Mechanism of Action

Hepatic synthesis of coagulation factors II, VII, IX, and X, 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)

Dosage

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 important guidance on initiation of anticoagulant therapy.

Oral:

Infants and Children (unlabeled use): 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 2-3: 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 (Monagle, 2008).

Adults: 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 2-5 mg daily for 2 days or 5-10 mg daily for 1-2 days (Ansell, 2008). Adjust dose according to INR results; usual maintenance dose ranges from 2-10 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).

I.V.: Adults: 2-5 mg/day administered as a slow bolus injection

Dosing adjustment in renal disease: No adjustment required, however, patients with renal failure have an increased risk of bleeding complications. Monitor closely.

Dosing adjustment in hepatic disease: Monitor effect at usual doses; 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

Administration: Oral

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

Administration: I.V.

Administer as a slow bolus injection over 1-2 minutes. Avoid all I.M. injections.

Administration: I.V. Detail

pH: 8.1-8.3

Monitoring Parameters

Prothrombin time, hematocrit, INR; 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 2-3.5 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 2-2.5 is recommended unless condition requires a higher INR target (eg, certain mechanical heart valves) (Bhatt, 2008).

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): 10.9-12.9 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.

Dietary Considerations

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

Patient Education

If dose is missed, take as soon as possible; do not double dose. Laboratory tests will be required. Follow prescriber's recommended diet and activity. Avoid excessive alcohol. Do not make major changes in your dietary intake of vitamin K (green vegetables). You will have a tendency to bleed easily while taking this drug. Report unusual bleeding or bruising, skin rash or irritation, unusual fever, persistent nausea or GI upset, pain in joints or back, swelling or pain at injection site, or unhealed wounds.

Geriatric Considerations

Before committing an elderly patient to long-term anticoagulation therapy, the risk for bleeding complications secondary to falls, drug interactions, living situation, and cognitive status should be considered. A risk of bleeding complications has been associated with increased age.

Additional Information

Prospective genotyping is available, and may provide important guidance on initiation of anticoagulant therapy. Commercial testing with PGxPredict™: WARFARIN is available from PGxHealth™ (Division of Clinical Data, Inc, New Haven, CT). The test genotypes patients for presence of the CYP2C9*2 or *3 alleles and the VKORC1 -1639G>A polymorphism. The results of the test allow patients to be phenotyped as extensive, intermediate, or poor metabolizers (CYP2C9) and as low, intermediate, or high warfarin sensitivity (VKORC1). Ordering information is available at 888-592-7327 or warfarininfo@pgxhealth.com.

Anesthesia and Critical Care Concerns/Other Considerations

Clinical Pearls/Comments: Tube-feeding formulas are often a rich source of vitamin K.

Management of Oral Anticoagulation Prior to Surgery:

Patients with low risk of thromboembolism: Stop warfarin therapy approximately 4 days before surgery, allow the INR to return to a near normal level, briefly administer postoperative prophylaxis (if the intervention itself creates a higher risk of thrombosis) using low-dose heparin or LMWH, and simultaneously begin warfarin therapy after surgery.

Patients with intermediate risk of thromboembolism: Stop warfarin therapy approximately 4 days before surgery, allow the INR to fall. Initiate low-dose heparin or prophylactic dose of LMWH beginning 2 days before surgery. Then commence full-dose heparin or LMWH, and warfarin therapy after surgery.

Patients with high risk of thromboembolism (eg, a recent [<3 months] history of venous thromboembolism, a mechanical cardiac valve in the mitral position, or an old model of cardiac valve [ball/cage]): Stop warfarin therapy approximately 4 days before surgery, allow the INR to return to a normal level, begin therapy with full-dose heparin or full-dose LMWH as the INR falls (approximately 2 days before surgery). Heparin can be administered as a SubQ injection on an outpatient basis, can then be given as a continuous I.V. infusion after hospital admission in preparation for surgery, and can be discontinued 5 hours before surgery with the expectation that the anticoagulant effect will have worn off at the time of surgery. It is also possible to continue the administration of SubQ heparin or LMWH and to stop therapy 12-24 hours before surgery with the expectation that the anticoagulant effect will be very low or will have worn off by the time of surgery.

Patients with low risk of bleeding: Continue warfarin therapy at a lower dose and operate at an INR of 1.3-1.5, an intensity that has been shown to be safe in randomized trials of gynecologic and orthopedic surgical patients. The dose of warfarin can be lowered 4-5 days before surgery. Warfarin therapy then can be restarted after surgery and supplemented with low-dose heparin or LMWH if necessary.

Heparin-Induced Thrombocytopenia (HIT) or Heparin-Induced Thrombotic Thrombocytopenia Syndrome (HITTS): When a patient develops HIT/HITTS, warfarin monotherapy is contraindicated. Rather, a direct thrombin inhibitor should be initiated. Warfarin anticoagulation should be postponed in the patient with HIT until substantial recovery of the platelet count has occurred. When appropriate, initiating warfarin at low doses and overlapping with a direct thrombin inhibitor for at least 5 days and until the INR is therapeutic for at least 48 hours is suggested.

Evidence-Based Information: Management of Intracerebral Hemorrhage (ICH) Due to Warfarin: Overall management of ICH is similar regardless of cause; however, iatrogenic spontaneous ICH may have specific treatments. According to the 2007 ACC/ASA Guidelines for the Management of Spontaneous Intracerebral Hemorrhage, warfarin-related ICH should be treated with I.V. vitamin K at a dose of 10 mg given slowly (not to exceed 1 mg/minute) (Class I recommendation). It is important to also administer fresh frozen plasma (FFP) since vitamin K may take several hours to normalize INR. Other options besides FFP include prothrombin complex concentrate (PCC) which contains high levels of vitamin K-dependent factors (II, VII, and X) and factor IX complex which contains factors II, VII, IX, and X (Class IIb recommendation). Use of rFVIIa has shown promise for this indication. Advantages to rFVIIa include faster onset of action compared to FFP and vitamin K and a 50% lower volume is required compared to FFP. Disadvantages include a short half-life (~2.6 hours) requiring multiple doses to maintain a normalized INR and an increased risk of thromboembolic complications. Dosing of rFVIIa ranges between 15-90 mcg/kg. The use of factor-containing products has a risk of thromboembolism. In patients at very high risk for thromboembolism, where it has been determined that benefits of warfarin exceed the risks, it may be reasonable to restart warfarin 7-10 days after the onset of ICH (Furie, 2011).

Cardiovascular Considerations

Factor VII half-life: 4-6 hours

Factor X half-life: 27-48 hours

Factor II half-life: 42-72 hours

Overlapping heparin 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 (factor VII depletion) may be seen early (first 24-48 hours) in warfarin therapy, it does not represent adequate anticoagulation. Factors II and X must be depleted which takes considerably longer.

Vitamin K-Rich Foods: Significant changes in vitamin K intake can upset warfarin stability. The list of usual foods with high vitamin K content are well known, however, unique ones continue to appear like green tea, chewing tobacco, a variety of oils (canola, corn, olive, peanut, safflower, sesame seed, soybean, and sunflower). Snack foods containing Olestra have 80 mcg of vitamin K added to each ounce. Some natural products may contain hidden sources of vitamin K.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Mouth ulcers and taste disturbance.

Signs of warfarin overdose may first appear as bleeding from gingival tissue. See Effects on Bleeding.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

May cause leukopenia; use caution with clozapine and carbamazepine; barbiturates and carbamazepine may decrease the anticoagulant effect of warfarin; chloral hydrate, alcohol, disulfiram, and SSRIs may enhance the anticoagulant effect

Nursing: Physical Assessment/Monitoring

Use caution with any condition that increases risk of bleeding or that may impact patient ability to comply with therapeutic regimen (eg, dietary vitamin K or C deficiency, hypertension, open wounds, TB, PUD, diabetes, thyroid or renal disease, recent surgery) or any condition that may impact patient's ability to comply with therapeutic regimen (eg, unreliable patient, alcoholism, history of falls or significant fall risk, unsupervised senile or psychotic patient). Assess potential for interactions with other prescriptions, OTC medications, or herbal products patient may be taking that may affect coagulation or platelet aggregation. Monitor for bleeding from any site, rash, urticaria, gastrointestinal upset, abdominal pain, diarrhea, or hypersensitivity reaction.

Dosage Forms

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]

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

Tablets (Coumadin)

1 mg (30): $46.99

2 mg (30): $50.99

2.5 mg (30): $52.99

3 mg (30): $49.99

4 mg (30): $49.99

5 mg (30): $49.99

6 mg (30): $56.99

7.5 mg (30): $60.99

10 mg (30): $63.99

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

References

Albers GW, Amarenco P, Easton JD, et al, “Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):630-69.

“American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 2001, 108(3):776-89.

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.

Ansell J, Hirsh J, Hylek E, et al, “The Pharmacology and Management of the Vitamin K Antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):160-98.

Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636.

Arepally GM and Ortel TL, “Heparin-Induced Thrombocytopenia,” N Engl J Med, 2006, 355 (8):809-17.

Bates SM, Greer IA, Pabinger I, et al, “Venous Thromboembolism, Thrombophilia, Antithrombotic Therapy, and Pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):844-86.

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.

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.

Broderick J, Connolly S, Feldmann E, et al, "Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults: 2007 Update: A Guideline From the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group," Stroke, 2007, 38(6):2001-23.

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.

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.

Dager WE and White RH, “Pharmacotherapy of Heparin-Induced Thrombocytopenia,” Expert Opin Pharmacother, 2003, 4(6):919-40.

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.

Douketis JD, Berger PB, Dunn AS, et al, “The Perioperative Management of Antithrombotic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):299-339.

“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.

Furie KL, Kasner SE, Adams RJ, et al, “Guidelines for the Prevention of Stroke in Patients With Stroke or Transient Ischemic Attack: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association,” Stroke, 2011,42(1):227-76

Fuster V, Ryden LE, Cannom DS, et al, “ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation-Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society,” J Am Coll Cardiol, 2006, 48(4):854-906.

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.

Geerts WH, Bergqvist D, Pineo GF, et al, “Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):381-453.

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.

Hirsh J, Guyatt G, Albers GW, et al, “Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):71-109.

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.

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.

Kearon C, Kahn SR, Agnelli G, et al, “Antithrombotic Therapy for Venous Thromboembolic Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):454-545.

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.

Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.

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.

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.

Monagle P, Chalmers E, Chan A, et al, “Antithrombotic Therapy in Neonates and Children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):887-968.

“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.

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.

Salem DN, O'Gara PT, Madias C, et al, “Valvular and Structural Heart Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):593-629.

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.

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.

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.

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.

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.

Suvarna R, Pirmohamed M, and Henderson L, “Possible Interaction Between Warfarin and Cranberry Juice,” BMJ, 2003, 327(7429):1454.

Wann SL, Curtis AB, January CT, et al, “2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Updating the 2006 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” Circulation, 2011, 123 (1):104-23.

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, 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)
• UniWarfin (IN)
• Varfine (PT)
• Waran (SE)
• Warfar (CO, KP)
• Warfarina (PE)
• Warfil 5 (DO)
• Warfin (PL)
• Warik (PH)
• Zydarin (TH)
• Zyfarin (PH)

Lexi-Comp.com

Last full review/revision March 2012

Content last modified March 2012